Osmosis High-Yield Physiology ATF

PHYSIOLOGY
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CONTENTS
SUB3'ECT
BIOSTATISTICS & EPIDEMIOLOGY PAGE
Carbohydratemetabolism Disease surveillance 53
Citric acid cycle (Krebs cycle) 1 Vaccination & herd immunity 54
Electron transport chain & oxidative Epidemiologymeasures
2
phosphorylation Direct standardization 55
Gluconeogenesis 4 Indirect standardization 55
Glycogen metabolism 6 Incidence & prevalence 58
Glycolysis 9 Measures of risk 58
Pentose phosphate pathway 10 Odds ratio 59
Fat & cholesterolmetabolism Attributable risk (AR) 60
Cholesterol metabolism 13 Mortality rates & case-fatality 60
Fatty acid synthesis 15 DALY &QALY 61
Fatty acid oxidation 18 Non-parametrictests
Ketone body metabolism 21 Chi-squared test 62
Nucleic acid metabolism Fisher's exact test 62
Nucleotide metabolism 23 Kaplan-Meier survival analysis 63
Protein metabolism Kappa coefficient 63
Amino acids & protein folding 29 Mann-Whitney U test 63
Enzyme function 31 Spearman's rank correlation
64
Amino acid metabolism 32 coefficient
Nitrogen & the urea cycle 33
Parametrictests
Protein structure & synthesis 38
ANOVA 65
Correlation 67
Hypothesis testing 68
sua:rEcT Linear regression 68
Logistic regression 69
BIOSTATISTICS & EPIDEMIOLOGY PAGE Type I & type II errors 69
Statisticalprobabilitydistributions
Introductorybiostatistics
Normal distribution & z-scores 71
Introduction to biostatistics 41
Standard error of the mean 72
Mean, median, & mode 43
Paired t-tests 72
Probability 44
One-tailed & two-tailed tests 72
Range, variance, & standard
46 Study design
deviation
Types of data 47 Sampling 74
Causation & validity Placebo effect & masking 74
Causality 48 Case-control (retrospective) study 74
Bias 49 Cohort study 75
Confounding 50 Cross-sectional (prevalence) study 76

Ecologic study 77
Interaction 50
Communityhealth Randomized control trial (RCT) 78
Modes of infectious disease Testing

52 Sensitivity (SN) & specificity (SF) 79
transmission
Outbreak investigations 52 Positive & negative predictive value 81
Test precision & accuracy 82
SUB:J'ECT SUB3'ECT
C.ARDIOVASC.ULAR PHYSIOLOGY PAGE C.ARDIOVASC.ULAR PHYSIOLOGY PAGE
Cardiovascularanatomy & physiology Hemodynamics
Cardiovascular anatomy & Blood pressure, blood flow, &
83 136
physiology resistance
Lymphatic anatomy & physiology 90 Pressures in the cardiovascular
137
Normal heart sounds 94 system
Abnormal heart sounds 95 Resistance to blood flow 141
Blood pressure regulation Laminar flow & Reynolds number 143
Baroreceptors 105 Compliance of blood vessels 144
Chemoreceptors 107 Normal variationsof the cardiovascular
Renin-angiotensin aldosterone system
109
system Cardiovascular changes during
146
Cardiac cycle exercise
Measuring cardiac output - Fick Cardiovascular changes during
111 147
principle hemorrhage
Cardiac & vascular function curves 111 Cardiovascular changes during
149
Altering cardiac & vascular function postural change
112
curves Specificcirculations
Pressure-volume loops 113 Cerebral circulation 152
Changes in pressure-volume loops 115 Coronary circulation 153
Cardiac work 116 Control of blood flow circulation 154
Cardiac preload 117 Microcirculation & Starling forces 155
Cardiac afterload 118 Thermoregulation
Law of Laplace 118 Cardiovascular temperature
157
Frank-Starling relationship 119 homeostasis
Stroke volume, ejection fraction, &

120
cardiac output
Cardiac electrophysiology
Action potentials in pacemaker cells 121 SUB3'ECT
Action potentials in myocytes 122
Electrical conduction in the heart 123 CELLULAR PHYSIOLOGY PAGE
Cardiac conduction velocity 123 Cellular structure& processes
Excitability & refractory periods 124 Cellular structure & function 160
Cardiac excitation-contraction Cell membrane 162
125
coupling Selective permeability of the cell
126 163
Cardiac length tension membrane
Cardiac contractility 126 Extracellular matrix 164
Electrocardiography Cell-cell junctions 166
ECG basics 128 Endocytosis & exocytosis 167
ECG normal sinus rhythm 129 Osmosis 168
ECG rate & rhythm 129 Resting membrane potential 169
ECG intervals 130 Cell signaling pathways 170
ECG axis 131 Cytoskeleton & intracellular motility 177
ECG transition 131 Nuclear structure 179
ECG cardiac hypertrophy &
133
enlargement
ECG myocardial infarction & ischemia 134
SUB:J'ECT SUB:J'ECT
CELLULAR PHYSIOLOGY PAGE EMBRYOLOGY PAGE
Cellular pathology Body system structures
Necrosis & apoptosis 181 Development of the skeletal system 221
Oncogenes & tumor suppressor Development of the muscular system 225
184
genes Development of the limbs 227
Hyperplasia & hypertrophy 185 Development of the cardiovascular
228
Metaplasia & dysplasia 186 system
Atrophy, aplasia, & hypoplasia 186 Fetal circulation 232
Free radicals & cellular injury 187 Development of the respiratory
235
lschemia 188 system
Inflammation 188 Development of the gastrointestinal
238
system
Development of the renal system 243
Development of the integumentary
SUB:J'ECT 247
system
Head & neck structure
DERMATOLOGY PAGE
Pharyngeal arches, pouches, & clefts 249
Skin structures Development of teeth 252
Skin anatomy & physiology 190 Development of the brain 253
Hair, skin, & nails 192 Development of cranial nerves &
256
Wound healing 194 autonomic nervous system
Development of the spinal cord 257
Development of the ear 258
Development of the eye 260
SUB:J'ECT
EMBRYOLOGY PAGE
Early weeks SUB:J'ECT
Human development days 1-4 196
Human development days 4-7 199
ENDOCRINE PHYSIOLOGY PAGE
Human development week 2 200 Anatomy & physiology
Human development week 3 201 Endocrine anatomy & physiology 262
Germ layers Pituitary hormones
Ectoderm 204 Adrenocorticotropic hormone 269
Mesoderm 205 Growth hormone 271
Endoderm 206 Thyroid hormone 273
Early structures Adrenal hormones
Development of the digestive system Synthesis of adrenocortical
209 276
& body cavities hormones
The hedgeog signalling pathway 212 Cortisol 278
Development of the placenta 214 Pancreatic hormones
Development of the umbilical cord 216 Glucagon 280
Development of the fetal membranes 218 Insulin 281
Development of twins 219 Somatostatin 283
SUB:J'ECT SUB:J'ECT
ENDOCRINE PHYSIOlOGY PAGE GENETICS PAGE
Calcium & phosphatehormonal Populationgenetics
regulation Mendelian genetics & Punnett
338
Calcitonin 284 squares
Parathyroid hormone 286 Independent assortment of genes &
339
Vitamin D 289 linkage
Inheritance patterns 341
Evolution & natural selection 344
Hardy-Weinberg equilibrium 344
SUB:J'ECT Epigenetics 345
Lac operon 345
GASTROINTESTINAl PHYSIOlOGY PAGE
Gene regulation 346
Anatomy & physiology Gel electrophoresis & genetic testing 347
Gastrointestinal anatomy & Polymerase chain reaction 348
293
physiology Transcription,translation,& replication
Gastrointestinalfunction DNA structure 349
Enteric nervous system 302 DNA replication 351
Gastrointestinal hormones 305 Transcription 354
Satiety 308 Translation 355
Upper gastrointestinaltract Cell cycle 357
Chewing & swallowing 309 Mitosis & meiosis 358
Salivary secretion 311 Genetic mutations & repair 360
Slow waves 313
Esophageal motility 316
Gastric motility 319
Gastric secretion 321 SUB:J'ECT
Digestion& absorption
HEMATOlOGY PAGE
Hydration 326
Carbohydrates & sugars 326 Blood components& function
Proteins 327 Blood components 364
Fats 328 Platelet plug formation (primary
365
Vitamins 330 hemostasis)
Intestinal fluid balance 331 Coagulation (secondary hemostasis) 367
Liver, gall bladder, and pancreas Role of vitamin K in coagulation 367
Bile secretion & enterohepatic Anticoagulation, clot retraction, &

332 369
circulation fibrinolysis
Liver anatomy & physiology 333 Blood groups & transfusions 370
Pancreatic secretion 337

SUB:J'ECT SUB:J'ECT
IMMUNOLOGY PAGE NEUROLOGY PAGE
Immune system Anatomy & physiology
Introduction to the immune system 372 Nervous system anatomy &
423
Vaccines 375 physiology
B & T cells Neuron action potential 433
Antibody classes 377 Anatomy & physiology of the eye 434
B cell activation & differentiation 378 Anatomy & physiology of the ear 440
B cell development 381 Autonomic nervous system
Cell mediated immunity of CD4 cells 383 Sympathetic nervous system 445
Cell mediated immunity of natural Parasympathetic nervous system 447
384
killer & CDS cells Adrenergic receptors 450
Cytokines 385 Cholinergic receptors 452
MHC class I & MHC class II Blood brain barrier & CSF
386
molecules Blood brain barrier 455
Somatic hypermutation & affinity Cerebrospinal fluid 456
389
maturation Brain functions
T cell activation 390 459
Sleep
T cell development 391 460
Consciousness
VDJ rearrangement 393 460
Learning
Contractionof the immune response Attention 460
Anergy, exhausion, & clonal deletion 395
Memory 461
B & T cell memory 396
Language 461
Contracting the immune response 399
Emotion 462
Innate immunity 462
Stress
Innate immune system 400
Motor nervous system
Complement system 402
Motor cortex 464
Motor neurons & muscle spindles 465
Pyramidal & extrapyramidal tracts 468
SUB:J'ECT Cerebellum 474
Basal ganglia: direct & indirect
477
MUSCULOSkELETAL PHYSIOLOGY PAGE pathway of movement
Spinal cord reflexes 480
Bones, joints, & cartilage
Sensory nervoussystem
Skeletal system anatomy &
405 Sensory receptor function 481
physiology
Cartilage 407 Somatosensory pathways 482
Bone remodeling & repair 410 Somatosensory receptors 484
Fibrous, cartilage, & synoial joints 411 Photoreception 486
Muscles Optic pathways 487
Muscular system anatomy & Auditory transduction & pathways 489

414 491
physiology Vestibular transduction
Slow twitch & fast twitch muscle Vestibulo-ocular reflex & nystagmus 494
418
fibers Olfactory transduction & pathways 494
Sliding filament model of muscle Taste & the tongue 497
419
contraction Spinal cord & nerves
ATP & muscle contraction 420 Brachia! plexus 500
Neuromuscular junction & motor unit 421 Cranial nerves 503
SUB:J'ECT
RENAL PHYSIOLOGY PAGE
Anatomy & physiology Water regulation
Renal anatomy & physiology 510 Osmoregulation 548
Acid-base physiology Kidney countercurrent multiplication 549
Acid-base map & compensatory Antidiuretic hormone 552
515
mechanisms Free water clearance 554
Buffering & Henderson-Hasselbalch
516
equation
Physiologic pH & buffers 517
Plasma anion gap 518 SUB:J'ECT
The role of the kidney in acid-base
518 REPRODUC.TIVE PHYSIOLOGY PAGE
balance
Metabolic acidosis 519 Female reproductivesystem
Metabolic alkalosis 520 Anatomy & physiology of the female
555
Respiratory acidosis 521 reproductive system
Respiratory alkalosis 522 Oxytocin & prolactin 559
Fluids in the body Menstrual cycle 561
Body fluid compartments 523 Pregnancy 562
Water shifts between body fluid Labor 565
525 570
compartments Breastfeeding
Renal clearance 528 Menopause 572
Renal blood flow regulation Estrogen & progesterone 573
Renal blood flow regulation 530 Male reproductivesystem
Measuring renal plasma flow & renal Anatomy & physiology of the male
532 576
blood flow reproductive system
Renal electrolyteregulation Testosterone 579
Glomerular filtration 533 Sexual development
Proximal convoluted tubule 535 Development of the reproductive
581
Loop of Henle 536 system
Distal convoluted tubule 537 Puberty & Tanner staging 586

TF/Px ratio & TF/Pinlin 538
Calcium homeostasis 539
Magnesium homeostasis 539
Phosphate homeostasis 540
Potassium homeostasis 540
Sodium homeostasis 541
Renal reabsorption& secretion
Tubular reabsorption & secretion 543
Tubular reabsorption of glucose 543
Tubular secretion of para-
545
animohippuric acid (PAH)
Urea recycling 547
Weak acids & bases - non-ionic
547
diffusion
NOTES
NOTES
CARBOHYDRATE METABOLISM
CITRIC ACID CYCLE

(KREBS CYCLE)
osms.it/citric-acid-cycle
▪ Generates energy in the form of GTP, MNEMONIC: T-rex Loves
NADH, and FADH2 and Cares For Nachos
▪ Occurs in mitochondria Five required cofactors
▪ Starts with acetyl-CoA → CO2 Thiamine
Lipoic acid
Process
CoA
▪ Acetyl-CoA + oxaloacetate (via citrate
FAD+
synthase) → citrate + CoA
NAD+
▪ Citrate (via aconitase) → isocitrate
▪ Isocitrate + NAD+ (via isocitrate
dehydrogenase) → α-ketoglutarate +
NADH + CO2
▫ Rate-limiting step
▪ α-ketoglutarate + NAD+ + CoA-SH
(α-ketoglutarate dehydrogenase) →
succinyl-CoA + NADH + CO2
▫ Requires five cofactors: thiamine, lipoic
acid, CoA, FAD+, NAD+
▫ See mnemonic
▪ Succinyl-CoA + phosphate + GDP (via
succinate thiokinase) → succinate + GTP
▪ Succinate + FAD+ (via succinate
dehydrogenase) → fumarate + FADH2 Figure 1.1 Mnemonic for the five cofactors
required by α-ketoglutarate dehydrogenase.
▪ Fumarate + H2O (via fumarase) → malate
▪ Malate + NAD+ (via malate dehydrogenase)
→ oxaloacetate + NADH
▫ Oxaloacetate then enters next cycle
▪ Generates one GTP molecule, three NADH
molecules, one FADH2 molecule
OSMOSIS.ORG 1
Figure 1.2 The citric acid (Krebs) cycle. Each acetyl-CoA molecule generates 12 ATP.
ELECTRON TRANSPORT CHAIN &

OXIDATIVE PHOSPHORYLATION
osms.it/etc-and-oxidative-phosphorylation
Oxidative phosphorylation ▫ FADH2 from cytoplasm comes through
▪ Generates energy as ATP glycerol-3-phosphate shuttle
▪ Occurs in inner mitochondrial membrane ▫ NADH donates electron to complex I
(contains flavin mononucleotide, iron-
Electron transport chain sulfur centers) → NAD+
▪ Series of proteins, lipids, metals that ▫ FADH2 donates electron to complex II
facilitates electron movement → proton (i.e. succinate dehydrogenase) → FAD
gradient used to create ATP ▫ Electrons from either complex flow into
▪ Starts with electron donors NADH, FADH2 coenzyme Q (ubiquinone)
▫ NADH from cytoplasm comes through ▫ Coenzyme Q passes electrons to
malate-aspartate shuttle cytochromes (proteins with heme
2 OSMOSIS.ORG
Chapter 1 Biochemistry: Carbohydrate Metabolism
groups — Fe3+ + e- ↔ Fe2+): complex III ▪ Protons can move back into mitochondria
(cytochromes b and c1) → cytochrome through F0 → proton gradient forms,
c → complex IV (cytochrome oxidase: powering F1: ADP → ATP
cytochromes a, a3) → oxygen ▫ Collectively called complex V
▪ Movement of electrons → electrical current ▪ An ADP/ATP antiport pumps ATP into
→ complexes I, III, IV use this energy to cytoplasm of the cell, supplies complex V
pump protons across inner mitochondrial with new ADP
membrane
Figure 1.3 The flow of electrons through the electron transport chain, which takes place in the
inner mitochondrial membrane.
OSMOSIS.ORG 3
Figure 1.4 Oxidative phosphorylation. The passing of electrons along the electron transport
chain generates an electrical current, which provides the energy that allows complexes I, III, and
IV to pump protons into the space between the inner and outer mitochondrial membranes. This
creates a gradient across the inner mitochondrial membrane. The protons use proton channel F0
to flow down the gradient, back into the mitochondrial matrix. F0 is attached to enzyme F1, an
ATP synthase, which uses the proton gradient to phosphorylate ADP → ATP.
GLUCONEOGENESIS
osms.it/gluconeogenesis
▪ Synthesis of glucose from non- pyruvate
carbohydrate substrates ▪ Obtaining ATP, glycerol
▫ E.g. amino acids, lactate, glycerol ▫ Triacylglyceride breakdown → fatty
▪ Occurs primarily in liver cells; also in acids and glycerol → acetyl CoA + ATP
epithelial cells of kidney, intestine (β-oxidation)
▫ Inside cytoplasm, mitochondria, ▪ Pyruvate (via pyruvate carboxylase) →
endoplasmic reticulum oxaloacetate
▪ Starts with glycogenolysis after glucose ▪ Oxaloacetate (malate dehydrogenase) →
depletion malate
▪ Malate leaves mitochondria; malate (via
Process malate dehydrogenase) → oxaloacetate
▪ Like backwards glycolysis, with three ▪ Oxaloacetate (via PEPCK) →
exceptions phosphoenolpyruvate (PEP)
▪ Obtaining pyruvate ▪ PEP undergoes reversed glycolysis
▫ Lactate (via lactate dehydrogenase) → reactions until dihydroacetone-phosphate
pyruvate (DHAP)
▫ Amino acids (not leucine, lysine); e.g. ▫ Alternatively, glycerol (via glycerol
alanine (via alanine transaminase) → kinase) → glycerol-3-phosphate;
4 OSMOSIS.ORG
glycerol-3-phosphate (via glycerol-3- ▪ Fructose-6-phosphate (via isomerase) →

phosphate dehydrogenase) → DHAP glucose-6-phosphate
▪ DHAP (via aldolase) → fructose-1,6- ▪ Glucose-6-phosphate (via glucose-6-
bisphosphate phosphatase) → glucose
▪ Fructose-1,6-bisphosphatase → fructose-
6-phosphate
Figure 1.5 The process of gluconeogenesis.
OSMOSIS.ORG 5
GLYCOGEN METABOLISM
osms.it/glycogen-metabolism
▪ Polymer of glucose molecules linked by ▪ Cleaved glucose-1-phosphate (via
glycosidic bonds phosphoglucomutase) → glucose-6-
▪ Stores energy in skeletal muscle, liver phosphate
▫ With glucose-6-phosphate
Glycogen synthesis ▪ In liver cells, glucose-6-phosphatase
▪ Glucose + phosphate (via hexokinase) → removes phosphate → free glucose into
glucose-6 phosphate blood
▪ Glucose-6 phosphate (via ▪ In skeletal muscle, glucose-6-phosphate →
phosphoglucomutase) → glucose-1- glycolysis pathway
phosphate + energy (UTP)
▪ Glucose-1-phosphate + UTP (via UDP- Regulation
glucose pyrophosphorylase) → UDP- ▪ Principles
glucose ▫ Glycogen synthase: active without
▪ UDP-glucose added (via glycogen phosphate
synthase) to glycogen branch/glycogenin ▫ Glycogen phosphorylase: active with
(→ alpha-1,4-glycosidic bond) phosphate
▪ Branching enzyme cuts off part of glucose ▪ Hormones
chain, creates branch (→ alpha-1,6- ▫ Insulin: binds to membrane tyrosine
glycosidic bond) kinase receptors → protein phosphatase
removes phosphates → glycogen
Glycogen breakdown, AKA glycogenolysis
synthase activates, glycogen
▪ Glucagon → liver breakdown of glycogen phosphorylase deactivates
▪ Epinephrine → skeletal muscle breakdown ▫ Glucagon: binds to membrane G-protein
of glycogen coupled receptors (in liver) → ATP
▪ Glycogen phosphorylase cleaves alpha-1,4 (adenylyl cyclase) → cAMP → kinase
bonds on branches; catalyzes phosphate A → adds phosphates → glycogen
transfer to glucose residue → one glucose- phosphorylase activates, glycogen
1-phosphate is released at a time synthase deactivates
▫ Repeats until branch is only 4 glucose
units long
▪ Debranching enzyme: 4-alpha-
glucanotransferase moves 3 glucose units
off branch, onto main chain; alpha-1,6-
glucosidase cleaves last remaining glucose
6 OSMOSIS.ORG
Figure 1.6 The process of glycogen synthesis.
OSMOSIS.ORG 7
Figure 1.7 Glycogen breakdown. The process is completed differently in the liver and skeletal
muscles due to the respective presence and absence of glucose-6-phosphatase in each.
8 OSMOSIS.ORG
Figure 1.8 The role of insulin in the regulation Figure 1.9 The role of glucagon in the
of glycogen levels. regulation of glycogen levels.
GLYCOLYSIS
osms.it/glycolysis
▪ Energy-producing breakdown of glucose glucose-6-phosphate
into pyruvate ▫ Uses one ATP molecule
▪ Occurs in cytoplasm of all cells ▪ Glucose-6-phosphate (via
phosphoglucoisomerase) → fructose-6-
PROCESS phosphate
▪ Glucose transporter (GLUT) carries glucose ▪ Fructose-6-phosphate (via
into cell phosphofructokinase-1) → fructose-1,6-
bisphosphate
▪ Kinases (hexokinase, glucokinase)
phosphorylate glucose → conformational ▫ Rate-limiting step
change, i.e. glucose can’t diffuse out) → ▫ Uses one ATP molecule
OSMOSIS.ORG 9
Enzyme activation ▪ 3-phosphoglycerate (via mutase) →
▪ Fructose-6-phosphate (via 2-phosphoglycerate (x2)
phosphofructokinase-2) → fructose-2,6- ▪ 2-phosphoglycerate (via enolase) →
bisphosphate phosphoenolpyruvate (PEP) + H2O (x2)
▫ Up-regulated by insulin; down- ▪ PEP + ADP (via pyruvate kinase) →
regulated by glucagon pyruvate + ATP (x2)
▫ Fructose-2,6-bisphosphate activates ▫ Creates two ATP molecules
phosphofructokinase-1 ▫ Up-regulated by fructose-1,6-
▪ Fructose-1,6-bisphosphate (via aldolase) bisphosphate (feed-forward regulation)
→ glyceraldehyde 3-phosphate (G3P) + ▫ Down-regulated by ATP, alanine
dihydroacetone-phosphate (DHAP) ▪ In total, process generates two ATP
▫ DHAP (via isomerase) → G3P → 2x molecules
G3P molecules per glucose ▪ In cells with oxygen, pyruvate enters citric
▪ G3P (via G3P-dehydrogenase) → acid cycle, electron transport chain to make
1,3-diphosphoglycerate (1,3-BPG); H+ + more ATP
NAD+ → NADH (x2) ▫ 30–32 in total
▫ 2x NADH enter electron transport chain
▪ 1,3-BPG + ADP (via phosphoglycerate
kinase) → 3-phosphoglycerate + ATP (x2)
▫ Creates two ATP molecules
PENTOSE PHOSPHATE PATHWAY

osms.it/pentose-phosphate-pathway
▪ Synthesis of ribose, NADPH from unused Reversible non-oxidative phase
glucose ▪ Two options:
▪ Occurs in cytoplasm of all cells ▫ Ribulose-5-phosphate (via isomerase)
→ ribose-5-phosphate
Irreversible oxidative phase
▫ Ribulose-5-phosphate (via epimerase)
▪ Glucose-6-phosphate + NADP+ (via → xylulose-5-phosphate
glucose-6-phosphate dehydrogenase) →
6-phosphogluconate + NADPH
▪ 6-phosphogluconate + NADP+
(6-phosphogluconate dehydrogenase) →
ribulose-5-phosphate + NADPH + CO2
10 OSMOSIS.ORG
Figure 1.10 Glycolysis.
OSMOSIS.ORG 11
Figure 1.11 Pentose phosphate pathway.
12 OSMOSIS.ORG
NOTES
NOTES
FAT & CHOLESTEROL
METABOLISM
CHOLESTEROL METABOLISM
osms.it/cholesterol-metabolism
▪ Cholesterol insoluble in water → moves ▪ Geranyl transferase condenses three
through blood stream with lipoproteins isopentenyl pyrophosphate molecules →
▪ Cholesterol used in cell membrane for farnesyl pyrophosphate
flexibility, durability ▪ Squalene synthase condenses two farnesyl
▫ At ↓ temperature, cholesterol squeezed pyrophosphate molecules → squalene
between phospholipid molecules, keeps ▪ Oxidosqualene cyclase converts squalene
membrane fluid into lanosterol (cyclization)
▫ At ↑ temperature, cholesterol pulls ▪ Lanosterol converted into
phospholipid molecules together 7-dehydrocholesterol, eventually
▪ Cholesterol used by adrenal glands, cholesterol
gonads; makes steroid hormones
Cholesterol synthesis regulation
▫ Adrenal glands form corticosteroids
▪ SREBP, INSIG1, SCAP (collection of
(e.g. cortisol, aldosterone); testes
proteins)
(testosterone); ovaries (estradiol,
progesterone) ▫ ↓ cholesterol → INSIG1 falls off of
SCAP-SREBP → SREBP cleaving →
binds sterol regulatory element → ↑
CHOLESTEROL SYNTHESIS HMG-CoA reductase gene expression
▪ Mevalonate pathway; occurs in smooth
endoplasmic reticulum
CHOLESTEROL USE & STORAGE
Pathway ▪ Majority of cholesterol used by liver, ends
▪ Two acetyl-CoA molecules joined by up as bile acids
acetyl-CoA acyltransferase → acetoacetyl- ▪ Include cholic acids, chenodeoxycholic
CoA, CoA acids
▪ HMG-CoA synthase combines acetoacetyl- ▫ Conjugation with taurine forms
CoA, acetyl-CoA → 3-hydroxy-3- taurocholic acid, taurochenodeoxycholic
methylglutaryl-CoA (HMG-CoA), CoA acid respectively
▪ HMG-CoA reductase reduces HMG-CoA ▫ Conjugation with glycine forms
into mevalonate, removes CoA-SH, water glycocholic acid, glycochenodeoxycholic
▫ Rate limiting cholesterol synthesis step acid respectively
▪ Mevalonate-5-kinase uses ATP to ▪ Stored in gallbladder
phosphorylate mevalonate → mevalonate- ▪ Released into intestines after meals, aids
5-phosphate fat digestion
▪ Phosphomevalonate kinase uses ATP to ▪ Most reabsorbed by intestine; some
phosphorylate mevalonate-5-phosphate → eliminated through feces
mevalonate pyrophosphate ▫ Enterohepatic circulation: reabsorbed
▪ Mevalonate pyrophosphate decarboxylase bile acids enter portal bloodstream,
removes carboxyl group → isopentenyl return to liver cells
pyrophosphate
OSMOSIS.ORG 13
Figure 2.1 Cholesterol synthesis via the mevalonate pathway.
14 OSMOSIS.ORG
Chapter 2 Biochemistry: Fat & Cholesterol Metabolism
Figure 2.2 Cholesterol synthesis regulation.
FATTY ACID SYNTHESIS

osms.it/fatty-acid-synthesis
▪ Fatty acids: simplest lipid form phosphorylation) → creates adenosine
▫ Long carbon, hydrogen chain atoms triphosphate (ATP)
▫ Classification: short, medium, long, very
long chain fatty acids FATTY ACID SYNTHESIS
▪ Short, medium chain fatty acids ▪ ATP inhibits enzymes needed for citric acid
▫ Primarily obtained from diet cycle
▪ Long, very long chain fatty acids ▫ Allows additional acetyl-CoA to be
▫ Synthesized by liver, fat cells funneled toward pathways involving
▪ Synthesis: combine acetyl-CoA molecules fatty acid synthesis
into palmitoyl-CoA
Stages
▫ 16 carbon chain fatty acid; precursor to
▪ Acetyl-CoA combines with oxaloacetate
longer chain fatty acids
→ forms citrate → crosses mitochondrial
membrane into cytoplasm
BEFORE FATTY ACID SYNTHESIS ▪ In cytoplasm, citrate lyase cleaves citrate
▪ Acetyl-CoA must be obtained into acetyl-CoA, oxaloacetate
▪ In response to insulin, cells take in glucose ▫ Malic enzyme converts oxaloacetate
▫ Consumed as carbohydrates into pyruvate (NADP+ → NADPH in
process), which can cross back into
▪ In cell, glycolysis breaks glucose down into
membrane
pyruvate molecules
▫ Then converted back into oxaloacetate
▪ Mitochondria convert pyruvate into acetyl-
by pyruvate carboxylase
CoA using pyruvate dehydrogenase
▪ Acetyl-CoA carboxylase adds carboxyl
▪ Typically, acetyl-CoA combines with
group to acetyl-CoA → forms malonyl-CoA
oxaloacetate, enters citric acid cycle →
forms citrate → forms electron carriers ▫ Rate limiting fatty acid synthesis step
( join electron transport chain in oxidative ▫ Requires ATP, biotin, carbon dioxide (A-
OSMOSIS.ORG 15
B-C) as cofactors ▪ Malonyl-CoA ACP transacylase removes
▫ Acetyl-CoA carboxylase: tightly CoA group from malonyl-CoA, attaching
regulated (hormonal, allosteric resulting malonate to ACP
regulation); hormonal regulation ▪ 3-ketoacyl-ACP synthase cuts off
uses insulin, glucagon to remove/ carbon (was added to malonate earlier),
add phosphate group on acetyl-CoA released as CO2 (leaving behind acetate)
carboxylase; insulin ↑ activity/vice versa; → condenses it with acetate on cysteine
allosteric regulation uses citrate, fatty residue → forms four carbon chain (using
acids to ↑/↓ acetyl-CoA carboxylase one NADPH molecule for each process)
activity by allosteric binding ▪ Malonyl-CoA added across seven cycles
▪ Multiple enzymes form fatty acid synthase forming 16 carbon chain fatty acid polymer
complex (acyl carrier protein (ACP) on one ▫ Each cycle uses one acetyl-CoA
end, cysteine amino acid on other) (converted into malonyl-CoA), two
▪ Acetyl-CoA ACP transacylase removes NADPH molecules
CoA group from acetyl-CoA, attaching ▪ In total, eight acetyl-CoA molecules
resulting acetate to ACP → moves to (including initial molecule) used along with
cysteine residue 14 NADPH molecules
Figure 2.3 Acetyl-CoA is produced by mitochondria using pyruvate molecules (made during
glycolysis). ATP inhibits citric acid cycle enzymes so that acetyl-CoA can be used in fatty acid
synthesis pathways.
16 OSMOSIS.ORG
Figure 2.4 The citrate shuttle transports acetyl-CoA out of the mitochondria by combining
it with oxaloacetate to form citrate. Once citrate is in the cytoplasm, it is converted back to
oxaloacetate and acetyl-CoA, allowing acetyl-CoA to be used in fatty acid synthesis.
Figure 2.5 Fatty acid synthesis. Malonyl-CoA added across seven cycles → 16 carbon chain
fatty acid polymer called palmitoyl-CoA.
OSMOSIS.ORG 17
FATTY ACID OXIDATION
osms.it/fatty-acid-oxidation
▪ AKA β-oxidation transferring one to nicotinamide
▪ Fatty acids broken down to produce energy adenine dinucleotide (NAD) → NADH,
▪ Takes place in mitochondria of heart, β-ketoacyl-CoA
skeletal muscles, liver cells ▫ β-ketothiolase cleaves off two carbon
atoms → acetyl-CoA, fatty acyl-CoA
molecule (two carbons shorter—which
OXIDATION PREPARATION can be further oxidized)
▪ Triglycerides (three fatty acids attached to
glycerol) in adipocytes → broken down by
hormone sensitive lipase OXIDATION CYCLE
▫ ↓ blood glucose → ↑ glucagon → ↑ ▪ One oxidation cycle: 1 NADH, 1 FADH2, 1
hormone sensitive lipase → ↑ fatty acid acetyl-CoA
breakdown ▪ Fatty acids with even number of carbon
▪ Fatty acids leave fat cells → enter atoms
bloodstream ▫ Oxidation repeats until just acetyl-CoA
▪ Albumin in blood binds to fatty acids → remains
carries them to target cells ▪ Fatty acids with odd number of carbon
▪ Fatty acid dissociates from albumin → atoms
diffuses into cell ▫ Oxidation repeats until three carbon
▪ Fatty acyl-CoA synthetase adds CoA to propionyl-CoA is left; propionyl-CoA is
end of fatty acid (→ fatty acyl-CoA), using broken down differently
up two ATP molecules ▪ Propionyl-CoA carboxylase
▪ Fatty acyl-CoA cannot cross cell ▫ Adds carboxyl group to propionyl-CoA
membrane, carnitine shuttle used → methylmalonyl-CoA
▫ Carnitine acyltransferase 1 (outer ▫ Cofactors required: ATP, biotin, carbon
membrane) replaces CoA on fatty acid dioxide (A-B-C)
with carnitine (→ fatty acyl-carnitine) ▪ Methylmalonyl-CoA mutase
▫ Fatty acyl-carnitine, CoA cross inner ▫ Rearranges carbon atoms on
mitochondrial membrane methylmalonyl-CoA → succinyl-CoA
▫ Carnitine acyltransferase 2 (inner ▫ Cofactor required: Vitamin B12
membrane) replaces carnitine on fatty ▪ Succinyl-CoA
acid with CoA (→ fatty acyl-CoA) ▫ Can enter citric acid cycle/used for heme
synthesis
OXIDATION PROCESS
▪ Occurs on ⍺, β carbon atoms of fatty acyl-
▪ Very long fatty acids (22 carbons atom/
longer)
CoA ▫ Peroxisomes may be needed
▫ Acyl-CoA dehydrogenase moves one ▫ Peroxisomal oxidation uses different
hydrogen from each carbon to nearby enzymes until fatty acid is smaller than
flavin adenine dinucleotide molecule 22 carbon atoms
(FAD) → FADH2, enoyl-CoA ▪ NADH, FADH2
▫ Enoyl-CoA hydratase transfers hydroxyl ▫ Can enter electron transport chain
group to β carbon → β-hydroxyacyl- ▫ Creates ATP → approximately three +
CoA two ATP molecules
▫ β-hydroxyacyl-CoA dehydrogenase
removes two hydrogens from β carbon
18 OSMOSIS.ORG
▪ Acetyl-CoA
▫ Can enter citric acid cycle
▫ Creates more NADH, FADH2 →
approximate total of 12 ATP molecules
Figure 2.6 Oxidation preparation requires the use of two ATP molecules and results in fatty
acyl-CoA being present in the mitochondrial matrix.
OSMOSIS.ORG 19
Figure 2.7 Oxidation preparation requires the use of two ATP molecules and results in fatty acyl-
CoA being present in the mitochondrial matrix.
Figure 2.8 Fatty acid oxidation when the fatty acid has an odd number of carbon atoms.
20 OSMOSIS.ORG
KETONE BODY METABOLISM

osms.it/ketone-body-metabolism
KETONE BODIES KETONE BODY BREAKDOWN
▪ Acetoacetate, β-hydroxybutyrate, acetone ▪ β-hydroxybutyrate, acetoacetate in blood
(all contain ketone C=O group) diffuses into peripheral tissue mitochondria
▪ Produced by liver mitochondria using ▫ β-hydroxybutyrate dehydrogenase
acetyl-CoA converts β-hydroxybutyrate back into
▫ During physiological states such as acetoacetate
fasting, carbohydrate-restrictive diets ▪ Thiophorase can add CoA from succinyl-
(e.g Atkins, ketogenic diet), intense CoA to acetoacetate → form acetoacetyl-
exercise, pathological states such as CoA, succinate
Type 1 diabetes mellitus, alcoholism ▪ β-ketothiolase cleaves acetoacetyl-
(lack of glucose to power cells) CoA with CoA → forms two acetyl-CoA
▪ Released into bloodstream → picked up molecules
by majority of cells → re-converted into ▫ Can enter citric acid cycle to make ATP
acetyl-CoA → enter mitochondria, produce
ATP
KETONE BODY SYNTHESIS

▪ Two acetyl-CoA molecules are joined
(acetyl-CoA acyltransferase) →
acetoacetyl-CoA + CoA
▪ HMG-CoA synthase
▫ Acetoacetyl-CoA + acetyl-CoA →
3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) + CoA (rate-limiting ketone
body synthesis step)
▪ HMG-CoA lyase removes acetyl-CoA from
HMG-CoA → acetoacetate
▪ Remaining ketone bodies formed
▫ β-hydroxybutyrate dehydrogenase adds
hydrogen from NADPH to acetoacetate
→ β-hydroxybutyrate
▫ Acetoacetate in blood spontaneously
loses a carbon → acetone (exhaled
through lungs)
OSMOSIS.ORG 21
Figure 2.9 Ketone body synthesis.
Figure 2.10 Ketone body breakdown.
22 OSMOSIS.ORG
NOTES
NOTES
NUCLEIC ACID METABOLISM
NUCLEOTIDE METABOLISM
osms.it/nucleotide-metabolism
Nucleotides ▪ RNA nucleosides (resulting nucleotide)
▪ Building blocks of DNA, RNA ▫ Adenine + ribose = adenosine
▪ Consist of 5 carbon sugar, phosphate (monophosphate → AMP)
group, nitrogenous base/nucleobase ▫ Guanine + ribose = guanosine
▫ 5 carbon sugar: deoxyribose (→ DNA) (monophosphate → GMP)
or ribose (→ RNA) ▫ Cytosine + ribose = cytidine
▫ Nucleobase: pyrimidine (cytosine, (monophosphate → CMP)
thymine for DNA, uracil for RNA) or ▫ Uracil + ribose = uridine
purine (adenine, guanine) (monophosphate → UMP)
▫ Sugar + nucleobase = nucleoside
Figure 3.1 Nucleotide components: a phosphate group, a sugar (deoxyribose or ribose), and a
nucleobase (adenine, guanine, cytosine, thymine, and uracil).
OSMOSIS.ORG 23
▪ DNA nucleosides (resulting nucleotide) ▪ DNA nucleotides start with diphosphates
▫ Adenine + deoxyribose = of RNA nucleotides
deoxyadenosine (monophosphate → ▫ Ribonucleotide diphosphate reductase
dAMP) reduces ribose to deoxyribose
▫ Guanine + deoxyribose = ▫ Molecules then lose phosphate groups
deoxyguanosine (monophosphate → → dCMP, dUMP, dAMP, dGMP
dGMP) ▫ Thymidylate synthetase converts dUMP
▫ Cytosine + deoxyribose = deoxycytidine into dTMP
(monophosphate → dCMP)
Nucleotide breakdown
▫ Thymine + deoxyribose =
deoxythymidine (monophosphate → ▪ Pyrimidine rings C,T,U broken down into
dTMP) CO2 + NH3, excreted through exhalation/
urine
De novo nucleotide synthesis ▪ Purine rings G,A degraded into uric acid,
▪ RNA nucleotides start with ribose-5- excreted through urine
phosphate
▫ Then for pyrimidine nucleotides (UMP Salvage pathway
and CMP) ▪ Guanine, hypoxanthine from purine
▫ Then for purine nucleotides (AMP and breakdown can be restored into GMP, AMP
GMP)
24 OSMOSIS.ORG
Chapter 3 Biochemistry: Nucleic Acid Metabolism
Figure 3.2 De novo synthesis of RNA pyrimidines. CTP naturally loses phosphate groups → CMP.
OSMOSIS.ORG 25
Figure 3.3 De novo synthesis of RNA purines from precursor iosine monophosphate (IMP).
Figure 3.4 DNA nucleotide synthesis from diphosphates of RNA nucleotides.
26 OSMOSIS.ORG
Chapter 3 Biochemistry: Nucleic Acid Metabolism
Figure 3.5 Breakdown of purines into uric acid.
OSMOSIS.ORG 27
Figure 3.6 Salvage pathways that restore AMP and GMP.
28 OSMOSIS.ORG
NOTES
NOTES
PROTEIN METABOLISM
AMINO ACIDS & PROTEIN FOLDING

osms.it/amino-acids-protein-folding
Figure 4.1 The 20 amino acids used by humans.
▪ Amino acids: organic compounds with

-NH2, -COOH groups
▪ Side chain gives specific properties
▫ Hydrophilic: polar side chains → acidic
(e.g. carboxyl); basic (e.g. amine)
▫ Hydrophobic: non-polar side chains →
alkyl, aromatic
▪ Molecular charge depends on pH
▫ Low pH: + amine, 0 carboxyl
▫ High pH: - carboxyl, 0 amine
▫ Neutral: + amine, - carboxyl →
zwitterion
▪ Zwitterion: compound with both positive,
negative charges
▫ Occurs in each amino acid at specific pH
(AKA pI/isoelectric point)
Figure 4.2 Amino acid structure.
OSMOSIS.ORG 29
▪ Proteins: amino acid chains connected by Primary, secondary, tertiary, quaternary
peptide bonds protein structures
▫ Peptide bond: amide bond formed ▪ Primary: linear amino acid sequence
between amino acids by condensation connected by peptide bonds
of -NH2 with -COOH → releases H2O ▪ Secondary: α-helix, β-pleated sheet
▫ Resonance: electrons shared across ▪ Tertiary: overall shape, including secondary
bond → partial double-bond character structures, with other features (e.g. disulfide
→ improved strength bridge, hydrophobic bonds)
▪ Amino acids: chiral molecules ▪ Quaternary: final level; combination
▫ Enantiomers/mirror images are distinct of multiple amino acid chains (e.g.
▫ Proteins only made of L-amino acids hemoglobin)
▪ Protein production occurs in ribosomes
Figure 4.3 Amide (peptide) bonds form

between amino acids through a condensation
reaction.
Figure 4.4 Enantiomers are two forms

that look like mirror images but are not Figure 4.5 The four levels of structure for
interchangeable, like a left and right shoe. proteins.
Proteins are only made out of levo-oriented
amino acids.
30 OSMOSIS.ORG
Chapter 4 Biochemistry: Protein Metabolism
ENZYME FUNCTION
osms.it/enzyme-function
▪ Enzymes: biochemical reaction catalysts
▪ Substrates bind to active site → enzyme-
substrate complex
▪ Not used up in reactions
▪ Highly specific (e.g. amylase in saliva →
large carbohydrate breakdown)
Figure 4.7 Michaelis–Menten graph: used

to visualize enzyme kinetics. With a fixed
amount of enzyme, the reaction velocity ↑ as
substrate is added, until the active sites on
all of the enzymes become saturated. At this
point, the reaction speed plateaus → Vmax.
▪ Km: substrate concentration when reaction

velocity is half of maximum
▫ ↑ enzyme affinity (e.g. activator
molecules) → ↓ Km
▫ ↓ enzyme affinity (e.g. competitive
inhibition) → ↑ Km
Figure 4.6 Transition state: intermediate step

in reaction with high energy. Enzymes speed
up reactions by binding substrate (enzyme-
substrate complex), which stabilizes the
transition state and decreases the amount
of extra energy required for the reaction to
proceed.
▪ Enzyme kinetics: catalysis rate

▪ Vmax: maximum reaction velocity with fixed
enzyme quantity
▫ ↑ substrate → ↑ velocity, until all
enzymes bind Figure 4.8 Km is found using a Michaelis–
▫ ↑ enzymes → ↑ Vmax Menten diagram by identifying ½ Vmax on
▫ ↓ enzymes → ↓ Vmax the y-axis, then finding the corresponding
▫ Non-competitive inhibition (inhibitory substrate concentration value on the x-axis.
molecule binds to active/allosteric site →
prevents substrate binding) → ↓ Vmax
OSMOSIS.ORG 31
▪ Lineweaver–Burk plot
▫ Based on Michaelis–Menten equation
V [S] 1 K m + [S]
V0 = max → =
K m + [S] V Vmax [S]
→ 0
Figure 4.10 Processes that ↑ Vmax ↓ 1/Vmax

→ the line slopes lower on the graph than
the control. Processes that ↓ Vmax ↑ 1/Vmax →
the line slopes higher on the graph than the
control.
Figure 4.9 The Lineweaver–Burk plot shows

Km and Vmax as functions of the x, y intercepts.
AMINO ACID METABOLISM

osms.it/amino-acid-metabolism
▪ Dietary protein broken down into amino Transamination
acids → used to synthesize other proteins ▪ Reversible reaction
▫ Excess amino acids used for energy/ ▫ Transfers nitrogen-containing amine
stored as fat/glycogen group to another molecule
aminotransferase + vitamin B6 cofactor) ⇄

▪ Portal vein delivers absorbed amino acids ▪ Amino group transferred (via
(and other nutrients) to liver after uptake by
small intestine → liver synthesizes needed alpha ketoglutarate (acceptor molecule) →
proteins (e.g. albumin, immunoglobulins), alpha-keto acid + glutamate
non-essential amino acids ▫ Glutamate oxidatively deaminated
▪ Amino acids delivered to cells throughout in liver mitochondria → ammonia
body via blood → enter cell by facilitated/ byproduct converted to urea (via urea
active transport → used for protein cycle) → eliminated (kidneys)
synthesis (e.g. hormones, enzymes)
▪ Ammonia (NH4+): toxic metabolic by- Deamination
product from amino acid catabolism → ▪ Nitrogen-containing amine group removal
converted to urea (liver) → eliminated (via deaminase) → amino acid utilized for
(kidneys) energy
▪ Produces ammonia → converted to urea →
renal excretion
Figure 4.11 Ammonia → urea in the liver.
32 OSMOSIS.ORG
Figure 4.12 Example of a transamination reaction with amino acid alanine. ALT switches
the amino group on alanine with the oxygen group on α-ketoglutarate, resulting in ketoacid
pyruvate and amino acid glutamate, which has the amino group. Glutamate is the only amino
acid that doesn’t have to transfer its amine group to another molecule. It undergoes oxidative
deamination, a process that removes hydrogens and an amino group.
NITROGEN & THE UREA CYCLE

osms.it/nitrogen-and-urea-cycle
▪ Ammonia (NH3): toxic protein catabolism ▪ Glutamine synthetase: NH3 + glutamate →
byproduct; detoxification by liver (forming glutamine
non-toxic urea) ▪ Glutamine transported through blood
▪ Glutaminase: glutamine → NH3 +
glutamate
▪ In liver mitochondria
Glucose-alanine cycle
▪ Only from muscle
▪ Glutamate dehydrogenase: NH3 + alpha-
ketoglutarate → glutamate
▪ Alanine transaminase: glutamate +
pyruvate → alpha-ketoglutarate + alanine
▪ Alanine transported through blood
▪ Alanine transaminase: alpha-ketoglutarate
Figure 4.13 Ammonia is composed of a + alanine → glutamate + pyruvate
nitrogen-containing amino group, an acidic
carboxyl group, and a side chain. Glutamate–NH3 conversion: two ways
▪ Glutamate dehydrogenase: glutamate →
NH3 + alpha-ketoglutarate
▪ NH3 reaches liver in two ways, sometimes ▫ Free NH3 enters urea cycle
as glutamate ▪ Aspartate transaminase: glutamate
Glutamine synthetase system + oxaloacetate → aspartate + alpha-
ketoglutarate
▪ From all tissues
▫ Aspartate carries NH3 into urea cycle
OSMOSIS.ORG 33
Figure 4.14 The glutamine synthetase system of ammonia reaching the liver.
34 OSMOSIS.ORG
Figure 4.15 The glucose-alanine cycle of ammonia reaching the liver.
OSMOSIS.ORG 35
Figure 4.16 Once glutamate is in a liver cell, there are two possible outcomes for it that depend
on which enzyme it encounters (glutamate dehydrogenase or AST). In Option #1, ammonia
enters the urea cycle; in Option #2, the ammonia group is carried into the urea cycle as part of
the amino acid aspartate.
Urea cycle ▪ Argininosuccinate lyase: argininosuccinate

▪ Starts in liver cells’ mitochondria → fumarate + arginine
▪ Carbamoyl phosphate synthetase 1 (CPS1) ▫ Fumarate → malate; malate
▫ NH3 + CO2 + 2ATP → carbamoyl → oxaloacetate (by malate
phosphate dehydrogenase); oxaloacetate +
glutamate → aspartate + alpha-
▫ N-acetylglutamate → ↑ CPS1 affinity for
ketoglutarate (by aspartate
ammonia (by allosteric binding)
transaminase) → aspartate can enter
▪ Ornithine transcarbamylase: ornithine next cycle
+ carbamoyl phosphate → citrulline +
▫ Arginine → urea + ornithine (by
phosphate
arginase) → ornithine can enter next
▪ Citrulline moves to cytoplasm cycle
▪ Argininosuccinate synthetase: citrulline + ▪ Resulting urea then enters blood, excreted
aspartate + ATP → argininosuccinate by kidneys
36 OSMOSIS.ORG
Figure 4.17 Illustration of the urea cycle, starting with the synthesis of carbamoyl phosphate
from ATP, ammonia, and carbon dioxide, with the help of enzyme CPS1.
OSMOSIS.ORG 37
PROTEIN STRUCTURE &
SYNTHESIS
osms.it/protein-structure-and-synthesis
▪ Proteins: functional structures composed of TRANSCRIPTION
amino acids; synthesized within cells ▪ Messenger RNA (mRNA) transcribes code
▪ Genes, housed within DNA, provide from DNA
blueprint for protein synthesis ▪ Begins at promoter
▪ Codon: nucleotide triplet containing ▫ Base sequence establishes transcription
sequence of three nucleotide bases (A, G, starting point
T, C)
▫ Codes for specific amino acid Initiation
▫ 64 codons code for 20 amino acids; > ▪ RNA polymerase separates DNA helix at
one codon for most amino acids (UUU, promoter site
UGC code cysteine)
Elongation
▫ One “start” codon; three “stop” codons
▪ RNA polymerase unwinds, rewinds DNA →
matches RNA nucleotides with DNA bases
→ links them together
Figure 4.19 Elongation: RNA polymerase

attaches complementary mRNA nucleotides
to the unzipped DNA template strand to build
an mRNA molecule.
Termination
▪ Ends at termination signal; base sequence
establishes transcription end point
Figure 4.18 The four nucleobases used in
Pre-mRNA formed
DNA are guanine, cytosine, thymine, and
adenine. In mRNA, uracil (U) is used rather ▪ Contains non-coding areas (introns)
than thymine. ▫ Spliceosomes snip out introns →
functional mRNA
▫ mRNA complex proteins added → guide
mRNA out of nucleus
38 OSMOSIS.ORG
Figure 4.20 Termination: when the two complementary sequences in the terminator sequence
get transcribed into mRNA, they bond with each other, creating a hairpin loop that causes the
RNA polymerase to detach from the DNA strand.
TRANSLATION
▪ Base sequence contained in mRNA
translated into assembled polypeptide
Three RNA types required

▪ mRNA: carries coded message out of
nucleus to ribosome in cytoplasm
▪ Ribosomal RNA (rRNA): “workbench” for
protein synthesis
▪ Transfer RNA (tRNA): brings amino acids
to workbench assembly site at ribosome
▫ Folded into “cloverleaf” shape
▫ Acceptor stem: attaches to amino acid
▫ Anticodon: complementary to mRNA
codon (tRNA binds with mRNA through
complementary base pairing)
OSMOSIS.ORG 39
Figure 4.21 Translation: as ribosomes line tRNA molecules up with their complementary codons,
the amino acids held by the tRNA bind with each other to form a protein, which is a chain of
amino acids. The process is terminated at a stop codon.
40 OSMOSIS.ORG
NOTES
NOTES
INTRODUCTORY BIOSTATISTICS
INTRODUCTION TO BIOSTATISTICS
osms.it/intro-biostatistics
▪ Statistics: process of collecting, organizing, ▪ Selection bias: sample does not accurately
analyzing data set variables reflect population
▪ Biostatistics: focus on data related to living ▫ Occurs when precautions to obtain
things representative sample are not used
▪ Descriptive statistics: summarizes, ▫ Randomization helps eliminate bias
describes population information
Case (data point)
▪ Inferential statistics: examines relationships
between two/more variables → applies ▪ Single observation (e.g. one individual
results of sample population to target visiting emergency room for influenza
population symptoms)
POPULATION & SAMPLE TYPES OF HYPOTHESES
Population Null hypothesis (H0)

▪ Group (people, specimens, events) with ▪ States that there is no relationship between
defined criteria (e.g. October–March variables
emergency room visits) ▪ Any observed relationship due to chance
▪ Parameter: numerical population (e.g. no relationship between body mass
description (e.g. range, mean, standard index (BMI), hypertension)
deviation)
Alternative hypothesis (research
▫ μ = population mean hypothesis)
▫ σ = population standard deviation ▪ States expected relationship between
variables (e.g. relationship between BMI,
Sample
hypertension)
▪ Subset drawn from population (e.g.
influenza-related October–March Hypothesis testing
emergency room visits) ▪ Statistical methods used to determine
▪ Represents population → inferences can be relationship strength between variables,
made about population how much of observed relationship is due
▪ Statistic: numerical sample description (e.g. to chance, significance of observations
▪ X = sample mean
range, mean, standard deviation) ▪ Statistical significance: relationship
between variables is caused by something
▪ SD = sample standard deviation other than chance
▪ Sampling error: sample does not accurately ▪ Usually defined by a p-value of < 0.05
reflect population (5%); “p” stands for “probability”
▫ Usually due to wide variation within ▫ Type 1 error: probability of incorrectly
sample rejecting null hypothesis (i.e. concluding
▫ ↑ sample size helps avoid sampling error significant relationship between
OSMOSIS.ORG 41
variables when there is not) ▫ What is effect of X (independent
▫ Type 2 error: incorrectly accepting variable) on Y (dependent variable); how
null hypothesis (i.e. concluding there is X related to Y?
is no significant relationship between ▫ E.g. what is the effect of lipid-lowering
variables, missing present association) drug (X) on individual’s cholesterol level
▪ Clinical significance: practical importance (Y)?
of study results that may not be statistically
significant GRAPHIC DESCRIPTION OF DATA
▪ When values are plotted on graph →
RELIABILITY & VALIDITY variety of frequency distributions (curves)
▪ Measurement characteristics used to collect result
data ▪ Properties of distributions: central
tendency, dispersion
Validity: accuracy
▪ Instrument actually measures variable Normal (Gaussian) curve
(concept, construct) it is supposed to ▪ Symmetrical distribution of scores around
measure (e.g. urine dipstick accurately mean
detects proteinuria) ▫ Forms classic bell shape
▪ Valid instrument must be reliable ▫ Values lie within two standard
deviations of mean
Reliability: repeatability
▫ Most natural phenomena show this type
▪ Instrument consistently yields same results of distribution
with repeated measurements (e.g. urine
▫ Parametric tests utilized in research
dipstick reliably detects proteinuria with
each measurement) Non-Gaussian curve
▪ Reliable instrument may/may not be valid ▪ Asymmetrical distribution of scores around
mean
TYPES OF VARIABLES ▫ Skewed (negatively/positively) curve
▪ Variable: defined characteristic being ▫ Kurtotic (flat/peaked) curve
studied; can assume different values (leptokurtic—thin, positive kurtosis;
▪ Independent variable: manipulated platykurtic—flat negative kurtosis)
(treatment) variable ▫ Nonparametric tests utilized in research
▪ Dependent variable: outcome variable;
influenced by independent variable
Figure 5.1 Visualization of normal (red), skewed (green) and kurtotic (blue and yellow)
distributions.
42 OSMOSIS.ORG
Chapter 5 Biostatistics & Epidemiology: Introductory Biostatistics
MEAN, MEDIAN, MODE

osms.it/mean-median-mode
▪ Central tendency measures Mode
▪ More curve symmetry → more alike mean, ▪ Central value appearing most often in data
median, mode sequence
▫ Bimodal (two modal), trimodal (three
Mean (X) modes), amodal
▪ Central value calculated by adding each
value in data set → dividing by total 17 19 20 20 61 61 62 100
number of data points
▪ Expressed as formula: total sum of ▫ Bimodal dataset with two mode values
individual data points X1, X2, ......., Xn, divided of 20, 61
by n (number of data points) ▪ Not affected by outliers
( X 1 + X 2 ,...,+ X n )
X=
n
▪ Can be influenced by an extreme value

(outlier) → skewed data
Median
▪ Calculates central value when possible
outliers present
▪ Divides set of data into two halves
▫ Half of values > median, half < median
▪ Most commonly used expression of central
tendency
▪ Arrange data in order of magnitude → find
midpoint
17 19 20 20 61 61 62 100
▪ Odd number of values → one “middle”

Figure 5.2 Mean, median, and mode in a
number
skewed curve.
▪ Even number of values → two middle-
values values (20, 61)
▫ Calculate median by averaging two
values: (20+61)/2 = 40.5
OSMOSIS.ORG 43
PROBABILITY
osms.it/probability
▪ Relative likelihood that event will/will not
occur
▪ To calculate chance that event/outcome
will occur → divide number of times event
happened by number of times event could
have happened
▫ E.g. event A is rolling a die and getting
a three
▫ Since a die has six sides, there are six
possible numbers, so the probability Figure 5.5 Probability of not rolling a three =
(P) of rolling a three is 1/ 6, or 0.167 1 - P(rolling a three).
(16.7%)
Rule 4
▪ Probability of two disjoint (mutually
exclusive) events = the sum of the first
event plus the second event
▫ P(A or B) = P(A) + P(B)
Rule 5
Figure 5.3 Probability of rolling a three on a ▪ Probability for two not disjoint (not mutually
six-sided die. exclusive) events = sum of the probability
of event A and the probability of event B,
minus the probability of event A and B
RULES together
▫ P(A or B) = P(A) + P(B) – P(A and B)
Rule 1
▪ Probability of event A can range anywhere Rule 6
from 0% to 100% ▪ Probability of two independent events =
▫ 0 ≤ P(A) ≤ 1 probability of the first event multiplied by
the probability of the second event
Rule 2 ▫ P(A and B) = P(A) x P(B)
▪ Sum of probabilities of all possible
outcomes = 1 Rule 7
▪ Conditional probability (probability of
event A, given what happens in event B) =
probability of event A and event B divided
by probability of event B
Rule 8
Figure 5.4 Visualization of Rule 2. ▪ Probability of events A, B = probability of
event A multiplied by conditional probability
of event B given event A occurred
Rule 3 (complement rule)
▪ Probability that event will not occur = 1
minus probability that it does occur
▫ P = 1 – P(A)
44 OSMOSIS.ORG
Figure 5.6 A visualization of the difference between mutually exclusive and not mutually
exclusive events.
Figure 5.7 Rule 7, conditional probability: determining P(A) and P(B) when event A depends
on event B. In this case, we are finding the probability that the roll of two dice adds up to seven
(event A) given that the first die is either a five or a six (event B). Once P(A) and P(B) are known,
they are used to solve for P(A given B).
OSMOSIS.ORG 45
RANGE, VARIANCE, & STANDARD
DEVIATION
osms.it/range-variance-standard-deviation
▪ Measures distribution of variables ▫ E.g. SD of individual weight: √650 =
25.5kg
Range ▪ In Gaussian curve
▪ Difference between highest, lowest value ▫ 68 - 95 - 99 rule: 68% of data points lie
▪ E.g. Range of individuals’ cholesterol levels within 1 SD from mean; 95% lie within
▫ 130, 150, 152, 158, 165, 289, 354 2 SD, 99% lie within 3 SD
▫ Range 354 - 130 = 224mg/dL ▪ Z-score = number of SD data point is away
▪ E.g. individual weight (in kg) from mean
▫ 10 + 45 + 50 + 55 + 90 ▫ Data point minus the population mean,
▫ Range = 90 - 10 = 80 divided by the population standard
deviation
Variance
x−µ
▪ Sum of squared deviations from mean,
divided by number of distributions σ
▫ E.g. blood glucose population mean =
∑(x − x)2 90g/dL, SD = 20g/dL, data point = 130g/
σ =
2
n dL (130 - 90 / 20 = 2)
▪ E.g. variance of individual weight (in kg) ▪ Coefficient of variation (CV) = SD/mean;
▫ (10 - 50)2 + (45 - 50)2 + (50 - 50)2 + (55 also expressed as percentage, obtained by
- 50)2 + (90 - 50)2 / (5) = 650 kg2 multiplying the CV by 100
Standard deviation (SD)

▪ Square root of variance
Σ(x − x)2
σ=
n
46 OSMOSIS.ORG
TYPES OF DATA
osms.it/types-of-data
▪ Determining type of data to be collected Continuous data
helps establish which sort of distributions ▪ Can take on infinite number of value (e.g.
can logically be used to describe variable weight, height, blood glucose)
▫ Mean, median, mode, standard deviation
Nominal data
can be calculated
▪ Can assume one of a limited number of
possible values (e.g. ABO blood types) Interval data
▫ No meaningful rank order; no median, ▪ Indicates meaningful quantitative difference
mean, standard deviation; mode used between two values; values can be placed
for analysis in clear, logical order
▫ Includes dichotomous variables (e.g. ▫ E.g. temperature on Celsius/Fahrenheit
normal, abnormal) scale; difference between 90° and 60°
measured as 30°
Ordinal data
▫ Arbitrary zero point
▪ Ordered in meaningful way (e.g. systolic
▫ Mean, median, mode, standard deviation
murmur ranking from 1–6)
can be calculated
▫ Follows order, but quantitative
differences not clear (do not indicate Ratio data
degree of difference between ▪ Has absolute, meaningful zero point
observations)
▪ Can use multiplication, addition, subtraction
▫ Median, mode can be used; mean to calculate ratios
usually not suitable to describe sample/
▪ Mean, median, mode using ratio data
population
Discrete data
▪ Measured in whole numbers (no decimal
values)
▫ E.g. number of pregnancies
Figure 5.8 Types of data.
OSMOSIS.ORG 47
NOTES
NOTES
CAUSATION & VALIDITY
CAUSALITY
osms.it/causality
▪ Consequential relationship between two ▫ Example: the longer you smoke, the
events (e.g. A caused B) higher your risk of developing lung
▫ Contrast with correlation: association cancer
between two events
Biologic coherence
▪ Consequential relationship may be direct/
▪ Causal mechanism for effect agrees with
indirect
current knowledge
▫ Direct: event caused direct consequence
▫ Example: factually known that cigarettes
which → effect (A → B)
contain carcinogenic agents
▫ Indirect: initial event → another event →
final effect (A → x → y → B) Biologic plausibility
▪ Correlation is not equal to causation ▪ Proposed mechanism of effect makes
▫ Two correlated events may seem sense according to current knowledge
to have consequential relationship; ▫ Example: because we know cigarettes
sometimes due to random chance/ contain carcinogenic agents, it makes
external factors/confounding (noncausal) sense that cigarette-smoke exposure
variables → higher probability of developing lung
cancer
ESTABLISHING CAUSALITY Consistency with other knowledge
▪ To establish causality between set of ▪ Association has been shown repeatedly
events, relationship must meet following
▫ Example: it has been repeatedly proven
criteria
that smoking confers higher risk of
Temporality developing lung cancer
▪ Cause happened before effect Specificity
▫ Event A followed by Event B ▪ Chances that effect is due to other causes
▫ Example: smoking → lung cancer ▫ Example: can there be another
Strength of association explanation for developing lung cancer
besides exposure to cigarette smoke?
▪ Relational closeness between two events
▫ Measured by relative risk, odds ratio, Experimental evidence
correlations, etc. ▪ When you remove cause, effect disappears
▫ Example: how closely is smoking related ▫ Example: if you stop smoking, your risk
to developing lung cancer? of developing lung cancer decreases
Dose-response relationship Analogy
▪ More exposure to cause → greater effect ▪ Similar events have been proven to cause
▫ Longer exposure to Event A → more risk similar effects
of Event B ▫ Example: smoking other substances has
48 OSMOSIS.ORG
Chapter 6 Biostatistics & Epidemiology: Causation & Validity
been known to cause lung pathology Not necessary but sufficient

▪ Presence of A not required, but is enough
CAUSAL RELATIONSHIP TYPES to cause B
▫ Example: gunshot to head sufficient to
Necessary and sufficient cause death, however, not necessary, as
▪ Presence of A required, present in there are many other causes of death
adequate amounts to cause B
Not necessary and not sufficient
▫ Example: autosomal dominant mutation
with complete penetrance both ▪ Presence of A not needed nor enough to
necessary, sufficient for disease to cause B
develop ▫ Example: urinary infection not
necessary nor sufficient to cause
Necessary but not sufficient pelvic inflammatory disease; urinary
▪ Presence of A required, not present in infection can be present without pelvic
adequate amounts to cause B inflammatory disease, individual can
▫ Example: heat required to cause burn, have pelvic inflammatory disease
however, low heat will not cause burn; it without having urinary tract infection
is necessary but not sufficient
BIAS
osms.it/bias
▪ Error in one step of study design/ ▫ Results of one group will be inherently
conduction/analysis → results interpretation different to other group’s results
that is different from truth ▫ Example: blood glucose levels of groups
▫ Many types of biases, no common measured by different machines; one
classification gave accurate results, other reported
inaccurate results
SELECTION BIAS Non-differential misclassification
▪ Errors made when choosing/following ▪ Measurement error likely to have occurred
population to be studied in both groups
▫ Can occur at different stages of study ▫ Results among two groups will not
▫ Most commonly occurs when chosen differ greatly
sample is not representative of ▫ Example: machine used to determine
population blood glucose levels for both groups
was inaccurate
MEASUREMENT BIAS
▪ AKA information bias OTHER BIAS TYPES
▪ Errors made when measuring data/results ▪ Information gathering, management can →
of interest other bias types
▫ Most commonly results in results ▪ AKA information bias
misclassification which can be
differential/non-differential Procedure bias
▪ People allocated to different groups not
Differential misclassification treated identically
▪ Error in measurement more likely to occur in ▫ Usually due to lack of blinding
one group than another
OSMOSIS.ORG 49
▫ Example: people in one group spend Lead-time bias
more time in hospital than other group ▪ Early diagnosis extends follow-up period,
making it seem as if event being studied
Recall bias took longer to progress
▪ Awareness of event/effect influences ▫ Example: early cervical cancer detection
individual’s recall of cause may make it seem as if cancer is less
▫ Most common in retrospective studies aggressive because of more time spent
▫ Example: after a person with cancer living with diagnosis
knows that radiation exposure is a
cancer development risk factor, the Observer-expectancy bias
person may place more emphasis on ▪ When belief in intervention’s effectiveness
exposure to radiation than someone interferes with reported treatment outcome
without cancer ▫ Example: researcher’s belief in drug
efficacy may interfere with reported
results
CONFOUNDING
osms.it/confounding
▪ Occurs when external event is related to ▫ Exercising known to improve overall
possible cause, outcome of interest but is health
not on causal pathway ▫ Exercising associated with healthy
▪ Example: study exploring relationship lifestyle, but is not result of healthy
between exercising, overall health, we lifestyle
know that
INTERACTION
osms.it/interaction
▪ Combination of two/more factors changes
disease incidence compared to influence
they would have had individually
▫ Describes way multiple factors interact
to produce event
Synergism
▪ Refers to potentiation effect multiple
factors may have on one another
▪ Example: 2 + 2 = 5
Antagonism
▪ Refers to inhibition effect multiple factors Figure 6.1 Biological interaction is when
may have on one another two exposures, like radon gas and cigarette
▪ Example: 2 + 2 = 3 toxins, work together to influence an
outcome, like lung cancer.
50 OSMOSIS.ORG
Chapter 6 Biostatistics & Epidemiology: Causation & Validity
Figure 6.2 A graph representing data collected from four groups with 100 people per group:
those with no exposure to radon or cigarette toxins (A), those with exposure to only cigarette
toxins (B), those with exposure to only radon (C), and those with exposure to both radon and
cigarette toxins (D). The multiplicative scale was used to calculate the expected joint effect of
radon and cigarette toxins based on their independent effects (columns B and C). These two
exposures are said to have a synergistic interaction because observed relative risk > expected
joint effect. If observed relative risk had been < expected joint effect, the interaction would have
been antagonistic.
OSMOSIS.ORG 51
NOTES
NOTES
COMMUNITY HEALTH
DYNAMICS OF OUTBREAKS ▪ Infective outbreaks depend on causative
▪ Outbreak: sudden increase in disease pathogen characteristics (such as mode of
occurrence in a specific time, place, transmission)
population (e.g. outbreaks of foodborne-
related norovirus acute gastroenteritis)
MODES OF INFECTIOUS DISEASE

TRANSMISSION
osms.it/transmission
TRANSMISSION Direct
▪ The passing of a pathogen-causing ▪ Interpersonal contact → infected individuals
communicable disease from an infected spread disease
host to another individual/group ▫ One-to-one (e.g. venereal infection with
sexual intercourse)
MODES OF TRANSMISSION ▫ One-to-multiple (e.g. influenza
▪ Depends on responsible organism’s with a violent sneeze in a crowded
characteristics environment)
Indirect
▪ Common vehicle (e.g. contaminated air,
water/food supply, needle-sharing)
▪ Vectors (e.g. mosquito/tick)
OUTBREAK INVESTIGATIONS
osms.it/outbreak-investigations
CHARACTERISTICS OF AN ▪ Direct transmission: often impossible to
OUTBREAK associate new cases to primary case (first
▪ Explosive: in epidemic curve, there is a fast, symptomatic case occurring in defined
abrupt rise in number of cases, followed by setting)
fast, abrupt fall
▪ Indirect transmission: infection limited to
individuals who share common exposure
52 OSMOSIS.ORG
Chapter 7 Biostatistics & Epidemiology: Community Health
STEPS TO INVESTIGATE AN Investigate cases by looking for interac-

OUTBREAK tions of time, person, place
▪ Are there interactions between variables?
Validate outbreak’s existence in a popula-
tion Develop hypotheses
▪ Define number of cases (numerator) ▪ Consider existing knowledge about the
▪ Define the extent of the population disease, findings from current investigation
susceptible to disease (denominator)
▪ Determine whether number of observed Test hypotheses
cases is more than expected number of ▪ Analyze data (e.g. case-control study,
cases laboratory tests such as chemical/
▪ Calculate the attack rate: proportion of immunological fingerprinting)
an initially disease-free population that Recommend measures for disease control,
develops disease prevention
▫ Proportion is used because the ▪ E.g. remove infection source, establish
individuals in the numerator (those who environmental controls (interrupt disease
have the disease) are included in the transmission), improve sanitation, immunize
denominator (the total population) susceptible individuals
DISEASE SURVEILLANCE
osms.it/disease-surveillance
▪ Essential public health tool, aimed at responsibility of case-reporting
predicting, observing, minimizing outbreaks individuals
▪ Based on systematic collection, analysis, ▫ Local outbreaks may be missed
interpretation of epidemiologic data
Active
▪ Monitored parameters examples
▪ Implementing surveillance program (e.g.
▫ Changes in disease incidence/mortality
field visits to clinics, hospitals, communities)
▫ Changes in quantity of risk factors for a
▪ Pros
disease in environment
▫ Reporting more accurate; individuals
▫ Completeness of vaccination coverage
recruited specifically for surveillance
▫ Prevalence of drug-resistant organisms program
▫ Local outbreaks are more likely to be
MODALITIES OF SURVEILLANCE identified
▪ Cons
Passive
▫ More expensive to develop, maintain
▪ Using existing data on reportable diseases
such as anthrax, cholera, gonorrhea
▪ Pros DIFFICULTIES
▫ Comparatively inexpensive, easy to ▪ Obtaining reliable data in low-income
develop countries → underreporting risk
▫ Areas that require urgent intervention ▫ Areas may be difficult to reach
are quickly identified by international ▫ Communication with central authorities
comparisons can be challenging
▪ Cons ▫ Resources such as diagnostic
▫ Surveillance is not the primary laboratories not always available
OSMOSIS.ORG 53
VACCINATION & HERD IMMUNITY
osms.it/vaccination-herd-immunity
HERD IMMUNITY BASICS HERD IMMUNITY & COMMUNITY
▪ Herd immunity: phenomenon in which HEALTH
entire population is indirectly protected ▪ The critical percentage of immune
against disease when critical percentage of individuals needed to achieve herd
members are immune immunity varies according to disease
▫ Immunity can be innate/acquired contagiousness (e.g. 94% in measles
through vaccination/by naturally [highly communicable] → increased
recovering from infection number of individuals need to be immune)
▫ The higher the proportion of immune ▪ Because of herd immunity, vaccination
people in a population, the less likely programs do not necessitate yield 100%
the encounter between a susceptible immunization rates, yet can achieve highly
person and an infected one → chain of effective protection by immunizing critical
infection is disrupted percentage of a population
▪ Herd immunity is important for public
Conditions health because individuals who cannot
▪ Host is a single species develop immunity or cannot be vaccinated
▪ Transmission of the organism must be depend on herd immunity (e.g. newborn
spread by direct contact infants, individuals with immunodeficiency
▪ No reservoir outside the human host due to HIV/AIDS, cancer, cancer
treatments)
▪ Infections must induce solid immunity
54 OSMOSIS.ORG
NOTES
NOTES
EPIDEMIOLOGY MEASURES
DIRECT STANDARDIZATION
osms.it/direct-standardization
STANDARDIZATION ▪ Used when event distribution in each age
▪ Methods used to compare health group within population is known
event rates of two/more populations ▪ Process for calculating direct
(e.g. mortality rates) by standardizing standardization for age-adjusted mortality
characteristics responsible for inter- rate
population differences ▫ Choose reference (standard) population
▪ E.g. remove confounding variables (age) (e.g. separate population such as a
when comparing two groups’ crude national-level population)
mortality rate (CMR) to get age-adjusted ▫ Multiply other population of interest’s
mortality rate age-specific mortality rates to number
▫ CMR: number of people who died in one of people in each age group of reference
group, divided by the group population population
(100,000 or 1,000) ▫ Add up number of expected deaths
from all age groups
DIRECT STANDARDIZATION ▫ Calculate age-adjusted mortality rate
▪ Compares differences in health events ▫ Compare two age-adjusted mortality
among two/more populations by calculating rates
age-adjusted rate
INDIRECT STANDARDIZATION
osms.it/indirect-standardization
▪ Used when number of events/mortality ▫ Multiply other population of interest’s
rates in each age group within population is age-specific mortality rates to number
not known of people in each age group of reference
▪ Process for calculating indirect population
standardization for age-adjusted mortality ▫ Add up number of expected deaths
rate from all age groups
▫ Choose reference population with ▫ Calculate standardized mortality ratio
known mortality rates (SMR)
OSMOSIS.ORG 55
Figure 8.1 Using direct standardization to find the age-adjusted mortality rate for City 2, using
City 1 as the reference population.
56 OSMOSIS.ORG
Chapter 8 Biostatistics & Epidemiology: Epidemiology Measures
Figure 8.2 Using indirect standardization to find the standardized mortality ratio for City 2,
using City 1 as the reference population.
OSMOSIS.ORG 57
INCIDENCE & PREVALENCE
osms.it/incidence-prevalence
▪ Measures number of people who have Relationship between incidence and
disease prevalence
▪ Reported as population percentage/ratio ▪ New disease cases (incidence) added to
(e.g cases per 1000) amount of disease present in population
(baseline prevalence) → ↑ prevalence
Incidence ▪ ↑ death rate, cure rate → ↓ prevalence (↓
▪ Number of new disease cases in population total disease cases)
over time period (usually one year)
▪ If incidence > death/cure rate → net ↑
▫ Affected by preventive measures prevalence; if incidence < death/cure rate →
(vaccination, diagnostic techniques) net ↓ prevalence
Prevalence
ALL cases
▪ Number of total (old, new) disease cases prevALence =
population at risk
in population in particular time point (point
prevalence) New cases
iNcidence =
▫ Shows disease commonness in group of population at risk
people
▫ Affected by cure rate, survival rate,
death rate, recurrence
MEASURES OF RISK
osms.it/measures-of-risk
▪ Probability that event will occur (e.g. ▫ Smokers are 10 times more likely to
disease development risk) develop bladder cancer
Absolute risk Relative risk =

Probability of event in exposed population
Probability of event in unexposed population
▪ Disease incidence in population who have
been exposed to specific risk factor
▫ E.g. 1 out of 50 (2%) diabetics will Absolute risk reduction (ARR)
develop cardiovascular disease (CVD) ▪ AKA risk difference
▪ Outcomes comparison (change in risk)
# of events in a group
Absolute risk = ▫ Between population that has received
# of individuals in that group
treatment for a disease, population that
has not received treatment
Relative risk (RR)
▪ ARR = risk (untreated) - risk (treated)
▪ Compares disease development probability
▫ E.g. 4% bladder cancer occurrence in
between exposed group, unexposed group
group that receives particular drug, 20%
▫ E.g. smokers’ bladder cancer incidence in group that does not receive drug
(30%), non-smokers’ bladder cancer
▫ ARR = 0.2 - 0.04 = 0.16 or 16%
incidence (3%)
▫ For every 100 individuals receiving drug,
▫ RR = 0.3/0.03 = 10
16 bad outcomes would be avoided
58 OSMOSIS.ORG
Number needed to treat

▪ Determines how many individuals should
be treated with medication to prevent one
person from developing bladder cancer
▫ Number needed to treat: 1/0.16 = 6.25
▫ About six people should be treated
1
# needed to treat =
Absolute risk reduction
ODDS RATIO
osms.it/odds-ratio
▪ Measures association between exposure 40 / 20 2
(e.g. risk factor, health characteristic), OR = = = 2.66
60 / 80 0.75
outcome (e.g. disease, mortality)
▫ OR = 1 → exposure does not affect
▫ E.g. Which group is at higher risk of
odds of outcome
experiencing an adverse outcome? Does
an intervention change risk degree for a ▫ OR > 1 → exposure associated with
group? higher odds of outcome
▪ Used in case-control studies: case group ▫ OR < 1 → exposure associated with
with identified outcome, control group lower odds of outcome
without identified outcome
▪ Calculated using 2X2 frequency table
▫ Divide odds of disease in exposed
individuals by odds of disease in
unexposed individuals
a / c ad
OR = =
b / d bc
OSMOSIS.ORG 59
ATTRIBUTABLE RISK (AR)
osms.it/attributable-risk
▪ AKA risk difference/excess risk 40 20 20
AR = − = 0.4 − 0.2 =
▪ Measures difference in disease risk 100 100 100
between exposed population, unexposed
population
AR
▫ Often used in cohort studies × 100
incidence in exposed
AR for exposed individuals
20
A C × 100 = 50%
AR = − 40
A+ B C + D
▪ 50% of bladder cancer incidence →
attributable to smoking in exposed
population
AR for population (PAR)
PAR = incidence in population - incidence in unexposed
60 20 10
PAR = − = 0.3− 0.2 =
200 100 100
10
× 100 = 50%
20
MORTALITY RATES &

CASE-FATALITY
osms.it/mortality_rates_case-fatality
▪ Mortality rate: death incidence in deaths from all causes in one year
population over period of time divided by total number of people at risk
in population at mid-year
Annual mortality rate ▪ Annual mortality = total number of deaths
▪ Mortality rate from all causes (crude death (850) ÷ total number of people at risk in
rate) population at mid-year (500,000) = 0.0017
▫ Calculated by taking total number of
60 OSMOSIS.ORG
▪ Percent: 0.0017 x 100 = 0.17% Case-fatality rate

▪ Per 100,000: 0.0017 x 100,000 = 170 ▪ Percent of people that die within certain
(170 death per 100,000 people during period of time post-diagnosis
year) ▫ Calculated by dividing number of post-
diagnosis deaths by total number of
Population-specific mortality rate diagnosed individuals, multiplied by 100
▪ Mortality rate for specific sub-population ▪ Measures disease severity
(e.g. biologically-female individuals; cancer-
40
related deaths, neonatal mortality) Case mortality rate from disease A = = 0.16 = 16%
250
▫ E.g. neonatal mortality rate = number
of deaths among children < 28 days old
(during given time interval) ÷ number of
live births (during same time interval) x
1,000
DALY & QALY

osms.it/DALY-QALY
▪ Disease burden measurement: impact of Quality-Adjusted Life Years (QALY)
health problem on individual/population ▪ Determines disease burden according to
quality of years of life, relative value of
Disability-Adjusted Life Years (DALY) interventions (e.g. cost-utility analysis);
▪ Determines disease burden according guides healthcare-resource prioritization
to years of life, or to compare specific ▪ Measures years of life with illness/disability
intervention’s effect (e.g. new medication (considered less than year of healthy life)
reducing diabetes risk)
▪ QALY = number of years lived x utility
▫ Morbidity, mortality combined into weight
single metric
▫ One healthy year of life = 1 QALY (1
▪ DALY: years of lost life due to premature year of life × 1 utility weight)
death (YLL) + years lived disability (YLD)
▫ One year of life lived in situation with
▫ YLL: number of deaths (N) x standard illness/disability (e.g. chronic pain) = 1
life expectancy at age of death in years year × 0.5 (utility weight) = 0.5 QALYs
(L)
▫ Death: assigned value of 0 QALYs
▫ YLD: number of incident cases (I) x
disability weight (DW) X average
duration of disability in years (L)
▫ DW: reflects disease severity on 0
(perfect health) to 1 (dead) scale
OSMOSIS.ORG 61
NOTES
NOTES
NON-PARAMETRIC TESTS
NON-PARAMETRIC TESTS ▪ For nominal/ordinal level variables
▪ For data that is assumed to not be
distributed normally
CHI-SQUARED TEST
osms.it/chi-squared_test
▪ Chi-square (𝜲2) goodness-of-fit test CHI-SQUARE TEST OF
▪ Test compares categorical variables INDEPENDENCE
▫ Assesses for significant association ▪ For analysis of contingency tables (or
▪ Examines whether collected data is crosstabs tables)
significantly different than theoretical model ▪ Investigates whether two/more categorical
▫ How “good is the fit” between data, variables are statistically significant
what is expected ▪ Used for multiple variables
▪ Null hypothesis: no significant difference ▪ Degrees of freedom = (# of rows – 1) x (# of
between theorized/expected, observed columns – 1)
▫ 𝜲2 = sum of [(observed – expected)2/

ratios ▪ Requires > 5 data points in all cells of table;
▪ Higher 𝜲2 results in lower p-value

whole numbers
▪ Use 𝜲2 table to find critical 𝜲2

expected]
▫ Adjusted for degrees of freedom [n – 1],
▪ Accept null hypothesis if 𝜲2 < critical 𝜲2

at selected p-value
FISHER'S EXACT TEST

osms.it/Fisher_exact_test
▪ Variant of chi-square test ▫ Use for 2 x 2 contingency tables (< 5 in
▫ Used with small sample size a cell)
▪ Used to determine exact probability of ▫ p-values calculated exactly
association between two categorical ▫ p < 0.05, unlikely to be random
variables (i.e. significance of association association
[contingency] between classifications)
62 OSMOSIS.ORG
Chapter 9 Biostatistics & Epidemiology: Non-parametric Tests
KAPLAN-MEIER SURVIVAL
ANALYSIS
osms.it/Kaplan-Meier_survival_analysis
▪ Estimates survival from lifetime data; population effect
measures fraction of survivors over ▫ Accounts for censored data; withdrawn
treatment time; simplest method of from study, lost to follow-up; alive at
computing survival over time last follow-up (i.e. right-censoring—data
▫ Plot of percent survival versus above a certain value, but otherwise
time; generated from status at last unknown)
observation, time to event ▫ Limited capacity to estimate survival
▫ Large sample size → approaches adjusted for covariates
KAPPA COEFFICIENT
osms.it/kappa-coefficient
▪ AKA Cohen’s kappa coefficient ▪ If kappa = 1
▪ Measure of inter-rater agreement ▫ Agreement is perfect
▪ Compares ability of different raters to ▪ If kappa = 0
classify categorical variables ▫ Agreement is no better than if
▪ Interobserver agreement: accounts for agreement happened by chance
agreement that occurs by chance, when ▪ Example for interpreting agreement based
raters measure same thing, using same on kappa coefficient
observation method ▫ None: < 0
▪ Calculated from observed, expected ▫ Fair: 0.20–0.40
frequencies from diagonal of contingency
▫ Moderate: 0.40–0.60
table
▫ Good: 0.60–0.80
▫ Very good: 0.80–1.00
MANN-WHITNEY U TEST
osms.it/Mann-Whitney_u_test
▪ Nonparametric test equivalent to unpaired ▫ Uses number ranks rather than raw data
t-test ▫ Provides p-value indicating whether
▪ Compares differences between two or not groups are significantly different
unpaired groups that are not normally from each other (p < 0.05; unlikely to
distributed happen by chance)
OSMOSIS.ORG 63
SPEARMAN'S RANK CORRELATION
COEFFICIENT
osms.it/Spearmans-rank-correlation-coefficient
▫ x and y increasing → +ve 𝞺; x and y

▪ Spearman’s rho (𝞺) ▪ Sign indicates direction of association
decreasing → –ve 𝞺
▪ Non-parametric equivalent of Pearson’s
▪ 𝞺 increases as correlation approaches

correlation coefficient
▪ Measure strength, direction of monotonic
association between two ranked variables perfect monotone relationship between
▫ Monotonic association means variables variables
increase together (i.e. as value of one ▪ Two formulas
variable increases value of other variable ▫ One for when there are no tied ranks
increases also/as value of one variable ▫ One for tied ranks
increases, other variable value will
▪ Use critical values (rs) from Spearman’s rank
decrease)
coefficient tables to determine significance
▫ Does not have to be linear, but must be of r (Spearman’s coefficient of sample)
entirely increasing/entirely decreasing
(may include plateaus)
▫ Use for continuous/discrete ordinal,
interval, ratio variables
64 OSMOSIS.ORG
NOTES
NOTES
PARAMETRIC TESTS
PARAMETRIC TESTS ▫ Independent observations
▪ ANOVA, t-tests ▫ Population standard deviations (SDs)
▪ Use for following data are same
▫ Randomly selected samples ▫ Data distributed normally/approximately
normally
ANOVA
osms.it/one-way_ANOVA
osms.it/two-way_ANOVA
osms.it/repeated-measures_ANOVA
▪ AKA analysis of variance 1-way ANOVA

▪ Determines differences between > two ▪ Between groups design
samples ▪ One independent variable
▫ Measures differences among ▫ May have multiple levels (e.g. drug
means A effect vs. drug B vs. placebo on
▪ F-ratio (F statistic) specified outcome)
▫ F = (variance between groups)
Factorial ANOVAs
(variance within each group)
▪ Factorial designs
▪ Computer program calculates p-value from
F; use F to accept/reject null hypothesis ▪ Two-way, three-way, four-way ANOVA,
more (two, three, four, etc. independent
▫ F approx. = 1; p large; accept null
variables)
hypothesis
▫ F large → p small (alpha set at 0.05 Single-factor repeated measures ANOVA
significant → reject null hypothesis) ▪ ANOVAs involving repeated measures/
▪ Assumptions within groups/subjects
▫ Samples drawn randomly; sample ▪ One independent variable with multiple
groups have homogeneity of variance levels tested within one subject group (e.g.
(i.e. from same population; interval, ratio drug A vs. drug B vs. placebo tested within
data) same individuals at different times)
▪ ↓ variation effect between sample groups
OSMOSIS.ORG 65
Figure 10.1 Examples demonstrating a one-way, two-way, and repeated measures ANOVA.
The one-way ANOVA has one independent variable (medication type) with multiple levels
(medications A, B, and C). The two-way ANOVA looks at two independent variables (medication
type and age category) that each have multiple groups (medications A, B, and C; younger and
older). The repeated measures ANOVA follows the same group of people over a period of time
to measure the effects of the same medication over time. In this case, the independent variable
is time, divided into three groups (one month, three months, and six months), and the dependent
variable is systolic blood pressure.
66 OSMOSIS.ORG
Chapter 10 Biostatistics & Epidemiology: Parametric Tests
Figure 10.2 All ANOVA tests assume that the groups have equal variance. A large variance
means that the numbers are very spread out from the mean; a small variance means that the
numbers are very close to the mean. Variances between groups are considered unequal when
the variance of one group is greater than twice the variance of the other group.
CORRELATION
osms.it/correlation
▪ Investigates relationships between ▫ Fraction of variation of variable of
variables; determines strength, type interest (x axis) due to another variable
(positive/negative) relationship of interest (y axis)
▪ Correlation coefficient: r ( –1 > r < +1) ▫ Remaining proportion due to natural
▫ Perfect positive correlation: r = +1 variability
▫ Perfect negative correlation: r = –1 ▫ Low R2 may indicate poor linear
▫ No correlation: r = 0 relationship, may be strong nonlinear
relationship
▫ Strong correlation: r > 0.5 < –0.5
▪ Eta-squared (η2): analogous to R2 for
▫ Weak correlation: 0 < r < 0.5, or 0 > r >
ANOVA
–0.5
▪ Correlation ≠ causation, consider
▪ Pearson product-moment coefficient:
interval/ratio data; calculates linear ▫ How strong is association?
relationship degree between two variables ▫ Does effect always follow cause?
▪ Confidence interval (CI): population based ▫ Is there a dose response?
on correlation coefficient ▫ Relationship biologically plausible,
▫ Indicates range within population coherent?
correlation coefficient lies ▫ Consistent finding?
▪ P-value for correlation coefficient based on ▫ Other factors involved?
null hypothesis ▫ Good experimental evidence?
▫ I.e. if true (p > 0.05), no correlation ▫ Analogous examples?
between variables
▪ Coefficient of determination: r2 or R2 (0 <
R2 < 1)
OSMOSIS.ORG 67
Figure 10.3 Scatterplots are used to plot measurements, with one measured variable on each
axis. Each data point represents one individual. A trend line is drawn to best represent the
collection of data points on the plot, with roughly half the points above the line and the other
half below the line. A perfect positive or negative correlation means that the trend line passes
through every single data point.
HYPOTHESIS TESTING
osms.it/hypothesis-testing
▪ Calculating sample size required to test ▫ Desired power; alpha (if not 0.05);
hypothesis confidence interval
▪ Equations used for calculating power can ▫ Statistical tests to be used
also be used to calculate sample size for a ▫ Data lost to follow-up
predefined alpha (0.05) ▫ Test group SD; population of interest
▪ Requires knowledge of expected frequency within test group
▫ Clinically important effect size (larger ▪ Statistician’s advice
sample size needed to detect smaller ▫ Optimize sample size, avoid
effects) underpowered studies, enable valid data
▫ Surrogate endpoint use rather than interpretation
direct outcome
LINEAR REGRESSION
osms.it/linear-regression
▪ Simple linear regression: assumes linear ▪ p-value for null hypothesis
relationship; slope ≠ 0; data points close to ▫ No linear correlation (i.e. slope = 0; p <
line 0.05 → real correlation suggested)
▪ Examine weight of two variables’ (x, y)
effects; predict effects of x on y
OTHER REGRESSION ANALYSES
▪ Fit best straight line to x, y plot of data
▪ Multiple linear regression
▫ Equation: y = bx + a (x and y are
▫ Examines effects of more than one
independent variables; b = slope of line
variable on y
(regression coefficient); a = intercept )
▪ Multiple nonlinear regression
▪ 95% CI for slope range; larger sample →
narrower CI; if range does not include zero ▫ Examines correlations among nonlinear
→ real correlation suggested data, more than one independent
variable
68 OSMOSIS.ORG
Chapter 10 Biostatistics & Epidemiology: Parametric Tests
▪ Logistic regression
▫ Predicts likelihood of categorical event
in presence of multiple independent
variables
LOGISTIC REGRESSION
osms.it/logistic-regression
▪ Predictive analysis: describes relationship ▪ Rule of 10: stable values if based
between binary dependent variable on minimum of 10 observations per
(i.e. takes one of two values), multiple independent variable
independent variables ▪ Regression coefficients: indicate
▪ Assumptions contribution of individual independent
▫ Dichotomous outcome (e.g. yes/no; variables; odds ratios
present/absent; dead/alive) ▪ Tests to assess significance of independent
▫ No outliers: assess using z scores variable
▫ No intercorrelations: assess using ▫ Likelihood ratio test; Wald test
correlation matrix ▪ Bayesian inference: prior (known)
▪ May use logit (assumes log distribution of distributions for regression coefficients;
event’s probability)/probit (model assumes conjugate prior; automatic software (e.g.
normal distribution) OpenBUGS, JAGS to simulate priors)
TYPE I & TYPE II ERRORS

osms.it/type-I-and-type-II-errors
POWER EFFECT SIZE
▪ Refers to test probability correctly rejecting ▪ Relationship strength between variables
false null hypothesis ▪ Statistical significance does not necessarily
▪ Power: (1 – beta) indicate clinical significance
▫ Likelihood that statistically non- ▪ Random variation (SD) may ↓ differences
significant result is correct (i.e. not false between outcomes of interest between
negative—type II error) hypothesis’ test groups
▪ Medical research X1 − X 2
▫ Power typically set at 0.80 ES =
▪ SD
▪ Increasing power
▫ ↓ type II error chance; ↑ type I error ▫ ES is effect size
chance ▫ X1 is the mean for Group 1
▪ Power increases when ↑ sample size, ↓ SD, ▫ X2 is the mean for Group 2
↑ effect size ▫ SD is the standard deviation from either
group
OSMOSIS.ORG 69
▪ Adjust for variation in test groups with
Cohen’s d (assumes each group’s SD is
same)
▫ Cohen’s d = (mean 1 – mean 2)/SD
▫ 0.2 = small effect size
▫ 0.5 = medium effect size
▫ > 0.8 = large effect size
SAMPLE SIZE
▪ Smaller sample size
▫ ↑ sampling error chance
▫ Lower power
▫ ↑ type II error chance (false negative)
Figure 10.4 A Type I error occurs when

BAYESIAN THINKING no true relationship exists between two
▪ Relates p-value to context variables, but the study concludes there is
▫ Can involve complex mathematics one; a type II error occurs when there is a true
▪ Measures event probability given relationship between two variables, but the
incomplete information study concludes there is no relationship.
▪ Joint distribution between given information
(usually probability density), experimental
results
70 OSMOSIS.ORG
NOTES
NOTES
STATISTICAL PROBABILITY
DISTRIBUTIONS
NORMAL DISTRIBUTION &

Z-SCORES
osms.it/normal-distributions-z_scores
NORMAL DISTRIBUTION Z-SCORES
▪ Data grouped around central value, no left/ ▪ Standardized score
right bias, in “bell curve” shape ▪ Uses data set mean, standard deviation to
▪ Probability distribution for normal random determine measurement location
variable x ▫ Represents deviation from mean
1 ▪ Expressed in standard deviations
1 −( )[( x− µ )/σ )2
▪ f(x) = e 2
▪ Sample z-score for measurement x
σ 2π
µ = mean of normal random variable x ▪ z=
x−u
▪
σ
▪ µ = population mean
▪ σ = standard deviation
▪ π = 3.1416 …
▪ e = 2.71828 … ▪ σ = standard deviation
▪ Normal distribution: μ = 0, σ = 1
OSMOSIS.ORG 71
STANDARD ERROR OF THE MEAN
osms.it/standard-error-of-mean
▪ AKA SEM, standard deviation ▪ σ = standard deviation
σ ▪ n = sample size
▪ σx =
n
PAIRED T-TESTS
osms.it/paired-t-test
▪ Statistical hypothesis test (parametric) x1 − x2
▪ Determines if two groups are statistically ▪
different (compares two groups’ means) s12 s2 2
+
▪ Groups can occur naturally (e.g. smokers n1 n2
compared to non-smokers)/groups can be ▪ x1 = mean of sample 1
created experimentally (e.g. control group
▪ x2 = mean of sample 2
compared to treatment group)
▪ n1 = sample size of sample 1
▪ t = difference between means
▪ n2 = sample size of sample 2
variance/sample size
▪ = sample mean - population mean ∑ (x − x )
1 1
2
sample standard error of the mean n1 − 1

▪ s12 = variance of sample 1 =
∑ (x 2
− x2 ) 2
▪ s22 = variance of sample 2 =

n1 − 1
ONE-TAILED & TWO-TAILED

TESTS
osms.it/one-tailed-two-tailed-tests
▪ Tails: ends of probability curve ONE-TAILED TESTS
▪ Alternative (research) hypothesis proposes ▪ Alternative hypothesis is directional (i.e.
groups under investigation are different in specifies direction of difference/relationship)
some way/relationship between them exists ▫ Extreme values of one of distribution
tails are of interest given difference type/
expected relationship (solid theoretical
72 OSMOSIS.ORG
Chapter 11 Biostatistics & Epidemiology: Statistical Probability Distributions
basis required for one-tailed test) TWO-TAILED TESTS

▫ Alternative hypothesis predicts ▪ Alternative hypothesis is non-directional
relationship between groups either (i.e. non-specified direction of difference/
positive/negative (e.g. Group A will score relationship)
higher on particular test than Group B) ▫ Extreme values on either tail of sampling
distribution support null hypothesis
rejection (e.g. Group A scores will be
different than Group B)
OSMOSIS.ORG 73
NOTES
NOTES
STUDY DESIGN
SAMPLING
osms.it/sampling
▪ Selection of individuals for study from ▪ Aims to represent, estimate characteristics
specific population of that population
PLACEBO EFFECT & MASKING

osms.it/placebo-effect-and-masking
WHAT IS THE PLACEBO EFFECT? intervention under study
▪ Refers to situation where study ▪ Useful in studying rate of side effects,
participant’s belief in treatment brings reactions to drug
about positive effect
▫ E.g. individuals given placebo drug tend WHAT IS MASKING?
to report improvements even when
▪ Subjects and/or investigators are unaware
treatment has no real effect
of treatment assignment
▪ Placebos can be affected by study
▫ Single blind: subjects are unaware of
participant’s psychological responses to
treatment assignment
context in which treatment is taking place
▫ Double blind: subjects, investigators are
▪ Placebo can be drug/pharmacologically
unaware of treatment assignment
inactive substance indistinguishable from
an active treatment/can be based on any ▫ Triple blind: treatment administrator
expectation the person may have about unaware of treatment assignment
CASE-CONTROL STUDY
osms.it/case-control_study
▪ Study that determines potential risk factors birth to child with condition A who had
in individuals with condition previously taken drug B during pregnancy
▪ May rely on individual recall, past medical ▫ All children either do or do not have
history, autopsy condition A
▪ Example: Percentage of people who gave ▫ We assess whether they did/did not
74 OSMOSIS.ORG
Chapter 12 Epidemiology: Study Design
take drug B during pregnancy Cons

▪ Potential problems matching cases and
Pros controls
▪ More easily examines rare diseases than ▫ E.g. study may be influenced by
prospective studies; less expensive and characteristics not being studied
time-consuming (confounding variables)
▪ Individuals not exposed to possible risk ▪ Potentially biased (relies on individual
factors recall)
▪ Past medical history used to determine ▫ E.g. study candidates may emphasize
potential multiple risk factors potential risk factors rather than controls
Figure 12.1 Case-control study design.
COHORT STUDY
osms.it/cohort-study
▪ Measures disease within group of ▪ Useful information on risk
individuals (cohort) over period of time ▪ Matching decreases influence of
▪ Focuses on disease development confounding variables
▪ Two types: prospective cohort,
Cons
retrospective cohort
▪ Expensive, time-consuming
▪ Follow-up with people over time can be
PROSPECTIVE COHORT STUDY difficult; subjects may be lost
▪ AKA longitudinal, concurrent cohort study
▪ Results not known until after intervention
RETROSPECTIVE COHORT
▪ Used to follow up on people who received (HISTORICAL COHORT,
treatment/were exposed to risk factors NONCONCURRENT PROSPECTIVE)
▪ Laboratory tests often used as surrogate STUDY
markers – for example, increase in
▪ Same prospective cohort study design but
hemoglobin immediately after blood
uses past data to determine future time
transfusion assumed to mean that
frame; study and obtention of results faster
transfusion was effective
▪ Use pre-existing population to decrease
▪ Example: RSV rates of premature birth
study duration
cohorts
▪ Can be conducted relatively quickly,
Pros inexpensively
▪ Easier to conduct than randomized ▫ E.g.mortality rates according to duration
controlled studies of smoking
OSMOSIS.ORG 75
Figure 12.2 Design of prospective and retrospective cohort studies with hypothetical time
frames. Exposed = smokers, not exposed = non-smokers, disease = lung cancer.
CROSS-SECTIONAL STUDY
osms.it/cross-sectional_study
▪ Study that observes a group of people at Cons
one point in time ▪ Establishes disease prevalence but not
▪ Examines relationship between an incidence (percentage of individuals who
exposure (variable), disease being may develop a particular disease within a
investigated year)
▪ Example: the relationship between ▪ Does not establish temporal relationship
endometrial cancer, hormone replacement between exposure and disease
therapy (HRT) ▪ Potentially biased if surveys used
▪ Retrospective studies: data quality may
Pros
be compromised due to poor recall/“recall
▪ Less time-consuming, expensive than bias,” where people are more likely to recall
longitudinal studies, as individual follow-up certain events
not necessary
▪ Good for establishing overall association
between exposure and disease
▪ Can establish disease prevalence (number
of individuals with particular disease in
their lifetime)
76 OSMOSIS.ORG
Chapter 12 Epidemiology: Study Design
Figure 12.3 Design of a cross-sectional (prevalence) study. Example: obesity is the exposure,
and high cholesterol is the outcome.
ECOLOGIC STUDY
osms.it/ecologic-study
▪ Observes at least one variable ▪ Examples
▫ Exposure/outcome ▫ Rate of cancer occurrence in one
▪ Measured at group level population
▪ At least one comparison group, disease ▫ Average sunlight exposure at different
occurrence compared between groups geographical locations
▪ Often used to make large-scale ▫ Comparing per capita dietary fat
comparisons consumption, cardiovascular disease
mortality
▫ Disease occurrence compared between
groups
OSMOSIS.ORG 77
RANDOMIZED CONTROL TRIAL
(RCT)
osms.it/randomized-control-trial
▪ Examines effectiveness of intervention (e.g. ▪ Study participants randomly assigned
medications, treatment protocols) either experimental group or control group
▪ Three features: randomization, control, ▪ Example: Effects of drug A versus drug B
manipulation on hypercholesterolemia in individuals with
▪ Considered gold standard of experimental type 2 diabetes mellitus
research, identifying cause-and-effect
relationships
Figure 12.4 A summary flowchart of the different types of study designs.
78 OSMOSIS.ORG
NOTES
NOTES
TESTING
SENSITIVITY (SN) &

SPECIFICITY (SF)
osms.it/sensitivity-specificity
▪ Validity measure; concerned with how SPECIFICITY
close test’s result is to truth (i.e. did test/ ▪ Population proportion tests negative for
instrument measure what it is intended to disease, free of disease
measure?) ▫ AKA true negative rate
▫ No perfect test → some miscalculation ▪ Highly specific test with negative result
degree inevitable (i.e. healthy individual
▪ Identifies all people who are truly free of
tests positive for disease → false
disease (true negatives), some sick people
positive; sick individual tests negative →
(false negatives)
false negative)
▪ Specificity: proportion containing all truly
▫ Sn, Sp: complementary test
negative, false negatives; two things
characteristic measures must be used
assumed
together
▫ Test with high specificity positive →
confirm disease
SENSITIVITY ▫ Test with high specificity negative →
▪ Population proportion who test positive for individual may/may not have disease
disease, have disease (ensure not false negative; further
▪ AKA true positive rate testing required)
▪ Highly sensitive test with positive result ▪ Positive test with high specificity → useful
identifies people who are truly diseased disease confirmation
(true positives), some healthy people (false
positives)
CUTOFF POINT
▪ Sensitivity: proportion containing all truly
▪ For continuous variables: sensitivity,
positive, false positives
specificity may overlap → midpoint usually
▪ Can assume two things sought (avoids misclassification)
▫ Test with high sensitivity is negative, ▪ Cutoff point needed to distinguish between
individual must be healthy → rule out normal/healthy, abnormal/unhealthy results
disease
▫ Test with high sensitivity is positive, High cutoff point
individual may/may not have disease ▪ Highly specific: low false positives
(ensure lack of false positive; further ▫ Everyone categorized as abnormal has
testing required) disease
▫ High sensitivity negative test → useful ▪ Poorly sensible: high false negatives
for ruling-out disease ▫ Not everyone categorized as normal is
free of disease
OSMOSIS.ORG 79
▪ I.e. previous hypertension definition stated ▫ First test sensitivity x second test
140/90mmHg as cutoff point sensitivity
▫ Highly specific: everyone categorized as ▪ Net specificity: proportion of healthy people
abnormal has disease that test negative on either first, second
▫ Poorly sensitive: not everyone test
categorized as normal is free of disease ▫ (First test specificity + second test
specificity) - (first test specificity *
Low cutoff point second test specificity)
▪ Poorly specific: high false positives
▫ Not everyone categorized as abnormal Simultaneous testing
has disease ▪ Two tests with different characteristics
▪ Highly sensitive: low false negatives performed at same time → more sensitive
results
▫ Everyone categorized as normal is free
of disease ▫ Simultaneous testing: three groups of
people
▪ I.e. new hypertension definition states
120/80mmHg as cutoff point ▫ People detected only by Test A
▫ Poorly specific: not everyone ▫ People detected only by Test B
categorized as abnormal has diseases ▫ People detected by both Test A and
▫ Highly sensitive: everyone categorized Test B
as normal is free of disease ▫ Pools all possibly relevant information →
more sensitive results
Cutoff point determined by test’s purpose ▪ Sensitivity, specificity calculations must
▪ Screening test include both tests’ characteristics
▫ Needs to detect all possible diseased → ▪ Net sensitivity: proportion of true cases
low cutoff point → highly sensitive → that test positive on either test A or B
low false negatives ▫ (Test A sensitivity + Test B sensitivity) -
▪ Confirmatory test (Test A sensitivity x Test B sensitivity)
▫ Need to be sure of disease presence → ▪ Net specificity: proportion of healthy people
high cutoff point → highly specific → that test negative on both tests A and B
low false positives ▫ Test A specificity x Test B specificity
SEQUENTIAL & SIMULTANEOUS

TESTING
Sequential testing
▪ AKA two-stage testing
▪ Consecutive tests performed with different
characteristics → obtain more specific
results
▫ Perform first test → positive → perform
second test → positive → disease likely
present
▫ Perform first test → negative → disease
Figure 13.1 Illustration showing how
not likely present
sensitivity and specificity are affected by
▪ Similar to “double checking” results moving the cut-off point.
▪ First test often easier/cheaper/less invasive
than second test
▪ Sensitivity, specificity calculations must
include both tests’ characteristics
▪ Net sensitivity: proportion of true cases
that test positive on both first, second test
80 OSMOSIS.ORG
Chapter 13 Biostatistics & Epidemiology: Testing
POSITIVE & NEGATIVE

PREDICTIVE VALUE
osms.it/positive-negative-predictive-value
▪ PPV: probability that if test is positive, ▪ Both measures directly influenced by
person has disease prevalence, test specificity
▫ Divide true positives, total positive test ▫ High prevalence: more likely that person
number has disease → ↑ PPV
▪ NPV: probability that if test is negative, ▫ Low prevalence: less likely that person
person is free of disease has disease → ↑ NPV
▫ Divide true negatives, total negative test ▫ Low prevalence: need a good test in
number confirming disease (high specificity) →
↑ PPV
OSMOSIS.ORG 81
TEST PRECISION & ACCURACY
osms.it/test-precision-accuracy
▪ Both concerned with how likely test to be ▪ Comparing test precision, accuracy
reproduced → return results close to truth ▫ Oximeter consistently (precisely) reports
▫ Neither measuring devices nor people true pO2 (accurately)
perfect → affects test precision, ▫ Oximeter consistently (precisely) reports
accuracy pO2 20% lower than truth (not accurate)
▪ Test precision: how repeatable test results ▫ Oximeter inconsistently (not precise)
are over time, regardless of result accuracy reports true pO2 (accurate)
▫ High precision test: consistently deliver ▫ Oximeter inconsistently (not precise)
similar results, regardless of whether reports pO2 20% lower than truth (not
true/not accurate)
▪ Test accuracy: how true test results are,
regardless of test repeatability
▫ High accuracy test: gives correct results;
cannot always be reproduced
82 OSMOSIS.ORG
NOTES
NOTES
CARDIOVASCULAR ANATOMY & PHYSIOLOGY
CARDIOVASCULAR ANATOMY &

PHYSIOLOGY
osms.it/cardiovascular-anatomy-physiology
CARDIOVASCULAR SYSTEM ▫ Sits on top of diaphragm (main

▪ Cardia-, cardi-, cardio- breathing muscle)
▫ Heart, which pumps blood ▫ Behind sternum (breast bone)
▪ Vascular: blood vessels (carry blood to ▫ In front of vertebral column
body, return it to heart) ▫ Between lungs
▪ Delivers oxygen, nutrients to organs, ▫ Enclosed, protected by ribs
tissues ▫ Right, left sides separated by muscular
▪ Removes waste (carbon dioxide, other septum
cellular respiration by-products) from
organs, tissues Heart wall layers
▪ Epicardium: covers surface of heart, great
vessels (AKA visceral pericardium)
MORPHOLOGY
▪ Myocardium: muscular middle layer
▪ Size: about size of person’s first (correlated
with person’s size) ▫ Cardiac muscle cells: striated branching
cells with many mitochondria,
▪ Shape: blunt cone-shaped
intercalated disks for synchronous
▪ Position: slightly shifted to left side contraction
▪ Location ▫ Cardiac myocytes: striated, branching
▫ Lies in mediastinum in thoracic cavity cells with fibrous cardiac skeleton
Figure 14.1 Heart location relative to other thoracic structures.
OSMOSIS.ORG 83
(supports muscle tissue, crisscrossing ▫ Serous pericardium: simple squamous
connective tissue collagen fibers); epithelium layer
coronary vessels (lie on outside of heart, ▫ Parietal pericardium: lines fibrous
penetrate into myocardium to bring pericardium
blood to that layer) ▫ Visceral pericardium (epicardium):
▪ Endocardium: innermost layer covers outer surface of heart
▫ Made of thin epithelial layer, underlying ▫ Cells of parietal, visceral pericardium
connective tissue secrete protein-rich fluid (pericardial
▫ Lines heart chamber, valve fluid) → fills space between layers
▪ Pericardium: double-layered sac (lubricant for heart, prevents friction)
surrounding heart
▫ Fibrous pericardium: outer layer; tough
fibrous connective tissue anchors heart
within mediastinum
Figure 14.2 Heart wall layers, from superficial to deep.
Figure 14.3 Layers of the pericardium (the double-layered sac surrounding the heart.)
84 OSMOSIS.ORG
Chapter 14 Cardiovascular Physiology: Cardiovascular Anatomy & Physiology
Atrioventricular valves ventricle → pulmonary valve → pulmonary

▪ Separate atria from ventricles trunk → pulmonary arteries → pulmonary
▪ Tricuspid valve arterioles → pulmonary capillaries → alveoli
▫ Three cusps with chordae tendinae ▪ Blood collects oxygen from alveoli, removes
(tether valve to papillary muscle) carbon dioxide
▫ Prevents blood backflow into right ▪ Oxygenated blood travels through
atrium (right ventricle contracts → pulmonary venules → pulmonary veins →
papillary muscles contract, keep chordae left atrium → bicuspid/mitral valve → left
tendineae taut) ventricle → aortic valve → aorta → organs,
tissues
▪ Bicuspid / mitral valve
▪ Deoxygenated blood returns to heart
▫ Two cusps: anterior, posterior leaflet
▫ Both have chordae tendineae tethered
to papillary muscles in left ventricle SYSTEMIC VS. PULMONARY
▫ Prevents blood backflow back into left CIRCULATION
atrium ▪ Pulmonary, systemic circulation both pump
same amount of blood
Semilunar valves
▪ Located where two major arteries leave Pulmonary circulation
ventricles ▪ Low pressure system
▪ Pulmonary valve ▪ Right side of heart pumps deoxygenated
▫ Three half-moon shaped cusps blood through pulmonary circulation to
collect oxygen
▫ Prevents blood backflow into right
ventricle ▫ Right atrium → right ventricle →
pulmonary arteries → lungs
▪ Aortic valve
▫ Three cusps Systemic circulation
▫ Prevents blood backflow into left ▪ High pressure system
ventricle ▪ Left side of heart pumps oxygenated blood
to systemic circulation
Blood flow physiology
▫ Pulmonary veins → left atrium → left
▪ Deoxygenated blood enters right side of
ventricle → aorta → body
heart via superior, inferior vena cava (veins)
▫ Left ventricle three times thicker than
▪ Coronary sinus (tiny right atrium opening)
right ventricle (↑ systemic circulation
collects blood from coronary vessels →
resistance)
right atrium → tricuspid valve → right
Figure 14.4 The four heart valves. The chordae tendineae and papillary muscles attached to the
atrioventricular valves prevent blood backflow into the atria.
OSMOSIS.ORG 85
Figure 14.5 Blood flow physiology starting with the superior and inferior vena cavae bringing
deoxygenated blood from the body to the right atrium of the heart.
VENTRICULAR SYSTOLE VS. of four heart chambers

DIASTOLE ▪ 15% (750ml/0.2gal) in systemic arteries
Systole ▫ 15% to brain
▪ Ventricular contraction/atrial relaxation ▫ 5% nourishes heart
▪ Occurs during S1 sound ▫ 25% to kidneys
▫ Aortic, pulmonic valves open → blood ▫ 25% to GI organs
pushed into aorta, pulmonary arteries ▫ 25% to skeletal muscles
▪ Systolic blood pressure ▫ 5% to skin
▫ Arterial pressure when ventricles ▪ 5% (250ml/0.07gal) in systemic capillaries
squeeze out blood under high pressure ▪ 65% (3.25L/0.86gal) in systemic veins
▫ Peripheral pulse felt ▪ Numbers can change (e.g. exercise)
Diastole
▪ Ventricular relaxation/atrial contraction
BLOOD FLOW TERMINOLOGY
▪ Occurs during S2 sound Preload
▫ Tricuspid, mitral valves open → blood ▪ Amount of blood in left ventricle before
fills ventricles contraction
▪ Diastolic blood pressure ▪ Determined by filling pressure (end diastolic
▫ Ventricles fill with more blood (lower pressure)
pressure) ▪ “Volume work” of heart
Afterload
BLOOD DISTRIBUTION
▪ Resistance (load) left ventricle needs
▪ Average adult: 5L/1.32gal total blood to push against to eject blood during
volume (not cardiac output) contraction
▪ 10% of total volume (approx. ▪ “Tension work” of heart
500ml/0.13gal) in pulmonary arteries,
▪ Components include
capillaries, pulmonic circulatory veins
▫ Amount of blood in systemic circulation
▪ 5% of total volume (250ml/0.07gal) in one
86 OSMOSIS.ORG
▫ Degree of arterial vessel wall Venous return

constriction (for left side of heart, main ▪ Blood-flow from veins back to atria
afterload source is systemic arterial
resistance; for right side of heart, main Ejection fraction (EF)
afterload source is pulmonary arterial ▪ Percentage of blood leaving heart during
pressure) each contraction
▪ EF = (stroke volumeend diastolic volume) *
Stroke volume (SV)
100
▪ Blood volume (in liters) pumped by heart
per contraction Frank–Starling Mechanism
▪ Determined by amount of blood filling ▪ Ventricular contraction strength related to
ventricle, compliance of ventricular amount of ventricular myocardial stretch
myocardium ▪ Maximum contraction force achieved
when myocardial actin, myosin fibers are
Cardiac output (CO)
stretched about 2–2.5 times normal resting
▪ Blood volume pumped by heart per minute length
(L/min)
▪ CO = SV * heart rate
▪ Example
BLOOD VESSEL LAYERS (“TUNICS”)
▫ SV = 70mL ejected per contraction Tunica intima (interna)
▫ HR = 70bpm ▪ Innermost layer
▫ CO = 70 * 70 = 4900mL/min = 4.9L/min
Figure 14.6 A: Total blood volume distribution in an average adult. B: Systemic arterial blood
distribution.
OSMOSIS.ORG 87
▪ Endothelial cells create slick surface for Types
smooth blood flow ▪ “Elastic” arteries (conducting arteries)
▪ Receives nutrients from blood in lumen ▫ Lots of elastin in tunica externa, media
▪ Only one cell thick ▫ Stretchy; allows arteries to expand,
▫ Larger vessels may have subendothelial recoil during systole, diastole
basement membrane layer (supports ▫ Absorbs pressure
endothelial cells) ▫ Largest arteries closest to heart (aorta,
main branches of aorta, pulmonary
Tunica media
arteries) have most elastic in walls
▪ Middle layer
▪ Muscular arteries (distributing arteries)
▪ Mostly made of smooth muscle cells, elastin
▫ Carry blood to organs, distant body
protein sheets
parts
▪ Receives nutrients from blood in lumen
▫ Thick muscular layer
Tunica externa ▪ Arterioles (smallest arteries)
▪ Outermost layer ▫ Artery branches when they reach
▪ Made of loosely woven fibers of collagen, organs, tissues
elastic ▫ Major systemic vascular resistance
▫ Protects, reinforces blood vessel; regulators
anchors it in place ▫ Bulky tunica media (thick smooth
▪ Vaso vasorum (“vessels of the vessels”) muscle layer)
▫ Tunica externa blood vessels are very ▫ Regulate blood flow to organs, tissues
large, need own blood supply ▫ Contract (vasoconstriction) in response
to hormones/autonomic nervous system,
↓ blood/↑ systemic resistance
ARTERIES
▫ Vasodilate (relax) ↑ blood flow to
Key features organs/tissues, ↓ systemic resistance
▪ High pressure, thicker than veins, no valves ▫ Ability to contract/dilate provides
thermoregulation
VEINS
Key features
▪ Low pressure
▪ Cannot tolerate high pressure but are
distensible → adapts to different volumes,
pressures
▪ Have valves (folds in tunica interna)
to resist gravity, keep blood flowing
unidirectionally heart
Types
▪ Venules: small veins that connect to
capillaries
CAPILLARIES
▪ Only one cell thick (flat endothelial cells)
▪ Oxygen, carbon dioxide, nutrients,
Figure 14.7 The three layers, or “tunics,” of a metabolic waste easily exchanged between
blood vessel. tissues; circulation through capillary wall by
diffusion
88 OSMOSIS.ORG
▪ Fluid moves out of vessel, into interstitial Key features

space (space between blood vessels, cells) ▪ Moves large amounts of water, substances
▫ Water-soluble substances (ions) cross in same direction through fenestrated
capillary wall through clefts, between capillaries
endothelial cells, through large pores in ▪ Material movement
fenestrated capillary walls ▪ Faster transport method
▫ Lipid-soluble molecules (oxygen, ▪ Regulates blood, interstitial volume
carbon dioxide) dissolve, diffuse across
▪ Filtration, reabsorption
endothelial cell membranes
▪ Continuous fluid mixing between plasma,
interstitial fluid
BULK FLOW
▪ Passive water, nutrient movement across Types
capillary wall down concentration gradient ▪ Filtration: bulk flow when moving from
blood to interstitium
▪ Reabsorption: bulk flow when moving from
interstitium to blood
Other characteristics
▪ Kidney: major site of bulk flow where
waste products are filtered out, nutrients
reabsorbed
▪ Fluid filters out of capillaries into interstitial
space (net filtration) at arteriolar end,
reabsorbed (net reabsorption) at venous
end
▫ Hydrostatic interstitial fluid pressure
draws fluid into capillary
▫ Hydrostatic capillary pressure pushes
fluid out of capillary
▫ Colloid interstitial fluid pressure pushes
fluid out of capillary
▫ Colloid capillary pressure draws fluid
into capillary
MICROCIRCULATION
▪ Microcirculation: arterioles + capillaries +
venules
▪ Arteriole blood flow through capillary bed,
to venule (nutrient, waste, fluid exchange)
▫ Capillary beds composed of vascular
shunt (vessel connects arteriole, venule
to capillaries), actual capillaries
▫ Terminal arteriole → metarteriole →
thoroughfare channel → postcapillary
venule
▫ Precapillary sphincter: valve regulates
blood flow into capillary
▫ Various chemicals, hormones,
Figure 14.8 Key features of different blood vasomotor nerve fibers regulate amount
vessel types. of blood entering capillary bed
OSMOSIS.ORG 89
LYMPHATIC ANATOMY &
PHYSIOLOGY
osms.it/lymphatic-anatomy-physiology
LYMPHATIC SYSTEM ▪ Carries particles away from inflammation
sites/injury towards bloodstream, stopping
Function first through lymph nodes that filter out
▪ Fluid balance harmful substances
▫ Returns leaked interstitial fluid, plasma ▪ Overlapping endothelial cells create valves;
proteins to blood, heart via lymphatic prevent backflow, infectious spread
vessels ▪ Lacteals: specialized lymphatic capillaries
▫ Lymph: name of interstitial fluid when in found in small intestine villi
lymph vessels ▫ Carry absorbed fats into blood
▫ Lymphedema: lymph dysfunctional/ ▫ Chyle: fat-containing lymph
absent (lymph node removal in cancer)
→ edema forms Larger lymphatics
▪ Immunity ▪ Capillaries → collecting vessels → trunks →
▪ Fat absorption ducts → angle of jugular, subclavian veins;
right lymphatic duct empties into right
Lymphatic capillaries angle, thoracic into left
▪ Collect interstitial fluid leaked by capillaries ▪ Collecting vessels have more valves, more
▪ Found in all tissues (except bone, teeth, anastomoses than veins
marrow) ▫ Superficial collecting vessels follow
▫ Microscopic dead-ended vessels unlike veins
blood capillaries, helps fluid remain ▫ Deep collecting vessels follow arteries
inside ▪ Lymphatic trunks
▫ Usually found next to blood capillaries ▫ Paired: lumbar, bronchomediastinal,
▪ Lymph moves via breathing, muscle subclavian, jugular
contractions, arterial pulsation in tight ▫ Singular: intestinal
tissues
Figure 14.9 Lymphatic vessels collect interstitial fluid (which is then called lymph) and return
it to the veins. Lymphatic capillaries have minivalves that open when pressure in the interstitial
space is higher than in the capillary and shut when pressure in the interstitial space is lower.
90 OSMOSIS.ORG
Figure 14.10 Lymphatic system structures and their locations in the body.
▪ Ducts ▫ Found in larger organs (lymph nodes)/

▫ Upper right lymphatic drains right arm; individually (mucosa)
right thorax; right side of head, neck
▫ Thoracic duct drains into cisterna chyli LYMPHOID ORGANS
(a dilation created to gather all lymph
drained from body area that’s not Spleen
covered by upper right lymphatic duct) ▪ Largest lymphoid tissue in body
▪ Located below left side of diaphragm
LYMPHOID CELLS ▪ Blood supplied by splenic artery; blood
▪ Lymphocytes: T subtype activate immune leaves spleen via splenic vein
response; B subtype → plasma cells, ▫ Capsules with projections into organ,
produce antibodies form splenic trabeculae
▪ Macrophages: important in T cell activation, ▪ Function
phagocytosis ▫ Macrophages remove foreign particles,
▪ Dendrocytes: return to nodes from pathogens from blood
inflammation sites to present antigens ▫ Red blood cell turnover
▪ Reticular cells: similar to fibroblasts; create ▫ Compound storage (e.g. iron)
mesh to contain other immune cells ▫ Platelet/monocyte storage
▫ Blood reservoir: stores about
LYMPHOID TISSUES 300mL/0.08gal
▪ Reticular connective tissue ▫ Fetal erythrocyte production
▪ Composition: macrophage-embedded ▪ Histology
reticular fibers ▫ White pulp: lymphocyte, macrophage
▪ Loose islands that surround central arteries
▫ Diffuse lymphoid tissue ▫ Red pulp: composed mostly of red
▫ Venules enter, filters blood blood cells, macrophages; macrophages
remove old red blood cells, platelets;
▫ Found in all organs
splenic cords (reticular tissues running
▪ Dense between venous sinusoids)
▫ Follicles/nodules
▫ Mostly contain germinal centers
OSMOSIS.ORG 91
Figure 14.11 In lymph nodes, dendritic cells present pieces of pathogens they come across to B
cells. If a dendritic cell presents something foreign to a B cell, the B cell turns into a plasma cell
and starts secreting antibodies, which flow into the lymph and exit the lymph node.
Figure 14.12 Spleen location, histology.
Lymph nodes ▪ Kidney-shaped formations

▪ Hundreds scattered throughout body, often ▫ Built like tiny spleens, 1–25cm/0.4–9.8in
grouped along lymphatic vessels long
▫ Superficial, deep ▫ Covered by capsule with trabeculae,
▫ Many found in inguinal, axillary, cervical extend inward; trabeculae divide nodes
regions sectionally
▪ Function ▪ Cortex
▫ Lymph filtration, immune system ▫ Subcapsular sinus, lymphoid follicle,
activation germinal center
92 OSMOSIS.ORG
▪ Medulla Appendix
▫ Medullary cord, medullary sinus ▪ Worm-like large bowel extension
▪ Lymph flows through afferent lymphatic ▪ Contains numerous lymphoid follicles
vessels → enters node through hilum → ▪ Fights intestinal infections
subcapsular sinus → cortex → medullary
sinus → exiting via efferent lymphatic
vessels in hilum
▫ Fewer efferent vessels than afferent
vessels, slows traffic down → allows
node to filter lymphatic fluid
▪ Swollen painful nodes indicate
inflammation, painless nodes may indicate
cancer
Thymus
▪ Located between sternum, aorta in
mediastinum
▪ Two lobes, many lobules composed of
cortex, medulla
▫ Cortex: T lymphocyte maturation site
(immature T lymphocytes move from
bone marrow to thymus for maturation)
▫ Medulla: contains some mature T
lymphocytes, macrophages, cell-clusters Figure 14.13 Thymus location.
called thymic corpuscles (corpuscles
contain special T lymphocytes
thought to be involved in preventing
autoimmune disease)
▪ Lymphocyte production site in fetal life
▫ Active in neonatal, early life; atrophies
with age
Bone marrow
▪ B cells: made, mature in bone marrow
▪ T cells: made in bone marrow, mature in
thymus
Mucosa-associated lymphoid tissue (MALT)

▪ Lymphoid tissue that is associated with
mucosal membranes
▪ Tonsils: lymphoid-tissue ring around
pharynx
Figure 14.14 Tubal, pharyngeal (adenoid),
▫ Have crypts (epithelial invaginations)
palatine, and lingual tonsils create a
which trap bacteria
lymphoid-tissue ring around pharynx.
▫ Palatine: paired tonsils on each side
of pharynx (largest tonsils, most often
inflamed)
▫ Lingual: near base of tongue
▫ Pharyngeal: near nasal cavity (called
adenoid when inflamed)
▫ Tubal: near Eustachian tube
▪ Peyer’s patches: small bowel MALT
OSMOSIS.ORG 93
NORMAL HEART SOUNDS
osms.it/normal-heart-sounds
HEART SOUNDS S1 heart sound
▪ “Lub”: low-pitched sound
Causes
▪ Marks beginning of systole/end of diastole
▪ Opening / closing cardiac valves
▪ Early ventricular contraction (systole) →
▪ Blood movement: into chambers, through
ventricular pressure rises above atrial
pathological constrictions, through
pressure → atrioventricular valves close →
pathological openings
S1
▪ S1: mitral, tricuspid closure
WHERE ARE THEY HEARD? ▫ Intensity predominantly determined by
▪ By auscultating specific points individual mitral valve component, loudest at apex
sounds can be isolated ▪ S1 (lub) louder, more resonant than S2
▫ These points are not directly above (dub)
their respective valves, but are where ▪ S1 displays negligible variation during
valve sounds are best heard; however, breathing
they generally map a representation of
different heart chambers S2 heart sound
▪ Knowing normal heart size, auscultation ▪ “Dub”: higher-pitched sound
locations allows for enlarged (diseased) ▪ Marks end of systole/beginning of diastole
heart detection ▪ S2: semilunar valves (aortic, pulmonic) snap
Optimal auscultation sites shut at beginning of ventricular relaxation
(diastole) → short, sharp sound
▪ Aortic valve sounds: 2nd intercostal, right
sternal margin ▪ Best heard at Erb’s point, 3rd intercostal
space on left, medial to midclavicular line
▪ Pulmonary valve sounds: 2nd intercostal
space, left sternal margin ▪ Splits on expiration
▪ Tricuspid valve sounds: 4/5th intercostal, left ▫ During expiration S2 split into earlier
sternal margin aortic component; later, softer pulmonic
component (A2 P2). Lower intrathoracic
▪ Mitral valve sounds: 5th intercostal space,
pressure during inspiration → ↑ right
midclavicular line (apex)
ventricular preload → ↑ right ventricular
systole duration → delays P2
NORMAL HEART SOUNDS ▫ ↓ left ventricular preload during
▪ Two sounds for each beat inspiration → shorter ventricular systole,
▫ Lub (S1), dub (S2) earlier A2
▪ Factors affecting intensity ▫ A2, P2 splitting during inspiration
▫ Intervening tissue, fluid presence, usually about 40ms
quantity ▫ A2, P2 intensity roughly proportional
▫ Mitral valve closure speed (mitral valve to respective systemic. pulmonary
contraction strength) circulation pressures
▫ P2 best heard over pulmonic area
94 OSMOSIS.ORG
Figure 14.15 Valves that close to produce S1 and S2 sounds and optimal auscultation sites.
ABNORMAL HEART SOUNDS

osms.it/abnormal-heart-sounds
ABNORMAL S1 drift towards each other before onset of
systole
Loud S1
▫ Shorter PR interval → less time to drift
▪ As left ventricle fills, pressure increases closure → wider closure distance →
▪ As left atrium empties, pressure increases louder S1
as it empties against increasingly pressure- ▫ Short PR interval → incomplete
loaded ventricle; as atrium approaches ventricular emptying → higher
empty, pressure begins to decrease ventricular filling pressure → ventricular
▪ Differential diagnosis: short PR interval, pressure crosses critical atrioventricular
mild mitral stenosis, hyperdynamic states valve closing threshold while atrial
▪ Short PR interval (< 120ms) pressures are still high → load snap
▫ Normally atrioventricular valve leaflets
OSMOSIS.ORG 95
▪ Mild mitral stenosis ventricle
▫ Significant force required to close
stenotic mitral valve → large ABNORMAL S2
atrioventricular pressure gradient
required Split S2
▫ Slam shut with increased force, ▪ Physiological S2 splitting
producing loud sound ▫ Expiration: S1 A2P2 (no split)
▪ Hyperdynamic states ▫ Inspiration: S1 A2....P2 (40ms split)
▫ Shortened diastole → large amount of ▪ Wide split
ongoing flow across valve during systole ▫ Detection: splitting during expiration
→ leaflets wide apart, pressure remains
▫ Expiration: S1 A2..P2 (slight split)
high
▫ Inspiration: S1 A2…....P2 (wide split)
▫ Results in forceful atrioventricular valve
closure ▫ Differential diagnosis: right bundle
branch block, left ventricle preexcitation,
Soft S1 pulmonary hypertension, massive
▪ Differential diagnosis: long PR intervals, pulmonary embolism, severe mitral
severe mitral stenosis, left bundle branch regurgitation, constrictive pericarditis
block, chronic obstructive pulmonary ▪ Fixed split
disease (COPD), obesity, pericardial ▫ Splitting during both expiration,
effusion inspiration; does not lengthen during
▪ Long PR intervals (> 200ms) inspiration
▫ Atrium empties fully → low pressure ▫ Expiration: S1 A2..P2 (slight split)
→ low ventricular pressure required ▫ Inspiration: S1 A2..P2 (slight split)
to close atrioventricular valves → ▫ Differential diagnosis: atrial septal
valves close when ventricle is in early defect, severe right ventricular failure
acceleration phase (low pressures) →
▪ Reversed split
soft sound
▫ Split during expiration, but not
▪ Severe mitral stenosis
inspiration
▫ Leaflets too stiff, fixed to change
▫ Expiration: S1 P2….A2 (moderate split)
position
▫ Inspiration: S1 P2A2
Variable S1 ▫ Differential diagnosis: left bundle branch
▪ Auscultatory alternans block, right ventricle preexcitation, aortic
▫ When observed with severe left stenosis/AR
ventricular dysfunction, correlate of
Abnormal single S2 variants
pulsus alternans
▪ Loud P2
▪ Differential diagnosis: atrioventricular
dissociation, atrial fibrillation, large ▫ Expiration: S1 A2P2
pericardial effusion, severe left ventricular ▫ Inspiration: S1 A2….P2!
dysfunction ▫ Diagnosis: pulmonary hypertension
▪ Left ventricular outflow obstruction
Split S1
▫ Absent A2
▪ S1 usually a single sound
▫ Expiration: S1 P2
▫ Near-simultaneous mitral, tricuspid
▫ Inspiration: S1 P2
valve closures; soft intensity of tricuspid
valve closure ▫ Diagnosis: severe aortic valve disease
▪ Splitting usually from tricuspid valve closure ▪ Fused A2/P2
being delayed relative to mitral valve ▫ Expiration: S1 A2P2
closure ▫ Inspiration: S1 A2P2
▪ Differential diagnosis: right bundle ▫ Differential diagnosis: ventricular septal
branch block, left-sided preexcitation, defect with Eisenmenger’s syndrome,
idioventricular rhythm arising from left single ventricle
96 OSMOSIS.ORG
ADDED HEART SOUNDS ▪ Auscultatory summary: S1... S2.S3… S1
S3 heart sound S4 heart sound

▪ S3 (ventricular gallop) ▪ S4 (atrial gallop): low pitched late diastolic
▫ Low-pitched early diastolic sound (pre-systolic) sound, best heard in mitral/
▫ Best heard in mitral/apex region apex region, left lateral decubitus position
▫ Left lateral decubitus position ▪ Associated with hypertension, left
ventricular hypertrophy, ischaemic
▪ Associated with volume overload
cardiomyopathy
conditions
▪ Pressure overload: thought to be caused by
▪ Early diastolic sound, produced in rapid
atrial contraction into stiff / non-compliant
filling phase → excessive volume filling
ventricle
ventricle in short period → rapid filling →
chordae tendineae tensing → S3 sound ▪ Chronic heart contraction effort against
increased pressure → hypertrophy → stiff
▪ Children/adolescents: may be normal
ventricle (concentric hypertrophy)
▪ Middle aged/elderly person: usually
▪ Always pathological
pathological
▪ Auscultatory summary: S4.S1...S2...S4.S1
▫ Over 40 years old: indicative of left
ventricular failure
Figure 14.16 Linear representation of A: normal (S1, S2), B: S3, and C: S4 heart sounds.
OSMOSIS.ORG 97
Summation gallop ▪ Location
▪ Superimposition of atrial, ventricular gallops ▫ Location on chest wall where murmur is
during tachycardia best heard
▪ Heart rate ↑ → diastole shortens more than ▪ Radiation
systole → S3, S4 brought closer together ▫ Location where murmur is audible
until they merge despite not lying directly over heart
▫ Generally radiate in same direction as
HEART MURMURS turbulent blood is flowing
▫ Aortic stenosis: carotid arteries
Key features ▫ Tricuspid regurgitation: anterior right
▪ Blood flow silent when laminar, thorax
uninterrupted ▫ Mitral regurgitation: left axilla
▪ Turbulent flow may generate abnormal ▪ Shape
sounds (AKA “heart murmurs”)
▫ How sound intensity changes from
▪ Murmurs can be auscultated with onset to completion
stethoscope
▫ Shape determined by pattern of
Causes pressure gradient driving turbulent flow,
▪ May be normal in young children, some loudest segment occurring at time of
elderly individuals greatest gradient (moment of highest
velocity)
▪ ↓ blood viscosity (e.g. anaemia)
▫ Three basic shapes: crescendo-
▪ ↓ diameter of vessel, valve, orifice (e.g.
decrescendo, uniform (holosystolic when
valvular stenosis, coarctation of aorta,
occurring during systole), decrescendo
ventricular septal defect)
▫ Crescendo-decrescendo, uniform
▪ ↑ blood velocity through normal structures
generally systolic; decrescendo murmurs
(e.g. hyperdynamic states—sepsis,
generally diastolic
hyperthyroid)
▪ Regurgitation across incompetent valve
(e.g. valvular regurgitation)
Describing heart murmurs

▪ Specific language used to describe
murmurs in diagnostic workup
▪ Timing: refers to timing relative to cardiac
cycle
▫ Systolic “flow murmurs”: aortic,
pulmonic stenosis; mitral, tricuspid
regurgitation; ventricular septal defect;
aortic outflow tract obstruction
▫ Diastolic: aortic, pulmonic regurgitation;
mitral, tricuspid stenosis
▫ Continuous murmurs are least common,
generally seen in children with
congenital heart disease (e.g. patent
ductus arteriosus, cervical venous hum)
▫ Occasionally may have two related
murmurs, one systolic, one diastolic;
gives impression of continuous murmur
(e.g. concurrent aortic stenosis, aortic
regurgitation) Figure 14.17 Three basic heart murmur
shapes: crescendo-decrescendo,
decrescendo, uniform/holosystolic.
98 OSMOSIS.ORG
▪ Pitch ▫ ↓ intrathoracic pressure → ↑ pulmonary

▫ High pressure gradients → high pitched venous return to right heart → ↑ right
murmurs (e.g. mitral regurgitation, heart stroke volume → right sided
ventricular septal defect) murmurs → ↑ intensity
▫ Large volume of blood-flow across ▫ Dilation of pulmonary vascular system
low pressure gradients → low pitched → ↓ pulmonary venous return to left
murmurs (e.g. mitral stenosis) side of heart → ↓ left heart stroke
▫ If both high pressure, high flow volume → left side murmurs → ↓
(severe aortic stenosis), both high, low intensity
pitches are produced simultaneously ▪ Expiration
→ subjectively unpleasant/“harsh” ▫ ↑ intrathoracic pressure → ↓ venous
sounding murmur return to right heart → ↓ right ventricle
▪ Intensity stroke volume → ↓ intensity of right
▫ Murmur loudness graded on scale from sided murmurs
I–VI ▫ ↑ pulmonary venous return to left side
▫ Dependent on blood velocity generating → ↑ left ventricle stroke volume → left
murmur; acoustic properties of sided murmur → ↑ intensity
intervening tissue; hearing; examiner ▪ Valsalva maneuver
experience; stethoscope used, ambient ▫ Forceful exhalation against closed glottis
noise presence ▫ ↓ venous return to heart → ↓ left
▫ I: barely audible ventricular volume → ↓ cardiac output
▫ II: faint, but certainly present ▫ Murmurs of hypertrophic obstructive
▫ III: easily, immediately heard cardiomyopathy, occasionally mitral
▫ IV: associated with thrill (palpable valve prolapse → ↑ intensity
vibration over involved heart valve) ▫ All other systolic murmurs → ↓ intensity
▫ V: heard with only edge of stethoscope ▪ Isometric handgrip
touching chest wall ▫ Squeeze two objects (such as rolled
▫ VI: heard without stethoscope (or towels) with both hands
without it making direct contact with ▫ Do not simultaneously Valsalva
chest wall) ▫ If unconscious, simulate by transient
▪ Quality arterial occlusion (BP cuffs applied
▫ Subjective, attempt to describe timbre, to both upper arms, inflated to 20–
depends on how many different base 40mmHg above systolic blood pressure
frequencies of sound are generated, for 20 seconds)
relative amplitude of various harmonics ▫ ↑ venous return, ↑ sympathetic tone →
▫ Mitral regurgitation: blowing/musical ↑ heart rate, systemic venous return
▫ Mitral stenosis: rumbling → ↑ cardiac output → murmurs from
mitral regurgitation, aortic regurgitation,
▫ Aortic stenosis: harsh
ventricular septal defect → ↑ intensity
▫ Aortic regurgitation: blowing
▫ Murmur from hypertrophic obstructive
▫ Still’s murmur (benign childhood): cardiomyopathy → ↓ intensity
musical
▫ Murmur from aortic stenosis → most
▫ Patent ductus arteriosus: machine-like commonly unchanged
Diagnostic maneuvers (dynamic ▪ Leg elevation
auscultation) ▫ Lying supine, both legs raised 45°
▪ Some maneuvers may elicit characteristic ▫ ↑ venous return → ↑ left ventricular
intensity/timing changes (changes in volume
hemodynamics during maneuvers) ▫ Murmur from hypertrophic obstructive
▪ Dynamic auscultation: listening for subtle cardiomyopathy → ↓ intensity
changes during physical maneuvers ▫ Murmurs from aortic stenosis, mitral
▪ Inspiration regurgitation may → ↑ intensity
OSMOSIS.ORG 99
▪ Müller’s maneuver ▫ Radiates to neck/carotids (murmur
▫ Nares closed, forcibly suck on incentive occurs in aorta, these are its first
spirometer/air-filled syringe for 10 branches)
seconds (conceptual opposite of ▫ Auscultatory summary: S1. Ejection
Valsalva) click. Crescendo-decrescendo murmur.
▫ ↓ venous return → ↓ left ventricular S2
volume → ↓ systemic venous resistance ▪ Pulmonic stenosis
murmur from hypertrophic obstructive ▫ Pulmonary valve auscultation site: 2nd
myopathy → ↑ intensity intercostal space, left sternal margin
▫ Murmur from aortic stenosis may → ↓ ▫ S1, closing of tricuspid valve, during
intensity systole
▪ Squatting to standing ▫ Heart contracts against closed pulmonic
▫ Abruptly stand up after 30 seconds of valve → pressure builds during systole,
squatting forcing open stenotic pulmonic valve →
▫ ↓ venous return → ↓ left ventricular valve pops open → ejection click
volume ▫ Flow rate increases as heart contracts
▫ Murmur from hypertrophic obstructive more forcefully to empty right ventricle
cardiomyopathy → ↑ intensity → murmur gets louder as flow across
▫ Murmur from aortic stenosis may → ↓ partially open valve increases →
intensity chamber empties → pressure, flow
diminishing → ↓ murmur intensity
▪ Standing to squatting
▫ Radiates to neck/carotids, back
▫ From standing upright, squat down
▫ Auscultatory summary: S1. Ejection
▫ If unable to squat, examiner can
click. Crescendo-decrescendo murmur.
passively bend knees up towards
S2
abdomen to mimic maneuver
▪ Mitral regurgitation
▫ ↑ venous return → ↑ left ventricular
volume ▫ Mitral valve auscultation site: 5th
intercostal space, midclavicular line/apex
▫ Murmur from hypertrophic obstructive
cardiomyopathy → ↓ intensity ▫ Holo-/pansystolic murmur (occurs for
systole duration)
▫ Murmur from aortic stenosis may → ↑
intensity ▫ Normal S1 as mitral valve closes →
in mitral regurgitation, valve cannot
▫ Murmur from aortic regurgitation → ↑
completely close → pressure builds in
intensity
left ventricle (with closed aortic valve)
Systolic murmurs → blood forced back through partially
▪ Aortic stenosis closed mitral valve → murmur occurs
along with S1 as long as pressures
▫ Aortic valve auscultation site: 2nd
remain high enough
intercostal, right sternal margin
▫ Aortic valve will open to redirect
▫ S1, closing of mitral valve, during
majority of blood → left ventricle
systole → heart contracts against closed
continues contracting → continuously
stenotic aortic valve → pressure must
raised pressures → blood continuously
rise during systole to force open stenotic
flowing through partially closed mitral
aortic valve → valve pops open →
valve (whole of systole)
produces ejection click
▫ As heart continues to contract, pressure
▫ Followed by ↑ flow as heart contracts
↑, but atrium becomes more compliant.
more forcefully to empty left ventricle
Even though blood-flow across partially
→ murmur intensity ↑ as flow across
closed valve may ↑, pressure in atrium
partially open valve ↑
does not significantly increase
▫ Chamber begins to empty → pressure,
▫ Left ventricle pressure notably higher
flow diminish → ↓ murmur intensity
than left atrium → sound does not
100 OSMOSIS.ORG
change throughout murmur mitral regurgitation may follow

▫ Referred to as “flat” murmur because ▫ Auscultatory summary: S1. Mid systolic
intensity does not change click with late systolic murmur. S2
▫ Radiates to axilla due to direction of
regurgitant jet Diastolic murmurs
▫ Auscultatory summary: S1. Flat ▪ Aortic regurgitation
murmur. S2 ▫ Aortic regurgitation auscultation site:
▪ Tricuspid regurgitation left parasternal border
▫ Tricuspid valve auscultation site: 4/5th ▫ Blood flows back through incompletely
intercostal, left sternal margin closed aortic valve
▫ Holo-/pansystolic murmur ▫ Occurs between S2, S1
▫ Normal S1 occurs due to tricuspid ▫ S2, aortic valve closure → mitral valve
valve closure → pulmonic valve closed, opens, heart in diastole → blood enters
pressure rises in right ventricle left ventricle through regurgitant valve,
through normal filling via mitral valve
▫ In tricuspid regurgitation, valve cannot
completely close → pressure builds in ▫ Initially, low pressure in ventricle
right ventricle → blood forced back out (compared to systemic blood pressure
through partially closed tricuspid valve forcing blood through regurgitant valve)
→ murmur is continuous as long as → ventricle fills → as pressure mounts,
pressures remain high enough less flow through regurgitant valve →
decrescendo murmur
▫ Pulmonic valve opens to redirect blood
→ left ventricle maintains contraction ▫ Early diastolic decrescendo murmur
(thus raises pressure) → blood ▫ Auscultatory summary: S1. S2. Early
continues flowing through partially diastolic decrescendo murmur. S1
closed tricuspid valve (through whole ▪ Pulmonic regurgitation
systole) ▫ Pulmonic regurgitation auscultation
▫ Arium becomes more compliant as it fills site: upper left parasternal border
→ atrium pressure does not significantly ▫ Blood flows back through incompletely
increase closed pulmonic valve
▫ Right ventricle pressure notably higher ▫ Occurs between S2, S1
than that of right atrium → murmur ▫ S2 aortic valve closure → tricuspid valve
sound does not change throughout opens, heart in diastole → incomplete
murmur pulmonic valve closure → right ventricle
▫ Referred to as “flat” murmur (intensity fills via incompletely closed pulmonic
does not change) valve as well as tricuspid valve
▫ Auscultatory summary: S1. flat murmur. ▫ Initially → low ventricle pressure allows
S2 for high flow through regurgitant
▪ Mitral valve prolapse valve → pressure rises, ↓ flow through
▫ Mitral valve auscultation site: 5th regurgitant valve → decrescendo
intercostal space, midclavicular line/apex murmur
▫ Mitral valve billows into left atrium → ▫ Early diastolic decrescendo murmur
clicking sound (unlike aortic stenosis, ▫ Auscultatory summary: S1. S2. Early
not associated with ejection of blood, diastolic decrescendo murmur. S1
non-ejection click, mid-late systolic) ▪ Mitral stenosis
▫ Ventricle contracts → mitral valve ▫ Mitral valve auscultation site: 5th
closure → S1 → pressure rises → intercostal space, midclavicular line/apex
mitral valve accelerates into left atrium ▫ Mitral valve can’t open efficiently
→ stops abruptly (chordae tendineae
▫ S2 → aortic valve closure →
restraint) → rapid tensing → click
milliseconds later, mitral valve should
▫ Often associated with mitral open (fill ventricle during diastole), only
regurgitation → after click murmur of small opening occurs
OSMOSIS.ORG 101
Figure 14.18 Causes of systolic murmurs.
102 OSMOSIS.ORG
▫ Beginning of diastole, highest flow of

blood comes from left atrium to left
ventricle (rapid filling), fills more blood
at beginning of diastole (beginning due
to highest pressure difference) → most
intense phase of murmur
▫ Aortic valve closure → mitral valve
opens, due to stenotic leaflets, they
can only open slightly → chordae
tendineae snap as limit is reached Figure 14.19 Diastolic murmurs are heard as
(similar to ejection snap) → opening a “whoosh” after S2.
snap from stenotic leaflets shooting
open (milliseconds after S2) →
highest intensity of murmur thereafter Murmur Identification
→ murmur diminishes as pressure ▪ Detect murmur?
equalises ▫ Yes/no
▫ End of diastole atrium contracts to ▪ Identify phase?
force remaining blood into left ventricle
▫ Systolic/diastolic: S1 -systole- S2
→ atrial kick sound (presystolic
-diastole- S1 (in tachycardia, feel pulse
accentuation at end of murmur)
→ tapping → ejection phase, therefore
▫ Auscultatory summary: S1. S2. Opening S1)
snap. Decrescendo mid diastolic rumble.
▪ Which valves normally open/which valves
Atrial kick. S1
normally closed
▪ Tricuspid stenosis
▫ Systole, aortic and pulmonic, open
▫ Tricuspid valve auscultation site: 4/5th (mitral and tricuspid, closed)
intercostal space, left sternal margin
▫ If systolic murmur, either open valves
▫ Tricuspid valve can’t open efficiently stenotic/closed valves regurgitant (1/4
▫ S2 → pulmonic valve closure → choice)
milliseconds later, tricuspid valve should ▫ Diastole, mitral and tricuspid, open
open (fill ventricle during diastole), only (aortic and pulmonic, closed) (1/4
small opening occurs choice)
▫ Beginning of diastole, high flow of ▪ To choose between four resultant options
blood comes from right atrium to right auscultate over respective areas, employ
ventricle (rapid filling), fills more blood maneuvers as required
at beginning of diastole (due to highest
pressure difference) → most intense
murmur phase MISCELLANEOUS HEART SOUNDS
▫ Pulmonic valve closure → tricuspid ▪ Mechanical valve clicks
valve opens (due to stenotic leaflets, ▫ Distinctly audible, harsh, metallic sound
they can only open slightly) → chordae ▪ Pericardial knock
tendineae snap as limit is reached ▫ Sound occasionally heard in constrictive
(similar to ejection snap) → opening pericarditis; similar in acoustics, timing
snap from stenotic leaflets shooting to S3
open (milliseconds after S2) → highest
▪ Tumor plop
murmur intensity thereafter → murmur
diminishes as pressures equalise ▫ Rare low-pitched early diastolic sound,
occasionally heard in atrial myxoma
▫ End of diastole atrium contracts to
presence
force remaining blood into left ventricle
→ atrial kick sound (presystolic ▫ Occurs when relatively mobile tumour
accentuation at end of murmur) moves in front of mitral valve during
diastole → functional mitral stenosis
▫ Auscultatory summary: S1. S2. Opening
along with low pitched diastolic
snap. Decrescendo mid diastolic rumble.
rumbling murmur
Atrial kick. S1
OSMOSIS.ORG 103
NOTES
NOTES
BLOOD PRESSURE REGULATION
REGULATION OF ARTERIAL using a sphygmomanometer
PRESSURE 1. Wrap blood pressure cuff around upper
▪ Must be maintained at a constant level of arm just above elbow
~100mmHg 2. Rapidly inflate cuff until pressure in it
▪ Changes in blood pressure activate exceeds systolic pressure (up to around
baroreceptors and/or chemoreceptors 180mmHg) to stop blood flow
(fast response) and renin-angiotensin- 3. Press lightly with the stethoscope bell over
aldosterone system (slow response), the brachial artery just below edge of cuff
causing a series of events that eventually 4. Reduce cuff pressure slowly and listen
bring blood pressure back to normal with stethoscope for sounds in the brachial
(discussed later) artery while simultaneously observing the
▪ Central mechanisms regulating blood mercury gauge
pressure are cardiac output, peripheral ▫ The first tapping sound (Korotkoff
resistance, and blood volume sound) represents systolic pressure
Cardiac output and peripheral resistance ▫ When the tapping sound disappears, it
relate to blood pressure represents diastolic pressure
▪ Pa = cardiac output x TPR
▫ Pa = mean arterial pressure HOMEOSTATIC IMBALANCES IN
▫ Cardiac output = cardiac output (mL/ BLOOD PRESSURE
min)
Normal blood pressure in adults
▫ TPR = total peripheral resistance
▪ Affected by age, weight, sex and race
(mmHg/mL/min)
▪ Systolic pressure: 90–120mmHg
▪ Mean arterial pressure varies directly
with cardiac output and total peripheral ▪ Diastolic pressure: 60–80mmHg
pressure, can be changed by altering one
Hypertension
or both
▪ Chronically elevated blood pressure
▪ Blood pressure varies directly with blood
volume because cardiac output depends on ▫ Systolic pressure: > 140mmHg
blood volume ▫ Diastolic pressure: > 90mmHg
▫ Cardiac output is equal to stroke volume Hypotension
(ml/min) times heart rate (beats/min)
▪ Low blood pressure
▫ Normal is 5–5.5L/min
▫ Systolic pressure: <90mmHg
▪ Pa is regulated by two mechanisms
▫ Diastolic pressure: <60mmHg
▫ Baroreceptor reflex: neurally mediated
▪ Often normal variation
(short-term, fast response)
▪ Acute hypotension
▫ Renin-angiotensin-aldosterone system:
hormonally mediated (long-term, slow ▫ Can be a sign of circulatory shock
response) ▪ Orthostatic hypotension
▫ Temporary drop in blood pressure
caused by rapidly standing up from a
MEASURING BLOOD PRESSURE
sitting or lying position
▪ Auscultatory method: an indirect method
▫ Common in the elderly
of measuring pressure by listening to
Korotkoff sounds in the brachial artery ▪ Chronic hypotension
▫ Often a sign of an underlying condition
104 OSMOSIS.ORG
Chapter 15 Cardiovascular Physiology: Blood Pressure Regulation
BARORECEPTORS
osms.it/baroreceptors
BARORECEPTOR REFLEX INTEGRATED FUNCTION OF
▪ Short term, fast neural response to change BARORECEPTORS
in blood pressure
Response to increased Pa
▪ Alters peripheral resistance and cardiac
▪ ↑ firing rate: carotid sinus nerve
output
(glossopharyngeal nerve, CN IX), aortic
▪ Mediated by baroreceptor cells arch nerve afferent fibers (vagus nerve, CN
▫ Specialized nerve endings called X)
mechanoreceptors, located in aortic arch ▪ Glossopharyngeal, vagus nerve fibers
and carotid sinus; sensitive to pressure synapse in nucleus tractus solitarius
or stretching of medulla, (transmits blood pressure
▫ Most sensitive to rapid pressure information)
changes ▪ Nucleus tractus solitarius governs
▪ Carotid sinus baroreceptors: responsive to coordinated response series; returns Pa
both decreases and increases in pressure down to normal levels
▪ Aortic arch baroreceptors: predominantly ▫ ↑ parasympathetic outflow to heart
responsive to increases in pressure ▫ ↓ sympathetic outflow to heart, blood
▪ Change in blood pressure activates reflex vessels
arc ▪ Decrease in sympathetic activity
▫ Baroreceptors → afferent neurons ▫ Complements increase in
→ brain stem centers → processing parasympathetic activity → decrease in
information and generating response → heart rate
efferent neurons → changes in the heart
▫ Decrease in cardiac contractility
and blood vessels
▫ Decreased heart rate + decreased
▫ Increase of blood pressure → stretching
cardiac contractility → decrease in
of baroreceptors → depolarizing
cardiac output→ decrease of Pa (Pa =
receptor potential (higher rate action
cardiac output × TPR)
potential)
▫ Arteriolar vasodilation → decrease in
▫ Decrease of blood pressure →
TPR → decrease of Pa ( Pa = cardiac
decreased stretch of baroreceptors →
output × TPR)
hyperpolarizing potential (lower rate
action potential) ▫ Vasodilation of veins → increased
compliance of veins → increased
▪ Sensitivity can be altered as a result of
unstressed volume → decreased
some diseases
stressed volume → reduction in Pa
▪ Chronic hypertension: result is adaptation
▪ Once Pa reduced back to the set-point
of baroreceptors
pressure (i.e., 100 mmHg), activity of the
▫ Baroreceptors are adjusted to monitor baroreceptors and the cardiovascular
pressure changes at higher setpoint brainstem centers return to baseline level
▪ Atherosclerosis: carotid sinus syndrome
▫ Baroreceptors are more sensitive; even
light pressure on the carotid sinus can
cause extreme bradycardia
OSMOSIS.ORG 105
Figure 15.1 Locations of arterial baroreceptors and pathways that transmit their signals.
CARDIOPULMONARY (LOW ▫ ANP causes generalized vasodilation

PRESSURE) BARORECEPTORS ▫ This vasodilatation in the kidney
▪ Located in the vena cava, pulmonary increases glomerular filtration rate
arteries and atria which results in increased Na2+ and H2O
▪ These baroreceptors are volume receptors - filtration and excretion → decreased
they detect changes in blood volume blood volume
▪ Increased blood volume and subsequent ▪ Decreased secretion in ADH
increases in venous and atrial pressure are ▫ Decreased water reabsorption in the
detected by cardiopulmonary baroreceptors collecting ducts → decreased blood
which generates several responses volume
▪ Increase of heart rate (Bainbridge reflex)
Cardiopulmonary baroreceptors responses
▫ Increased cardiac output → increased
▪ Secretion of atrial natriuretic peptide (ANP),
renal perfusion → increased Na+ and
a polypeptide hormone secreted by the
H2O excretion
myocytes in the atrial wall
106 OSMOSIS.ORG
Figure 15.2 Locations of cardiopulmonary baroreceptors and pathway that transmits their signals.
CHEMORECEPTORS
osms.it/chemoreceptors
CHEMORECEPTOR REFLEX ▫ Decrease of pO2 causes an increase
▪ Blood pressure regulation pathway that in ventilation which decreases the
involves chemoreceptors for O2 in the aortic parasympathetic outflow to heart → ↑
and carotid bodies heart rate → ↑ cardiac output
▪ Central and peripheral chemoreceptors
CENTRAL CHEMORECEPTORS
PERIPHERAL CHEMORECEPTORS ▪ Located in the medulla
▪ Located in carotid bodies (near common ▪ Most sensitive: CO2, pH
carotid artery bifurcation, in aortic bodies ▪ Less sensitive: O2
along aortic arch) ▪ Reflex arc
▪ Very sensitive partial pressure of O2 ▫ Decrease in brain blood flow →
decreases increased pCO2, decreased pH →
▫ Also sensitive to partial pressure of CO2 chemoreceptors (afferent neurons)
increases (pCO2), pH decreases increase firing of action potential
▪ Reflex arc (hyperpolarization potential) → efferent
▫ Decreased pO2 → chemoreceptors neurons → increased sympathetic
(afferent neurons) increase firing of outflow → arterial vasoconstriction in
action potential (hyperpolarization skeletal muscle, renal and splanchnic
potential) → efferent neurons → circulation → increased total peripheral
increased sympathetic outflow → pressure
arterial vasoconstriction in skeletal
muscle, renal and splanchnic circulation
→ increased total peripheral pressure
▪ These chemoreceptors are also involved in
control of breathing
OSMOSIS.ORG 107
Figure 15.3 Locations of peripheral chemoreceptors and locations in the brainstem to which
they transmit their signals.
Figure 15.4 Central chemoreceptors are located in the medulla of the brainstem and are most
sensitive to changes in CO2 and pH levels.
108 OSMOSIS.ORG
RENIN-ANGIOTENSIN
ALDOSTERONE SYSTEM
osms.it/renin-angiotensin_aldosterone_system
▪ Hormonally mediated, slow regulation of ▫ Stimulates the synthesis and secretion

blood pressure of aldosterone in the glomerulosa cells
▪ Regulates Pa by regulating blood volume of the adrenal gland
▫ Aldosterone causes Na+ reabsorption to
Direct renal mechanism increase in principal cells of renal distal
▪ Increase of Pa causes increased filtration tubule, collecting duct
rate in the tubules ▫ Increased Na+ concentration →
▪ In this situation, the kidney cannot reabsorb increased osmolarity → increased ECF
filtrate fast enough → more fluid leaves the and blood volume
body in urine → blood volume and blood ▪ Angiotensin II
pressure drops ▫ Stimulates Na+- H+ exchange →
Indirect renal mechanism increased Na+ reabsorption
▪ Renin-angiotensin aldosterone system ▫ Stimulates antidiuretic hormone (ADH)
secretion
▪ Decrease of Pa and/or decrease of Na+
concentration causes decrease in kidney ▫ Acts on hypothalamus (stimulates thirst,
perfusion which in turn causes a series of water intake)
events ▫ Causes vasoconstriction of the arterioles
▪ Cells of the macula densa sense the change → increased total peripheral resistance
in blood volume/osmolarity and in turn (TPR)
stimulate renin production Antidiuretic hormone (ADH)
▫ Renin is an enzyme secreted ▪ Hormone produced in hypothalamus,
by juxtaglomerular cells of the secreted by pituitary gland’s posterior lobe
juxtaglomerular apparatus of the
▪ Stimulated by low blood volume, increase
nephron
of serum osmolarity and angiotensin II
▫ Renal sympathetic nerves and beta-1
▪ Receptors for ADH
agonists also cause renin production
▪ V1 receptors: vasoconstriction of arterioles
▪ Renin converts angiotensinogen to
angiotensin I ▪ V2 receptors: increase water reabsorption
by principal cells of the renal collecting duct
▪ Angiotensin-converting enzyme (ACE) in
the lungs and kidneys converts angiotensin
I to angiotensin II
OSMOSIS.ORG 109
Figure 15.5 Macula densa cells are chemoreceptors located in the distal convoluted tubule.
When they sense a ↓ in Pa and/or Na+, Cl-, they stimulate renin production by nearby
juxtaglomerular cells. Renin initiates angiotensin II activation, which acts in multiple areas to
increase blood pressure.
Figure 15.6 RAAS system summary.
110 OSMOSIS.ORG
NOTES
NOTES
CARDIAC CYCLE
MEASURING CARDIAC OUTPUT -

FICK PRINCIPLE
osms.it/Fick-principle
▪ Model used to measure cardiac output (CO) ▪ 250mL/minute = total O2 consumption
▫ Output of left, right ventricles equal (70kg, biologically-male individual);
during normal cardiac function pulmonary venous O2 content = 0.20/mL;
▪ Steady state: rate of O2 consumption = pulmonary arterial O2 content = 0.15/mL
amount of O2 leaving lungs via pulmonary
vein - amount of O2 returning via Cardiac Output =
pulmonary arteries x CO 250mL/min = 5000mL/min
0.20mL - 0.15mL
▪ Pulmonary blood flow of right heart = CO
of left heart: used to calculate CO
▪ Also measures blood flow to individual
Cardiac Output = organs
O2 consumption ▫ Renal blood flow = renal O2
[O2] pulmonary vein - [O2] pulmonary artery consumption / renal arterial O2 - renal
venous O2
CARDIAC & VASCULAR FUNCTION

CURVES
osms.it/cardiac-and-vascular-function-curves
▪ Curves depicting functional connections independent variable; CO, dependent
between vascular system, right atrial variable
pressure, and CO ▫ ↑ venous return → ↑ RA pressure → ↑
LV end-diastolic volume (EDV)/preload,
CARDIAC FUNCTION CURVE (CO myocardial fiber stretch → ↑ CO
CURVE) ▫ LV CO (L/min) = LV venous return/
▪ Plot of relationship between left ventricle preload (RA pressure in mmHg)
(LV) CO, right atrial (RA) pressure ▫ Relationship remains intact with steady
▪ Based on Frank–Starling relationship state of venous return
describing CO dependence on preload ▫ RA pressure 4mmHg → curve levels off
▫ Preload (determined by RA pressure), at maximum 9L/min
OSMOSIS.ORG 111
VASCULAR FUNCTION CURVE Mean systemic pressure (MSP)
▪ Plot of relationship between venous return, ▪ Pressure equal throughout vasculature
RA pressure ▪ Influenced by blood volume, distribution
▪ Independent of Frank–Starling relationship
▫ Venous return independent variable; RA Total peripheral resistance (TPR)
pressure dependent variable ▪ Primarily determined by pressure in
▫ Venous return, RA pressure: inverse arterioles; determines slope of curve
relationship ▪ ↓ TPR (↓ arteriolar resistance) → ↑ flow
▪ ↑ RA pressure → ↓ pressure gradient from arterial to venous circulation → ↑
between systemic arteries, RA → ↓ venous venous return → clockwise rotation of
return to RA; CO curve
▪ ↑ TPR (↑ arteriolar resistance) → ↓ flow
from arterial to venous circulation → ↓
venous return → counterclockwise rotation
of curve
ALTERING CARDIAC & VASCULAR

FUNCTION CURVES
osms.it/altering-cardiac-vascular-function-curves
▪ Curves combined → changes in CO to right, (3) no change in TPR
visualized, cardiovascular parameters ▪ ↓ circulating volume (e.g. hemorrhage)
altered ▫ Opposite effect
▪ Curves can be displaced by changes in ▪ Changes in venous compliance are similar
blood volume, inotropy, TPR to blood volume changes
▫ ↓ venous compliance → changes similar
INOTROPIC AGENTS to ↑ circulating volume
▪ Alters cardiac curve ▫ ↑ venous compliance → changes similar
▪ Positive inotropic agents (e.g. digoxin) at to ↓ circulating volume
any level of RA pressure
▫ ↑ contractility, stroke volume (SV), CO TOTAL PERIPHERAL RESISTANCE
→ (1) cardiac curve shifts upward, (2) ▪ Alters both curves due to changes in
vascular function curve not affected, (3) afterload (cardiac curve), venous return
x-intercept (steady state) shifts upward, (vascular curve)
to left
▪ ↑ TPR → ↑ arterial pressure → ↑ afterload
▪ Negative inotropic agents (e.g. beta- → ↓ CO → (1) downward shift of cardiac
blockers) curve, (2) counterclockwise rotation of
▫ Opposite effect vascular curve, (3) ↓ venous return, (4) RA
pressure unchanged, ↓/↑ (depending on
BLOOD VOLUME cardiac, venous curve alteration), (5) curves
intersect at altered steady state
▪ Alters vascular curve
▪ ↓ TPR (arteriolar dilation)
▪ ↑ circulating volume (e.g. blood transfusion)
▫ Opposite effect
▫ ↑ MSP → (1) curves intersect at ↑
CO, RA pressure, (2) parallel shift of
x-intercept (steady state), vascular curve
112 OSMOSIS.ORG
Chapter 16 Cardiovascular Physiology: Cardiac Cycle
PRESSURE-VOLUME LOOPS
osms.it/pressure-volume_loops
▪ Graphs represent pressure, volume Ventricular ejection
changes in LV during one heartbeat (one ▪ Pressure in left ventricle > aortic pressure
cardiac cycle/“stroke work”) → aortic valve opens → blood ejected
▪ Pressure in left ventricle on y axis, volume
of left ventricle on x axis Isovolumic relaxation
▪ Ventricle starts relaxing → aortic pressure >
LV pressure → aortic valve closes
FOUR PHASES
▪ End of systole
Ventricular filling during diastole ▪ ESV = 70mL
▪ At end of this phase:
▫ Mitral valve closed STROKE VOLUME (SV)
▫ Left ventricle filled (EDV); relaxed, ▪ STROKE VOLUME (SV)
distended ▪ Amount of blood pumped by ventricles in
▫ EDV = 140mL one contraction
Isovolumic contraction ▪ SV = EDV - ESV
▪ Systole begins (ventricular contraction)
▪ No changes to ventricular volume (mitral, STROKE WORK (SW)
aortic valve closed) ▪ Work of ventricles to eject a volume of
▪ Pressure builds blood (i.e. to eject SV)
▪ Represented by area inside of loop
Figure 16.1 Measurements that can be obtained from the pressure-volume loop graph. Pulse
pressure is measured in mmHg and reflects the throbbing pulsation felt in an artery during
systole. Pulse pressure = systolic blood pressure - diastolic blood pressure. Stroke volume is
measured in mL and is blood volume ejected by left ventricle during every heartbeat. Stroke
volume = end-diastolic volume - end systolic volume.
OSMOSIS.ORG 113
Figure 16.2 The four phases of the pressure-volume loop and the condition of the heart during
each phase.
114 OSMOSIS.ORG
CHANGES IN PRESSURE-VOLUME
LOOPS
osms.it/changes_in_pressure-volume_loops
▪ Cardiac parameters change → volume- (ESV) → ↓ SV → loop narrower, taller
pressure loops change (smaller SV, higher pressure; stroke work
▪ ↑ preload (↑ EDV) → ↑ strength of remains relatively stable)
contraction → ↑ stroke volume → larger ▪ ↑ contractility → blood under ↑ pressure
loop → longer ejection phase → left ventricular
▪ ↑ afterload → ↑ ventricular pressure during pressure = aortic pressure → ↑ SV, stroke
isovolumetric contraction → ↑ less blood work, ↓ ejection fraction (EF), EDV → loop
leaves ventricle → ↑ end-systolic volume widens
Figure 16.3 Changes in stroke work as a result of increased preload (B), afterload (C), and
contractility (D) represented on pressure-volume loop graphs.
OSMOSIS.ORG 115
CARDIAC WORK
osms.it/cardiac-work
▪ Work heart performs as blood moves from ventricular pressure < aortic pressure →
venous to arterial circulation during cardiac aortic valve closes (S2); causes dicrotic
cycle notch on aortic pressure curve
▪ All valves closed
PHASES OF CARDIAC WORK ▪ Ventricular volume
▫ Constant
Atrial systole ▪ Complete ventricular repolarization
▪ Begins when atria, ventricles in diastole ▪ ECG
▪ Atrioventricular (AV) valves open → passive ▫ T wave ends
ventricular filling
▪ Atrial depolarization → atria contract (atrial Rapid ventricular filling
kick during systole) → completes ventricular ▪ Ventricular diastole continues → ventricular
filling (EDV) pressure < atrial pressure → AV valves
▪ Venous pulse: “a” wave (↑ atrial pressure) open
▪ ECG ▪ Passive ventricular filling (ventricles
▫ P wave, PR interval relaxed, compliant)
▪ S3 (normal in children) produced by rapid
Isovolumetric ventricular contraction filling
▪ Ventricular contraction begins (ventricular
systole) → ventricular pressure > atrial Reduced ventricular filling (diastasis)
pressure → AV valves close (S1); semilunar ▪ Ventricular diastole continues; ventricles
valves closed relaxed
▪ ECG ▪ Mitral valve open
▫ QRS complex ▪ Changes in heart rate (HR) alter length of
diastasis
Rapid ventricular ejection
▪ Ventricular systole continues → left
ventricular pressure > aortic pressure → TYPES OF CARDIAC WORK
aortic valve forced open → blood ejected Internal work
(SV) (blood also ejected into pulmonary
▪ Pressure work: within the ventricle to
vasculature via pulmonic valve)
prepare for ejection
▪ ↑ aortic pressure
▪ Quantified by multiplying isovolumic
▪ Atrial filling begins contraction time by ventricular wall stress
▪ ECG ▪ Accounts for 90% of cardiac work
▫ ST segment
External work
Reduced ventricular ejection ▪ Volume work: ejecting blood against
▪ ↓ ventricular ejection velocity arterial resistance; product of pressure
▪ ↑ atrial pressure developed during ejection, SV
▪ Ventricular repolarization begins ▪ Represented by area contained in pressure-
▪ ECG volume loop
▫ T wave ▪ Accounts for 10% of cardiac work
Isovolumetric ventricular relaxation Myocardial oxygen consumption

▪ Ventricles relaxed (ventricular diastole); ▪ Pressure work > volume work
116 OSMOSIS.ORG
▪ Aortic stenosis → ↑↑ pressure work → ↑↑ ▪ Pressure work: LV (aortic pressure

oxygen consumption, ↓ CO 100mmHg) > RV (pulmonary pressure
▪ Strenuous exercise → ↑ volume work → ↑ 15mmHg)
oxygen consumption, ↑ CO ▫ ↑ systemic pressure (e.g. hypertension)
→ ↑ LV pressure work → ventricular
LV and right ventricle (RV) wall hypertrophy
▪ Volume work: CO LV = RV CO ▫ Law of Laplace for sphere (e.g. heart):
thickness of heart wall increases →
greater pressure produced
CARDIAC PRELOAD
osms.it/cardiac-preload
▪ EDV: volume load created by blood Atrial contraction
entering ventricles at end of diastole before ▪ Early ventricular diastole → ventricles
contraction relaxed, passively fill with blood from atria
▪ Establishes sarcomere length, ventricular via open AV valves → late ventricular
stretch as ventricles fill (length-tension diastole atrial systole (atrial kick) →
relationship) additional blood into ventricles
▪ Accounts for 20% of ventricular preload
FACTORS AFFECTING PRELOAD Resistance from valves
Venous pressure ▪ Stenotic mitral, tricuspid valves create
▪ Includes blood volume, rate of venous inflow resistance → ↓ filling → ↓ preload
return to RA ▪ Stenotic pulmonic, aortic valves create
▪ ↑ blood volume, venous return → ↑ preload outflow resistance → ↓ emptying → ↑
preload
Ventricular compliance
HR
▪ Flexibility: ability to yield when pressure
applied ▪ Normal heart rate allows adequate time for
ventricles to fill
▪ Compliant, “stretchy” ventricles → ↑ preload
▪ Tachyarrhythmias → ↓ filling time → ↓
▪ Noncompliant, stiff ventricles → ↓ preload
preload
OSMOSIS.ORG 117
CARDIAC AFTERLOAD
osms.it/cardiac-afterload
▪ Amount of resistance ventricles must FACTORS AFFECTING AFTERLOAD
overcome during systole
LV
▪ Establishes degree, speed of sarcomere
shortening, ventricular wall stress (force- ▪ Systemic vascular resistance (SVR)
velocity relationship) ▪ Aortic pressure
▪ ↑ afterload → ↓ velocity of sarcomere
RV
shortening
▪ Pulmonary pressure
▪ ↓ afterload → ↑ velocity of sarcomere
shortening Resistance from valves
▪ Stenotic pulmonic, aortic valves create
outflow resistance → ↑ afterload
LAW OF LAPLACE
osms.it/law-of-Laplace
▪ Describes pressure-volume relationships of ▪ T= Pxr
spheres h
▪ Blood vessels ▫ T = wall tension
▫ > radius of artery = > pressure on ▫ P = pressure
arterial wall ▫ r = radius of ventricle
▪ Heart ▫ h = ventricular wall thickness
▫ Wall tension produced by myocardial ▪ Dilation of heart muscle increases tension
fibers when ejecting blood depends on that must be developed within heart wall to
thickness of sphere (heart wall) eject same amount of blood per beat
▪ Laplace’s formula: tension on myocardial ▪ Myocytes of dilated left ventricle have
fibers in heart wall = pressure within greater load (tension)
ventricle x volume in ventricle (radius) / wall ▫ Must produce greater tension to
thickness overcome aortic pressure, eject blood →
↓ CO
118 OSMOSIS.ORG
FRANK–STARLING RELATIONSHIP
osms.it/Frank-Starling_relationship
▪ Loading ventricle with blood during
diastole, stretching cardiac muscle → force
of contraction during systole
▪ Length-tension relationship
▫ Amount of tension (force of muscle
contraction during systole) → depends
on resting length of sarcomere →
depends on amount of blood that fills
ventricles during diastole (EDV)
▫ Length of sarcomere determines
amount of overlap between actin,
myosin filaments, amount of myosin
heads that bind to actin at cross-bridge
formation
▫ Low EDV → ↓ sarcomere stretching →
↓ myosin heads bind to actin → weak
contraction during systole → ↓ SV
▫ Too much sarcomere stretching
prevents optimal overlap between actin,
myosin → ↓ force of contraction → ↓ SV Figure 16.4 Graphical representation of the
▪ Allows intrinsic control of heart = venous Frank–Starling relationship and sarcomere
return with SV length at low, mid-range, and high EDVs.
A mid-range EDV (B), where the volume
▪ Extrinsic control through sympathetic
of blood returning to the ventricles is
stimulation, hormones (e.g. epinephrine),
increasing but is not too large (C), allows for
medications (e.g. digoxin) → ↑ contractility
best myosin-actin binding → ↑ strength of
(positive inotropy), SV
contractions → ↑ stroke volume.
▪ Negative inotropic agents (e.g beta-
blockers) → ↓ contractility → ↓ SV
Figure 16.5 Graphical representation of

positive and negative inotropic effects on the
Frank–Starling relationship.
OSMOSIS.ORG 119
STROKE VOLUME, EJECTION
FRACTION, & CARDIAC OUTPUT
osms.it/stroke-volume-ejection-fraction-cardiac-output
SV
▪ Volume of blood (mL) ejected from ventricle
with each contraction
▪ Calculated as difference between volume
of blood before ejection/EDV, after ejection
(ESV)
▪ EDV (120mL) - ESV (50mL) = 70mL
▪ SV affected by preload, afterload, inotropy
EF
▪ Fraction of EDV ejected with each
contraction
▪ SV (70)/EDV (120) = 58 (EF)
▪ Average = 50–65%
CO
▪ Volume of blood ejected by ventricles per
minute
▪ SV (120) x HR (70) = 4900mL/min
120 OSMOSIS.ORG
NOTES
NOTES
CARDIAC
ELECTROPHYSIOLOGY
ACTION POTENTIALS IN
PACEMAKER CELLS
osms.it/pacemaker-cell-action-potentials
Pacemaker cells
▪ Groups of cardiac muscle cells with ability
to spontaneously create action potential
(automaticity) and comprise intrinsic
conduction system
▪ Directly influenced by sympathetic and
parasympathetic nervous systems
▪ Comprise about 1% of heart cells
▪ Differ in speed of spontaneous
depolarization
▪ Cells with fastest rate of depolarization at
any given time determine heart rhythm
▫ Remaining/slower cells called latent Figure 17.1 Locations of pacemaker cells
pacemakers within the heart.
SA node
▪ Primary pacemaker cells located in wall of Action potentials in pacemaker cells
right atrium
▪ Rapid electrical changes across membrane
▪ Rate: 60–100bpm of pacemaker cells
▫ Usually determines normal heart rhythm ▪ Conducted to rest of heart
Latent pacemaker cells Action potential phases
▪ AV node ▪ Phase 4: sodium moves into cell through
▫ Located at base of right atrium, near funny channels (open in response to
septum hyperpolarization); slowly depolarizes cell
▫ Rate: 40–60bpm until threshold potential met
▪ Bundle of His ▫ Responsible for instability of resting
▫ Divides into right and left bundle membrane potential
branches, travels through septum ▪ Phase 0: strong inward calcium current;
between ventricles responsible for rapid depolarization
▫ Rate: 20–40bpm ▪ Phase 3: strong potassium current moves
▪ Purkinje fibers out of cell; responsible for repolarization
▫ Spread throughout ventricles ▫ Phases 1, 2 absent in pacemaker cells
▫ Rate: 20–40bpm → no plateau
OSMOSIS.ORG 121
Figure 17.2 Graph depicting the action
potential of a pacemaker cell.
ACTION POTENTIALS IN
MYOCYTES
osms.it/myocyte-action-potentials
Myocytes ▫ Phase 3: calcium current moving into

▪ Receive signal from from pacemaker cells cell stops; potassium current moving
causing them to contract out of cell continues; repolarization
▪ Able to depolarize, spread action potentials continues
▪ Action potential phases: ▫ Phase 4: potassium current moving
out of cell approaches equilibrium
▫ Phase 0 (depolarization phase): rapid
between inside, outside of cell; sodium,
influx of sodium into cell (inward
calcium current moving into cell balance
current); responsible for rapid
outward potassium current; resting
depolarization
membrane potential achieved
▫ Phase 1: sodium current stops,
potassium slowly flows out of cell;
depolarization stops, re-polarization
starts
▫ Phase 2: calcium current moves into cell,
balances potassium current moving out
of cell; charge balance between inside,
outside of cell creates plateau
122 OSMOSIS.ORG
Chapter 17 Cardiovascular Physiology: Cardiac Electrophysiology
ELECTRICAL CONDUCTION
IN THE HEART
osms.it/heart-electrical-conduction
▪ Transmission of electrical signals across ▫ These structures responsible for

heart cells leads to rhythmic myocardial electrical conduction, spontaneous
contraction depolarization; do not generate
▪ Intercalated discs connect cells and allow contractile force
myocardium to act as syncytium
▫ Contain desmosomes (holds cells
together) and gap junctions (areas of
low resistance to electrical flow)
▪ Cardiac action potential: sequential flow of
electrons across ion channels in cardiac cell
membranes, resulting in electrical activation
of myocardial cells
▫ Depolarization: cation movement into
cell, producing positive cell charge
relative to outside
▫ Polarization: anion movement into cell,
producing negative cell charge relative
to outside
▪ Pathway of electrical conduction
▫ Sinoatrial node (SA node) → atrial Figure 17.3 Desmosomes and gap junctions
internodal fibers → atrioventricular node present at intercalated discs allow the
(AV node) → bundle of His → Purkinje myocardium to act as a syncytium.
fibers → ventricular myocytes
CARDIAC CONDUCTION VELOCITY

osms.it/cardiac-conduction-velocity
▪ Speed at which depolarization wave ▪ Rapid conduction through Purkinje fibers
spreads among myocardial cells ensures adequate blood ejection
▫ Measured in meters per second (m/s) ▫ Speed: 2–4m/s
▪ Each myocardial structure has a different
Velocity depends on two factors
conduction speed related to its purpose
▪ Amount of ions going into cell during action
▫ Slowest: AV node
potential
▫ Fastest: Purkinje fibers
▫ More ions → faster depolarization →
▪ AV delay: slow conduction through AV faster spread
node ensures adequate ventricular filling
▫ Fewer ions → slower depolarization →
▫ Speed: 0.01–0.05m/s slower spread
▫ Blood flows from atria to ventricles
OSMOSIS.ORG 123
▪ Interconnectedness of myocardial ▫ Fewer gap junctions → fewer
conduction cells interconnected cells → increased
▫ More gap junctions → more resistance to ion flow between cells
interconnected cells → less resistance to
ion flow between cells
Figure 17.4 Conduction speeds of different myocardial structures.
EXCITABILITY & REFRACTORY

PERIODS
osms.it/excitability-refractory-periods
Refractory period Excitability

▪ Time in which myocardial cell cannot be ▪ Ability of myocardial cells to depolarize in
depolarized response to incoming depolarizing current
▪ Absolute refractory period: no stimulus, no ▪ Supranormal period: < normal stimulus
matter its size, can depolarize cell may produce action potential large enough
▫ Phases 0, 1; part of phase 2 to be conducted
▪ Effective refractory period: large stimulus ▫ Resting membrane potential has not yet
can generate action potential been achieved
▫ However, too weak to be conducted ▫ Membrane potential closer to threshold
▪ Relative refractory period: large stimulus than normal, refractory periods over
can generate action potential
▫ Big enough to be conducted
124 OSMOSIS.ORG
CARDIAC EXCITATION-
CONTRACTION COUPLING
osms.it/cardiac_excitation-contraction_coupling
▪ Plateau in action potential of myocyte

membrane allows influx of calcium,
stimulating muscle contraction
▫ Calcium enters cell via L-type voltage
gated channels
▫ Higher intracellular Ca2+ triggers
release of more Ca2+ from sarcoplasmic
reticulum through ryanodine receptors
(AKA calcium-induced release)
▫ Released Ca2+ attaches to troponin C
→ tropomyosin moves → actin-myosin
cross bridges → contraction
▪ Cross bridges last as long as Ca2+ occupies
troponin
▫ Tension is proportional to intracellular
Ca2+ concentration
▪ Intracellular Ca2+ removed by two
mechanisms that induce relaxation, keep
Ca2+ from damaging cell contents
Figure 17.5 Depolarization of a
▫ Ca2+ ATPase uses ATP energy, Na+/
cardiomyocyte by calcium-induced calcium
Ca2+ ATP exchanger uses Na+ inward
release.
current to remove Ca2+ from cell through
sarcolemmal membrane, remove Na+
through Na+/K+ ATPase
▫ Ca2+ ATPase removes Ca2+ into
sarcoplasmic reticulum; calsequestrin
2 inside sarcoplasmic reticulum binds
Ca2+, keeping it inside
OSMOSIS.ORG 125
CARDIAC LENGTH TENSION
osms.it/cardiac-length-tension
▪ Degree filament overlap correlates to ▪ ↑ resting tension: small changes produce ↑
tension tension
▫ Lmax = 2.2 µm is maximal tension ▪ Frank–Starling basis; ↑ fiber length →
▫ In shorter/longer cells, tension will be stronger contraction
decreased ▫ Preload = LV end-diastolic volume (L), if
▪ ↑ L → ↑ Ca2+ sensitivity of troponin C → ↑ ↑ means ventricular fiber length ↑
Ca2+ release from sarcoplasmic reticulum ▫ Afterload = aortic pressure; if preload ↑
▪ Can extend to ventricle length/tension → afterload tension and pressure ↑
relationship curve
▫ Cardiac muscle < elastic than skeletal;
only ascending curve demonstrates its
contraction
CARDIAC CONTRACTILITY
osms.it/cardiac-contractility
▪ Positive inotropes: ↑ force of myocardial faster, systole shorter; Frank–Starling
contraction effective
▪ Negative inotropes: ↓ force of myocardial ▫ Na+/K+ ATPase phosphorylation;
contraction increases relaxation due to secondary
▪ Proportional to Ca2+ concentration channel activations
▫ Proportional to Ca2+ released ▫ Troponin I phosphorylation; Ca2+ binds
▫ Depends on storage, current size less troponin C → effect on excitation
contraction coupling, prolongs filling,
higher ejection fraction
WHAT AFFECTS INOTROPISM? -
AUTONOMIC NERVOUS SYSTEM Parasympathetic
▪ Negative inotropic effects: ↓ contractility on
Sympathetic atria via muscarinic receptors
▪ Positive inotropic effects: ↑ contractility ▪ Acidosis also has negative inotropic effect
▪ Causes faster relaxation, faster refill, → ↓ contractility
increased heart rate (HR) ▪ Gk (type of Gi), adenylyl cyclase couple,
▪ Increased tension development rate resulting in
▫ ϐ1 receptor is Gs coupled, activates ▫ Decreased Ca2+ plateau current
adenylyl cyclase → cAMP produced ▫ ACh increases IkACh
▫ pKA activated → phosphorylation → ↑ ▫ → ↓ action potential duration → ↓ Ca2+
sarcolemmal Ca2+ channel activity → ↑ current → ↓ AP width
contraction
▪ Phosphodiesterase metabolises cAMP,
▫ Phospholamban phosphorylation; stops inhibit phosphodiesterase, increase
sarcoplasmic Ca2+ ATPase inhibition, contractility IP3 stimulates Ca release in
decreasing time of IC Ca2+, making HR SR, increases force of contraction
126 OSMOSIS.ORG
Heart rate (HR) WHAT AFFECTS INOTROPISM? -

▪ HR increases contractility DRUGS
▪ Diastole affected more than systole Cardiac glycosides
▪ Ca can’t be removed as quickly as it ▪ Digoxin, digitoxin, ouabain; congestive
accumulates → new equilibrium heart failure treatment
▫ ↑ action potentials/time: increased total ▫ Inhibit Na+/K+ ATPase; + inotropic, ↑
trigger Ca2+, increased inward current intracellular Na+ changes Na/Ca →
▫ ↑ Ca2+ influx → ↑ stores; phospholamban decreases exchange → intracellular
phosphorylated, thus inhibited calcium increases → increases tension
▪ Positive staircase effect/Bowditch ▫ Nifedipine also acts on Ca2+ by blocking
staircase/Treppe phenomenon ryanodine receptors
▫ On first, beat still no extra Ca2+
▫ Afterward, Ca2+ accumulates until max Beta adrenergics
Ca2+ storage achieved ▪ Isoproterenol, norepinephrine, epinephrine,
▪ Postextrasystolic potentiation dopamine, dobutamine
▫ Same effect as positive staircase ▫ ↑ cAMP → ↑ contractility
▫ Extrasystole < powerful, but creates
one more chance for calcium entry
▫ Because the voltage channels are open
more, postextrasystolic beat has higher
tension than extrasystolic
OSMOSIS.ORG 127
NOTES
NOTES
ELECTROCARDIOGRAPHY (ECG)
ECG BASICS
osms.it/ECG-basics
▪ ECG traces provide information on heart’s ▫ PR segment: end of P wave to
electrical activity, rate, rhythm beginning of QRS complex; signifies AV
▫ Depolarization waves moving towards nodal delay
electrode → positive deflection ▪ QRS complex: ventricular depolarization
▫ Depolarization waves moving away ▪ T wave: ventricular repolarization
from electrode → negative deflection ▪ QT interval: time from start of Q wave to
▪ 12 lead ECG (EKG) records heart electrical end of T wave; represents time taken for
activity during heartbeat ventricular depolarization, repolarization
▫ Six limb leads (I, II, III, AVR, AVL, AVF) ▪ U wave: sometimes seen after T wave
▫ Six chest leads (V1–V6) (not shown), represents purkinje fiber
▪ P wave: atrial depolarization repolarization
▫ PR interval: beginning of atrial
contraction to beginning of ventricular RECORDING ECGs
contraction (time for impulse to reach ▪ Recorded on 1mm graph paper (10mm =
ventricles form sinus node) 1mV)
Figure 18.1 Lead placement in the coronal and transverse plane.
128 OSMOSIS.ORG
Chapter 18 Cardiovascular Physiology: Electrocardiography
▫ x-axis = time (1mm = 0.04s) ▫ Electrodes placed on shoulders,

▫ y- axis = voltage (10mm = 1mV) abdomen to record limb leads
▪ Limb leads: I, II, III, AVR, AVL, AVF ▪ Chest leads (precordial): V1 –V6
▫ Bipolar leads: I, II, III ▫ Septal leads: V1,V2
▫ Unipolar leads: AVR, AVL, AVF ▫ Lateral leads: V5,V6
(augmented voltage for right arm, left ▫ Anterior leads: V3,V4
arm, left foot ▫ Six chest leads provide six viewpoints of
▫ Lateral leads: I, aVL, V5, V6 cardiac activity, in horizontal plane
▫ Inferior leads: II, III, AVF
▫ Six limb leads provide six viewpoints of
cardiac activity, in frontal plane
ECG NORMAL SINUS RHYTHM

osms.it/ECG-normal-sinus-rhythm
▪ P waves precede QRS complexes in 1:1 ▪ P waves
relationship ▫ Upright in leads I, II, AVF
▪ SA node (sinus node), dominant centre of ▫ Amplitude < 2.5mm in limb leads
automaticity ▫ Sinus arrhythmia: can be normal if
▫ Normal sinus rhythm 50–90bpm sinus rate varies with respiratory cycle,
▪ Constant RR interval relatively mild/abnormal if sinus rate
▪ Predictable recurring wave pattern varies unpredictably,very dramatic
(P-waves, QRS, T waves)
ECG RATE & RHYTHM

osms.it/ECG-rate-rhythm
RATE DETERMINATION ▫ Locate R wave peak on large block line
▪ Box method: measure R-R interval by large as “start”
boxes ▫ Count subsequent number of complete
▫ ECG grid: thick lines 5mm apart (0.20s); R waves in 10s strip (total strip)
thin lines 1mm (0.04s) ▪ To calculate heart rate
▫ Locate R wave peak on thick line as ▫ Count number of QRS complexes across
“start” entire recording, multiply by six for heart
▫ Label blocks (thick lines): 300; 150; rate; used to estimate heart rate during
100; 75; 60; 50 irregular rhythms
▫ Locate next R wave peak to estimate
heart rate
▪ Fast heart rates: use fine division within
boxes for more accurate estimates
▪ Slow heart rates: use 2.5s marks at top of
trace paper
OSMOSIS.ORG 129
Figure 18.2 The Box method measures distance between R-R intervals to calculate the heart
rate.
ECG INTERVALS
osms.it/ECG-intervals
PR INTERVAL & SEGMENT ▫ QTc interval corrected for heart rate;
▪ Normal interval 0.12–0.20s 0.35–0.44s for normal heart rate
▫ Measure duration(s) from start of P to (60–100bpm)
start of Q ▫ Long QTc (> 500ms) → prone to rapid,
▪ Normal segment: usually isoelectric, may potentially fatal ventricular rhythm
be displaced
QRS INTERVAL
▪ Normal QRS: <0.10–0.12s (slight variation
between references)
▫ Measured from start of Q to end of S
▪ QRS amplitude (voltage): wide range of
normal limits
▫ Low voltage: < 5mm limb leads, <
10mm chest leads
▫ Increased voltage can indicate left
ventricular hypertrophy, right ventricular
hypertrophy, may be normal Figure 18.3 An ECG interval includes a
▫ Narrow (< 0.12s) / wide (> 0.12s) segment and one or more waves and should
be completed within a specific amount of
QT INTERVAL time to be considered healthy.
▪ Normal QT < 50% RR interval, only for
normal heart rates
▪ Measure QT from start of Q to end of T
▪ Measure RR interval as time between R-R
130 OSMOSIS.ORG
ECG AXIS
osms.it/ECG-axis
▪ Mean direction (vector) of ventricular
depolarization wavefront
▫ Mean QRS vector normally downward
from AV node through stronger left
ventricle
▪ Normal axis range -30º to +90º of frontal
plane
▪ Limb leads indicate vector deviation in
frontal plane
▫ Divided into four quadrants Figure 18.4 The green shows a normal
range. The red bottom left quadrant would
indicate right ventricular hypertrophy while
the top right would indicate left ventricular
hypertrophy.
ECG TRANSITION
osms.it/ECG-transition
▪ Chest leads provide information on vector ABNORMAL RATES & RHYTHMS
rotation in horizontal plane ▪ Conventionally defined, sinus bradycardia
▫ Normal: gradual transition of QRS <60bpm
through leads V1–V6 ▫ True normal adult resting heart rate is
▫ QRS complex switches from 50–90bpm
predominantly negative to positive ▪ Sinus tachycardia > 100bpm
either between V2, V3 or between V3, ▪ If SA node fails, other latent ectopic
V4 pacemakers capable of automaticity
▫ Atria, AV junction, His bundle, bundle
R WAVE PROGRESSION branches can set heart rate
▪ Early: tall R wave in V1, V2 ▫ Each foci has unique rate (atrial foci
▪ Delayed R: transition point between V4, 60–80bpm; junctional foci 40–60bpm;
V5/between V5, V6 ventricular foci 20–40bpm)
▫ R amplitude > S; no progression through ▫ Overdrive suppression: mechanism
V5, V6 by which only foci/node with highest
▪ Reverse: decreasing amplitude firing frequency rate conducts impulses,
suppresses other pacemaker sites
ASSESSMENT FOR NORMAL Heart blocks

REGULAR RHYTHM ▪ Sinus block
▪ Is there a P before every QRS complex? ▫ SA node temporarily ceases to conduct
▪ Is there a QRS after every P? impulse; usually resumes, may cause
▪ Are the P waves normal? escape rhythm
OSMOSIS.ORG 131
▪ AV block ▫ Broad QRS < 120ms
▫ First degree: prolonged PR interval > ▫ Dominant S wave in V1
0.2s ▫ Absence of Q waves, broad monophasic
▫ Second degree: some P waves R wave in lateral leads
conducted to ventricles, followed by ▪ Left anterior fascicular block
QRS complex while some not ▫ Impulses conducted to left ventricle via
▫ Third degree: atria, ventricles beat left posterior fascicle
asynchronously with no conduction ▫ Left axis deviation
through AV node (complete dissociation
▫ Increased R wave peak time in aVL
between P, QRS complexes)
▫ Small Q waves, tall R waves in leads 1,
Bundle branch blocks aVL
▪ Left bundle branch block (LBBB) ▫ Small R waves, deep S waves in leads
▫ Activation of left ventricle delayed II, III, aVF
causing left ventricle to contract later ▫ Increased QRS voltage in limb leads
than right ventricle ▫ Prolonged R wave peak time in aVL >
▫ Broad QRS < 120ms 45ms
▫ Secondary R wave (R’) in leads V1-3 ▪ Left posterior fascicular block
▫ Slurred S wave in lateral leads (I, avL, ▫ Impulses conducted to left ventricle via
V5–6) left anterior fascicle
▫ Secondary repolarization abnormalities ▫ Right axis deviation
in right precordial leads (ST depression, ▫ Increased R wave peak time in aVF
T wave inversions) ▫ Small R waves with deep S waves in
▪ Right bundle branch block (RBBB) leads I, aVL
▫ Activation of right ventricle delayed ▫ Small Q waves with tall R waves in
causing right ventricle to contract later leads II, III, aVF
than left ventricle ▫ Increased QRS voltage in limb leads
Figure 18.5 The QRS transition zone usually occurs in the V3 and V4 lead. V1 and V2 are
mostly positive while V5 and V6 are mostly negative.
132 OSMOSIS.ORG
ECG CARDIAC HYPERTROPHY &

ENLARGEMENT
osms.it/ECG-cardiac-hypertrophy-enlargement
ATRIAL DILATION/ENLARGEMENT ▪ Sum of S wave depth in V1 + R wave
▪ Biphasic P waves > one small box in lead height in either V5/V6 > 35mm
V1 ▪ Possible left axis deviation
▪ Initial component of wave larger ▪ Left ventricular ‘strain pattern’
▫ Right atrial enlargement ▫ Downsloping ST segments, T wave
▪ Terminal component of wave larger inversions in lateral leads
▫ Left atrial enlargement
▪ Amplitude of P wave in any limb lead >
2.5mm
▫ Probable right atrial enlargement
RIGHT VENTRICULAR
HYPERTROPHY
▪ V1–V6 all consisting of small r waves, deep
S waves (no R wave transition)
▪ Tall R wave in V1 that progressively
shortens across to V6 (reverse R wave
transition)
▪ Possible right axis deviation
Figure 18.6 Hypertrophy is an enlargement

LEFT VENTRICULAR of the muscle wall while an increase in
HYPERTROPHY volume is known as dilation.
▪ Deep S wave in lead V1
▪ Tall R wave in V5 and/or V6
OSMOSIS.ORG 133
ECG MYOCARDIAL INFARCTION &
ISCHEMIA
osms.it/ECG-cardiac-infarction-ischemia
MYOCARDIAL INFARCTION NECROSIS
▪ Complete/partial blockage in coronary artery ▪ Pathologic Q wave; > 0.04s, amplitude < ⅓
causing myocardial damage - ¼mm the R wave height
▪ ST elevation MIs (STEMIs): complete artery ▫ Non-pathological q waves < 0.04s
blockage considered normal
▫ ST elevation present on ECG; emergency ▪ Ignore AVR lead; record leads with Q
▪ Non-ST elevation MIs (NSTEMIs): partial (pathological), q (physiological) waves; ST
artery blockage depression/elevation; inverted T waves
▫ ST elevations not present on ECG ▪ Anterior left ventricular infarction (q in V5,
▫ Less emergent than STEMI V6)
▫ Chest leads anterior location; Q waves in
leads V1, V2, V3 /V4
ISCHEMIA ▪ Posterior infarction
▪ Inverted T waves; slight to deep; most
▫ Large R in leads V1, V2; possible Q in V6
pronounced in chest leads
▫ Mirror test: invert, examine reflection for
▪ Angina: transient T wave inversion; may
vQ, ST elevation in leads V1, V2
occur without infarction
▪ Lateral infarction: Q in leads I, AVL
▪ Inverted T wave in any leads V2–V6 are
abnormal ▪ Inferior infarction: Q in leads II, III, AVF
▫ Suggest ischemia, variety of other
pathologies
▪ Acute or recent infarction: elevated ST
segment (slight to extensive)
▫ One of the earliest ECG signs of
infarction
▫ Returns to baseline over time
▪ Restricted coronary blood flow: flat
depressed ST segment
▫ Suggests subendocardial infarction; any
ST depression
134 OSMOSIS.ORG
OSMOSIS.ORG 135
NOTES
NOTES
HEMODYNAMICS
BLOOD PRESSURE, BLOOD FLOW, &

RESISTANCE
osms.it/blood-pressure-blood-flow-resistance
(d/2)2 × 𝜋, we get (2 / 2)2 × 𝜋 = 3.14cm2

PRESSURE (P) ▪ Using the equation for area (A) of a circle,
▪ Force over area → blood pressure is force
of blood over blood vessel surface area ▪ Since cardiac output = blood flow →
convert L/min to cm3/s → 1000cm3 in a L,
60 seconds in a minute, multiplying those
BLOOD FLOW (Q)
equals 83cm3/sec
▪ Volume (cm3) blood flow through vessel
▪ Rearranging formula, velocity equals flow
over period of seconds (s)
rate divided by area, equals about 26cm/s,
▪ E.g. Q = 83cm3/s about 1km/hr
Determined by two factors
▪ ∆P = Pressure gradient (mmHg); difference TOTAL PERIPHERAL RESISTANCE
in pressure between two blood vessel ends (TPR)
▪ R = Resistance (mmHg/mL per min) ▪ Resistance of entire systemic vasculature
▫ Q=∆P/R ▫ Can be measured by substituting
▪ Q directly proportional to pressure gradient cardiac output for flow (Q), pressure
▫ Increased pressure gradient → difference between aorta, vena cava for
increased blood flow ΔP
▪ Q inversely proportional to resistance ▪ Resistance within an organ
▫ Increased resistance → decreased blood ▫ Can be measured by substituting
flow organ blood flow for flow (Q), pressure
difference in pressure between organ
artery, vein for ΔP
BLOOD FLOW VELOCITY (v)
▪ Major mechanism for changing blood flow
is changing resistance
▪ Blood flow velocity (v) is distance (cm)
traveled in certain amount of time (s)
136 OSMOSIS.ORG
Chapter 19 Cardiovascular Physiology: Hemodynamics
PRESSURES IN THE
CARDIOVASCULAR SYSTEM
osms.it/cardiovascular-system-pressures
▪ Blood pressure highest in large arteries ▪ For person with normal blood pressure of
(e.g. brachial artery), about 120/80mmHg 120/80mmHg
▫ MAP= ⅓ 120 + ⅔ 80 = 93mmHg
SYSTOLIC BLOOD PRESSURE ▪ Diastole lasts longer than systole; roughly
▪ First/top number equal to diastolic pressure plus one-third
pulse pressure
▪ Pressure in aorta caused by ventricular
contraction pulse.pressure
MAP = Diastolic pressure +
▪ During systole, heart contracts → transfers 3
kinetic energy (140mmHg) to blood →
▪ For person with normal blood pressure of
aortic elastic walls stretched, where some
120/80mmHg
kinetic energy stored as elastic energy of
120mmHg
walls (form of potential energy) → blood MAP = 80mmHg + = 93mmHg
3
pressure drops to 120mmHg (systolic
pressure) ▪ MAP demonstrated using relationship of
blood flow, blood pressure, resistance,
applying the following equation
DIASTOLIC BLOOD PRESSURE ▪ Q=∆P/R → Pi - Pf = Q x R
▪ Second/bottom number ▫ Pi = mean arterial pressure (MAP)
▪ Pressure caused by recoil of arteries during ▫ Pf = central venous pressure (CVP)
diastole
▫ Q = blood flow, equals cardiac output
▪ During diastole, heart relaxes, aortic valves (CO)
close → kinetic energy drops to 50mmHg
▫ R = resistance; combined resistance
→ potential energy of stretched aortic
of all of blood vessels of systemic
walls adds to kinetic energy again when
circulation equals systemic vascular
walls recoil → pressure rises to 60mmHg
resistance (SVR)
(diastolic pressure) → allows blood to move
forward ▪ Applying this equals the following
▪ Pulse pressure: difference between ▫ MAP - CVP = CO x SVR
systolic, diastolic pressure ▪ CVP is a small number, usually ignored;
equation simplified
Mean arterial pressure (MAP/Pa) ▫ MAP = CO x SVR
▪ Average blood pressure during cardiac ▪ Based on this relationship → increased
cycle including systolic, diastolic blood resistance will cause increased blood
pressure pressure
▪ MAP, pulse pressure decline with distance
from heart
MAP measured in two ways

▪ Diastole lasts longer than systole, therefore
MAP is equal to one third systolic pressure
plus two thirds diastolic pressure
▫ MAP = ⅓ systolic pressure + ⅔ diastolic
pressure
OSMOSIS.ORG 137
Figure 19.1 Visualization of MAP equation components.
PRESSURE GRADIENT ▪ Pulse pressure lower in aorta than in large

▪ Pressure gradient pressure difference arteries → because pressure from blood
between two ends of blood vessel travels faster than blood itself; pressure
▫ Gradient from aorta to arteriole ends waves bounce off branch points in arteries
which increases pressure even more
▪ Pressures in different parts of
cardiovascular system not equal, keeps ▪ Systolic pressure higher in large arteries
blood moving than aorta, blood keeps moving forward
▪ Blood flow generated by heart pumping ▪ Diastolic pressure is lower than in large
action, moves along pressure gradient arteries → mean arterial pressure mostly
from high pressure areas (arteries) to low affected by diastolic pressure → mean
pressure areas (veins) arterial pressure is higher in aorta → driving
force for blood flow
▪ Fluctuations on arterial side
▫ For example: aortic systolic pressure
1. Blood ejected into aorta → pressure
is 115mmHg; diastolic pressure is
rises
85mmHg → Mean arterial pressure is
2. Small amount of blood backflows into 95mmHg; large artery systolic pressure
ventricles is 120mmHg; diastolic pressure is
3. Valves close → pressure drops 80mmHg → mean arterial pressure is
4. Dicrotic notch/incisura pressure drop 93mmHg
followed by small pressure increase as a
result of valve recoiling
5. Aorta settles, heart relaxes → pressure
drops
138 OSMOSIS.ORG
Figure 19.2 The five stages of fluctuation in arterial pulse pressure.
SYSTEMIC CIRCULATION Veins

▪ Mean pressure in aorta results from two ▪ Systolic pressure drops even further →
factors 4mmHg in vena cava, 2mmHg in right
▫ Blood volume (cardiac output) atrium
▫ Compliance (low compliance → high ▫ Venous pressure too low to promote
pressure) venous return to heart
▪ Pressure remains high in large arteries ▪ Factors that facilitate venous return
because of high elastic recoil ▫ Muscular pump: as muscles contract,
relax they compress surrounding veins,
Small arteries force blood towards heart
▪ Pressure decreases; biggest pressure drop ▫ Respiratory pump: during inhalation,
is in arterioles (30mmHg) abdominal pressure increases, forces
▫ Occurs because arterioles develop high blood in local veins forward
resistance to flow ▫ Sympathetic vasoconstriction: as
smooth muscle in veins contracts, blood
Capillaries
pushed towards heart
▪ Pressure drops for 30mmHg to 10mmHg
▪ Two causes for pressure drop
▫ Fluid filtration in capillaries
PULMONARY CIRCULATION
▪ Right ventricle → lungs → left atrium
▫ Increase frictional resistance
▪ Pulmonary arteries: systolic pressure
▪ Pressure drop is less than in arterioles
25mmHg; diastolic pressure 8mmHg
▫ Many capillaries running in parallel →
▫ Mean arterial pressure → 25 (⅓) + 8 (⅔)
reduces total resistance (total resistance
= 14mmHg
for vessels in parallel is less than
resistance in any individual vessel) ▪ Capillaries: pressure drops to 10mmHg
▪ Pulmonary vein: pressure drops to 8mmHg
▪ Left atrium: pressure drops to 2–5mmHg
OSMOSIS.ORG 139
Figure 19.3 Visualizing pressures throughout the systemic cardiovascular system.
Figure 19.4 Visualizing pressures in the pulmonary circulation.
140 OSMOSIS.ORG
RESISTANCE TO BLOOD FLOW

osms.it/resistance-to-blood-flow
RESISTANCE Series resistance
▪ Opposition to flow → amount friction as ▪ Sequential flow from one vessel to next
blood passes through blood vessels ▪ Illustrated by arrangement of blood vessels
▪ Determined by within an organ
▫ Blood viscosity ▪ Major artery → smaller arteries → arterioles
▫ Total length blood vessels → capillaries → venules → veins
▫ Diameter blood vessels ▪ Total resistance of system arranged
in series is equal to sum of individual
Poiseuille Equation resistances
▪ Describes relationship between resistance, Rtotal = Rarteries + Rarterioles + Rcapillaries + Rvenules + Rveins
blood vessel diameter, blood viscosity
8ηl ▪ Blood flow at each part of system
R= is identical but pressure decreases
πr4 progressively (greatest decrease in
arterioles)
▫ 𝜂 = blood viscosity
▫ R = resistance
Parallel resistance
▫ l = length of blood vessel
▪ Simultaneous flow through each parallel
▫ r4 = radius (diameter) blood vessel vessel
raised to fourth power
▪ Illustrated by arrangement of arteries
Points expressed by Poiseuille equation branching off aorta
▪ Resistance to blood flow is directly ▪ Cardiac output → aorta → branching →
proportional to blood viscosity, blood vessel cerebral, coronary, renal system etc. →
length capillaries → venules → veins → vena cava
→ right atrium
▪ Resistance to flow is inversely proportional
to radius to fourth power (r4) → when ▪ Total resistance less than any individual
radius decreases, resistance increases by resistance
fourth power → e.g radius decreases by 1 1 1 1 1 1
one half, resistance increases 16-fold = + + + + + ...
Rtotal R1 R2 R3 R4 R5
▫ Numbered subscripts represent

SERIES & PARALLEL RESISTANCE cerebral, renal, coronary, other systems
▪ Resistance also depends on blood vessel ▪ Blood flow in each system is only small
arrangement → series/parallel portion of total blood flow → no pressure
lost in major arteries (remains same as in
aorta)
OSMOSIS.ORG 141
Figure 19.5 Calculating the total resistance for this system involves finding the total parallel
resistance first and then adding R1, RParallel, and R5. The total blood flow in series, Q, is equal
across all parts of the system. Individual vessels in the parallel system have different Qs, since
the blood flow is split between each of the vessels, but they add up to QTotal.
142 OSMOSIS.ORG
LAMINAR FLOW &

REYNOLDS NUMBER
osms.it/laminar-flow-and-Reynolds-number
LAMINAR FLOW
▫ v = 4Q / 𝜋d2
▪ Since velocity depends on diameter
▪ Smooth blood flow through blood vessels
→ blood velocity highest in center, lowest ▫ Decrease in diameter (e.g. thrombus,
towards blood vessel walls → zero at walls atherosclerotic plaque) → velocity
increases → Reynolds number
TURBULENT FLOW increases
▪ Laminar flow disrupted; blood flows axially, ▪ Values of Reynolds number
radially → kinetic energy wasted → more ▫ If < 2000 → laminar flow
energy needed to drive blood ▫ If > 2000 → increased likelihood of
turbulent flow
Reynolds Number
▫ If > 3000 → turbulent flow
▪ Determines whether flow likely to be
laminar/turbulent
SHEAR
ρ dv ▪ Friction between blood, vessel walls
NR =
η
▫ Highest at vessel wall, lowest in center
▫ ρ = blood density
▫ NR = Reynolds number → difference in blood flow velocity
▪ Difference in velocity is parabolic → moving
▫ d = blood vessel diameter away from walls velocity increases quickly,
near middle change in velocity low
▫ η = blood viscosity
▫ v = blood flow velocity
▪ Shear inhibits red blood cell aggregation,
lowers viscosity
▪ As viscosity decreases (e.g. anemia),
Reynolds number increases
▪ As velocity increases (e.g. increased cardiac
output), Reynolds number increases
Figure 19.6 Reynolds number is a way to predict whether a fluid is going to be laminar (smooth)
or turbulent. Differences in velocity across a blood vessel cause shear.
OSMOSIS.ORG 143
COMPLIANCE OF BLOOD VESSELS
osms.it/compliance-of-blood-vessels
COMPLIANCE (C) ELASTANCE (E)
▪ AKA capacitance/distensibility: ability of ▪ Inverse of compliance
blood vessels to distend, hold an amount of ▫ Blood vessel ability to recoil back after
blood with pressure changes distension
▪ C=V/P ▪ E=P/V
▫ C = compliance of blood vessel (mL/ ▫ E = elastance of blood vessel (mmHg/
mmHg) mL)
▫ V = volume of blood (mL) ▫ P = pressure (mmHg)
▫ P = pressure (mmHg) ▫ V = volume of blood (mL)
▪ High volume, low pressure → high
compliance (veins); low volume, high During systole
pressure → low compliance (arteries) ▪ Heart contracts → transfers kinetic energy
▪ Arteriosclerosis → low compliance → low (140mmHg) to blood → stretches aortic
ability to hold an amount of blood at same elastic wall, where some kinetic energy
pressure → blood backs up in veins stored as elastic energy of walls (form of
▫ Arteries also become less compliant potential energy) → blood pressure drops
with age to 120mmHg (systolic pressure)
▫ If compliance decreases in veins During diastole
(venoconstriction) → volume decreases ▪ Heart relaxes, aortic valves close → kinetic
(shift from veins to arteries) energy drops to 50mmHg → potential
energy of stretched aortic walls adds to
kinetic energy again when walls recoil
→ pressure rises to 60mmHg (diastolic
pressure) → allows blood to move forward
during diastole
▪ Pulse pressure: 120mmHg - 60mmHg =
60mmHg
▪ Elastance buffers, dampens pulse pressure
→ Windkessel effect
▪ Without elastic properties, blood pressure
would be 140/50mmHg with pulse
pressure 90mmHg
Figure 19.7 The same pressure will expand

the volumes of vessels differently depending
on their compliance.
144 OSMOSIS.ORG
Figure 19.8 Windkessel effect: elastance dampens pulse pressure by lowering systolic pressure
and increasing diastolic pressure.
Systole: aorta’s walls stretch with high pressure contractions and store some energy as elastic
energy. Since the total energy is the same as it would be without elastic arteries, there must be
less kinetic energy and pressure energy to make room for the elastic energy → lower systolic
blood pressure.
Diastole: elastic walls recoil, releasing the stored elastic energy and converting it to pressure
energy and kinetic energy → more pressure energy.
OSMOSIS.ORG 145
NOTES
NOTES
NORMAL VARIATIONS
▪ Physiological adaptations within
cardiovascular system in response to
changes such as hemorrhage, exercise,
postural changes
CARDIOVASCULAR CHANGES
DURING EXERCISE
osms.it/cardiovascular-changes-exercise
▪ Involves central nervous system (CNS),
local mechanisms
▫ CNS responses: changes in autonomic
nervous system (ANS) due to inputs
from cerebral motor cortex
▫ Local responses: exercise causes ↑
blood flow, O2 delivery to skeletal
muscles
▪ Exercise results in ↑ sympathetic (ß1
receptors), ↓ parasympathetic activity to
heart → ↑ cardiac output due to ↑ heart rate
+ ↑ stroke volume
▪ Muscle changes also occur
▫ ↑ metabolites (lactate, potassium,
adenosine) are produced → metabolites
stimulate local vasodilation → ↑ blood
flow → ↓ overall total peripheral
resistance (TPR)
OVERALL RESPONSE TO EXERCISE

▪ Central command: ↑ cardiac output (CO),
vasoconstriction in some vascular beds
(excludes exercising skeletal muscle,
cerebral, coronary circulations)
▫ ↑ CO → ↑ heart rate, contractility
▫ ↑ contractility → ↑ stroke volume → ↑
pulse pressure
▫ ↑ CO due to ↑ venous return
(sympathetic vein constriction,
squeezing action of skeletal muscle on
veins)
146 OSMOSIS.ORG
Chapter 20 Cardiovascular Physiology: Normal Variations of the Cardiovascular System
Figure 20.1 Flowchart showing cardiovascular response to exercise.
DURING HEMORRHAGE
osms.it/cardiovascular-changes-hemorrhage
▪ Blood loss → ↓ arterial pressure → ▫ Kidney secretes renin from renal
compensatory responses to restore arterial juxtaglomerular cells → ↑ angiotensin I
pressure production → converted to angiotensin
▫ Response mediated by baroreceptor II (causes arteriolar vasoconstriction,
reflex, renin-angiotensin-aldosterone stimulates aldosterone secretion)
system (RAAS), vascular actions ▪ Capillary changes favor fluid reabsorption
▫ ↑ sympathetic outflow to blood
Decrease in arterial pressure vessels, angiotensin II → arteriolar
▪ Hemorrhage → ↓ total blood volume → vasoconstriction → ↓ capillary
↓ venous return to heart, ↓ right atrial hydrostatic pressure (Pc)→ restricts
pressure → ↓ cardiac output → ↓ Pa as a filtration out of capillaries, favors
product of cardiac output, TPR absorption
Return of arterial pressure
▪ Baroreceptors in carotid sinus detect ↓ Pa OTHER RESPONSES IN
→ relay information to medulla via carotid HEMORRHAGE
sinus nerve → ↑ sympathetic outflow to ▪ Hypoxemia (↓ arterial PO2): carotid, aortic
heart, blood vessels; ↓ parasympathetic bodies chemoreceptors sense ↓ PO2 → ↑
outflow to heart → ↑ heart rate, ↑ sympathetic outflow to blood vessels → ↑
contractility, ↑ TPR, constriction of veins vasoconstriction, TPR, Pa
▪ ↓ mean arterial pressure → ↓ perfusion to ▪ Cerebral ischemia: local ↑ PCO2
kidney → response via RAAS
OSMOSIS.ORG 147
▪ ↓ blood volume → ↓ return of blood to heart
→ detection by atria volume receptors
→ ADH secretion to maintain adequate
blood pressure → water reabsorption
by renal collecting ducts → arteriolar
vasoconstriction
148 OSMOSIS.ORG
Figure 20.2 Flowchart showing cardiovascular responses to hemorrhage.
DURING POSTURAL CHANGE
osms.it/cardiovascular-changes-postural
▪ Standing up quickly → lightheadedness, into interstitial fluid, ↓ intravascular
sometimes fainting (due to delayed volume
constriction of lower extremity blood ▫ Severe ↓ blood pressure → syncope
vessels → orthostatic hypotension)
▫ ↓ in systolic blood pressure > 20mmHg/ Response of baroreceptor reflex
diastolic blood pressure > 10mmHg ▪ Responsible for homeostatic blood pressure
within three minutes of standing maintenance
▪ Initiating event: pooling of blood in ▪ Carotid sinus baroreceptors detect ↓ Pa →
extremities sends information to medullary vasomotor
▫ Moving from supine to standing center → inactivates medulla vagal
position: blood pools in veins of lower neurons, activates sympathetic neurons
extremities → ↓ venous return to heart, → ↑ sympathetic outflow to heart, blood
↓ cardiac output → ↓ mean arterial vessels, ↓ parasympathetic outflow to heart
pressure to normalize Pa
▫ Venous pooling → ↑ hydrostatic ▪ ↑ systemic vascular resistance, cardiac
pressure in leg veins → ↑ fluid filtration output act in negative feedback mechanism
to maintain Pa
OSMOSIS.ORG 149
150 OSMOSIS.ORG
Figure 20.3 Flowchart showing cardiovascular response to postural change.
OSMOSIS.ORG 151
NOTES
NOTES
SPECIFIC CIRCULATIONS
CEREBRAL CIRCULATION
osms.it/cerebral-circulation
▪ Cerebral circulation: managed almost Anterior segment
entirely by local (intrinsic) control ▪ Supplied by internal carotid arteries
(autoregulation; active, reactive hyperemia) ▪ Enter skull in carotid canal, branch out
▫ ↑ pCO2 (↑H+, ↓pH) → arteriolar ▫ Ophthalmic arteries: supply eyes, orbits,
vasodilation → ↑ blood flow → CO2 forehead, nose
removal (most vasoactive metabolites
▫ Anterior cerebral artery: medial part of
too big to cross blood-brain barrier →
frontal, parietal lobes; anastomoses with
do not affect cerebral tissue
counterpart via anterior communicating
▫ Hyperventilation works by artery (part of circle of Willis)
same mechanism → ↓ pCO2 →
▫ Middle cerebral artery: supplies lateral
vasoconstriction (used to reduce
sides of temporal, parietal, frontal lobes
swelling in situations of cerebral edema)
Posterior segment
CEREBRAL BLOOD SUPPLY ▪ Supplied by vertebral arteries
SEGMENTATION ▪ Enter skull through foramen magnum,
▪ Cerebral blood supply separated into branch out
anterior, posterior segments ▫ Right, left vertebral arteries fuse in
▪ Anterior, posterior circulatory segments skull → basilar artery which supplies
join via arterial posterior communicating brainstem, cerebellum, pons
arteries, form circle of Willis ▫ Posterior cerebral arteries: supply
▫ Back-up circulation in case of blood occipital lobes, inferior parts of temporal
vessel occlusion lobes
152 OSMOSIS.ORG
Chapter 21 Cardiovascular Physiology: Specific Circulations
CORONARY CIRCULATION
osms.it/coronary-circulation
▪ Coronary arteries: blood vessels delivering CORONARY CIRCULATION CONTROL
oxygenated blood to heart (myocardium) ▪ Coronary circulation managed primarily
▪ Cardiac veins: blood vessels retrieving by local (intrinsic) control, secondarily by
deoxygenated blood from heart sympathetic nervous system
▪ ↑ oxygen demand → ↑ blood flow
CORONARY ARTERIES ▪ Active hyperemia via local (intrinsic) control
▪ Two coronary arteries emerge from base of triggers
aorta, surround heart in coronary sulcus ▫ Hypoxia → build-up of metabolites
ADP, AMP → degraded to adenosine
Left coronary artery (potent vasodilator) → binds to coronary
▪ Two branches; supplies left atrium, left vascular smooth muscle → ↓ calcium
ventricle, interventricular septum influx into cells → vasodilation → ↑
▫ Circumflex artery: supplies left atrium, blood flow, oxygen delivery
posterior wall of left ventricle ▪ Other intrinsic control of vascular tone
▫ Anterior interventricular artery: supplies provided by endothelial factors
interventricular septum, anterior walls of ▫ Endothelium-derived nitric oxide:
ventricles relaxes arterial smooth muscle
▫ Prostacyclin: vasodilator
Right coronary artery
▫ Endothelium-derived hyperpolarizing
▪ Two branches; supplies right atrium, right factor (EDHF): vasodilator
ventricle, part of left ventricle, electrical
▫ Endothelin 1: vasoconstrictor
conduction system
▪ Reactive hyperemia
▫ Right marginal artery: supplies lateral
right side of heart, superficial parts of ▫ Brief arterial occlusion period during
ventricle systole → ↓ blood flow → ↑ O2 debt →
vasodilation during diastole → ↑ blood
▫ Posterior interventricular artery:
flow → O2 demands are met
supplies interventricular septum,
posterior walls of ventricles
OSMOSIS.ORG 153
CONTROL OF BLOOD FLOW
CIRCULATION
osms.it/blood-flow
▪ Blood flow regulation ▪ Metabolic hypothesis for autoregulation,
▫ Intrinsic (local): humoral, myogenic active, reactive hyperemia
control ▫ O2 distribution changes in response to
▫ Extrinsic (systemic): hormonal, neural O2 consumption via altering arteriolar
resistance
▫ ↑ metabolism → ↑ vasodilating
LOCAL (INTRINSIC) BLOOD FLOW metabolites (CO2, H+, K+, lactate,
CONTROL adenosine) → arteriole vasodilation
Mechanisms → ↓ resistance → ↑ blood flow, O2
distribution
▪ Humoral: mediated by vasoactive
substances ▫ Certain tissues more susceptible
to certain metabolites (coronary
▫ Histamine, nitric oxide (arteriole dilation)
circulation—PO2, adenosine; cerebral
▫ Endothelin, serotonin circulation—PCO2)
▪ Autoregulation: maintains constant blood
flow via direct control of arterial resistance
▫ Present in organs such as kidneys, brain,
NEURAL & HORMONAL (EXTRINSIC)
heart, skeletal muscle (e.g. ↓ coronary
CONTROL
artery pressure → compensatory ▪ Neural: sympathetic nervous system acts
arteriole vasodilation → ↓ vessel on vascular smooth muscle
resistance → constant blood flow) ▫ ɑ1: vasoconstriction → skin, intestines
▪ Active hyperemia: ↑ blood flow directed to ▫ β2: vasodilation → lungs, skeletal
organ/tissue associated with ↑ metabolic muscles
activity (e.g. ↑ blood flow in active skeletal ▪ Hormonal: vasopressin released from
muscle) anterior pituitary → vasoconstriction
▪ Reactive hyperemia: temporary ↑ blood
flow following ischemia (↓ blood flow) in
organ (e.g. arterial occlusion → ↓ blood flow
→ ↑ O2 debt → vasodilation, ↑ blood flow)
▪ Myogenic hypothesis for autoregulation
▫ Focus on arteriolar resistance: vascular
smooth muscle contracts upon
stretching (↑ wall tension) and vice versa
▫ ↑ blood flow → arteriole stretching →
contraction → ↑ resistance → constant
blood flow
▫ ↓ blood flow → ↓ arteriole stretching →
relaxation → ↓ resistance → constant
blood flow
▫ Explained by law of Laplace: ↑ pressure
(P) + ↓ radius (r) → tension (T) remains
constant (T=P x r)
154 OSMOSIS.ORG
Chapter 21 Cardiovascular Physiology: Specific Circulations
MICROCIRCULATION &
STARLING FORCES
osms.it/microcirculation-starling-forces
▪ Microcirculation: vascular network involving ▪ Vesicular transport: large molecule
capillaries, lymphatic vessels exchange (proteins) via pinocytic vesicles
(caveolae)
Capillaries ▫ In some tissues (kidney, intestine)
▪ Vessels: thin walls lined with endothelial proteins pass through capillary
cells fenestrations
▪ Arterioles → metarterioles → capillaries → ▪ Osmosis: if capillary wall has aqueous
venules → veins pores, pressure gradient across membrane,
▫ Metarterioles end in precapillary driven by Starling forces
sphincters → smooth muscle ring
controls blood flow/capillary exchange
rate by constricting/relaxing STARLING FORCES
▫ Capillary blood flow regulated by ▪ Capillary filtration/absorption depend on
intrinsic (local), extrinsic (systemic) Starling forces: hydrostatic, colloid osmotic
control (oncotic) pressure
▫ Filtration: fluid movement from
capillaries → interstitium
CAPILLARY EXCHANGE ▫ Absorption: fluid movement from
▪ Capillaries: exchange sites for nutrients, interstitium → capillaries
waste, fluids between interstitial, vascular
space Hydrostatic pressure
▫ Afferent blood: capillaries → interstitial ▪ Pressure exerted by fluid against capillary
space → tissue wall
▫ Efferent blood: tissue → interstitial ▪ Capillary hydrostatic pressure (Pc)
space → capillaries ▫ Favors filtration: tends to move fluid out
of capillaries
Capillary exchange types
▫ Blood pressure ↓ throughout capillary
▪ Simple diffusion: substance exchange
beds → arterial (37mmHg) > venous
through lipid bilayer/between capillary
(17mmHg) pressure
wall’s epithelial cells
▪ Interstitial fluid hydrostatic pressure (Pi)
▫ Depends on driving force (partial
pressure gradient), available diffusion ▫ Opposes filtration: pressure exerted
area outside capillary wall
▫ Driving force: substances move across ▫ Tends to move fluid into capillary
their own partial pressure gradient ▫ Contains very little fluid → Pi considered
(towards ↓ concentration area) zero, slightly positive/slightly negative
▫ Lipid soluble substances (O2, CO2) pass (1mmHg)
through lipid bilayer Colloid osmotic pressure (oncotic pressure)
▫ Water soluble substances (ions, glucose, ▪ Pressure gradient: large non-diffusible
amino acids) pass between endothelial molecules (e.g. plasma proteins)
cells through fluid-filled intercellular
▫ Capillary oncotic pressure (πc)
clefts/fenestrations
(25mmHg): created by plasma proteins
(primarily albumin; reflection coefficient
= 1.0); opposes filtration
OSMOSIS.ORG 155
▫ Interstitial oncotic pressure (πi) LYMPH
(0mmHg): contains very little protein; ▪ Lymphatic capillaries drain excess fluid +
favors filtration some proteins from interstitial space into
venous system
Flow direction
▫ Lymphatic capillaries → lymphatic
▪ Arterial end of capillary vessels → thoracic duct/right lymphatic
▫ Blood pressure’s outward driving force > duct → subclavian vein
inwardly directed oncotic pressure force ▫ One way valves → unidirectional flow
→ fluid moves out of vessel
▪ Venous end of capillary Edema
▫ Oncotic pressure inward driving force > ▪ Abnormal buildup of fluid in interstitial
outwardly directed hydrostatic pressure space
→ fluid moves into vessel ▪ Causes
▪ Most fluid leaving capillary at arterial end ▫ Imbalance of Starling forces
reenters capillary before leaving venous ▫ ↑ hydrostatic capillary pressure (↑
end volume—e.g. heart failure; obstruction;
▪ Fluid remaining in interstitial space e.g. thrombosis)
recovered by lymphatic vessels ▫ ↓ oncotic capillary pressure (↓
▪ Fluid movement through capillary wall is plasma protein —e.g. liver failure,
dependent on Starling force malnourishment, nephrotic syndrome
▫ ↑ capillary permeability (burns/
Starling equation
inflammation)
▪ Jv = Kf [( Pc - Pi) - (πc - πi)]
▫ Impaired drainage (immobility; lack of/
▫ Jv = fluid movement (mL/min) irradiated lymphatic nodes; parasitic
▫ Kf = hydraulic conductance (wall to infections of lymphatic nodes—e.g.
water permeability; depends on tissue, filariasis)
wall structure—e.g. fenestrated, non-
fenestrated)
156 OSMOSIS.ORG
NOTES
NOTES
BODY TEMPERATURE REGULATION
BODY TEMPERATURE REGULATION

(THERMOREGULATION)
NORMAL BODY TEMPERATURE production

▪ 37 ± 0.5 °C (98.6 ± 0.9 °F) ▫ Piloerection (goosebumps) → heat
▪ Hypothalamic thermoregulatory center acts trapping
as a thermostat ▪ Thyroid hormones released from
▫ Sets temperature set-point hypothalamus → ↑ metabolic rate → ↑ heat
▪ Thermoreceptors production
▫ Peripheral (in skin) → sense surface ▪ Non-shivering thermogenesis using brown
temperature adipose tissue
▫ Central (in the body core—e.g. ▫ Activation of primary motor center for
hypothalamus itself) → sense core shivering in the posterior hypothalamus
temperature → skeletal muscle contraction →
shivering → ↑ heat production
▪ Temperature variations activate
thermoreceptors → thermoreceptors ▫ Behavioral changes (adding garments,
inform hypothalamus → hypothalamus tightening the arms across the chest,
activates heat regulation mechanisms → moving around)
temperature returns to baseline
Heat dissipation
▪ Body region variations
▪ Inhibition of sympathetic activity in skin
▫ Core: higher temperature, more stable blood vessels → blood goes to skin → ↑
▫ Skin: lower temperature, more variable heat loss
▪ Core temperature varies with throughout ▪ Activation of sympathetic cholinergic fibers
the day innervating sweat glands → ↑ sweating →
▫ Lower during sleep ↑ heat loss
▫ Higher when awake ▪ Behavioral changes (removing garments,
reducing movements, fanning air over
body)
BODY TEMPERATURE
MAINTENANCE Fever
▪ Body temperature maintained by balancing ▪ Body temperature elevation due to change
heat-generation, heat loss in hypothalamic set-point
Heat generation ▪ Pyrogens act on hypothalamus →
hypothalamus releases prostaglandins
▪ Activation of sympathetic nervous system
→ hypothalamic set-point temperature
▫ Vasoconstriction of skin arterioles → increases → heat-generating mechanisms
blood bypasses skin → ↓ heat loss kicks in → body temperature rises and
▫ Adrenal glands release catecholamines reaches new baseline temperature
(epinephrine, norepinephrine) → ▫ Aspirin reduces fever by inhibiting
increased metabolic rate → ↑ heat prostaglandins production
OSMOSIS.ORG 157
▪ Benefits of fever ▫ Depolarizing muscle relaxants:
▫ Inhibit bacterial growth by making Succinylcholine, Decamethonium
growing conditions less favorable ▪ Potentially fatal
▫ Increase efficiency of immune cells ▪ Treatment
▫ Dantrolene (skeletal muscle relaxant)
HYPERTHERMIA
▪ Elevation of body temperature without HYPOTHERMIA
change in hypothalamic set-point ▪ Abnormally low temperature
▪ Normal mechanisms of thermoregulation ▫ Diagnosis: core temperature <
are overwhelmed by various factors 35°C/95°F
▫ Excessive environmental temperature ▪ Compensatory mechanisms responding to
▫ Impaired ability to dissipate heat cold stress are overwhelmed
▫ Excessive heat production ▪ ↓ core body temperature → ↓↓ metabolic
rate → myocardial irritability, cold diuresis
Heat exhaustion (↓ renal blood flow, water resorption)
▪ Excessive sweating → significant water ▫ Progressive oliguria as ↓ core
and electrolyte loss → ↓ blood volume → ↓ temperature → ↓ intravascular volume,
arterial pressure ↑ hematocrit, central nervous system
depression
Heat stroke
▪ Hyperthermia > 40°C/105.1°F Risk factors
▪ Potentially fatal ▪ Prolonged cold exposure
▪ Causes ▫ E.g. inadequate clothing/shelter, cold
▫ High environmental temperature water immersion
▫ Periods of intense physical activity ▪ Impaired thermoregulation
▪ Risk factors ▫ E.g. hypothalamic dysfunction,
▫ Susceptible individuals: infants, children metabolic derangement
(higher metabolic rate; ineffective ▪ ↑ heat loss
sweating; physical, psychological ▫ Multisystem trauma, shock, spinal cord
limitations); elderly (pre-existing transection
conditions; physical, psychological ▪ Iatrogenic
limitations)
▫ Cold IV fluid administration, inadequate
▫ Medications: ones that inhibit heat- operating room warming
dissipating mechanisms (beta blockers,
▪ ↑ risk populations
diuretics)
▫ Older adults (↓ physiologic reserve, ↓
Malignant hyperthermia sensory perception, chronic medical
▪ Genetic alteration of ryanodine receptor 1 conditions)
(RYR1) in the muscle cells ▫ Children (↑ body surface area to
▪ Normally: cell depolarization → RYR1 body mass ratio, ↓ glycogen stores,
activation → calcium release from young infants unable to use shivering
sarcoplasmic reticulum into cytoplasm → thermogenesis)
muscle contraction
Complications
▪ In malignant hyperthermia: cell
▪ Cardiac arrhythmias, myocardial infarction,
depolarization → RYR1 hyperactivation →
pulmonary edema, pulmonary embolism,
excessive calcium release → inappropriate
lactic acidosis, disseminated intravascular
muscle contraction, ↑↑ metabolic rate →
coagulation (DIC), coma, death
excessive heat production
▪ Triggered by drugs Signs & symptoms
▫ Anesthetic gas: Alothane, Sevoflurane, ▪ Mild hypothermia
Desflurane ▫ Core temperature 32–35°C/90–95°F
158 OSMOSIS.ORG
Chapter 22 Body Temperature Regulation
▫ Shivering, tachypnea, tachycardia,

confusion
▪ Moderate hypothermia
▫ Core temperature 28–32°C/82–90°F
▫ ↓ shivering and muscle rigidity,
hypoventilation, bradycardia, ↓ cardiac
output, lethargy, arrhythmias, loss of
pupillary reflexes
▪ Severe hypothermia
▫ Core temperature < 28ºC/82°F
▫ Apnea, ↓ cardiac activity → ventricular
arrhythmias → asystole, coma, loss of
ocular reflexes, ↓↓ metabolic rate
Rewarming treatment
▪ Warmed blankets/forced warm-air system;
heated, humidified oxygen; warmed
crystalloid IV fluid; pleural, peritoneal lavage
using warm saline solution; vasopressors
▪ Extracorporeal blood rewarming
▫ Venovenous rewarming, hemodialysis,
continuous arteriovenous rewarming
(CAVR), cardiopulmonary bypass (CPB),
extracorporeal membrane oxygenation
(ECMO)
OSMOSIS.ORG 159
NOTES
NOTES
CELLULAR STRUCTURES & PROCESSES
CELLULAR STRUCTURE &

FUNCTION
osms.it/cellular-structure-and-function
CELL STRUCTURE BASICS ▫ Larger subunit: has ribozyme to catalyze
▪ Basic structural, biological, functional unit peptide bond formation (for bonds
that comprise organism between amino acids)
▪ Smallest self-replicating life-form
Endoplasmic reticulum
▪ Over 200 types in human body
▪ Membrane-enclosed organelle
▪ Cells → tissue → organ → organ systems
▪ Appearance: stack of membranous,
→ organism
flattened disks (cisterns)
Basic constituents ▪ Rough endoplasmic reticulum (RER)
▪ Plasma membrane ▫ Contains bound ribosomes on surface
▪ Cytoplasm ▫ Site of packaging, folding of proteins
▫ Fluid suspension designated for secretion, lysosomal
degradation, plasma membrane
▫ Composition: cytosol, organelles
insertion; proteins packed into vesicles,
sent to Golgi apparatus for further
CYTOSOL modification
▪ Intracellular fluid ▫ RER cisterna continuous with nuclear
▫ Composition: water; dissolved/ envelope
suspended organic, inorganic chemicals; ▪ Smooth endoplasmic reticulum (SER)
macromolecules; pigments; organelles ▫ No ribosomes
▪ Site of most cellular activity ▫ Site of lipid, steroid synthesis, Ca2+ ions
storage (muscles), glycogen metabolism,
ORGANELLES detoxification (liver)
▪ Specialized cellular subunits carry out Golgi apparatus (complex)
essential functions
▪ Membrane-enclosed organelle
Ribosomes ▫ Appearance: collection of fused,
▪ Composition: rRNA, ribosomal proteins flattened sacs (cisterns) with associated
vesicles, vacuoles
▪ Can exist freely in cytoplasm/bound to
endoplasmic reticulum (forms rough ▪ Two sides
endoplasmic reticulum) ▫ Cis side: receives proteins from RER
▪ Turns mRNA into protein via translation (entry)
▪ Organized into two subunits (40s, 60s) ▫ Trans side: opposite side, releases
vesicles towards plasma membrane
▫ Small subunit: binding sites for mRNA,
(exit)
tRNA
160 OSMOSIS.ORG
Chapter 23 Cellular Physiology: Cellular Structures & Processes
▪ Post-translational modification site (e.g. ▫ In glucose absence, mitochondria can

phosphorylation, glycosylation, sulfonation) use fatty acids as fuel via beta oxidation
of proteins, lipids, hormones → sorted, (only medium sized fatty acids used;
packaged into secretory vesicles → longer ones chopped by peroxisome)
secreted out of cell/lysosomal fusion/plasma ▪ Mitochondria number: correlates with cell
membrane insertion activity/energy requirements
Mitochondria Nucleus
▪ Double membrane-enclosed organelle; ▪ Large, membrane-enclosed organelle
synthesizes ATP for cell via aerobic present in all cells except mature
respiration erythrocytes
▫ Outer smooth membrane: encloses ▪ Contains genetic material (DNA, tightly
whole organelle packed into chromatin); coordinates cellular
▫ Inner membrane: forms folds, caverns activities
called cristae (contain proteins needed ▪ Most cells contain one nucleus; some
for aerobic respiration); encloses cells have more (e.g. skeletal muscle cells,
mitochondrial matrix (contains osteoclasts, hepatocytes)
mitochondrial DNA, ribosomes) ▪ Usually spherical, may take on other shapes
▪ Intermembrane space: space between ▫ Lobulated (e.g. polymorphonuclear
inner, outer membrane leukocytes)
▪ In cytoplasm glucose undergoes glycolysis, ▫ Elongated (e.g. columnar epithelium)
glucose cleaved into pyruvate
▫ Pyruvate enters mitochondria →
citric acid cycle (Krebs cycle), electron
transport chain (require oxygen)
Figure 23.1 Cellular structures and their functions.
OSMOSIS.ORG 161
CELL MEMBRANE
osms.it/cell-membrane
▪ Semipermeable membrane made from ▪ Semipermeable
phospholipid bilayer; surrounds cell ▫ Allows passage of certain molecules
cytoplasm through membrane (O2, CO2, etc.)
▫ Denies passage of others (large
Phospholipid bilayer
molecules such as proteins, glucose)
▪ Two-layered polar phospholipid molecules
▪ Certain molecule transportation (ions, H2O)
comprising two parts
allowed through embedded membrane
▫ Negatively charged phosphate “head”
proteins (ion channels, pumps)
(hydrophilic; oriented outwards)
▫ Fatty acid “tail” (hydrophobic; oriented
inwards)
Figure 23.3 Transport proteins move

molecules that can’t freely diffuse across
the cell membrane. Channels form a
tunnel through which water and ions flow.
Carriers have a binding site for a specific
molecule and gates at both ends that open
sequentially. Enzymes, or ATPases, actively
pump ions in/out of the cell against their
concentration gradients.
Figure 23.2 Phospholipid parts and their

arrangement in a cell membrane.
162 OSMOSIS.ORG
SELECTIVE PERMEABILITY OF
THE CELL MEMBRANE
osms.it/cell-membrane-selective-permeability
▪ Cell membrane controls which molecules Channels
enter, leave ▪ Non-specific; open to allow water, small
▫ Passive transport: no energy required polar molecules through (e.g. voltage-gated
▫ Active transport: energy required → calcium channel)
adenosine triphosphate (ATP)
Carrier proteins
▪ Very specific, only allow certain molecules
PASSIVE TRANSPORT to bind (e.g. glucose transporter protein
GLUT4)
Simple diffusion
▪ Random molecular motion
▪ Small, nonpolar molecules move from ↑ ACTIVE TRANSPORT
concentration → ↓ concentration
Primary
Fick’s law ▪ Uses ATP
▪ Three factors affect diffusive flux ▫ Enzymes called ATPases use ATP as
▪ Concentration gradient fuel; (e.g. Na+-K+ ATPase, Ca2+ ATPase,
H+-K+ ATPase)
▫ Larger differences in solute
concentration on each side of ▫ May create concentration/
membrane → ↑ driving force → ↑ net electrochemical gradients
diffusion
Secondary
▫ Equal concentrations → no net diffusion
▪ Uses existing electrochemical gradients
(e.g.CO2, O2 movement between alveoli,
▫ One solute, normally Na+, moves
blood)
with concentration gradient through
▪ Membrane surface area transporter → supplies energy
▫ ↑ surface area available for diffusion → ↑ transporter needs to → another solute
diffusion rate; vice versa (e.g. microvilli in against concentration gradient in same/
small intestines amplify surface area → opposite direction as Na+ (e.g. sodium-
↑ nutrient, water absorption) glucose SGLT1 transporter)
▪ Distance separating each side of
membrane (e.g. thickness) Bulk transport
▫ ↑ distance molecules must travel → ↓ ▪ AKA vesicular transport
net diffusion; vice versa (e.g. pulmonary ▪ Endocytosis
edema → ↑ distance between ▫ Cell membrane invaginates, pulling
compartments → ↓ net diffusion) something in from outside (e.g.
pathogen phagocytosis)
Facilitated diffusion
▪ Exocytosis
▪ Uses transport proteins (e.g. channels,
▫ Vesicle inside cell pushes something out
carrier proteins)
(e.g. hormone secretion)
▪ Allows larger/polar molecules to move
across membrane
OSMOSIS.ORG 163
Figure 23.4 Endocytosis and exocytosis.
EXTRACELLULAR MATRIX
osms.it/extracellular-matrix
▪ Environment surrounding cells ▫ Starts as procollagen → cleaved into
▪ Varies between tissues (epithelial, tropocollagen → arranged into collagen
connective, muscular, and nervous) fibrils
▫ Four types: type I (bone, skin, tendon),
type II (cartilage), type III (reticulin, blood
THREE MAJOR MOLECULES vessels), type IV (basement membrane)
Adhesive proteins ▪ Elastin
▪ Adhere cells together (communication with ▫ Elastic, returns tissue to original shape
extracellular fluid) ▪ Keratin
▫ E.g. integrins, cadherins ▫ Tough, found in hair, nails
Structural proteins Proteoglycans

▪ Give tissues tensile, compressive strength ▪ Fill space between cells, hydrate, cushion
▪ Collagen cells
▫ Resists tension, can stretch ▫ Consists of protein core with sugar
chains
164 OSMOSIS.ORG
Figure 23.6 The three kinds of structural

proteins in the extracellular matrix and their
functions.
Figure 23.5 Cadherins and integrins are both

adhesive proteins which hold cells together.
Figure 23.7 Collagen production steps.
Figure 23.8 Structure of proteoglycans, which hydrate and cushion cells.
OSMOSIS.ORG 165
CELL-CELL JUNCTIONS
osms.it/cell-cell_junctions
▪ Protein structures that physically connect Adherens junctions
cells ▪ E.g. in skin
▪ Improve cellular communication, tissue ▪ Anchor cells together, provide strength;
structure; allow transport of some consist of three major components
substances between cells, create ▫ Actin filaments: provide cellular shape
impermeable barrier for others
▫ Protein plaques: anchor membrane,
▪ Only found between immobile cells; bind to actin filaments
abundant in epithelial tissue (e.g. in skin)
▫ Cadherins: attach to protein plaques,
connect to cadherins on other cells
THREE JUNCTION TYPES
Gap junctions
Tight junctions ▪ E.g. in heart
▪ E.g. in gastrointestinal tract/brain ▪ Connect adjacent cells, allow rapid
▪ Seal adjacent-cell plasma membranes, communication; formed by connexins →
especially near apical surface; prevent create tubular structure (allows charged
passage of water, small proteins, bacteria particles to pass)
▫ Formed by claudins, occludins ▫ In cardiac myocytes: gap junctions
embedded in cellular plasma create coordinated heart contractions
membranes ▫ In infected cells: gap junctions send
▫ In “leaky” epithelia, tight junctions may cytokines to neighboring cells, triggering
allow certain molecules to pass (e.g. K+, apoptosis, preventing infectious spread
Na+, Cl- in kidney’s proximal tubules— (“bystander effect”)
due to ion pores)
Figure 23.9 The three types of cell junctions.
166 OSMOSIS.ORG
ENDOCYTOSIS & EXOCYTOSIS

osms.it/endocytosis-and-exocytosis
▪ Transports material in/out of cell ▪ Edges of pit come together, clathrin
▪ Requires adenosine triphosphate (ATP) for proteins link up
energy ▪ Vesicle pinches off; clathrin detaches,
returns to cell membrane
ENDOCYTOSIS ▪ Vesicle merges with endosome to separate
receptors into second vesicle
▪ Cells engulf extracellular material
PHAGOCYTOSIS
▪ AKA cell eating
▪ Used by white blood cells (e.g.
macrophages, neutrophils)
Process
▪ Cell extends arm-like projects (AKA
pseudopods) around target
▪ Cell membrane slowly engulfs target,
invaginates to form vesicle
▪ Vesicle separates from cell membrane to
form phagosome
Figure 23.10 The three types of endocytosis.
▪ Phagosome fuses with lysosome, target is
digested
▪ Debris released by exocytosis EXOCYTOSIS
▪ Cells expel material into extracellular space
PINOCYTOSIS (e.g. neurotransmitters, hormones)
▪ AKA cell drinking ▪ Last phagocytosis step
▪ Used by most cells to take in extracellular
fluid; non-specific Process
▪ Golgi apparatus creates vesicle from
Process various proteins, lipids, hormones
▪ Cell membrane invaginates around ▪ Motor proteins use ATP to carry vesicle
extracellular fluid along cytoskeleton
▪ Edges of invagination come together to ▪ Vesicle is pressed against cell membrane
form vesicle until rupture → spills contents into
▪ Motor proteins use ATP to carry vesicle into extracellular space
cytosol
RECEPTOR-MEDIATED
ENDOCYTOSIS
▪ Used by cells to take in specific molecules
(e.g. iron, cholesterol)
Process
▪ Clathrin-covered pits/coated pits with
receptors bind certain molecules Figure 23.11 Exocytosis: expulsion of
material into extracellular space.
OSMOSIS.ORG 167
OSMOSIS
osms.it/osmosis
▪ Passive water-flow across selectively SELECTIVELY-PERMEABLE
permeable (semipermeable) cellular MEMBRANE
membrane; primarily determined by ▪ Allows small molecules (e.g. water) across,
solute concentration differences (osmotic but not larger molecules/ions
pressure)
Isotonic solution
Factors affecting water movement across ▪ Side A = side B
membrane
▪ If solute concentration is same on each
▪ Molecules (e.g. water molecules, ions) side of membrane → net water movement
tend to move around (kinetic energy) + across membrane is zero (equilibrium)
movement is disordered, random (entropy)
→ larger solutes tend to block openings in Hypertonic/hypotonic solution
semipermeable membrane ▪ Side A > side B or side B > side A
▪ If solute ions positively charged, they attract ▪ If solute concentration is greater on one
slightly negatively charged oxygen atom in side (hypertonic) → net water migration
water molecule; if solute ions are negatively across membrane is from hypotonic side
charged, they attract slightly positively toward hypertonic side
charged hydrogen atoms in water molecule
→ water molecules partially attached to ion
→ movement through membrane impeded CELLULAR EFFECT
▪ Water molecules tend to move from ▪ Red blood cell in hypertonic solution → net
hypotonic side (more water/less solutes) to movement of water molecules out of cell →
hypertonic side (less water/more solutes) cell shrinks (crenation)
▪ Red blood cell in hypotonic solution → net
movement of water molecules into cell →
cell swells, may burst (lyses)
Figure 23.12 Net water molecule movement between isotonic, hyper/hypotonic solutions.
168 OSMOSIS.ORG
RESTING MEMBRANE POTENTIAL

osms.it/resting-membrane-potential
▪ Electric potential across cell membrane ⎛ [ION]out ⎞
Vm = 30.75 × log ⎜ ⎟
▫ Given by weighted (based on ⎝ [ION]in ⎠
membrane permeability) sum of ▫ Double charge:
equilibrium potentials for all ions ▫ Value is flipped for negative ions
▪ High concentrations of Na+, Cl-, Ca2+ ▪ Resting membrane potential is sum
outside cell; high concentrations of K+, A- of equilibrium potentials of major ions
(various anions) inside cell → concentration multiplied by their membrane permeabilities
gradients are established
▫ Sodium-potassium pump uses ATP to
move two K ions into cell, three Na ions
out
▫ Potassium concentration = 150mMol/L
inside cell, 5mMol/L outside
▪ Concentration gradients establish
electrostatic gradients
▫ Concentration gradient pushes
potassium out through potassium leak
channels, inward rectifier channels
▫ Anions remain in cell → negative charge
builds up → potassium is pulled back
into cell
▪ Equilibrium (Nernst) potential: electrostatic
gradient equal to concentration gradient Figure 23.13 Equilibrium potential = electric
(-92mV for potassium) potential for attracting K+ back into the cell
▪ Nernst equation: equilibrium potential for that’s needed to balance the concentration
an ion gradient pushing K+ out of the cell.
⎛ [ION]out ⎞
▫ Single charge: Vm = 61.5 × log ⎜ ⎟
⎝ [ION]in ⎠
Figure 23.14 The resting membrane potential is closest to the equilibrium potential of the most
permeable ion (K+). Change in permeability → change in resting membrane potential.
OSMOSIS.ORG 169
CELL SIGNALING PATHWAYS
osms.it/cell-signaling-pathways
INTRACELLULAR SIGNAL Cell signalling pathway stages
CLASSIFICATION 1. Reception: ligand binds to receptor
▪ Classified according to distance between 2. Transduction: receptor changes activating
signaling, target cells intracellular molecules
▫ Autocrine: cell signals nearby cells 3. Response: signal triggers a response in the
of same type, including itself (e.g. target cell
monocytes secrete interleukin-1 β)
▫ Paracrine: cell signals nearby cells of
different type (e.g. ECL cells secrete MAJOR TRANSMEMBRANE
histamine → signals D cells to secrete RECEPTOR CLASSES
somatostatin)
G protein-coupled receptors
▫ Endocrine: cell signals distant cells (e.g.
▪ Seven-pass transmembrane receptors
pituitary gland secretes TSH → signals
thyroid gland) ▪ Activate guanine nucleotide-binding (G)
proteins inside cell
▪ Signalling molecules (ligands) bind to
receptors; can be hydrophobic/hydrophilic ▫ G proteins have three subunits: alpha,
beta, gamma
▫ Hydrophobic: can’t float in extracellular
space → brought to target cells ▫ Alpha binds guanosine diphosphate
by hydrophilic carrier proteins; can (GDP) when inactive
diffuse over cell membranes → bind to ▫ When ligand binds, alpha releases
receptors inside cell GDP, binds guanosine triphosphate
▫ Hydrophilic: can float in extracellular (GTP) instead → alpha separates from
space → reach target cells themselves; beta, gamma → alpha interacts with
can’t diffuse over cell membranes → proteins turning GTP back into GDP →
bind to cell surface (transmembrane) reattaches
receptors
Figure 23.15 Autocrine, paracrine, and endocrine signals refer to signal distance from its target
cell. Hydrophobic and hydrophilic ligands refer to the affinity of the ligand for water.
170 OSMOSIS.ORG
Figure 23.16 Mechanism of action of G-protein coupled receptors.
▪ Three types of G protein with different ▪ Composition: extracellular, ligand-binding

pathways domain; intracellular, enzymatic domain
▫ Gq: activates phospholipase C in cell ▪ Three main enzyme-coupled receptor types
membrane → phospholipase C cleaves ▫ Receptor tyrosine kinases: when ligand
phosphatidylinositol 4,5-bisphosphate binds, these phosphorylate their own
into inositol trisphosphate, diacylglycerol tyrosine residues → conformational
→ inositol trisphosphate opens calcium change creates binding site for other
channels in endoplasmic reticulum signalling proteins
(calcium flows to cytoplasm, changing ▫ Tyrosine kinase associated receptors:
electrical charge distribution in cell when ligand binds, these phosphorylate
→ cell depolarization); diacylglycerol various proteins to relay signal to
binds to protein kinase C which tyrosine kinases inside cell
phosphorylates target proteins
▫ Receptor serine/threonine kinases:
▫ Gs: stimulates adenylate cyclase → when ligand binds, type II receptors of
adenylate cyclase removes phosphate this kind phosphorylate type I receptors,
from adenosine triphosphate which in turn phosphorylate various
(ATP) creating cyclic adenosine proteins to relay signal to serine/
monophosphate (cAMP) → cAMP binds threonine kinase domain inside cell
to regulatory subunit of protein kinase A
→ catalytic subunit of protein kinase A Ion channel receptors
phosphorylates target proteins ▪ Ion channels which open when specific
▫ Gi: inhibits adenylate cyclase → negative ligands bind
feedback on Gs ▪ Allow ions (e.g. chloride, calcium, sodium,
potassium) to flow through
Enzyme-coupled receptors
▪ Resulting shift in electric charge distribution
▪ Single-pass transmembrane receptors
triggers response
▪ Trigger enzymatic activity inside cell when
specific ligands bind
OSMOSIS.ORG 171
Figure 23.17 Gq pathway.
Figure 23.18 Gs pathway.
Figure 23.19 Gi pathway.
172 OSMOSIS.ORG
Figure 23.20 Types of enzyme-coupled receptors and their pathways.
Figure 23.21 Mechanism of action for ion channel receptors.
OSMOSIS.ORG 173
HORMONAL MECHANISMS ▪ Second messengers: intracellular signalling
▪ All cells receive, process outside signals via molecules released by cells → triggers
specific proteins (receptors) physiological changes in response to
▫ Ligand (signalling molecule—e.g. hormone/ligand–receptor interaction
hormone) binds to receptor → ▫ Include: cyclic AMP (cAMP), cyclic GMP
physiological response (cGMP), inositol trisphosphate (IP3),
▪ Target tissue sensitivity to hormone effect diacylglycerol (DAG), Ca2+
controlled by receptor quantity/affinity ▫ Involved in cellular processes:
▫ ↑ receptor quantity → ↑ maximal proliferation, differentiation, migration,
response survival, apoptosis
▫ ↑ receptor affinity → ↑ response
likelihood G PROTEINS
▪ Membrane-bound proteins: act as
HORMONE RECEPTOR molecular switches, couple hormone
UPREGULATION/DOWNREGULATION receptors to effector enzymes
▪ Heterotrimeric proteins → three subunits →
Downregulation alpha (α), beta (β), gamma (γ)
▪ External stimulus → cell ↓ hormonal ▪ Can be stimulatory (Gs)/inhibitory (Gi)
receptor quantity/affinity ▫ Activity determined by α subunit (αs/αi),
▫ Chronic exposure to excessive signalling that contains GTPase activity
molecules (e.g. neurotransmitters/
drugs → ligand-induced target receptor Binding
desensitization/internalization) ▪ α subunit binds guanosine diphosphate
▫ Hormones may alter other hormonal (GDP)/triphosphate (GTP)
receptor sensitivity (e.g. in uterus— ▫ GDP binding → inactive state
progesterone downregulates its own ▫ GTP binding → active state → coupling
receptor, estrogen receptor) ▫ Guanosine nucleotide-releasing factors
▫ Mechanisms: ↓ new receptor synthesis, (GRFs) facilitate GDP dissociation
↑ existing receptor degradation, ▫ GTPase-activating factors (GAPs)
inactivating receptors facilitate GTP hydrolysis
Upregulation ▪ GRFs, GAPs relative activity
▪ External stimulus → cell ↑ hormonal ▫ ↑ G protein activation rate
receptor quantity/affinity ▪ Final signal transduction occurs via cyclic
▫ Repeated exposure to receptor adenosine monophosphate (cAMP) signal
antagonists/prolonged ligand absence pathway/phosphatidylinositol signal
→ upregulation pathway
▫ Hormone may upregulate receptors for
other hormones (e.g. in uterus estrogen ADENYLYL CYCLASE MECHANISM
upregulates its own receptor, also ▪ Hormones acting via cAMP mechanism:
luteinizing hormone (LH) receptors in adrenocorticotropic hormone, luteinizing
ovaries) hormone, follicle-stimulating hormone,
▫ Mechanisms: ↑ new receptor synthesis, thyroid-stimulating hormone, antidiuretic
↓ existing receptor degradation, hormone (V2 receptor), human chorionic
activating receptors gonadotropin, melanocyte-stimulating
hormone, corticotropin-releasing hormone,
SECOND MESSENGER SYSTEMS calcitonin, parathyroid hormone, glucagon
▪ Primary extracellular signalling molecules ▪ Hormone binds to receptor coupled to Gs/
often hydrophilic → cannot cross cell Gi protein → adenylyl cyclase activation/
membrane → second messenger system inhibition → intracellular cAMP ↑/↓
carries, amplifies signal across cell ▪ Stimulatory receptor events
membrane ▫ Hormone binds to receptor →
174 OSMOSIS.ORG
conformational change in αs subunit → STEROID HORMONE MECHANISM

αs subunit releases GDP → replacement ▪ Hormones acting via steroid hormone
by GTP → αs subunit detaches from Gs mechanism: glucocorticoids, estrogens,
protein progesterone, testosterone, aldosterone,
▫ αs subunit-GTP complex migrates 1,25-dihydroxycholecalciferol, thyroid
within cellular membrane → binds → hormone
activates adenylyl cyclase ▪ No cell membrane-mediated transduction
▫ Activated adenylyl cyclase catalyzes step
adenosine triphosphate (ATP) → ↑ ▫ Steroid hormone diffuses across cell
cAMP (second messenger) membrane → binds to cytosolic (or
▫ Intrinsic GTPase activity in G protein nuclear) receptor proteins (monomeric
→ GTP converts → GDP → αs subunit phosphoproteins) → DNA transcription,
inactive again protein synthesis initiated
▪ cAMP acts as second messenger → ▪ Receptor proteins
hormonal signal amplification → final ▫ Part of intracellular receptor gene
physiological reaction superfamily
▪ Intracellular cAMP → protein kinase ▫ Each receptor protein has six domains
A activation → intracellular protein (A–F)
phosphorylation → physiological response ▫ Steroid hormone binds E domain near
▪ Phosphodiesterase degrades intracellular C terminus (central C domain binds to
cAMP → 5’ adenosine monophosphate DNA via zinc fingers)
(inactive metabolite) → hormonal response ▪ Steroid-receptor protein complex →
cessation conformational change in receptor protein
→ activation → enters nucleus
PHOSPHOLIPASE C MECHANISM ▪ Hormone-receptor complex combines
▪ Hormones acting via phospholipase with similar hormone-receptor complex
C mechanism: gonadotropin-releasing (dimerization)
hormone, thyrotropin-releasing hormone, ▪ New complex binds at C-domain via zinc
growth hormone-releasing hormone, fingers to specific DNA sequences (steroid-
angiotensin II, antidiuretic hormone (V1 responsive elements), located in target
receptor), oxytocin genes’ 5’ region
▪ Receptor Gq phospholipase C complex: ▪ DNA-bound active hormone-receptor
embedded in cell membrane complex acts as transcription factor for
▪ In neutral state (no bound hormone) αq specific genes → messenger RNA (mRNA)
subunit binds GDP → inactive Gq protein transcription
▪ Hormone binding → GDP release from ▪ mRNA leaves nucleus → translated into
αq subunit → GTP binding → αq subunit new protein with physiological action
detaches from Gq protein specific to original hormone
▫ αq-GTP complex migrates within cell
membrane → activates phospholipase TYROSINE KINASE MECHANISM
C → DAG, IP3 released from ▪ Hormones acting via tyrosine kinase
phosphatidylinositol 4,5-diphosphate mechanism: insulin, insulin-like growth
(PIP2) factor 1, growth hormone, prolactin
▫ IP3 → Ca2+ intracellular stores released ▪ Primary mechanism: tyrosine kinases
(from endoplasmic/sarcoplasmic phosphorylates protein tyrosine residues
reticulum)
▪ Two main categories
▫ DAG, IP3 → activate protein kinase C →
▫ Receptor tyrosine kinases → intrinsic
protein phosphorylation → physiological
kinase activity within receptor
response
OSMOSIS.ORG 175
▫ Tyrosine kinase–associated receptors → GUANYLYL CYCLASE MECHANISM
no intrinsic kinase activity, associated ▪ Hormones acting via guanylyl cyclase
noncovalently with proteins without mechanism include: atrial natriuretic
kinase activity peptide, nitric oxide (NO)
▪ Extracellular receptor domain binds ligand;
Receptor tyrosine kinases (RTKs)
intracellular domain has guanylyl cyclase
▪ Three structural domains activity
▫ Extracellular binding domain: binds ▪ Ligand binding → guanylyl cyclase
hormone activation → GTP to cGMP conversion
▫ Hydrophobic transmembrane domain: ▪ cGMP activates cGMP-dependent kinase
membrane anchor → protein phosphorylation (proteins
▫ Intracellular domain: tyrosine kinase responsible for physiological response)
activity
▪ Hormone binding → activation Intracellular forms (e.g. NO receptor)
▫ Activation → phosphorylates itself, ▪ Cytosolic guanylyl cyclase mediates signal
other proteins conversion
▪ Monomer-type RTKs ▪ NO synthase cleaves arginine (in vascular
▫ E.g. epidermal growth factor receptors, endothelial cells) → citrulline, NO
nerve growth factor ▪ NO diffuses from endothelial cells into
▫ Hormone binding to extracellular adjacent vascular smooth muscle → binds,
domain → receptor dimerization → activates soluble (cytosolic) guanylyl
intrinsic tyrosine kinase activation → cyclase → GTP conversion → cGMP →
tyrosine moieties phosphorylation of smooth muscle relaxation
itself, other proteins → physiological
response SERINE/THREONINE KINASE
▪ Dimer-type RTKs MECHANISM
▫ E.g. insulin, insulin-like growth factor ▪ Involved in cell proliferation regulation,
receptors apoptosis, cell differentiation, embryonic
▫ Hormone binding → intrinsic tyrosine development
kinase activation → tyrosine moieties ▪ G protein-linked receptors → adenylyl
phosphorylation of itself, other proteins cyclase, phospholipase C-linked
→ physiological response mechanism
▪ Hormone binding → protein kinase
Tyrosine kinase-associated receptors activation → serine, threonine moieties
▪ E.g. growth hormone phosphorylation → physiological response
▪ Three structural domains ▫ Ca2+-calmodulin-dependent protein
▫ Extracellular binding domain: binds kinase (CaMK), mitogen-activated
hormone protein kinases (MAPKs) phosphorylate
▫ Hydrophobic transmembrane domain: serine, threonine in subsequent reaction
membrane anchor cascade
▫ Intracellular domain: no tyrosine kinase
activity; non-covalently associated with
tyrosine kinase (e.g. Janus kinase family)
▫ Hormone binds to extracellular domain
→ receptor dimerization → associated
protein’s tyrosine kinase activated →
tyrosine moieties phosphorylation of
associated protein, hormone receptor,
other proteins
176 OSMOSIS.ORG
CYTOSKELETON &
INTRACELLULAR MOTILITY
osms.it/cytoskeleton-and-intracellular-motility
▪ Non-membrane-bound organelles Microtubules
comprising complex protein filament ▪ Approx. 25nm
network ▪ Dynamic structures made of alternating
▪ Provide structural stability, shape, proteins
organization, intracytoplasmic motility, cell ▫ α- and β-tubulins; polymerize to form
motility microtubules
▪ Stretch across cell
TYPES ▪ Functions
▫ Intracellular transport (e.g. vesicle
Microfilaments
movement, melanin transport within
▪ Actin filaments: approx. 7nm pigmented cells)
▪ Dynamic structures made of actin ▫ Structural integrity
monomers
▫ Cell division (form mitotic spindle)
▫ Arranged in long twisting chain
▫ Cilia, flagella structural components
▪ Form network just below cell membrane
▪ Functions Intermediate filaments
▫ Muscle contraction: slide closer ▪ Approx. 8–10nm
together, further apart ▪ Static structures made of various fibrous
▫ Diapedesis: create pseudopodia for proteins (e.g. keratin, desmin, vimentin)
white blood cells (like neutrophils) depending on cell type
▫ Cell division: allows cell to pinch-off, ▪ Rope-like structure; forms branching
divide into two cells during mitosis network
▫ Microvilli function ▪ Functions
▫ Mechanical cell membrane support ▫ Organelle, cell-cell anchoring
▫ Play key role in providing structural
integrity, cell shape
OSMOSIS.ORG 177
Figure 23.22 Cytoskeleton components and their functions.
178 OSMOSIS.ORG
NUCLEAR STRUCTURE
osms.it/nuclear-structure
NUCLEAR ENVELOPE NUCLEOLUS
▪ Encloses, separates nucleus from ▪ Dense non-membrane-bound structure;
cytoplasm some cells have more than one nucleolus
▪ Composed of selectively permeable ▪ Contains rDNA → transcribed into rRNA
membrane phospholipid bilayer ▪ Assembles ribosomal subunits
Nuclear pores
▪ Form where membranes fuse together at NUCLEOPLASM
various intervals ▪ Protoplasmic material
▪ Each pore lined with nuclear pore complex ▫ Composed of complex water, molecule,
(nucleoporin) to facilitate communication ion mixture
between nucleus, cytoplasm ▪ Contains nucleolus, chromatin
▪ Allow bidirectional macromolecule
movement
CHROMATIN
Outer membrane ▪ Helical fiber
▪ Anchoring proteins that hold nucleus in ▫ Composed of 46 DNA molecules
place within cytoplasm wrapped around proteins (histones)
▪ Continuous with RER ▪ Histones help regulate DNA, gene
expression
Inner membrane ▪ Chromosomes become visible as chromatin
▪ Covered by nuclear lamina fibers become tightly coiled during cellular
▪ Thin filamentous protein network, creates division
web within nucleus; provide support for
chromatin
Figure 23.23 Nuclear envelope components.
OSMOSIS.ORG 179
Nucleosome
▪ Eight histones packed together in four
stacks of two; DNA wraps around them
twice
▪ Strung on strand of DNA-like “beads on
string”
Two chromatin types

▪ Euchromatin: loosely packed DNA, actively
being transcribed into RNA
▪ Heterochromatin: densely packed DNA, Figure 23.24 The nucleoplasm contains the
inactive (not being transcribed) nucleolus and chromatin.
Figure 23.25 In the nucleus, DNA wraps around collections of histone proteins to form
nucleosomes.
Figure 23.26 During cell division, chromosomes make an exact copy of themselves. The two
are connected at the centromere. Each copy is called a sister chromatid. During cell division, the
sister chromatids separate so that there is one copy of their genetic material in each daughter
cell.
180 OSMOSIS.ORG
NOTES
NOTES
CELLULAR PATHOLOGY
NECROSIS & APOPTOSIS

osms.it/necrosis-and-apoptosis
▪ Two main ways by which cells die Fibrinoid necrosis
▪ Occurs in malignant hypertension/vasculitis
NECROSIS ▪ Fibrin/inflammation damages blood vessel
▪ Cell death by injury/disease walls
▫ External triggers (e.g. infection, Also includes oncosis
temperature) ▪ Toxins/ischemia damage mitochondria
▫ Internal triggers (e.g. ischemia) ▪ ATP can no longer be synthesized (e.g.
Coagulative necrosis ionic pumps)
▪ Occurs in hypoxic tissue ▪ Sodium, water flow into cell → swelling
▪ Structural proteins bend out of shape ▪ Cell bursts, triggers inflammatory process
▪ Lysosomal proteins become ineffective at
removing affected proteins APOPTOSIS
▪ Cell dies, some structure remains ▪ Programmed cell death
▪ Based on caspase cascade
Gangrenous necrosis
▫ Pro-caspases cleaved into caspases,
▪ Also occurs in hypoxic tissue
activating caspase 3
▪ Dry gangrene: tissue dries up
▫ Caspase 3 causes activation of cascade
▪ Wet gangrene: if infection, liquefactive of caspase proteins
necrosis also occurs
▫ Cleaves various integral proteins,
Liquefactive necrosis degrading cellular components (e.g.
nucleus, organelles, cytoskeleton)
▪ Hydrolytic enzymes digest dead cells into
creamy substance ▫ Cell loses structure, resulting in blebs,
which break off, undergo phagocytosis
Caseous necrosis
Intrinsic/mitochondrial pathway
▪ Occurs in fungal/mycobacterial infections
▪ Induced by stress (e.g. radiation)
▪ Cell disintegrate (not fully) → cottage
cheese consistency ▪ Process
▫ Intracellular proteins BAX, BAK pierce
Fat necrosis mitochondrial membrane
▪ Occurs in response to fatty organ trauma ▫ This allows SMACS, cytochrome C to
▪ Adipose cell membranes ruptured flow out of mitochondria
▪ Fatty acids combine with calcium, causing ▫ SMACS binds to proteins that otherwise
dystrophic calcifications inhibit apoptosis
▪ Can occur in pancreas as result of ▫ Cytochrome C binds to ATP, APAF-1,
inflammation (AKA pancreatitis) forming apoptosome
▫ Pro-caspase 9 cleaves into caspase 9,
activating caspase 3
OSMOSIS.ORG 181
Figure 24.1 The intrinsic/mitochondrial apoptosis pathway.
182 OSMOSIS.ORG
Chapter 24 Cellular Physiology: Cellular Pathology
Extrinsic/death receptor pathway cell (AKA death domain)

▪ Process ▫ Death domain changes shape, binds
▫ External cell initiates apoptosis by various proteins to form internal
releasing various signaling proteins signalling complex
▫ Signaling proteins bind to death ▫ Pro-caspase 8 cleaves into caspase 8,
receptors on cell membrane activating caspase 3
▫ Cytosolic end of protein dives deep into
Figure 24.2 Two examples of the extrinsic/death receptor pathway. In example 1, a macrophage
recognizes an old cell, a pathogenic cell, or a cell that has completed its task. It releases TNF-α,
which binds to the death receptor tumor necrosis factor receptor 1. In example 2, when a
cytotoxic T cell detects that a cell is expressing foreign antigens, the T cell expresses FAS ligand
on its membrane. FAS ligand binds to the death receptor called FAS receptor. In both cases, the
death domain binds other proteins to form DISC and the caspase cascade leads to apoptosis.
OSMOSIS.ORG 183
ONCOGENES & TUMOR
SUPPRESSOR GENES
osms.it/oncogenes-tumor-suppressor-genes
▪ Code for proteins involved in progression of

cell cycle
▫ Positive regulation: oncogenes stimulate
cell growth, division
▫ Negative regulation: tumor suppressor
genes stop cell cycle progression,
promote apoptosis
Proto-oncogenes
▪ Code for growth factors, growth factor
receptors (e.g. receptor tyrosine kinase) Figure 24.3 Burkitt lymphoma can occur
▪ Signal transduction proteins (e.g. RAS due to translocation between portions
GTPase), transcription factors (e.g. MYC), of chromosomes 8 and 14, resulting in
apoptosis inhibitors (e.g. BCL-2) overexpression of proto-oncogene MYC.
▪ Active when cell needs to grow, divide
▪ Translocations, amplifications, point
mutations turn proto-oncogenes into
oncogenes
▫ Overexpression
▫ E.g. in Burkitt lymphoma, MYC
moved from chromosome 8 to near
IgH promoter on chromosome 14
→ overexpression of cyclins, cyclin-
dependent kinases
▫ E.g. in chronic myeloid leukemia with
Philadelphia chromosome
Tumor suppressor genes Figure 24.4 When a translocation occurs

between the long arms of chromosomes
▪ Code for various tumor suppressors, other
9 and 22, the resulting chromosome 22
protein inhibitors
with part of chromosome 9 is called the
▪ Active throughout cell cycle Philadelphia chromosome. It contains fusion
▪ Various mutations cause uncontrolled cell gene BCR-ABL, whose protein BCR-ABL has
growth, division tyrosine kinase activity (on/off switch for cell
division). Since it’s always on, myeloid cells
keep dividing → leukemia.
184 OSMOSIS.ORG
HYPERPLASIA & HYPERTROPHY

osms.it/hyperplasia-hypertrophy
▪ Two ways by which cells adapt to stress ▪ Pathological processes: e.g. excessive
▪ Often happen together in tissues with stem hormonal stimulation → excessive
cells endometrial growth
▪ Sometimes associated with cancer: cells
mutate → dysplasia
HYPERPLASIA
▪ Organ/tissue cells ↑ in number
▪ Only happens in organs with stem cells that HYPERTROPHY
can differentiate, mature ▪ Organ/tissue cells ↑ in size
Types Causes
▪ Compensatory hyperplasia: in organs that ▪ Physiological processes: e.g. ↑ functional
regenerate (e.g. skin) demand → muscle cells produce more
▪ Hormonal hyperplasia: in organs regulated myofilaments
by hormones (e.g. endocrine) ▪ Pathological processes: e.g. hypertension
→ cardiac myocytes produce more
Causes myofilaments
▪ Physiological processes: e.g. pregnancy →
enlargement of breast
Figure 24.5 An analogy to describe the difference between hyperplasia and hypertrophy.
When the workload is bigger than one lumberjack can handle, she gets stressed. Hyperplasia is
like hiring more lumberjacks to help; hypertrophy is like the one lumberjack getting bigger and
tougher so she can cut down more trees on her own.
OSMOSIS.ORG 185
METAPLASIA & DYSPLASIA
osms.it/metaplasia-and-dysplasia
METAPLASIA
▪ Mature differentiated cell transforms into
new mature cell type
▪ Often caused by environmental stressor
▫ E.g. tobacco smoke: pseudostratified
columnar epithelial cells in airways →
stratified squamous epithelium
▪ Reversible if stimulus reverted
DYSPLASIA
▪ Tissue develops large number of immature
cells
▪ Precancerous state
▪ Four pathological changes to cell
▫ Anisocytosis (AKA unequal cells)
▫ Poikilocytosis (AKA abnormally-shaped
cells)
▫ Hyperchromatism (AKA excessive
pigmentation)
▫ Increases number of mitotic figures
(AKA more mitosis)
Figure 24.6 Example of metaplasia caused

by exposure to tobacco smoke.
ATROPHY, APLASIA, & HYPOPLASIA

osms.it/atrophy-aplasia-hypoplasia
▪ Three ways by which cellular, bodily ▪ May be associated with ↓ cell number (e.g.
growth fails/reverts apoptosis)
▫ E.g. orthopedic casting of an extremity
ATROPHY ▪ May be associated with ↓ cell size
▪ Cell/organ/tissue size reduction ▫ Loss of nerve/hormonal supply
▪ Causes include disuse, denervation, ▫ Ubiquitin proteasome pathway:
ischemia, nutrient starvation, interruption of proteasome destroys polyubiquitinated
endocrine signals filaments/vacuoles destroy ubiquitin-
186 OSMOSIS.ORG
tagged organelles (e.g. muscle atrophy) HYPOPLASIA

▪ Reduced size/abnormal shape of organ/
APLASIA tissue
▪ Failure of organ/tissue to form properly ▪ Growth fails during embryogenesis in some
precursor cells
▪ Growth fails during embryogenesis with no
precursor cells
FREE RADICALS & CELLULAR

INJURY
osms.it/free-radicals-and-cellular-injury
FREE RADICAL DEFENSE AGAINST FREE

▪ Chemical species with unpaired electron in RADICALS
outer orbit
Antioxidants
▫ Physiologic causes: e.g. oxidative
▪ E.g. vitamins A, C, E
phosphorylation, enzyme activity
▪ Eliminate free radicals by donating
▫ Pathologic causes: e.g. ionizing
electrons
radiation, inflammation, metal
interactions, drugs/chemicals) Metal carrier proteins
▪ May result in cellular injury ▪ E.g. transferrin for iron, ceruloplasmin for
copper
FREE RADICAL CELLULAR INJURY ▪ Bind, carry metals to prevent free radical
MECHANISMS production
Lipid peroxidation Enzymes

▪ Free radicals “steal” electron from lipids on ▪ Eliminate various free radical species
cell membrane ▫ Superoxide dismutase → superoxide
▪ Damages cell membrane, entire cell ▫ Catalase → hydrogen peroxide
▫ Glutathione peroxidase → hydroxyl
Protein oxidation
radical
▪ Free radicals oxidize proteins, including
DNA, inside cell
▫ DNA oxidation → mutations → cancer
Figure 24.7 Oxygen is an example of a molecule that can become a free radical.
OSMOSIS.ORG 187
ISCHEMIA
osms.it/ischemia
▪ Reduction in blood flow to organ/tissue → Outcomes
oxygen shortage ▪ Sometimes, congestion → ↑↑ pressure →
▫ Caused by blockage/compression of fluid forced out/edema
blood vessel ▪ ↓↓ oxygen → cell death (e.g. tissue necrosis,
infarction)
Arterial ischemia
▫ Ischemic penumbra: ischemic but still
▪ ↓ arterial blood flow → ↓ oxygen received viable tissue
▪ E.g. atherosclerosis: plaque blocks arteries ▫ Collateralization: growth of collateral
to heart → ischemic heart disease vessels to serve ischemic tissue
Venous ischemia ▪ Time to reperfusion: time taken to re-
▪ ↓ venous blood flow → ↓ drainage → ↓ establish perfusion before cells die
blood flow → ↓ oxygen received ▫ Short → cells survive → reversible
▪ E.g. Budd–Chiari syndrome: clot blocks ▫ Long → cells die → irreversible
hepatic vein → liver ischemia → edema/
hepatomegaly
INFLAMMATION
osms.it/inflammation
▪ Immune response described by four key cells
signs: ▪ Activate cells, sparking inflammatory
▫ Calor: heat response
▫ Dolor: pain ▪ Mast cells contain granules with
▫ Rubor: redness inflammatory mediators
▫ Tumor: swelling ▫ E.g. histamine, serotonin, cytokines, and
▪ May also involve “functio laesa” (AKA loss eicosanoids
of function) ▪ → separate endothelial cells on nearby
▪ Triggered by external, internal factors capillaries
▪ External ▪ Macrophages eat any invading pathogens
▫ Non-microbial: allergens, irritants, toxic ▪ Cytokines cause capillaries to enlarge, ↑
compounds vascular permeability
▫ Microbial: virulence factors, pathogen ▪ Endothelial cells release nitric oxide for
associated molecular patterns (PAMPs) vasodilation, ↑ vascular permeability
▪ Internal ▪ Leukocytes, especially neutrophils,
attracted through capillaries by
▫ Damage associated molecular patterns
chemokines, microbial products; squeeze
(DAMPs)
through membrane
Example process ▫ AKA extravasation
▪ PAMPs, DAMPs recognized by pattern ▪ Leukocyte follows gradient of inflammatory
recognition receptors (PRRs) on immune mediators
188 OSMOSIS.ORG
▪ Neutrophils phagocytose pathogens ▪ Dendritic cells phagocytose pathogens,

immediately before destroying themselves present antigens to T lymphocytes,
▪ Antibodies bound to pathogens activate activating adaptive immune system
complement system ▪ Ends with tissue repair
▫ Aids in opsonization, kills pathogens by
lysis
Figure 24.8 1: DAMPs and PAMPs activate immune cells. 2: Macrophages phagocytose
pathogens at the site of inflammation. Mast cells release inflammatory mediators that widen
the distance between adjacent endothelial cells. 3: Endothelial cells release nitric oxide → ↑
vasodilation, vascular permeability.
Figure 24.9 1: Neutrophils are the first leukocytes recruited during the acute inflammatory
process. They squeeze through the gap between endothelial cells (extravasation) and follow
the gradient of inflammatory mediators to the site of inflammation. 2: Neutrophils quickly
phagocytose pathogens. While this is happening, complement proteins are activated by the
presence of pathogens and help with opsonization (they bind to microbes so leukocytes can
more easily eat them). Some can also kill pathogens by forming a channel in their membranes.
OSMOSIS.ORG 189
NOTES
NOTES
SKIN STRUCTURES
SKIN ANATOMY & PHYSIOLOGY

osms.it/skin-anatomy-and-physiology
▪ Skin is body’s largest organ Stratum basale
▫ Seven percent of total body weight ▪ Innermost layer: single columnar stem cell
▪ Comprises integumentary system, layer; dividing, producing keratinocytes
appendages (hair, nails, oil, sweat glands) ▫ Keratinocytes contain cholesterol
▫ Protects body (infection, abrasion, precursors activated by UVB light →
dehydration, etc) vitamin D (regulates calcium absorption)
▫ Regulates body temperature ▪ Also contains melanocytes (secrete
▫ Detects pain, sensation, pressure melanin, giving skin its color)
▫ Essential for vitamin D production ▫ UVB light stimulates melanin secretion
→ placed into melanosomes, moved up
▪ Three layer division
by keratinocytes → scatters UVB light
▫ Epidermis, dermis, hypodermis → natural sunscreen (prevents skin
cancer from excessive UVB light)
Stratum spinosum
▪ Second layer: comprises 8–10 keratinocyte
cell layers which can no longer divide
▫ Proteins on keratinocytes help them
adhere together
▫ Dendritic cells seek out invading
microbes
Stratum granulosum
▪ Third layer: comprises 3–5 keratinocyte cell
layers undergoing keratinization (flatten
Figure 25.1 The three layers of the skin, from out, die) → epidermal skin barrier formed
superficial to deep, include: the epidermis, ▫ Keratohyalin granules in keratinocytes
dermis, and hypodermis. contain keratin precursors which
aggregate, cross-link → keratin bundles
▫ Lamellar granules in keratinocytes
EPIDERMIS contain glycolipids (secreted to cell
▪ Epidermis surface, glues cells together)
▫ Stratified squamous epithelium
Stratum lucidum
▫ Thin outermost layer
▪ Fourth layer: comprises 2–3 dead
▪ Multiple layers of developing keratinocytes keratinocyte cell layers that have secreted
(contain keratin) most of their lamellar granules
▫ Make, secrete glycolipids; prevent water ▫ Only found in thick skin (e.g. palms,
seeping into/out of body soles of feet)
190 OSMOSIS.ORG
Chapter 25 Dermatology: Skin Structures
Stratum corneum ▫ Blood vessels dilate when hot (blood

▪ Uppermost layer: comprises 20–30 dead moves closer to surface → allows heat
keratinocyte cell layers glued together with loss)/contract when cold (blood moves
glycolipids away from surface → prevents heat
▫ Dead keratinocytes secrete defensins to loss)
fight pathogens ▫ Sweat glands ↑ secretion when hot (↑
▫ Cells from stratum lucidum push up → heat to evaporate sweat)/↓ when cold (↓
cells from this layer shed → skin flakes/ heat to evaporate sweat)
dandruff
Figure 25.3 The papillary layer of the dermis

contains multiple types of nerve endings.
Figure 25.2 The five layers of the epidermis.
Stratum basale is the deepest layer and
stratum corneum is the most superficial.
DERMIS
▪ Dermis
▫ Central layer
▫ Two layer division (papillary layer;
deeper, thicker reticular layer)
Papillary layer
▪ Fibroblasts (producing collagen) arranged Figure 25.4 Contents of the reticular layer of
in papillae the dermis.
▪ Contains blood vessels, macrophages,
nerve endings (e.g. Meissner’s corpuscles
for fine touch, free nerve endings for pain) HYPODERMIS
▪ Responsible for fingerprints (↑ gripping, ▪ Hypodermis (subcutaneous tissue) inner
sensing abilities) layer
▫ Contains adipocytes (store fat),
Reticular layer
fibroblasts, macrophages, blood vessels,
▪ Fibroblasts (produces elastin for flexibility) nerves, lymphatics
▪ Contains oil, sweat glands; lymphatic, ▫ Insulates deeper tissues; provides
blood vessels; hair follicles; macrophages; padding; anchors skin to underlying
nerves (e.g. Pacinian corpuscle for pressure, muscle with connective tissue (e.g.
vibration) collagen)
▪ Collagen packed tightly → ↑ support
▪ Regulates temperature with blood vessels,
sweat glands
OSMOSIS.ORG 191
HAIR, SKIN, & NAILS
osms.it/hair-skin-and-nails
▪ Skin appendages include hair, nails, skin arrector pili muscles, apocrine glands,
glands (oil/sebaceous, sweat/sudoriferous) nerve receptors
▫ Regulate body temperature; ▪ Composition: shaft, root, bulb
environmental protection ▫ Hair matrix: active hair growth
▫ Originate in dermis site, found inside bulb; contains
▪ Hair, nails comprised of long, filamentous keratinocytes, melanocytes; blood
protein (keratin) supplied by papilla
▫ Keratin: produced by keratinocytes ▪ Keratinocytes die, flatten out → hard
during keratinization (cells rapidly keratin fills up cell → gradually get pushed
replicate, die) up follicle forming hair
▫ Soft keratin (produced by skin); hard ▫ Hair growth: includes growth, resting
keratin (produced by hair, nails) phases
▫ Keratinocytes in bulb replicate set
number of times → follicle eventually
HAIR stops producing hair/produce vellus
▪ Includes vellus hairs (short, thin); terminal hairs instead (genetically determined) →
hairs (more visible, growth starts at baldness
puberty)
▪ Melanocytes produce melanin (protein
▪ Found everywhere pigments that give hair color)
▫ Exceptions: palms, soles of feet, lips ▫ Melanocytes move melanin into
▪ Hair strands sit in follicle; epidermal tissue melanosomes → taken up by
dips into dermis keratinocytes
▫ Associated with sebaceous glands,
Figure 25.5 Composition of hair and associated structures.
192 OSMOSIS.ORG
▫ ↑ age → ↓ melanin → faded, white hair SUDORIFEROUS GLANDS

▪ Nerve receptors around bulb stimulated ▪ AKA sweat glands
when hair shaft moves
Eccrine (merocrine) glands
▪ Arrector pili muscle contracts, pulls hair (e.g.
cold weather/frightened) → goosebumps ▪ Found everywhere
▫ Exceptions: lips, ear canal, clitoris, glans
of penis
NAILS
▪ Coil-shaped structure; in dermis; duct
▪ Grow from proximal to distal fingertips/toes opens into pore on skin surface
▫ Surrounded on either side by nail folds ▪ Sweat: hypotonic (mostly water,
▫ Closed off proximally by eponychium → electrolytes); dermcidin (destroys bacteria);
forms cuticle (dead skin keratinocytes cools body (evaporation)
that cover junction between nail, skin) ▪ Sympathetic nervous system activation
▪ Nail matrix composition: lunula, nail plate during ↑ cardiovascular activity, fight-or-
▫ Lunula: white, crescent-shaped part of flight response, fear/anxiety
nail near eponychium
▫ Free edge: nail plate portion hanging Apocrine glands
over skin ▪ Found in armpits, genitals
▪ Modified keratinocytes in matrix form plate ▫ Become active during puberty
by keratinization (similar to hair) ▪ Similar to eccrine glands
▪ Nails grow continually through life (unlike ▫ Bigger, fewer; produce secretions with ↑
hair) lipids, proteins
▫ Secretions metabolized by bacteria →
body odor
▪ Several modified apocrine gland types
▫ Ceruminous glands: in ear; produce
cerumen; protects eardrum (with ear
canal hairs)
▫ Mammary glands: in breasts; produce
milk
Figure 25.6 Superior view and cross section

of a finger illustrating components of the nail.
SEBACEOUS GLANDS
▪ Secrete sebum (softens hair shaft, prevents
moisture-loss, deters pathogens) onto hair
follicles/through pores → skin surface
▪ During puberty: ↑ androgen hormones →
↑ sebum production → blocks pores, plugs Figure 25.7 The two types of sweat glands
hair follicles → enclosures allow infection (sudoriferous glands).
development (e.g. acne, folliculitis)
OSMOSIS.ORG 193
WOUND HEALING
osms.it/wound-healing
▪ Damaged tissue repair process Penetrating trauma wound healing
▫ Acute wounds heal quickly (days– ▪ Penetrating trauma wound healing steps
weeks) (e.g. cutting finger → damaged epidermis,
▫ Chronic wounds heal slowly (months) dermis, interstitial space)
▪ Hemostasis (first step)
Regenerative tissue capacity ▫ Blood vessels constrict → platelets
▪ Classification: labile, stable, permanent adhere to site → forms platelet plug →
▪ Labile tissues (e.g. skin, connective tissue, fibrin mesh reinforces platelet plug →
intestines) forms blood clot
▫ Heal well: stem cells constantly divide ▪ Inflammation (second step)
→ rapid, effective healing ▫ Damaged cells release chemokines,
▪ Stable tissues (e.g. liver, endocrine glands, cytokines → neutrophils, macrophages
proximal kidney tubules) recruited; blood vessels dilate →
▫ Heal slowly: mature differentiated cells immune cells clear debris, digest dead/
divide/regenerate by hyperplasia damaged cells, destroy microbes →
▪ Permanent tissues (e.g. skeletal muscle, blood clot, dead macrophages combine,
cartilage, neurons) form scab
▫ Heal poorly: lack of stem cells, no ▪ Epithelization/migration (third step)
hyperplasia → replaced by scar tissue ▫ Basal cells (epidermal stem cells)
(fibrosis) → function loss proliferate, replace lost/damaged cells →
rejuvenated epidermal layer (approx. 48
Open wounds hours)
▪ Open wounds healed by primary, ▪ Fibroplasia (fourth step)
secondary, tertiary intention ▫ Fibroblasts in dermis proliferate,
▪ Primary intention (most surgical wounds) secrete collagen (assemble → form
▫ Wound edges fuse (e.g. stitching/ collagen fibrils → collaged bundles)
gluing) → stem cells (e.g. epidermis) → blood vessel growth stimulated
approximate, regenerate damaged (angiogenesis); fibroblasts also produce
tissue (minimal scarring) glycoproteins, sugars → create
▪ Secondary intention granulation tissue in dermal layer
▫ Wound edges too far apart (e.g. ▪ Maturation (fifth step)
pressure ulcers, tooth extraction, severe ▫ Collagen cross-linking: covalent bonds
burns) → stem cells do not approximate form between collagen bundles,
→ wound replaced by connective tissue improving tensile strength
growing from base upwards (slower ▫ Collagen remodeling: fibroblasts
healing; more scar tissue) degrade subpar collagen
▪ Tertiary intention (delayed closure) ▫ Contraction: myofibroblasts produce
▫ Wound cleaned, debrided → contractile proteins, pulling wound’s
purposefully left open (↓ bacterial edges together
contamination likelihood) → closed ▫ Repigmentation: melanocytes
by primary intention/left open for proliferating, restoring color to damaged
secondary intention skin
194 OSMOSIS.ORG
Chronic wounds
▪ Healing prevention factors → chronic
wounds
▫ Narrowed capillaries: prolonged
compression/disease (e.g. diabetes,
atherosclerosis) → ↓ blood flow →
damaged tissue cannot be reached
by immune cells, insufficient oxygen/
nutrients → tissue necrosis
▫ Infection: pathogens compete for
oxygen; cause ongoing damage,
inflammation
▫ Edema: disrupts fibroblast activity,
collagen deposition, collage cross linking
Figure 25.8 The five steps of penetrating

trauma wound healing.
OSMOSIS.ORG 195
NOTES
NOTES
EARLY WEEKS
HUMAN DEVELOPMENT DAYS 1–4

osms.it/human_development_days_1-4
FERTILIZATION ▪ Ovulation → spermatozoa driven by
▪ Oocyte, spermatozoa fuse → zygote chemoattractants (produced by cumulus
▫ Oocyte viable 12–24 hours after cells of oocytes) to ampulla of uterine tube
ovulation; sperm cells retain fertilizing
Two required processes
power 24–48 hours after ejaculation
▪ Capacitation: epithelial interactions
▫ Coitus must occur no more than two
between sperm, uterine wall
days before/24 hours after ovulation for
fertilization ▫ Glycoprotein coat, seminal plasma
proteins covering acrosomal region
▪ Ejaculation → 200 million spermatozoa
removed → easier enzyme release →
enter vaginal canal → alkaline seminal fluid
acrosomal reaction
neutralizes acidic vaginal fluid
▪ Acrosomal reaction: after binding to zona
▪ Only 1% enter cervix → travel through
pellucida
uterus → ampullary region of uterine tube
(most likely place for fertilization) ▫ Release of enzymes (e.g. acrosin,
hyaluronidase) needed to penetrate
▪ Cervix → oviduct
zona pellucida
▫ 30 minutes to 6 day journey
Figure 26.1 Sperm pathway through the uterus.
196 OSMOSIS.ORG
Chapter 26 Embryology: Early Weeks
PHASES OF FERTILIZATION ZYGOTE TO BLASTOCYST

IMPLANTATION
Phase I: penetration of corona radiata
▪ Capacitated spermatozoa allowed to pass Cleavage
through corona radiata ▪ Series of fast mitotic divisions of zygote →
increase number of cells, decrease size
Phase II: penetration of zona pellucida, ▪ 36 hours after fertilization → first cleavage
sperm binding division → two cells (blastomeres)
▪ Zona pellucida: glycoprotein layer ▫ Second division → four blastomeres;
surrounding oocyte; AKA “jelly coat” third division → eight blastomeres; etc.
▫ Facilitates binding of sperm cell, induces ▪ After third cleavage, blastomeres form
acrosomal reaction mediated by ligand compact ball of cells connected by tight
zona pellucida sperm-binding protein 3 junctions (compaction)
(ZP3)
▪ Three days after fertilization, cells
▪ Approx. 500 spermatozoa arrive at this of compacted embryo divide again
layer → mulberry-shaped 16-cell morula
▪ Sperm-binding initiates release of (composed of two zones: inner, outer cell
acrosin (hydrolytic enzyme) → sperm cell mass)
penetrates zona pellucida → sperm makes ▪ Four to five days after fertilization, embryo
contact with oocyte → cortical reaction consists of approx. 100 cells
(release of lysosomal enzymes from cortical
▪ Fluid accumulates within internal cavity
granules of oocyte) → cortical granules
initiate zona reaction, prevent further (blastocoel) → blastocyst
sperm penetration (polyspermy) by forming ▪ Blastocyst: fluid-filled hollow cell, two
protective hyaline layer, inactivate receptor zones
sites on zona pellucida ▫ Trophoblast: single layer of large
▫ Cortical reaction also activates oocyte to flattened cells, stemming from morula’s
prepare for second meiotic division outer cell mass; gives rise to placenta
▫ Embryoblast: 20–30 pluripotent cells
Phase III: fusion of oocyte, sperm cell located on one side, stemming from
▪ Interactions between integrins, ligands → inner cell mass; gives rise to embryo
adhesion of sperm, oocyte
▫ Fusion of sperm, egg plasma
membranes
▪ Secondary oocyte completes meiosis II
→ forms female pronucleus, second polar
body
▪ Head, tail of spermatozoa enters oocyte →
travels to female pronucleus (containing 23
chromosomes) using tail, energy generated
by mitochondria
▪ Tail, mitochondria detach → sperm nucleus
becomes male pronucleus
▪ Male, female pronuclei move toward each
other → merge into single nucleus → cell
becomes diploid (zygote contains maternal,
paternal genetic information)
▪ Preparation for mitotic division
OSMOSIS.ORG 197
Figure 26.2 Phases of fertilization.
Phase I: sperm penetrates corona radiata.
Phase II: penetration of zona pellucida, sperm binding.
Phase III: fusion of sperm, oocyte; pronuclei fuse to form diploid zygote cell.
198 OSMOSIS.ORG
Figure 26.3 Process of going from zygote to blastocyst.
HUMAN DEVELOPMENT DAYS 4–7

osms.it/human_development_days_4-7
DAY 7 ▪ Uterus at implantation in secretory phase
▫ High progesterone released from corpus
Implantation
luteum develops endometrium for
▪ Trophoblast binds to uterine wall with implantation
L-selectin, integrin receptors
▫ Blastocyst implants into decidua basalis,
▫ Penetrates between epithelial cells along superior posterior wall of uterus
Figure 26.4 Implantation, syncytiotrophoblast proliferation, and development of spiral arteries

under the influence of progesterone secreted by the corpus luteum.
OSMOSIS.ORG 199
HUMAN DEVELOPMENT WEEK 2
osms.it/human-development-week-2
DAY 8 DAY 12
▪ Progesterone levels continue to rise →
Trophoblast
decidua undergoes decidual reaction
▪ Proliferates, forms two layers
▫ Decidual cells enlarge, become coated in
▪ Cytotrophoblast (cellular trophoblast): sugar-rich fluid (helps sustain embryo)
inner layer of mononucleated cells
▫ Blastocyst embeds in endometrial
▫ Produces primary chorionic villi, stroma
protrudes into syncytiotrophoblast
▫ Lacunae form within
▪ Syncytiotrophoblast: outer multinucleated syncytiotrophoblast (erodes endometrial
mass of cells (without distinct cell sinusoids)
boundaries)
▫ Lacunae fuse with sinusoids → fill
▫ Invades decidua basalis with finger-like with maternal blood → uteroplacental
processes; makes enzymes that erode circulation established
uterine cells; blastocyst burrows into
decidua basalis surrounded by pool
of blood leaked from degraded blood DAY 13
vessels ▪ Secondary yolk sac forms within
▫ Human chorionic gonadotropin (hCG) exocoelomic cavity
maintains viability of corpus luteum → ▪ Hypoblast cells: differentiate into
secretes estrogen, progesterone until extraembryonic mesoderm cells outside
week eight (hCG: basis for pregnancy embryo
tests) ▫ Mesoderm cells: line inside of
cytotrophoblast, syncytiotrophoblast;
Embryoblast line chorionic cavity
▪ Differentiates into two layers, forms flat ▪ Epiblast: gives rise to embryo’s germ layers
disc (endoderm, mesoderm, ectoderm)
▪ Hypoblast: small cuboidal cells adjacent to ▪ Amniotic cavity develops above bilaminar
blastocyst → yolk sac disk, becomes lined with epiblast cells
▪ Epiblast: columnar cells
▫ Cavity forms inside → amniotic cavity
▫ Lined with amnioblasts
DAY 9
▪ Lacunar stage of trophoblast development
▫ Vacuoles appear in syncytium →
vacuoles fuse → form large empty
spaces (lacunae)
▪ At abembryonic pole, flattened cells (from
hypoblast) form exocoelomic (Hauser)
membrane → line inner surface of
cytotrophoblast
▫ Hauser membrane, hypoblast line
exocoelomic cavity (primitive yolk sac)
200 OSMOSIS.ORG
Figure 26.5 Summary of the growth that occurs during the second week of development.
HUMAN DEVELOPMENT WEEK 3

osms.it/human-development-week-3
DAY 14 (invagination)
▪ Syncytiotrophoblast cells form little ▪ After invagination, cells differentiate
protrusions called primary villi into three new layers of embryonic disc
▪ Villi form around fetus; lacunae form (trilaminar disc)
between villi ▪ Cells of trilaminar disc multipotent (ability to
▪ Arteries, veins merge within lacunae → differentiate into many tissues, organs)
form large pool of blood ( junctional zone) ▫ Some epiblast cells displace ventral
▪ Villi submerged within junctional zone hypoblast layer, form endoderm
▫ Invaginated epiblast cells between
Gastrulation newly formed endoderm, epiblast →
▪ Major event, establishes three germ layers mesoderm layer
▪ Begins with formation of primitive groove ▫ Rest of epiblast forms ectoderm layer
(narrow depression into center of epiblast
layer)
DAY 15
▫ Starts at caudal end, grows towards
cranial end → cranial-caudal axis ▪ Two areas of ectoderm layer (cranial, caudal
region) push ventrally, fuse with endoderm
▫ Groove forms on dorsal side of embryo
(exclude mesoderm layer) → form two
→ dorsal-ventral axis
bilaminar regions in otherwise trilaminar
▫ Two sides of groove: left, right side of disc
body (bilateral symmetry)
▫ Cranial bilaminar region develops
▪ Primitive node forms at cephalic end of into oropharyngeal membrane →
primitive groove disintegrates in fourth week to form
▫ Contains primitive pit, surrounded by mouth opening
slightly elevated area of ectoderm ▫ Caudal bilaminar region develops into
▪ Primitive groove, node, pit → form primitive cloacal membrane → disintegrates in
streak seventh week to form anal opening,
▪ Epiblast cells migrate towards primitive genitourinary tracts
groove → move to bottom, slide under
OSMOSIS.ORG 201
Figure 26.6 Day 14: formation of the primitive streak and trilaminar disc.
DAY 17 penetrate primary villi → grow toward

▪ Group of mesoderm cells form solid rod decidua
(notochord) ▫ Tertiary villi: form when mesodermal
▫ Notochord: transient embryonic cells differentiate into small blood
structure (nucleus pulposus of vessels → form villus capillary system →
intervertebral disc: remnant in adult life) fetal contribution to placenta
▫ Solid structure → helps influence how
embryo folds
▫ Secretes protein called Sonic HedgeHog
(SHH) → guides tissue differentiation
DAY 20
▪ Mesoderm cells around notochord
differentiate into three specialized types of
cells
▫ Paraxial mesoderm, intermediate
mesoderm, lateral plate mesoderm;
make different tissues, organs
▪ Notochord starts process called neurulation
Figure 26.7 Day 15: bilaminar regions of
→ stimulates cells of ectoderm to form
trilaminar disc.
neural plate
▪ Neural plate folds, forms neural groove with
edges called neural folds
▪ Neural plate continues to grow, neural folds
come together, pinch off from surface of
ectoderm to form neural tube between
ectoderm, mesoderm
▪ Trophoblast continues to develop:
vasculogenesis
▫ Primary villi: made up of
cytotrophoblastic core covered by
syncytial layer
▫ Secondary villi: form when Figure 26.8 Day 17: formation of notochord
extraembryonic somatic mesoderm cells from mesoderm cells.
202 OSMOSIS.ORG
Figure 26.9 Day 20: differentiation of mesoderm near neural plate into paraxial, intermediate,
and lateral plate mesoderm; formation of neural tube in process called neurulation.
Figure 26.10 During week 3, extraembryonic mesoderm cells migrate into the primary villi,
forming secondary villi. The secondary villi differentiate into fetal vessels known as the villous
capillary system, which is the fetal contribution to the placenta.
OSMOSIS.ORG 203
NOTES
NOTES
GERM LAYERS
ECTODERM
osms.it/ectoderm
▪ Beginning of week 3 ▪ Surface ectoderm forms ectodermal
▫ Ectoderm layer broader in cephalic thickenings, otic, lens placodes, near cranial
region than in caudal region end of ectoderm
▪ Notochord initiates neurulation, forming ▫ Otic placodes form otic vesicles →
neural tube between mesoderm, ectoderm cochlea, inner ear
▪ On dorsal side of neural tube as neural ▫ Lens placodes → lens, cornea of eyes
folds fuse, neural crest cells migrate ▪ Other ectoderm cells form sensory
▫ Form new cell layer between ectoderm, epithelium (e.g. lining of nose, mouth)
neural tube ▪ Other ectoderm cells form epidermis layer
▫ As neural crest cells migrate throughout of fetal skin, associated structures (e.g.
fetus, they give rise to tissues including hair, nail, sweat glands, pituitary gland,
peripheral nervous system (sensory mammary glands)
ganglia, sympathetic neurons, Schwann ▪ Ectoderm, parietal layer of mesoderm
cells), skin melanocytes, part of facial fold around with two sides meeting up in
bones, adrenal gland chromaffin cells, midline
thyroid parafollicular (C) cells ▫ Forms anterior body wall, everywhere
▪ Neural tube has an opening on each end except middle where yolk sac still
▫ Cranial neuropore (top): closes around pouches out → gut tube formed inside
day 25 embryo’s body (tube inside of tube)
▫ Caudal neuropore (bottom): closes
around day 28
Figure 27.1 Development of neural tube and neural crest cells.
204 OSMOSIS.ORG
Chapter 27 Embryology: Germ Layers
Figure 27.2 The neural tube initially has Figure 27.3 The surface ectoderm forms
openings at each end, called cranial and thickenings—the lens and otic placodes—
caudal neuropores. Both pores close by that become eye and ear structures,
around day 28. respectively.
MESODERM
osms.it/mesoderm
▪ Day 20 Paraxial mesoderm
▫ Mesoderm cells around notochord ▪ Starts to segment into paired tissue
differentiate into three specialized types blocks called somites, one of each sitting
of cells that will form different tissues, alongside notochord, neural tube above it
organs ▫ About three somite pairs form per day in
▫ Paraxial mesoderm, intermediate craniocaudal direction
mesoderm, lateral plate mesoderm ▫ By week five, there are 42–44 pairs of
somites
▫ Number of somites can be used to
determine embryo age
▪ Somites divide into three regions
▫ Sclerotome: gives rise to bone, cartilage
▫ Myotome: gives rise to muscles
▫ Dermatome: gives rise to dermis skin
layer
Intermediate mesoderm
▪ Gives rise to urogenital structures (e.g.
adrenal cortex, kidneys, ovaries, testes)
Lateral plate mesoderm

▪ Gives rise to serous membranes, soft
tissues of arms, legs, muscular gut wall,
Figure 27.4 The three types of mesoderm
heart, circulatory system
that develop around day 20.
OSMOSIS.ORG 205
▪ Serous membranes ▫ Two layers of visceral membrane come
▫ Become visceral, parietal serous together to form mesentery (suspends
membranes gut tube in abdominal cavity)
Figure 27.5 The paraxial mesoderm segments into somites. The somites then divide into three
regions which develop into distinct body structures.
Figure 27.6 Membranes of the lateral mesoderm and their derivatives.
ENDODERM
osms.it/endoderm
▪ Day 15
▫ Cranial, caudal ectoderm regions push
ventrally, fuse with endoderm layer
▫ Two bilaminar regions formed
▫ Cranial bilaminar region →
oropharyngeal membrane → mouth
▫ Caudal bilaminar region → cloacal
membrane → opening of anus,
genitourinary tracts Figure 27.7 Cranial and caudal bilaminar
regions of the embryo (lateral view).
206 OSMOSIS.ORG
Chapter 27 Embryology: Germ Layers
▪ Week 4 Foregut
▫ Embryo folds in two directions ▪ Around week 4
▫ Longitudinal plane: cranial, caudal folds; ▫ Once oropharyngeal membrane
embryo begins to curl into fetal position; breaks down, foregut (including
folding shapes part of yolk sack into gut pharynx) connects to primitive mouth
tube with rest remaining connected in (stomodeum)
middle via vitelline duct ▪ Around week 5
▫ Transversal plane: lateral plates of ▫ Foregut gives rise to trachea, lungs
mesoderm split into parietal (somatic)
mesoderm layer, visceral (splanchnic) Midgut
mesoderm layer; parietal mesoderm ▪ Remains connected to yolk sac which sits
follows ectoderm, forms chest wall, outside body via vitelline duct (yolk stalk)
abdominal body wall; visceral layer of which passes through umbilical ring
mesoderm follows endoderm, forms gut ▪ Over time vitelline duct gets thinner,
tube collapses; in some people it remains as
▪ Endoderm becomes epithelial cell lining Meckel’s diverticulum
of gastrointestinal tract, while mesoderm
becomes muscular wall Hindgut
▪ In addition to gastrointestinal, respiratory ▪ Around week 7
tract epithelium ▫ Once cloacal membrane breaks down,
▫ Endoderm gives rise to tonsils, thyroid, upper two thirds of anal canal (derived
parathyroid glands, thymus, part of liver, from endoderm) meet up with lower one
gallbladder, pancreas third of anal canal, called proctodeum
▫ Endoderm cells form parts of ear, (derived from ectoderm)
epithelial lining of urethra, urinary ▫ Pectinate line: in adults, the line where
bladder the upper two thirds (endoderm) and
lower third (ectoderm) of the anal canal
meet up
GUT TUBE STRUCTURE
▪ Gut tube divided into foregut, midgut,
hindgut
Figure 27.8 Week 4: the embryo folds in the longitudinal and transverse planes.
OSMOSIS.ORG 207
Figure 27.9 Locations and derivatives of the foregut, midgut, and hindgut (lateral view).
208 OSMOSIS.ORG
NOTES
NOTES
EARLY STRUCTURES
DEVELOPMENT OF THE
DIGESTIVE SYSTEM & BODY
CAVITIES
osms.it/digestive-system-and-body-cavities-development
▪ Endoderm forms gut tube epithelium ▫ Parietal mesoderm → gives rise to

▪ The rest derives from mesoderm serous membrane that lines abdominal,
thoracic cavity (parietal pleural,
▫ Around week 3 lateral mesoderm
peritoneal, pericardial membrane), soft
splits into parietal (somatic) mesoderm
tissues of arms, legs
→ adheres to ectoderm; visceral
(splanchnic mesoderm) → adheres to ▫ Visceral mesoderm → gives rise to
endoderm serous membrane that lines various
organs (visceral pleural, peritoneal,
▫ Space between the split is called
pericardial membrane), muscular wall of
intraembryonic coelom/intraembryonic
gut, heart, circulatory system
cavity
▫ Two visceral peritoneal membranes
▫ Eventually becomes thoracic, abdominal
come together, form mesentery
cavity
(suspends gut tube in abdominal cavity)
Figure 28.1 During week 3, lateral mesoderm splits into parietal and visceral mesoderm. They
give rise to serous membranes that cover various body parts.
OSMOSIS.ORG 209
▪ During week 4 embryo begins to curl into middle via vitelline duct
fetal position ▫ Combined parietal mesoderm, ectoderm
▫ Combined visceral mesoderm, folds down with amnion forming lateral
endoderm layer folds rostrally, caudally body folds
→ shapes part of yolk sac forming ▫ Eventually merge, become anterior body
primitive gut tube wall of embryo
▫ The rest of yolk sac is connected in
Figure 28.2 Appearance of the embryo in week 4 in caudal (A) and mid- (B) sections.
DEVELOPMENT OF BODY CAVITIES cavities, one pericardial cavity

▪ Around day 22, thick plate of visceral ▪ In week 7, pleuropericardial folds extend
mesoderm called septum transversum ventrally from body wall, fuse with septum
forms just cranial to vitelline duct transversum
▫ Divides primitive body cavity into ▫ Forms pleuroperitoneal membrane,
thoracic cavity, abdominal cavities which seals thoracic cavity from
▪ Around week 5, two tissue flaps called the peritoneal cavity
pleuropericardial folds, grow out of lateral ▫ Pericardial, pleural cavities in thorax,
body wall, fuse together peritoneal cavity in abdomen
▫ Divides thoracic cavity into two pleural
210 OSMOSIS.ORG
Chapter 28 Embryology: Early Structures
Figure 28.3 Development of body cavities on day 22 and during weeks 5 and 7.
OSMOSIS.ORG 211
DEVELOPMENT OF THE pairs of somites penetrate pleuroperitoneal
DIAPHRAGM membranes
▪ Develops from four components ▫ Form muscular portion of diaphragm
▫ Septum transversum, pleuroperitoneal ▪ Septum transversum forms tendinous
membranes, dorsal mesentery of portion of diaphragm
esophagus, from somites at levels C3– ▪ Mesoderm of lumbar region gives rise to
C5 two crura of diaphragm
▪ Mesodermal cells from third, fourth, fifth
Figure 28.4 Location of the developed diaphragm.
THE HEDGEHOG SIGNALING

PATHWAY
osms.it/hedgehog-signaling-pathway
▪ Pathway which plays key role in structuring
general body shape
▪ Mediated by sonic hedgehog proteins
secreted by notochord → proteins diffuse
through interstitial fluids
▪ Functions of sonic hedgehog protein
▫ Binds to patched receptor on embryonic
cell membrane
▫ Patched receptor inhibits cell
differentiation; sonic hedgehog protein Figure 28.5 The notochord is a solid line
inhibits patched of mesoderm at the center of the embryo. It
▫ Inhibits the inhibitor → facilitates cell secretes different kinds of hedgehog proteins.
differentiation
212 OSMOSIS.ORG
▫ Sonic hedgehog proteins control gene ▪ Homeobox gene products are transcription
expression → gene expression depends factors called Hox proteins
on amount of sonic hedgehog protein ▪ Homeobox genes arranged into four
reaching embryonic cells, duration of clusters on four different chromosomes
exposure ▫ HOXA, HOXB, HOXC, HOXD
▫ Notochord secretes different kinds of ▪ Genes toward 3’ end of chromosomes
hedgehog proteins control cranial structure development,
▫ Embryonic cells are exposed to different genes toward 5’ end control caudal
combinations of proteins that helps structure development
distinguish their position relative to each ▪ Highly conserved genes across vast
other (awareness in space), their course evolutionary distances
of differentiation
▫ Demonstrated by the fact that a fly can
function perfectly well with chicken Hox
REGULATION BY HOMEOBOX GENES protein its place
▪ Homeobox genes code for transcription ▪ Mutations in Hox genes can result in body
factors that activate gene cascades which parts, limbs in the wrong place along the
regulate segmentation, craniocaudal body e.g. extra fingers/toes
patterning
Figure 28.6 SHH and other notochord proteins diffuse through the embryo, creating a
concentration gradient that tells embryonic cells where they are located in three dimensional
space. The unique combinations of proteins determine into which tissues the cells differentiate.
OSMOSIS.ORG 213
DEVELOPMENT OF THE
PLACENTA
osms.it/placenta-development
▪ The placenta is co-created by fetus, mother of decidua basalis tissue that maternal
▪ Around day 14, syncytiotrophoblast cells spiral arteries, veins pass through to get
form little protrusions called primary villi to junctional zone
▫ Villi form all the way around fetus ▪ Fetal contribution: derived from chorionic
▪ Cells clear out from between primary villi plate (trophoblast, extraembryonic
mesoderm)
▫ Leave behind empty spaces called
lacunae ▫ Chorionic frondosum: numerous villi
that emerge from chorionic plate
▪ Maternal arteries. veins grow into decidua
basalis, merge with lacunae ▫ Junctional zone between basal plate,
chorionic plate
▫ Maternal arteries fill lacunae with
oxygenated blood ▪ Space forms around fetus called chorionic
cavity
▫ Maternal veins pick up deoxygenated
blood ▫ Contains amniotic cavity, yolk sac,
embryo
▫ Junctional zone formed as arteries, veins
continue to merge ▫ Chorion laeve: chorionic cavity
wall where syncytiotrophoblast villi
▪ Formation of feto-placental circulation
regressed
begins on day 9
▫ Outside of chorion laeve, thin layer of
▫ Day 9, lacunar stage: vacuoles form
decidua (decidua capsularis)
lacunae in syncytiotrophoblast;
endometrial sinusoids start to grow into ▪ On ultrasound, chorionic cavity shows up
decidua basalis as relatively large, dark space
▫ Day 12: sinusoids merge with syncytial ▫ Used to identify pregnancy even before
lacunae, filling them with blood fetus can be seen
▫ Day 14: cells of cytotrophoblast ▪ During fourth, fifth months of development,
penetrate syncytiotrophoblast, form walls called decidual septa form
primary villi ▫ Divide placenta into 15–20 different
▫ Day 16: extraembryonic mesoderm regions called cotyledons
cells penetrate into primary villi forming ▪ Each cotyledon contains about 100
secondary villi, later differentiate into spiral arteries providing steady supply of
small blood vessels (tertiary villi) oxygenated blood
▪ Around day 17, feto-placental circulation ▪ Oxygen, glucose, molecules like
established immunoglobulins, hormones, certain toxins
▫ Fetal mesoderm cells enter primary villi are able to move across into fetal capillaries
→ form fetal arteries, capillaries, veins ▫ Carbon dioxide moves out of fetal
within each villi capillaries, enters blood in junctional
▫ Villi capillaries connect to umbilical cord zone
blood vessels → links maternal, fetal ▪ Placenta covers about 15–30% of uterine
circulation wall at any given time during development
▪ Placenta grows, thickens
PLACENTAL STRUCTURE ▫ At full term, is 20cm/7.9in across (size
of frisbee)
▪ Maternal contribution: derived from uterine
endometrium ▪ During third stage of labor placenta is
expelled from body as afterbirth
▫ Basal plate (decidual plate): thick layer
214 OSMOSIS.ORG
Figure 28.7 Formation of feto-placental circulation: primary villi form. Cells clear out between
primary villi, forming lacunae. Tiny maternal arteries and veins merge with lacunae, and the
lacunae fill with oxygenated blood. Lacunae merge to form a single pool, the junctional zone.
Figure 28.8 Fetal and maternal contributions to the placenta.
Figure 28.9 Contents of the chorionic cavity.
OSMOSIS.ORG 215
Figure 28.10 Decidual septa form in months
four and five that divide the placenta into Figure 28.11 The placenta covers
regions called cotyledons. approximately 15–30% of uterine wall and is
about 20cm/7.9in across at full term.
DEVELOPMENT OF THE
UMBILICAL CORD
osms.it/umbilical-cord-development
▪ Umbilical cord is a long flexible stalk membrane for umbilical cord
containing two arteries, one vein; connects ▪ Around week 6: physiological umbilical
fetus to placenta herniation
▪ Forms from three structures ▫ Due to rapid intestinal growth, part of
▫ Body (connecting) stalk: short band intestine herniates through umbilical
of extraembryonic mesoderm that ring into umbilical cord; withdraws back
connects embryo to chorion at week 2 into abdominal cavity by end of third
▫ Vitelline duct: open connection between month
yolk sac, midgut at week 3 ▪ After umbilical cord formation, vitelline duct,
▫ Allantois: small hindgut outpocketing yolk sac shrink, eventually disappear
that grows into umbilical cord at week 3 ▫ If vitelline duct does not regress all the
▪ In week 4: amniotic cavity folds down, way → Meckel’s diverticulum
around embryo → body stalk, vitelline duct, ▪ Allantois continues developing into bladder
allantois pushed together, form umbilical ▫ Remnant of allantois: fetus → urachus;
cord → emerge out of umbilical ring (fibrous adult → median umbilical ligament
tissue ring that develops on abdominal wall ▪ Final umbilical cord: contains two umbilical
at location where they emerge) arteries, one umbilical vein, gelatinous
▪ Between weeks 4–8: cells lining amniotic substance called Wharton’s jelly which
cavity produce amniotic fluid → amnion protects umbilical vessels
swells, takes up most of space in chorionic ▪ After birth: umbilical vein → round ligament
cavity of liver, umbilical arteries; medial umbilical
▫ Amnion folds → covers body stalk, ligaments
vitelline duct forming an outer
216 OSMOSIS.ORG
Figure 28.12 Formation of the umbilical cord and structures within it.
OSMOSIS.ORG 217
Figure 28.13 Cross section of the umbilical cord revealing its components and their remnants.
DEVELOPMENT OF THE FETAL

MEMBRANES
osms.it/fetal-membrane-development
▪ AKA extraembryonic membranes: tissues extraembryonic coelom/chorionic cavity
that form in uterus during first few weeks ▫ Cavity continues to expand until there
of development is only a thin layer of extraembryonic
▫ Amnion, yolk sac, chorion, allantois mesoderm lining amniotic cavity/yolk
sac, cytotrophoblast
AMNION ▪ Cavity does not form at body stalk where
embryoblast remains attached to chorion
▪ On day 8, space appears between epiblast,
cytotrophoblast → amniotic cavity ▫ At this point, chorion contains
extraembryonic mesoderm,
▪ Cells from epiblast migrate to form thin
cytotrophoblast, syncytiotrophoblast
layer around amniotic cavity, separating it
from cytotrophoblast → amnion ▪ Chorion develops chorionic villi, invades
endometrium, eventually helps form fetal
part of placenta
YOLK SAC
▪ On day 9, hypoblast cells migrate to form
ALLANTOIS
thin membrane around blastocoel, forming
yolk sac walls → yolk sac fills with vitelline ▪ Develops as an outpouching of hindgut
fluid during week 3
▫ Vitelline fluid provides nourishment for ▫ Serves as canal through which urine is
embryo eliminated, before urethra develops
▪ Nutrients in yolk sac eventually consumed, ▫ Degenerates into fibrous structure called
yolk sac, vitelline duct shrink, disappear urachus, remains attached to urinary
bladder
▪ During week 4, allantois, vitelline duct,
CHORION body stalk combine to form umbilical cord
▪ By day 10, epiblast cells differentiate into ▪ Between weeks 4–8, amnion secretes
extraembryonic mesoderm amniotic fluid → amniotic cavity swells,
▫ Settle between amniotic cavity/yolk sac, folds down around embryo → protects,
cytotrophoblast → creating thick layer insulates embryo → continues to grow
of extraembryonic mesoderm tissue → amnion, chorion fuse together, form
between the two amniotic sac
▫ A space forms within this layer →
218 OSMOSIS.ORG
Figure 28.14 Four fetal membranes include: amnion, chorion, allantois, yolk sac.
DEVELOPMENT OF TWINS
osms.it/twin-development
FRATERNAL (DIZYGOTIC) TWINS IDENTICAL TWIN CATEGORIES

▪ Occur at rate of about 10 per 1,000 births ▪ Categorized by how, when division occurs
worldwide → affects how identical twins share space,
▪ Originate from two separate eggs resources in uterus
(hyperovulation) fertilized individually by
Dichorionic-diamniotic
two different sperms → zygotes have
completely different genetic makeups ▪ Division occurs within 2–3 days following
fertilization
▫ Hyperovulation may be due to an
overabundance of follicle-stimulating ▪ Embryos develop completely separately
hormone (FSH) from one another
▪ Mothers of fraternal twins tend to be older ▪ Have separate placentas, amniotic sacs
(> 35 years), taller, heavier on average, with
Monochorionic-diamniotic
shorter, more frequent menstrual cycles →
high levels of follicle-stimulating hormone ▪ Division occurs between 3–8 days
following fertilization
▪ Embryos share a single placenta, separate
IDENTICAL (MONOZYGOTIC) TWINS amniotic sacs
▪ Occur at a rate of about 4 per 1000 births
worldwide Monochorionic-monoamniotic
▪ Originate from single zygote that splits ▪ Division occurs between 8–13 days after
into two groups of cells → zygotes have fertilization
identical genetic makeup ▪ Embryos share both placenta, amniotic sac
▪ The split can occur at any time during first
thirteen days of development
▪ Identical DNA → identical physical traits
that have a strong genetic basis → sex,
hair, eye color, blood type, other physical
features
OSMOSIS.ORG 219
Figure 28.15 The way the womb is shared by identical twins depends on the time frame in
which the zygote split in two.
220 OSMOSIS.ORG
NOTES
NOTES
BODY SYSTEM STRUCTURES
DEVELOPMENT OF THE
SKELETAL SYSTEM
osms.it/axial-skeleton-development
▪ Follows gastrulation (AKA formation of
ectoderm, mesoderm, endoderm)
Axial skeleton
▪ Skull, vertebrae, rib cage, sternum
▪ Derived from mesoderm
▪ Exception: some skull bones come from
ectoderm
Appendicular skeleton
▪ Pelvic, shoulder girdles; bones in limbs
▪ Derived from mesoderm Figure 29.1 Cross section through an
Pathways of bone development embryo demonstrating ectoderm, mesoderm,
and endoderm. Paraxial and lateral plate
▪ AKA ossification
mesoderm give rise to bones and muscles.
▪ Two pathways
▫ Endochondral, intramembranous
Endochondral ossification
▪ Almost all bones
▫ Exceptions: clavicles; parietal, frontal
bones of skull; maxilla; mandible; nasal
bone; parts of temporal, occipital bones
▪ Hyaline cartilage serves as bone formation
model
▫ Mesenchymal cells differentiate into
chondrocytes, which form cartilaginous
model
▫ Bone develops by replacing cartilage
Figure 29.2 Axial and appendicular skeletons.
OSMOSIS.ORG 221
Figure 29.3 Endochondral ossification: the primary ossification center is at the center of
the cartilage model. Blood vessels enter the primary ossification center, bringing nutrients,
osteoblasts, and osteoclasts. Osteoblasts replace chondrocytes at the primary ossification center
and replace cartilage with bone. Osteoclasts start to break down the center of bone, which leads
to the formation of bone marrow.
Intramembranous ossification
▪ Clavicle, flat bones (e.g. parietal bones,
mandible)
▪ Bone develops directly on membranous
sheaths
▫ Mesenchymal cells differentiate into
osteoblasts, secrete osteoid (AKA
unmineralized matrix)
▫ Osteoid calcifices after deposition of
calcium phosphate
DEVELOPMENT OF THE SKULL

Neurocranium
▪ Encases brain Figure 29.4 Lateral view of membranous
neurocranium. It is composed of the flat
▪ Three parts
bones that form a hard, protective shell
▫ Membranous neurocranium, around the brain.
cartilaginous neurocranium/
chondrocranium, viscerocranium
Membranous neurocranium Cartilaginous neurocranium

▪ Comprises flat bones that cradle brain ▪ AKA chondrocranium
▪ AKA cranial vault ▪ Bones around base of skull
▪ Derived from neural crest cells, paraxial ▪ Derived from neural crest cells, paraxial
mesoderm mesoderm; become prechordal, chordal
chondrocranium, respectively
▪ Ossifies via intramembranous ossification
▪ Ossifies via endochondral ossification
222 OSMOSIS.ORG
Chapter 29 Embryology: Body System Structures
Figure 29.5 Lateral view (left) and superior

view (right) of bones comprising cartilaginous
neurocranium.
Viscerocranium
▪ Facial bones
Figure 29.6 The viscerocranium arises
▪ Six pharyngeal arches; facial bones arise primarily from the first pharyngeal arch with
from first arch stapes arising from the second arch. The
▫ Dorsal side: maxilla, zygomatic bones, viscerocranium is composed of the facial
parts of temporal bone bones (illustrated here in a lateral view).
▫ Ventral side: Meckel’s cartilage
undergoes intramembranous
ossification; becomes mandible
▫ Dorsal tip of mandibular process,
second pharyngeal arch → become
incus, malleus, stapes
Temporary skull structures

▪ Skull bones not fully fused at birth
▫ Allows molding of fetal head during
passage through birth canal
▫ Closes by 18 months old, allows brain
growth
▪ Sutures: narrow gaps between bone plates
filled with fibrous tissues
Figure 29.7 Lateral and anterior view of the
▪ Fontanelles: wide sutures where > two anterior fontanelle where the frontal and
bones meet parietal bones meet.
▫ Anterior fontanelle most prominent
▫ Where two parietal, two frontal bones
meet
OSMOSIS.ORG 223
VERTEBRAE, RIBS, & STERNUM
Spinal vertebrae
▪ Week 4: develop from somites
▪ Sclerotome portion undergoes
resegmentation
▫ Sclerotome cells from cephalic portion
of somite fuse with caudal portion of
neighboring somite Figure 29.9 Relationship between vertebrae,
▪ Sclerotome cells surround notochord, spinal intervertebral discs, spinal cord, and spinal
cord; transform into mesenchymal cells nerves.
▪ Mesenchymal cells form vertebrae through
endochondral ossification
▪ Ribs then emerge from costal facets of
thoracic vertebrae
Figure 29.10 Rib development arises from

costal processes of thoracic vertebrae.
Sternum
▪ Arises from parietal mesoderm layer in
anterior body wall
Figure 29.8 Spinal vertebrae development ▪ Cartilaginous bars form on either side of
occurs by resegmentation of somites. midline, fuse
▫ Differentiate into manubrium, main body
of sternum, xiphoid process
Intervertebral discs
▪ Arise from mesenchymal cells between
cephalic, caudal sclerotome segment
▪ Notochord enlarges in area of intervertebral
disc, contributing to nucleus pulposus
▫ Intervertebral disk formed as nucleus
pulposus surrounded by annulus
fibrosus
▪ Myotomes bridge intervertebral discs, form
vertebral muscles Figure 29.11 Sternum development arises
▪ Primary spinal curves established: thoracic, from parietal mesoderm.
sacral
224 OSMOSIS.ORG
DEVELOPMENT OF THE
MUSCULAR SYSTEM
osms.it/muscular-system-development
KEY POINTS Somites
▪ Mesoderm: becomes vast majority of ▪ Ventral region of each somite forms
muscles sclerotome
▪ Paraxial mesoderm: becomes skeletal ▫ AKA bone-forming cells
muscle ▪ Upper region of each somite forms
▪ Visceral/splanchnic mesoderm: becomes dermatome plus two muscle-forming areas
cardiac muscle, some smooth muscle ▪ Cells of ventrolateral, dorsomedial lip of
▪ Ectoderm: becomes remaining smooth somites migrate ventral to dermatome,
muscle proliferate there to form dermomyotome
▫ Exception: some cells of ventrolateral lip
DEVELOPMENT OF SKELETAL migrate into parietal mesoderm layer of
MUSCLE lateral plate mesoderm; these contribute
to abaxial domain, discussed below
Mesodermal cells ▪ Lateral somitic frontier separates somite
▪ Form myogenic cells, which undergo clusters from parietal mesoderm into two
mitosis domains
▪ Form postmitotic myoblasts ▫ Primaxial domain: consists of somites
▫ Synthesize actin, myosin around neural tube; receives signals for
▪ Fuse, form multinucleated myotubes differentiation from notochord, neural
tube; forms shoulder, back, intercostal
▫ Myotubes synthesize actin, myosin,
muscles
troponin, tropomyosin, other muscle
proteins ▫ Abaxial domain: receives signals
for differentiation from lateral plate
▪ Proteins aggregate, form myofibrils (AKA
mesoderm; forms infrahyoid, abdominal
muscle fibers/cells)
wall, limb muscles
Paraxial mesoderm
▪ Divides into segments, AKA somitomeres,
in craniocaudal sequence
▪ Seven somitomeres form head, neck
muscles
▫ Contribute to pharyngeal arches’
formation
▪ Remaining somitomeres form 35 pairs of
somites for trunk region
▪ Undergo epithelialization
▫ AKA form balls of epithelial cells
Figure 29.12 Divisions of mesoderm created

by lateral somitic frontier.
OSMOSIS.ORG 225
DEVELOPMENT OF CARDIAC DEVELOPMENT OF SMOOTH
MUSCLE MUSCLE
▪ Develops from visceral (i.e. splanchnic) ▪ Paraxial mesoderm cells from first seven
mesoderm surrounding endothelial heart somite pairs form smooth muscle of head
tube ▫ Includes tongue, jaw muscles, throat
▪ Myoblasts adhere via special attachments, muscles
which later become intercalated discs ▫ Develops in response to signals
▪ Patterning of striations forms branch-like released by neural crest cells
lines ▪ Visceral/splanchnic mesoderm surrounding
▫ Unlike straighter lines of skeletal gut tube → becomes digestive system
muscles muscles
▪ Ectoderm → becomes sphincter, dilator
muscles of pupils, mammary glands, sweat
glands
▪ Proepicardial cells, neural crest cells →
becomes smooth muscle of aorta, arteries
Figure 29.13 Cross section through an embryo demonstrating the origins of skeletal, cardiac,
and smooth muscle.
Figure 29.14 Different regions of the somite form different body structures. The myotome is
responsible for skeletal muscle formation.
226 OSMOSIS.ORG
DEVELOPMENT OF THE LIMBS

osms.it/limb-development
Limb buds: overview Limb muscle development
▪ End of week 4: limb buds visible on ▪ Derived from dorsolateral cells of somites
ventrolateral body wall ▫ AKA myotomes
▪ Limb bud structure ▫ Myotomes from C4-T2 migrate to upper
▫ Mesenchymal core: forms connective limb
tissue, bones ▫ Myotomes from L2-S2 migrate to lower
▫ Myotomes: form muscles limb
▫ Ectoderm cover: forms epidermis of skin ▪ During migration to limbs, myotomes form
two compartments
Connective tissue & bones ▫ Anterior condensation → flexor,
▪ Development determined by series pronator muscles of upper limb; flexor,
of interactions between ectoderm, adductor muscles of lower limb
mesenchyme ▫ Posterior condensation → extensor,
▪ Ectoderm at the limb apex proliferates, supinator muscles of upper limb;
forms apical ectodermal ridge (AER) → extensor, abductor muscles of lower
induces adjacent mesenchyme to remain limb
undifferentiated, rapidly proliferating cells ▫ Ventral primary branches of spinal
▫ AKA undifferentiated zone nerves, mesenchyme divide; form
▪ Ectoderm further influences mesenchyme dorsal, ventral branches to these
▪ Mesenchyme differentiates into cartilage, compartments
muscle; forms three components proximo- ▫ Week 7: limbs rotate
distally ▪ Upper limb rotates 90° laterally
▫ Stylopod: becomes humerus/femur ▫ Lower limb rotates 90° medially
▫ Zeugopod: becomes radius/ulna, tibia/
fibula
▫ Autopod: becomes carpals, metacarpals,
metatarsals
▪ Week 6: limb bud apexes flatten, become
hand, foot plates
▪ Fingers, toes formed via localized apoptosis
induced by AER
▫ Separates hand, foot plates into five
parts
▪ Mesenchyme underneath differentiates into
chondrocytes
▫ Chondrocytes form primary hyaline Figure 29.15 Limb muscle development:
cartilage models of future bones myotomes migrate to limbs, forming anterior
▪ As chondrogenesis stops, joint formation and posterior condensations that are
induced innervated by ventral and dorsal branches of
▫ Condensed mesenchyme differentiates the spinal nerve's primary ventral branches.
into dense fibrous tissue (forms articular
cartilage, synovial membrane, menisci,
ligaments of joint)
OSMOSIS.ORG 227
DEVELOPMENT OF THE
CARDIOVASCULAR SYSTEM
osms.it/cardiovascular-system-development
▪ Begins during week 3 LATERAL FOLDING OF EMBRYO
▪ Mesoderm cells travel through primitive ▪ Embryo folds into cylindrical shape as
streak to embryo’s head, form horseshoe- lateral borders meet at midline
shaped area with two limbs ▫ Two endocardial tubes fuse, forming
▫ AKA primary heart field primitive heart tube
▪ Vascular endothelial growth factor (VEGF) ▪ Left, right vitelline veins also fuse, forming
signals limbs’ cells to organize into two sinus venosus
tubes ▫ AKA inflow tract
▪ Lateral mesoderm splits into somatic, ▪ Aortae fuse, forming aortic sac
splanchnic layers ▫ AKA outflow tract
▫ Concurrently, primitive pericardial cavity ▪ Primitive pericardial cavities fuse around
forms lateral to each tube heart tube, forming pericardial cavity
▪ At inferior end, each endocardial tube ▪ Heart tube remains attached to pericardial
connects to vitelline vein stemming from cavity by sheet of mesoderm called dorsal
yolk sac mesocardium; heart tube now has two
▪ Mesoderm cells also form pair of layers (endothelial lining, cardiac myoblasts)
longitudinal vessels (AKA dorsal aortae) ▪ Endothelial lining forms endocardium
▪ Cardiac myoblasts form myocardium
▫ Some myocardial cells in sinus venosus
begin to produce rhythmic electrical
discharge
▪ Mesenchymal cells of dorsal mesocardium
form proepicardial organ
▫ These cells proliferate, migrate over
myocardium, form epicardium
Figure 29.16 Early development of the Figure 29.17 Structures formed as a result of
cardiovascular system starting in week 3. lateral folding of the embryo.
228 OSMOSIS.ORG
CRANIOCAUDAL FOLDING OF ▪ Primitive atrium: becomes left, right atria

EMBRYO ▪ Primitive ventricle: forms left ventricle
▪ Cylindrical embryo folds down its length, ▫ Separated from bulbus cordis by
forming shrimp-like shape bulboventricular sulcus
▫ Heart pushed toward chest ▪ Bulbus cordis: forms right ventricle, outflow
▪ By week 4: heart tube reaches thorax, tracts for both ventricles
circulating blood can be seen travelling ▪ Truncus arteriosus: at top of heart tube
through heart tube ▫ Pumps blood through aortic sac into
early version of circulatory system
LOOPING OF THE HEART TUBE

▪ Heart tube folds into “C” shape
▪ Truncus arteriosus and bulbus cordis move
down, to right
▫ Form top portion of “C”
▪ Primitive ventricle bends to right of midline,
slightly to front
▫ Forms middle portion of “C”
▪ Primitive atrium, sinus venosus
Figure 29.18 Craniocaudal folding of the
▫ Form bottom of “C”
embryo places heart tube in thorax.
▪ Enlarging ventricle moves left
▫ Crosses over midline again, covers
PARTITION OF THE HEART TUBE primitive atrium
▪ Visceral pericardium attaches to outside of
Sections of the heart tube heart, forms epicardium
▪ Sinus venosus: left, right sinus horn bring
in blood
▪ Primitive atrium, primitive ventricle
separated by atrioventricular sulcus
Figure 29.19 Heart tube sections and the structures they become.
OSMOSIS.ORG 229
Figure 29.20 During week 4, the heart tube undergoes looping: tube lengthens, walls thicken,
and sections move towards appropriate locations to continue development.
FURTHER PARTITIONING OF THE Formation of ventricles

HEART ▪ Muscular ridge of tissue grows upward
▪ Mesoderm proliferates on anterior, posterior from apex, fuses with thinner membranous
walls of atrioventricular canal region coming down from endocardial
▫ Forms anterior, posterior endocardial cushions
cushion ▫ Forms left, right ventricles
▫ Cushions grow towards each other, fuse ▪ End of week four: cardiac loop starts to
▪ Heart now separated into left, right take shape of adult heart
atrioventricular canals
▪ Endocardial cells proliferate on ventricular
side of each canal
▫ These form leaflets of mitral, tricuspid
valves
▪ Canals now divided into atria, ventricles
Formation of the atria

▪ Crescent-shaped septum primum grows
downward between future left, right atria
▫ Opening (AKA ostium primum) remains
▪ Septum primum continues to grow, fuses Figure 29.21 Fusion of the endocardial
with endocardial cushion, closes ostium cushions separates the heart into right and
primum completely left atrioventricular canals.
▪ Ostium secundum appears in center of
septum primum
▪ Septum secundum grows downward just
to right of septum primum, covers ostium
secundum
▫ Leaves small opening (AKA foramen
ovale)
▪ Septum secundum acts as one-way valve,
allowing blood flow from left to right atrium
▪ After birth, closure of foramen ovale is
facilitated by Figure 29.22 Structures contributing to the
formation of the atria and ventricles.
▫ ↓ in right atrial pressure due to occlusion
of placental circulation
▫ ↑ in left atrial pressure due to ↑
pulmonary venous return
230 OSMOSIS.ORG
DEVELOPMENT OF THE ARTERIAL DEVELOPMENT OF THE VENOUS

SYSTEM SYSTEM
▪ Develops from sinus venosus
Development of the aorta
▪ Week 4: sinus venosus receives
▪ Starts with division of truncus arteriosus
deoxygenated blood from sinus horns,
▪ Two endocardial cushions appear on right- opens in center of primitive atrium
superior, left-inferior walls
▪ Each horn receives blood from vitelline/
▪ Cushions grow with spiraling trajectory, omphalomesenteric veins, umbilical veins,
wrap around each other common cardinal veins
▪ Form aorticopulmonary septum ▪ Next, sinus venosus becomes asymmetric,
▫ Divides into root of aorta, pulmonary shifts to right
artery ▫ Caused by left to right shunts
▫ Semilunar valves develop shortly after ▪ Right sinus horn enlarges; becomes
smooth-walled part of right atrium; forms
openings for superior, inferior vena cavas
▪ Left sinus horn shrinks; persists as coronary
sinus, oblique vein of left atrium
DEVELOPMENT OF THE
CONDUCTING SYSTEM
▪ Special group of myocardial cells in wall
of sinus venosus organize, synchronize
Figure 29.23 Anterior view of heart their electrical discharge, form pacemaker
visualizing development of the aorta and centers
pulmonary artery.
▫ Cells in wall of sinus venosus: form
sinoatrial node
▫ Cells in atrioventricular septum: form
Arteries of head & neck region, pulmonary
atrioventricular node
arteries
▫ Cells in interventricular septum: form
▪ Come from five aortic arches
bundle of His
▪ 1st arch: maxillary artery
▫ Rest of ventricular myocardium: form
▪ 2nd arch: stapedial artery modified cardiac myocytes, which
▪ 3rd arch: two common carotid arteries, part become Purkinje fibers
of internal carotid arteries
▪ 4th aortic arch
▫ Left 4th arch: aortic arch
▫ Right 4th arch: right subclavian artery
▪ 6 arch: pulmonary arteries, ductus
th
arteriosus
Remaining arteries
▪ Develop mainly from right, left dorsal aortae
→ fuse during lateral folding, form dorsal
aorta
▪ Dorsal aorta sprouts posterolateral arteries;
lateral arteries; ventral arteries (AKA
vitelline, umbilical)
Figure 29.24 Aortic arches and their
derivatives. The arches exist from weeks four
to six and sprout from aortic sac.
OSMOSIS.ORG 231
Figure 29.25 The heart's conducting system.
FETAL CIRCULATION
osms.it/fetal-circulation
KEY POINTS to systemic circulation → right, left
▪ Placenta: low-resistance circuit, organ of common iliac arteries → internal, external
gas exchange iliac arteries → umbilical arteries →
▪ Fetal systemic circulation: low-resistance deoxygenated blood back to placenta
circuit
▪ Lungs: filled with fluid, hypoxic CHANGES AT BIRTH
vasoconstriction ▪ Pulmonary circulatory pressure ↓ while
▫ High-resistance circuit, no role in gas systemic circulation ↑
exchange ▫ When umbilical cord cut, low-resistance
▪ Right side of heart pressure > left side of circuit removed → systemic circulation
heart pressure increases
▪ Ductus venosus, foramen ovale, ductus ▫ Lung fluid replaced by air as neonate
arteriosus shunt blood away from fetal takes first breaths/cries
lungs ▫ Oxygen diffuses into blood vessels
surrounding alveoli, pulmonary
Pattern of flow
arterioles relax, pulmonary resistance
▪ Placenta → umbilical vein → divides into falls, blood flows into lungs
left, right umbilical vein
▪ Closing of ductus arteriosus
▪ Left umbilical vein → portal vein → liver →
▫ Pressure changes cause decreased
hepatic vein → inferior vena cava → right
blood flow through ductus arteriosus
atrium
▫ Complete closure: 12–24 hours after
▪ Right umbilical vein → ductus venosus
birth
(bypasses liver) → inferior vena cava →
right atrium ▫ Physical remnant: ligamentum
arteriosum
▪ Right atrium → left atrium via foramen
ovale ▪ Closing of foramen ovale
▫ Small amount of blood from right atrium ▫ Pressure in right side of heart falls, seals
enters right ventricle, pulmonary artery, foramen ovale
lungs ▫ Physical remnant: fossa ovalis
▪ Blood shunted from pulmonary artery to ▪ Umbilical vein forms round ligament of liver
aorta by small blood vessel ▪ Ductus venosus forms ligamentum
▫ AKA ductus arteriosus venosum of liver
▪ Aorta → oxygenated blood delivered
232 OSMOSIS.ORG
Figure 29.26 The fetal right atrium receives blood from the inferior vena cava (via liver and
ductus venosus) and the superior vena cava.
OSMOSIS.ORG 233
Figure 29.27 In the fetal circulatory system, blood can travel from the right atrium to the aorta
through either the foramen ovale or the ductus arteriosus. The majority of the blood takes the
first path from the higher pressure right atrium to the lower pressure left atrium, bypassing the
right ventricle entirely. The blood that does flow into the right ventricle is shunted from the high
pressure pulmonary artery to the lower pressure aorta through the ductus arteriosus.
Figure 29.28 The aorta sends blood to the entire body through its various branches. The interior
iliac arteries each give rise to an umbilical artery. These arteries travel alongside the umbilical
vein and bring deoxygenated blood back to the placenta, where CO2 is delivered and O2 is
picked up. This cycle repeats until birth.
234 OSMOSIS.ORG
Figure 29.29 The fetal circulatory adaptations and their physical remnants after birth. The
umbilical arteries and vein are surrounded by a substance called Wharton's jelly in the umbilical
cord. Once exposed to the cold air, Wharton's jelly shrinks and squeezes the umbilical blood
vessels, causing them to wither. The arteries constrict and flatten, and are mostly gone within
a few months; only a small portion remains and subsequently function as the superior vesical
arteries, which supply blood to either side of the bladder.
DEVELOPMENT OF THE
RESPIRATORY SYSTEM
osms.it/respiratory-system-development
KEY POINTS
▪ Week 4: starts developing
▫ Lung bud sprouts from foregut portion
of digestive tract
▪ Endoderm, mesoderm: form lower
respiratory tract structures
▫ Larynx, trachea, lungs
Figure 29.30 Week 4: lung bud sprouts from

foregut.
OSMOSIS.ORG 235
DEVELOPMENT OF THE LARYNX ▪ Composition of lung bud
▪ Begins as slit between 4 , 6 pharyngeal
th th
▫ Endoderm: gives rise to epithelial,
arches glandular structures of trachea, lungs
▪ Endoderm of arches: forms laryngeal ▫ Visceral mesoderm: gives rise to
epithelium, glands muscles, cartilage, connective tissue
▪ Mesoderm of arches: forms laryngeal ▪ Lung bud bifurcates into two bronchial
muscles, cartilages buds
▪ Arches carry the laryngeal branches of
vagus nerve
▪ Week 5: laryngeal orifice forms
▫ Laryngeal epithelium turns into
laryngeal ventricles, which give rise to
vocal cords
▪ Week 6: epiglottis forms
▪ Week 12: laryngeal orifice has adult shape;
thyroid, cricoid, arytenoid cartilages
Figure 29.33 At the loose end, the lung bud

bifurcates into two bronchial buds which give
rise to the lungs.
STAGES OF LUNG DEVELOPMENT

Pseudoglandular stage: weeks 5–16
▪ Bronchial buds differentiate
Figure 29.31 The endoderm and mesoderm
of the pharyngeal arches contribute to larynx ▫ Left and right main/primary bronchi
formation. ▫ Three lobar/secondary bronchi for right
lung lobes, two for left lung lobes
▪ Lobar/secondary bronchi: divide into 10
segmental/tertiary bronchi on right, eight
on left
▫ AKA lung segments
▪ Segmental/tertiary bronchi divide
repeatedly until 15–25 terminal bronchioles
formed
▪ Lungs now consist of simple columnar
Figure 29.32 Key timing and features in epithelium
larynx development. Canalicular stage: weeks 16–26
▪ Terminal bronchioles continue to divide,
form respiratory bronchioles
DEVELOPMENT OF THE TRACHEA
& LUNGS ▪ Respiratory bronchiole divides into three to
six alveolar ducts
▪ Week 4: two tracheoesophageal ridges
grow towards one another, fuse into ▪ Prominent capillary network forms
septum ▪ Week 24: primitive alveoli appear closer to
▪ Septum divides foregut into two regions trachea
▫ Posterior: esophagus ▪ Lungs now consist of simple cuboidal
epithelium
▫ Anterior: lung bud
▫ Unsuitable for gas exchange
236 OSMOSIS.ORG
Terminal sac stage: week 26–birth

▪ More primitive alveoli form
▪ Epithelial lining of terminal sacs
differentiate
▪ Flat cells in direct contact with endothelium
of the capillaries
▫ AKA type I pneumocytes, form blood-air
barrier
▫ Also includes basement membrane
▪ Pulmonary surfactant produced by large,
cuboidal cells
▫ AKA type II pneumocytes
Alveolar stage: week 36–8 years old

▪ Terminal sacs partitioned by secondary
septae
▪ Number of adult alveoli increase
▫ 0–70 million at birth, 300–400 at eight
years old
▪ Number of respiratory bronchioles
increases with lung size
Figure 29.34 The stages of lung

development.
OSMOSIS.ORG 237
DEVELOPMENT OF THE
GASTROINTESTINAL SYSTEM
osms.it/gastrointestinal-system-development
Primitive gut tube arches
▪ Forms during week 3 ▪ Week 4: tracheoesophageal septum divides
▪ Extends from buccopharyngeal membrane foregut below pharynx into two regions
to cloacal membrane ▫ Esophagus: posterior
▪ Divided into three parts according to ▫ Lung bud: anterior
arterial supply ▪ Esophageal epithelium, glands derived from
▫ Foregut, midgut, hindgut foregut endoderm
▫ Epithelium proliferates, initially fills
Foregut
lumen
▪ Supplied by celiac trunk
▫ By week 8: becomes hollow tube via
▪ Gives rise to superior part of digestive tube recanalization
▫ Pharynx to first half of duodenum ▪ Esophageal muscles, adventitia derived
▫ Also liver, gallbladder, pancreas from surrounding mesoderm
Midgut Stomach & duodenum
▪ Supplied by superior mesenteric artery ▪ Begin as small dilation of foregut
▪ Briefly, midgut communicates with yolk sac ▪ Ventral mesogastrium attaches ventral
via vitelline duct border to anterior body wall
▪ Dorsal mesogastrium attaches dorsal
Hindgut
border to posterior body wall
▪ Supplied by inferior mesenteric artery
▫ Dorsal border: grows faster, forms
greater curvature
DERIVATIVES OF THE FOREGUT ▫ Ventral border: lesser curvature
▪ Stomach undergoes 90°, clockwise rotation
Pharynx & esophagus
along its length
▪ Pharynx develops from 4th, 6th pharyngeal
▫ Pulls dorsal, ventral mesogastria with it
Figure 29.35 The primitive gut tube at week 3, including subdivisions and their blood supplies.
238 OSMOSIS.ORG
Figure 29.36 The pharynx and esophagus are derivatives of the foregut. The
tracheoesophageal septum divides the foregut into the esophagus posteriorly and the lung bud
anteriorly. The esophageal endoderm (epithelium) initially proliferates and fills the lumen, but
recanalization is complete by week 8.
▫ Greater curvature moves to right side of Liver & gallbladder

body, lesser curvature to left ▪ Liver bud, AKA hepatic diverticulum, gives
▫ Stomach now has anterior, posterior rise to liver, gallbladder, biliary duct system
faces ▫ Forms inside ventral mesogastrium,
▪ Ventral mesogastrium: becomes lesser extends into sheet of mesoderm that
omentum separates developing heart from midgut
▪ Dorsal mesogastrium: grows, bends as (AKA septum transversum)
stomach rotates ▫ Contains mesoderm, endoderm
▫ Forms cavity (AKA omental bursa) ▪ Foregut endoderm forms hepatocytes
between stomach, posterior body wall ▫ During week 12: hepatocytes start
▪ Omental bursa: communicates with producing bile during mesoderm
peritoneal cavity through omental foramen ▫ Forms Kupffer cells, hematopoietic
▫ Omental bursa grows, fills with tissue
peritoneal fluid ▫ During week 6: produce red blood cells
▫ Develops two projections: upper recess, ▪ Liver bud divides into two parts
lower recess ▫ Larger, superior portion: becomes liver
▪ Upper recess: extends behind developing ▫ Smaller, inferior part: becomes
liver gallbladder
▪ Lower recess: extends downward over
developing intestines Pancreas
▫ Sheets of dorsal mesogastrium that ▪ Two pancreatic buds eventually fuse to
form lower recess fuse, forming greater form entire organ
omentum ▫ Dorsal bud: forms tail, body, part of
▪ Stomach rotates once more on frontal plane head
▫ Repositions superior end of stomach ▫ Ventral bud: forms most of head
▫ Forms cardiac sphincter, pylorus ▪ Week 10: begins secreting insulin
▫ Turns duodenum into C-shaped loop,
with middle of “C” on right side
▪ First two sections of duodenum: derived
from last part of foregut
▪ Tiny tissue buds on last portion of foregut
grow, develop into liver, gallbladder,
pancreas
OSMOSIS.ORG 239
Figure 29.37 Lateral view of the embryo visualizing the stomach and associated structures
before any rotation has taken place. The stomach presents as small foregut dilation beneath
esophagus. Starting at week 5, the liver grows between the layers of the ventral mesogastrium
and the spleen grows between the layers of the dorsal mesogastrium.
Figure 29.38 The two rotations events in the development of the stomach.
240 OSMOSIS.ORG
Physiologic gut herniation

▪ During rapid gut tube growth, primary
intestinal loop herniates through vitelline
duct, develops inside umbilical cord
▪ Primary intestinal loop protrudes inside
umbilical cord, superior mesenteric artery
grows between loop’s two limbs
▫ Cranial limb: initially develops above
superior mesenteric artery
▫ Caudal limb: develops below superior
mesenteric artery
▪ First, loop rotates 90° counterclockwise
around axis of superior mesenteric artery
▫ Moves cranial limb to right side of artery,
inferior limb to left
▪ Cranial limb becomes convoluted
▫ Marks future jejunal, ileal anses
▪ Caudal limb develops small dilation
▫ Eventually becomes cecum, appendix
▪ Week 10: loop rotates final 180°, moves
into abdominal cavity
▫ Formerly caudal limb now frames
developing small intestine loops,
becomes ascending colon, right 2⁄3 of
transverse colon
DERIVATIVES OF THE HINDGUT

▪ Left 1⁄3 of transverse colon, descending
colon, sigmoid colon, upper part of anal
canal derive from hindgut
▪ Begins after caudal limb of midgut, extends
to cloacal membrane
▪ Anal canal’s lower portion derives from
Figure 29.39 Anterior view: the liver, primitive anus (AKA proctodeum)
gallbladder, and pancreas develop from
▫ Proctodeum: pit of ectoderm that forms
tissue buds at the distal end of the foregut.
below cloacal membrane
▪ Week 4: Urorectal septum forms
DERIVATIVES OF THE MIDGUT ▫ Separates cloaca into anterior urogenital
▪ Key elements sinus, posterior anal canal; covered
by urogenital, anal membranes,
▪ Parts of small, large intestines derive from
respectively
midgut
▪ End of week 7: separation completed
▫ Small intestine: third, fourth sections of
duodenum; jejunum; ilium ▫ Anal membrane ruptures, forming
continuous anal canal
▫ Large intestine: cecum, appendix,
ascending colon, proximal 2⁄3 of ▫ Anal canal opens in embryo’s tail-region
transverse colon
OSMOSIS.ORG 241
Figure 29.40 The process of physiologic gut herniation.
Figure 29.41 Hindgut structures at week 7

when the anal membrane has ruptured to
form a continuous anal canal.
242 OSMOSIS.ORG
DEVELOPMENT OF THE
RENAL SYSTEM
osms.it/renal-system-development
▪ Begins in week 4 ▫ Nephrotomes: chunks of tissue that
▪ Intermediate mesoderm on each side of break off nephrogenic cord
embryo condenses, forming cylindrical
Mesonephros
structure (AKA urogenital ridge)
▪ Arises in thoracic, upper lumbar region of
▪ Urogenital ridge runs parallel to future
nephrogenic cord
spinal column; has two portions
▪ Consists of mesonephric duct, mesonephric
▫ Genital ridge: becomes gonads
tubules
▫ Nephrogenic cord: becomes urinary
▪ Mesonephric duct: develops from
structures
pronephric duct
▫ Extends pronephric duct to cloaca
▪ Mesonephric tubules: hollow, S-shaped
tubes
▫ Connect to mesonephric duct on one
end
▫ On other end, form cup (AKA Bowman’s
capsule) around clump of capillaries
(AKA glomerulus)
▫ Glomerulus extracts fluid from
capillaries, fluid flows down duct,
becomes urine, drained through
mesonephric duct into cloaca
▫ After week 10, permanent kidneys take
over, mesonephros regresses
Metanephros
▪ Week 5: develops in pelvic region
▪ Forms permanent kidneys
Figure 29.42 Week 4: urogenital ridge
▪ Intermediate mesoderm near the
formation.
mesonephric duct differentiates into
metanephric mesoderm (AKA metanephric
blastema)
▪ Three structures emerge from nephrogenic
▪ This induces mesonephric duct to sprout
cord in cranio-caudal fashion
ureteric bud
▫ Pronephros, mesonephros, metanephros
▫ Ureteric bud connected mesonephric
Pronephros duct via the ureteric stalk
▪ Beginning of week 4: arises in neck region ▪ Ureteric bud lengthens, secretes growth
▪ End of week 4: regresses factors
▪ Does not produce urine ▪ This causes metanephric mesoderm to
grow (AKA reciprocal induction)
▪ Consists of pronephric duct, nephrotomes
▪ Ureteric bud grows into metanephric
▫ Pronephric duct: tube that runs length
mesoderm
of nephrogenic cord
▫ Metanephric mesoderm surrounds end
OSMOSIS.ORG 243
Figure 29.43 Locations and components of the pronephros and mesonephros.
Figure 29.44 Development of the kidney from the metanephros.
of ureteric bud, leaving just ureteric stalk ▫ End of tube (AKA distal convoluted
uncovered tubule) connects with collecting tubules
▪ Week 6: ureteric stalk lengthens, forms ▫ Other end forms proximal convoluted
ureter tubule; becomes Bowman’s capsule,
▪ Weeks 7–8: ureteric bud divides in half, glomerulus
forms renal pelvis ▫ Portion between distal, proximal
▪ Division continues: two major calyces convoluted tubules lengthens, forms
become minor calyces, then millions of loop of Henle
collecting tubules ▪ Week 10: nephrons start producing urine
▪ Initially, kidneys nourished by internal iliac
Nephrons
arteries
▪ Week 8: start forming
▪ As permanent kidneys develop, they move
▪ Cells in collecting tubules signal adjacent up from pelvis to reach upper abdomen
metanephric mesoderm to form round cell
▫ Renal arteries form, lower branches
clusters (AKA metanephric vesicles)
degenerate
▫ Vesicles elongate, bend into S-shaped
tube
244 OSMOSIS.ORG
Figure 29.45 Nephron development begins at week 8.
1: Metanephric tissue cap signals adjacent metanephric mesoderm to form round cell clusters
called metanephric vesicles.
2: Vesicles elongate, curve; end of tube connects with collecting duct.
3: Proximal and distal convoluted tubules (PCT, DCT).
4: Tube lengthens between PCT, DCT → loop of Henle.
Figure 29.46 The kidneys are originally nourished by the internal iliac arteries. As kidneys
ascend, the aorta forms branches at higher and higher levels to supply them. The renal arteries
develop once the kidneys have reached their final position and earlier branches degenerate.
OSMOSIS.ORG 245
DEVELOPMENT OF THE BLADDER ▪ Bottom portion of urogenital sinus grows
& URETHRA towards genital tubercle
▪ Week 4: begins developing ▫ Forms clitoris (female), penis (male)
▪ Wall of tissue forms in cloaca (AKA
urorectal septum)
▫ Splits cloaca into posterior anal canal,
anterior urogenital sinus
▫ Top portion of urogenital sinus forms
primitive bladder
▪ Ureters develop from ureteric stalk, open
into mesonephric ducts
▫ Drain into bladder
▪ Weeks 5–6: mesonephric ducts get
absorbed into bladder
▫ Form vesical trigone (AKA smooth part
of bladder) Figure 29.47 Week 4: the urorectal septum
▪ Middle portion of urogenital sinus forms forms, splitting cloaca (forming urogenital
urethra (female); prostatic, membranous sinus, anal canal).
parts of urethra (male)
Figure 29.48 Development of the bladder and urethra.
1: Top portion of the urogenital sinus stretches out to form primitive bladder.
2: During weeks 5 and 6, the mesonephric ducts are absorbed into the bladder, forming the
smooth part of the bladder wall called the vesical trigone.
3: Outcomes for the middle and bottom portions of the urogenital sinus in individuals who are
genetically male and female.
246 OSMOSIS.ORG
DEVELOPMENT OF THE
INTEGUMENTARY SYSTEM
osms.it/integumentary-system-development
DEVELOPMENT OF THE SKIN ▪ Hair bud invaginates at terminal end,
forming hair papillae
Epidermis
▪ Each hair papilla fills with mesoderm
▪ Derived from single layer of surface
▫ Vessels, nerves develop
ectoderm
▪ Cells of hair bud’s center become
▪ In second month: cells divide, forms layer of
keratinized, forming hair shaft
periderm (AKA epitrichium)
▪ Peripheral cells form the epithelial hair
▪ Cells of periderm desquamated during
sheath
second ½ of prenatal life, form vernix
caseosa ▪ Mesenchyme surrounding hair bud forms
dermal root sheath, attached arrector pili
▪ Neural crest cells invade epidermis, form
muscle
melanocytes
▪ By end of third month, first hair appears as
▫ Move to keratinocytes in skin, hair bulb
lanugo
▫ Produce skin, hair pigmentation
▫ Begins to shed at term
▪ Cells in basal layer proliferate, form
▪ Sebaceous gland forms from small bud in
intermediate zone
mesoderm
▪ By end of fourth month, four layers
▫ Secretes sebum
complete
▫ Basal/germinative layer, spinous layer, Nails
granular layer, horny layer ▪ By end of third month, nail fields form from
▪ Hair, nails, glands all develop as epidermal thickenings at tips of digits
proliferations ▪ Nail fields form nail root through migration
Dermis ▪ Growth proximal, dorsal to each side of
digit
▪ Derived from mesenchyme from three sites
▪ Tissue proliferates around each nail field,
▪ Lateral plate mesoderm: produces dermis
forming shallow depression
of limbs, body wall
▪ Epidermis at nail roots differentiates into
▪ Paraxial mesoderm: produces dermis of
fingernails, toenails
back
▫ Reaches tips by ninth month of
▪ Neural crest cells: dermis of neck, face
development
▪ During third, fourth months, dermis forms
many irregular papillary structures (AKA Sweat glands
dermal papillae) ▪ Eccrine glands
▫ Project upward into epidermis ▫ Forms over most of body
▫ Contain Meissner corpuscles (AKA ▫ Buds arise from germinative layer
tactile sensory receptors) ▫ Buds grow into dermis
Hair ▫ Terminal part coils, forms secretory part
▪ Week 12: hair follicles form from cells of of glands
stratum basale ▪ Apocrine glands
▪ Begins as epidermal proliferation that ▫ Develop during puberty over hairy parts
penetrates into dermis (AKA hair bud) of the body
▫ Arise from epidermal buds that produce
OSMOSIS.ORG 247
hair follicles
Mammary glands
▪ Modified sweat glands
▪ Arise as bilateral bands of thickened
epidermis (AKA mammary lines/mammary
ridges)
▪ Week 7: these lines extend from from base
of forelimb to base of hindlimb
▫ Most of the line disappears, except in
thoracic region
▪ Mammary lines penetrate mesenchyme,
give rise to 16–24 sprouts that form small
buds
▪ By end of intrauterine life, sprouts are
canalized, form lactiferous ducts
▪ Lactiferous ducts initially open into small
epithelial pit
▫ Shortly after birth, proliferate, transform
into nipple
▪ At puberty, lactiferous ducts stimulated
by estrogen, progesterone to form alveoli,
secretory cells
248 OSMOSIS.ORG
NOTES
NOTES
HEAD & NECK STRUCTURE
PHARYNGEAL ARCHES, POUCHES,

& CLEFTS
osms.it/pharyngeal-arches-pouches-clefts
▪ Week 4: pharyngeal apparatus begins First pharyngeal arch
to form, develop into various head, neck ▪ Innervated by mandibular branch of
structures trigeminal nerve (CN V3)
▪ Bars of mesoderm form six pharyngeal ▪ Bones
arches in craniocaudal fashion ▫ Forms maxilla, mandible temporal,
▫ Numbered from one to six zygomatic bones
▫ 5th quickly regresses, does not form any ▫ Two small portions of mandible form
structures incus, malleus bones of middle ear
▪ Between pharyngeal arches, four ▪ Muscles
pharyngeal clefts cover each arch’s external ▫ Muscles that help with chewing:
part with ectoderm temporalis, masseter, pterygoid
▪ Four pharyngeal pouches line each arch’s muscles, tensor tympani muscles
internal part with endoderm ▫ Muscles that help with swallowing:
▪ Each pharyngeal arch carries its own tensor veli palatini, mylohyoid muscles,
cranial nerve anterior belly of digastric muscle
Figure 30.1 Locations of the pharyngeal arches, clefts, and pouches.
OSMOSIS.ORG 249
Figure 30.2 Bones and muscles originating from the first pharyngeal arch.
Second pharyngeal arch Fourth pharyngeal arch

▪ Innervated by facial nerve (CN VII) ▪ Innervated by superior laryngeal branch
▪ Bones vagus nerve (CN X)
▫ Lesser horns, upper portion of hyoid ▪ Muscles
bone ▫ Levator palatini, pharyngeal constrictors,
▫ Styloid process of temporal bone cricothyroid muscle
▫ Stapes bone of middle ear Sixth pharyngeal arch
▪ Muscles ▪ Innervated by recurrent laryngeal branch of
▫ Stylohyoid muscle, posterior belly of CN X
digastric muscle ▪ Muscles
▫ Stapedius muscle of middle ear ▫ Rest of intrinsic muscles of larynx
Third pharyngeal arch
▪ Innervated by glossopharyngeal nerve (IX) PHARYNGEAL CLEFTS AND
▪ Bones POUCHES
▫ Rest of hyoid bone
First pharyngeal cleft, pouch
▪ Muscles
▪ Form ear
▫ Stylopharyngeus muscle in throat
▪ Cleft gives rise to external auditory meatus,
ear drums
250 OSMOSIS.ORG
Chapter 30 Embryology: Head & Neck Structure
Figure 30.3 Bones and muscles originating from the second pharyngeal arch.
Figure 30.4 Structures originating from the third, fourth, and sixth pharyngeal arches. Muscles
from fourth and sixth not shown.
▪ Pouch gives rise to internal auditory ▪ Dorsal portion of fourth pouch becomes
meatus, AKA middle ear, eustachian tube superior parathyroid gland
▪ Ventral portion becomes ultimo-pharyngeal
Second-fourth clefts body
▪ Fade as embryo grows ▫ Contains cells which differentiate into
▫ Cells lining second pharyngeal pouch parafollicular/C-cells, migrate into
multiply, migrate to form primitive tonsils thyroid
Third, fourth pouches Thyroid and parathyroid glands
▪ Both divide into dorsal, ventral portions ▪ Thyroid develops from endoderm at base
▪ Dorsal portion of third pouch becomes of tongue independent of pharyngeal
inferior parathyroid gland apparatus, descends down neck
▪ Ventral portion becomes primitive thymus ▪ Parathyroid glands latch onto thyroid
▫ Later descends down to chest
OSMOSIS.ORG 251
Figure 30.5 Thyroid develops from endoderm at base of tongue independent of pharyngeal
apparatus, descends down neck. Parathyroid glands latch on as it passes by them.
DEVELOPMENT OF TEETH
osms.it/development-of-teeth
▪ Tooth development, AKA odontogenesis, ▪ As enamel thickens, ameloblasts retreat
involves epithelial, neural crest-derived into stellate reticulum, regress
mesenchymal interaction ▪ Also form enamel knot, which regulates
▪ Week 6: basal layer of oral epithelium has early tooth development
formed C-shaped dental lamina
Root formation
▫ Gives rise to 10 dental buds in each jaw
▪ Inner and outer dental epithelial layers
Cap stage invade underlying mesenchyme, form
▪ Invagination of deep surface of buds → epithelial root sheath
dental cap ▪ Pulp begins to narrow as more dentin laid
▪ Each dental cap consists of: down
▫ Outer dental epithelium ▫ Forms canal containing nerves, blood
▫ Inner dental epithelium vessels
▫ Central core of stellate reticulum ▪ Mesenchymal cell differentiation
▪ Mesenchyme forms dental papilla, which ▫ Cementoblasts produce cementum
form odontoblasts (AKA type of specialized bone)
▫ Produce dentin ▫ Periodontal ligament gives structural
integrity to tooth
▪ Remainder of dental papilla forms pulp
▪ As root lengthens, it pushes crown into oral
Bell stage cavity
▪ Dental cap grows, indentation deepens, ▫ Deciduous teeth (AKA milk teeth) arise
forming bell-shaped configuration 6–24 months of age
▪ Inner dental epithelium cells transform into ▪ Permanent teeth buds form during third
ameloblasts month of development, remain dormant
▫ Produce enamel deposited over dentin until sixth year of life
252 OSMOSIS.ORG
DEVELOPMENT OF THE BRAIN

osms.it/development-of-the-brain
DEVELOPMENT OF BRAIN ▫ Innervation: striated muscle of
VESICLES pharyngeal arches, AKA pharynx
▪ Neural plate folds, forming neural tube ▪ General visceral efferent
▪ Rostral region develops into brain ▫ Cranial nerve III (metencephalon); IX, X
▪ Week 4: primary brain vesicles develop (myelencephalon)
▪ Week 6: vesicles develop ▫ Innervation: parasympathetic pathway
to sphincter pupillae; smooth muscles of
Primary vesicle: forebrain/prosencephalon airways, heart, salivary glands, viscera
▪ Secondary vesicles
Alar plate neuroblasts
▫ Telencephalon: cerebral hemispheres,
caudate, putamen, amygdaloid, ▪ Contain three groups of sensory relay
claustrum, laminal terminalis, olfactory nuclei
bulbs, hippocampus ▪ General visceral afferent
▫ Diencephalon: epithalamus, ▫ Cranial nerve X (myelencephalon)
subthalamus, thalamus, hypothalamus, ▫ Innervation: viscera, AKA
mammillary bodies, neurohypophysis, gastrointestinal tract
pineal gland, globus pallidus, renina, iris, ▪ Special afferent
ciliary body, optic nerve (CN II), optic ▫ Cranial nerves VII, IX (metencephalon,
chiasm, optic tract myelencephalon); VIII (metencephalon)
Primary vesicle: midbrain/mesencephalon ▫ Innervates: tongue, palate, epiglottis,
▪ Secondary vesicle AKA taste; cochlea, semicircular canals,
AKA balance, hearing
▫ Mesencephalon
▪ General somatic afferent
Primary vesicle: hindbrain/ ▫ Cranial nerves V, VII (metencephalon);
rhombencephalon IX (myelencephalon)
▪ Secondary vesicles ▫ Innervation: touch, temperature, pain in
▫ Metencephalon: pons, cerebellum head, neck
▫ Myelencephalon: medulla
MYELENCEPHALON
DEVELOPMENT OF HINDBRAIN/ ▪ Gives rise to medulla oblongata
RHOMBENCEPHALON ▫ Transitional zone between brain, spinal
▪ Alar, basal plates separated by sulcus cord
limitans ▪ Alar plate sensory neuroblasts give rise to
▫ Cochlear nuclei, vestibular nuclei, spinal
Basal plate
trigeminal nucleus, solitary nucleus,
▪ Contains three groups of motor nuclei dorsal column nuclei, inferior olivary
▪ General somatic efferent nuclei
▫ Cranial nerves III, IV, VI ▪ Basal plate motor neuroblasts give rise to
(metencephalon); XII (myelencephalon) ▫ Nuclei of CN X, IX, XI
▫ Innervation: somatic striated muscle ▪ Roof plate lined by ependymal cells covered
(extrinsic eye muscles, tongue) by vascular mesenchyme, AKA pia mater
▪ Special visceral efferent ▫ Collectively known as tela choroidea
▫ Cranial nerves V, VII (metencephalon); ▫ Projects into ventral cavity, invaginations
IX, X (myelencephalon) form choroid plexus
OSMOSIS.ORG 253
▫ Choroid plexus produces cerebrospinal DEVELOPMENT OF THE
fluid PROSENCEPHALON
Diencephalon
METENCEPHALON ▪ Develops from median portion of
▪ Develops from rostral rhombencephalon, prosencephalon
gives rise to cerebellum, pons ▪ Consists of one roof plate, two alar plates;
Cerebellum basal plate regresses
▪ Functions as center for coordination, ▪ Alar plates give rise to
posture ▫ Epithalamus: also develops from
▪ Neuroectoderm cells proliferate roof plate; gives rise to pineal body,
habenular nuclei, commissure, posterior
▫ In ventricular zone, form cerebellar
commissure, tela choroidea, third
nuclei, Purkinje cells, golgi cells
ventricle choroid plexus
▫ In external germinal layer, form basket,
▫ Thalamus: gives rise to thalamic
granule, stellate cells
nuclei, lateral geniculate body, medial
▫ External, internal germinal layers form geniculate body
astrocytes, oligodendrocytes, Bergmann
▫ Subthalamus: gives rise to subthalamic
cells
nucleus; zona incerta; lenticular,
Pons thalamic fasciculi (AKA fields of Fortel)
▪ Serves as pathway for nerve fibers ▫ Hypothalamus: also develops from floor
between spinal cord, cerebrum, cerebellum plate; gives rise to hypothalamic nuclei,
mammillary bodies, neurohypophysis
▪ Base of pons contains
▪ Optic vesicles, cups, stalks derivatives of
▫ Pontine nuclei from alar plate
diencephalon
▫ Corticobulbar, corticospinal,
▫ Give rise to retina, iris, ciliary body, CN II,
corticopontine fibers from cell bodies in
optic tract
cerebral cortex; pontocerebellar fibers
▪ Hypophysis (AKA pituitary) develops from
▫ Alar plate sensory neuroblasts (CN V,
two different structures
CN II, CN III)
▪ Anterior lobe/adenohypophysis
▫ Basal plate motor neuroblasts (CN V,
CN VI, CN VII) ▫ Develops from Rathke’s pouch
▫ Ectodermal diverticulum of primitive oral
cavity/stomodeum
DEVELOPMENT OF
▪ Posterior lobe/neurohypophysis
MESENCEPHALON
▫ Develops from the infundibulum
▪ Gives rise to midbrain
▫ Neuroectodermal evagination of
▪ Basal plate neuroblasts give rise to motor
hypothalamus
nuclei
▫ Oculomotor (III) nucleus → general Telencephalon
somatic efferent column ▪ Gives rise to cerebral hemispheres, caudate,
▫ Edinger–Westphal nucleus of putamen, amygdaloid, claustrum, lamina
oculomotor nerve (III) → general visceral terminalis, olfactory bulbs, hippocampus
efferent ▪ Week 5: cerebral hemispheres begin
▫ Substantia nigra emerging as two outpocketings of
▫ Red nucleus prosencephalon
▫ Trochlear (IV) nucleus, part of CN V ▫ Contain cerebral cortex, white matter,
migrate to metencephalon lateral ventricles
▪ Alar plate sensory neuroblasts gives rise to
Basal ganglia
superior, inferior colliculi
▪ Basal part of hemispheres grow, bulge into
▪ Crus cerebri contains corticobulbar,
the lateral ventricles, giving rise to part of
corticospinal, corticopontine fibers
hemisphere wall (AKA corpus striatum)
254 OSMOSIS.ORG
▪ Expands: gives rise to caudate nucleus, ▪ Neocortex: AKA isocortex

putamen, amygdaloid nucleus, claustrum ▪ Allocortex: subdivided into 2 parts
▪ Divided by fibers of internal capsule ▫ Archicortex: includes hippocampal
▫ Single layer of ependymal cells form formation
choroid plexus ▫ Paleocortex: includes olfactory cortex
▫ Thickened wall of hemisphere forms ▪ Telencephalon also gives rise to olfactory
hippocampus bulbs, tracts
▫ Only globus pallidum arises from
neuroblasts of subthalamus that
migrated into the hemispheres
DEVELOPMENT OF COMMISSURES
▪ Bundles of nerve fibers connecting
Hemispheres corresponding areas in right, left
▪ Rapid, extensive growth of hemispheres hemispheres
creates many convolutions (AKA gyri) ▪ Cross in midline of brain via lamina
▫ Separated by grooves (AKA sulci) terminalis (AKA commissural plate)
fissures ▪ Anterior commissure
▪ Hemispheres develop frontal, parietal, ▫ Appears first
occipital, temporal lobes, which overlie ▫ Connects olfactory bulbs, middle,
insula inferior temporal gyri
▪ Hippocampal commissure/fornix
Cerebral cortex
commissure
▪ Develops from paleopallium/archipallium,
▫ Appears second
neopallium
▫ Fibers arise in hippocampus → connect
▪ Initially has neuroepithelial, mantle,
to lamina terminalis → mammillary
marginal layers
body, hypothalamus
▪ Neuroblasts proliferate, migrate to subpial
▪ Corpus callosum
regions to differentiate into mature neurons
▫ Appears third
▫ Continues until all layers are formed
▫ Largest commissure
▪ Early formed neuroblasts have deep
position in cortex, whereas later formed ▫ Forms bundle in lamina terminalis,
neuroblasts more superficially positioned connects two homologous neocortical
areas of cerebral hemispheres
▪ Classified into neocortex, allocortex
OSMOSIS.ORG 255
DEVELOPMENT OF
CRANIAL NERVES & AUTONOMIC
NERVOUS SYSTEM
osms.it/development-cranial-nerves-ANS
DEVELOPMENT OF CRANIAL ▫ Neural crest cells give rise to
NERVES postganglionic sympathetic neurons of
▪ By week 4: nuclei for all cranial nerves sympathetic chain ganglia, prevertebral
present sympathetic ganglia, adrenal chromaffin
▪ Except olfactory (I), optic (II) nerves, all cells
cranial nerves arise from hindbrain ▪ Cell bodies of preganglionic neurons reside
▪ Motor nuclei derived from rhombomeres at T1–L2 of spinal cord
produced by neuroepithelium ▪ Preaortic ganglia located at major vessel
▫ Gives rise to motor nuclei of cranial branches
nerves IV, V, VI, VII, IX, X, XI, XII
Parasympathetic nervous system
▫ Motor neurons for these nuclei reside
▪ Ganglia arise from basal plate of neural
within brain
tube, neural crest cells
▪ Cranial nerve sensory ganglia originate
▫ Basal plate gives rise to preganglionic
from neural crest cells, ectodermal placodes
parasympathetic neurons of cranial
nerve nuclei—CN III (midbrain), CN VIII
DEVELOPMENT OF AUTONOMIC (pons), CN IX, X (medulla), spinal cord at
NERVOUS SYSTEM S2–S4
▪ Comprised of efferent motor fibers ▫ Neural crest cells give rise to
▫ Innervate smooth muscle, cardiac postganglionic parasympathetic
muscle, secretory glands neurons of ciliary ganglion (CN III),
▫ Divided into sympathetic, pterygopalatine ganglion (CN VII),
parasympathetic systems submandibular ganglion (CN VII), enteric
ganglion (Meissner, Auerbach, CN X),
Sympathetic nervous system ganglia of abdominal, pelvic cavities
▪ Ganglia arise from basal plate of neural ▪ Neuron cell bodies reside in brainstem, S2–
tube, neural crest cells S4 of spinal cord
▫ Basal plate gives rise to preganglionic
sympathetic neurons in intermediolateral
horns of spinal cord
256 OSMOSIS.ORG
DEVELOPMENT OF THE
SPINAL CORD
osms.it/development-spinal-cord
NEURAL TUBE ▫ Contain sympathetic portion of
▪ Neural plate folds in cephalocaudal manner, autonomic nervous system
forming neural tube ▪ Dorsal midline portion (AKA roof plate)
▫ Open at each end, forming cranial, ventral midline portion (AKA floor plate) of
caudal neuropores neural tube do not contain neuroblasts
▪ Three layers: neuroepithelial cells/ ▫ Serve as crossover pathways
ventricular zone, mantle layer/intermediate
zone, marginal layer/outermost layer CELL DIFFERENTIATION
Neuroepithelial cells Development of nerve cells
▪ Form thick layer of pseudostratified ▪ Start out as round, apolar cells
epithelium
▪ Differentiate as primitive axons, dendrites
▫ Rapid division forms more develop
neuroepithelial cells, produces
▫ Bipolar neuroblast differentiates into
neuroepithelium
multipolar neuroblast
▫ Neuroepithelium gives rise to
▫ Eventually develops into neuron
neuroblasts (AKA primitive nerve cells)
Development of glial cells
Mantle layer
▪ Glioblasts formed by neuroepithelial cells
▪ Forms around neuroepithelial layer
that migrate to the mantle and marginal
▪ Composed of neuroblasts that migrated layers
from neuroepithelial layer
▪ Differentiate into glial cells
▪ Gives rise to gray matter of spinal cord
▫ Protoplasmic astrocytes, fibrillar
Marginal layer astrocytes: provide support, metabolic
▪ Contains neuroblast nerve fibers functions
▪ Gives rise to white matter ▫ Oligodendroglial cells: myelination in
CNS
▪ Myelination → color
▫ Microglia cells: phagocytic activity
Thickening of mantle layer ▪ Neuroepithelial cells cease to produce
▪ Ventral, dorsal thickening occurs as more neuroblasts, glioblasts
neuroblasts form ▫ Differentiate into ependymal cells, which
▪ Ventral thickening produces basal plates line central canal of spinal cord
▫ Basal plates form ventral motor horn of
spinal cord DEVELOPMENT OF SPINAL NERVES
▪ Dorsal thickening produces alar plates AND GANGLIA
▫ Alar plates form dorsal sensory horn of ▪ Week 4: development of spinal nerves
spinal cord begins
▪ Sulcus limitans divides basal, alar plates ▪ Motor nerve fibers arise from cell bodies in
▪ Intermediate horn develops between motor, basal plates (AKA ventral horns)
sensory horns ▫ Form bundles (AKA ventral motor roots)
▫ Located at T1–T12, L2/L3 ▪ Processes from nerve cell bodies in spinal
cord ganglia
OSMOSIS.ORG 257
▫ Form bundles (AKA dorsal sensory ▫ Originate from neural crest cells
roots) ▫ Each Schwann cell myelinates just one
▪ Spinal nerves split into rami containing both axon of peripheral nerve, wrapping
motor, sensory fibers around axon to form neurilemma (AKA
▪ Dorsal primary rami myelin, sheath)
▫ Innervate dorsal axial musculature,
Myelination in CNS
vertebral joints, skin of back
▪ Carried out by oligodendrocytes
▪ Ventral primary rami
▫ One oligodendrocyte can myelinate ≤
▫ Innervate limbs, ventral body wall
50 axons
▫ Form brachial, lumbosacral plexus
▫ Myelination of corticospinal tracts
incomplete until first one-two years of
MYELINATION OF THE NERVOUS postnatal life
SYSTEM
Myelination in PNS
▪ Carried out by Schwann cells
DEVELOPMENT OF THE EAR

osms.it/development-of-the-ear
▪ Comprised of internal, middle, outer ear ▪ Week 7: cochlear duct cells give rise to
spiral organ of Corti
DEVELOPMENT OF THE INTERNAL ▫ Cochlear duct remains connected to
EAR saccule via ductus reuniens
▪ Around day 22, otic placodes formed ▫ Mesenchyme surrounding cochlear duct
differentiates into cartilaginous shell
▪ Ectoderm thickens each side of
rhombencephalon ▪ Week 10: large vacuoles appear in cartilage
▪ Sides invaginate, form otic/auditory vesicles ▫ Form two perilymphatic spaces: scala
(AKA otocysts) vestibuli, scala tympani
▪ Otocystic cells of vesicles differentiate ▫ Cochlear duct now separated from scala
into ganglion cells for vestibulocochlear/ vestibuli by vestibular membrane, from
statoacoustic ganglia scala tympani by basilar membrane
▪ Each vesicle divides, forming two ▫ Lateral wall of cochlear duct remains
components that will become membranous attached to cartilage by spiral ligament
labyrinth ▫ Median angle of cochlear duct
▫ Ventral component: forms saccule, connected to cartilaginous process
cochlear duct called modiolus
▫ Dorsal component: forms utricle,
semicircular canals, endolymphatic duct DEVELOPMENT OF ORGAN OF
CORTI
DEVELOPMENT OF THE COCHLEA ▪ Epithelial cells of cochlear duct form two
ridges
▪ Week 6: cochlear duct forms as saccule
forms tubular outgrowth ▫ Inner ridge gives rise to spiral limbus
▫ Cochlear duct spirally penetrates ▫ Outer ridge gives rise to sensory hair
mesenchyme cells of auditory system
▫ Completes 2.5 turns by week 8 ▪ Tectorial membrane covers sensory cells
258 OSMOSIS.ORG
while attached to spiral limbus Ossicles

▫ Sensory cells, tectorial membrane: ▪ Appear during the first half of fetal life
organ of Corti ▪ Remain embedded in mesenchyme until it
dissolves in eighth month
DEVELOPMENT OF SEMICIRCULAR ▫ Space around ossicles forms
CANALS ▪ Endodermal epithelium of primitive
▪ Week 6: flattened outpouchings appear on tympanic cavity covers space’s wall
dorsal component/utricle of otic vesicle ▫ Connects ossicles to cavity wall like
▫ Central portion of their walls eventually mesentery
disappear, semicircular canals develop ▪ During late fetal life, tympanic cavity
▪ Each canal has two ends expands dorsally to form tympanic antrum
▫ Crus ampullare: dilated end ▪ After birth, epithelium of tympanic cavity
▫ Crus nonampullare: does not dilate extends to the mastoid process
▫ Cells in ampullae form crista ampullaris ▫ Forms air sacs (AKA pneumatization)
▪ Maculae acusticae develop in walls of ▫ Mastoid air sacs communicate with
utricle, saccule tympanic antrum, tympanic cavity
▫ Maintenance of equilibrium: change
in position of head, body generates DEVELOPMENT OF THE EXTERNAL
impulses in sensory cells of cristae, EAR
maculae; carried by cranial nerve VIII/ ▪ External auditory meatus derived from
vestibular fibers dorsal portion of first pharyngeal cleft
▪ During third month, epithelial cells of
DEVELOPMENT OF THE MIDDLE meatus’ floor proliferate, form solid
EAR epithelial plate (AKA meatal plug)
▪ Composed of tympanic cavity, Eustachian ▫ During seventh month meatal plug
tube/auditory tube dissolves, creating definitive eardrum
▪ Tympanic cavity develops from first ▫ Meatal plug persists until birth →
pharyngeal pouch/endoderm congenital deafness
▪ Pouch expands, reaches floor of first ▪ Composition of eardrum
pharyngeal cleft ▫ Ectodermal epithelial lining of auditory
▫ Distal part of pouch widens, becomes meatus
primitive tympanic cavity ▫ Endodermal epithelial lining of tympanic
▫ Proximal part remains narrow, becomes cavity
auditory tube ▫ Intermediate mesoderm layer of
connective tissue
DEVELOPMENT OF THE OSSICLES ▪ Auricle
▫ Auricle develops from six mesenchymal
Malleus and incus proliferations/auricular hillocks at dorsal
▪ Derived from cartilage of first pharyngeal ends of first, second pharyngeal arches
arch surrounding first pharyngeal cleft
▫ Tensor tympani muscle innervated by ▫ These proliferations later fuse, form
mandibular branch of trigeminal nerve definitive auricle
Stapes
▪ Derived from cartilage of second arc
▫ Stapedius muscle innervated by facial
nerve
OSMOSIS.ORG 259
DEVELOPMENT OF THE EYE
osms.it/development-of-the-eye
KEY POINTS Iris
▪ Day 22: begins with formation of optic ▪ Three layers
grooves on both sides of forebrain ▪ Outer, pigmented layer of optic cup
▪ As neural tube closes, optic grooves form ▪ Inner, neural layer of optic cup
outpouchings (AKA optic vesicles) ▪ Richly vascularized connective tissue layer
▪ Optic vesicles reach surface ectoderm, containing pupillary muscles
induce lens formation ▫ Sphincter, dilator pupillae develop from
▫ Optic vesicles invaginate, form double ectoderm of optic cup
layered optic cups ▪ Pars ciliaris retinae
▫ Inferior surface of optic cup forms ▫ Externally covered by mesenchyme
choroid fissure pathway for hyaloid layer, forms ciliary muscle
artery
▫ Internally connected to lens by
▪ Week 7: choroid fissure closes, gives rise to suspensory ligament/zonula
pupil
▪ Ectoderm cells elongate, form lens placode
▪ Lens placode invaginates, forms lens
DEVELOPMENT OF THE LENS
vesicle ▪ Cells of optic vesicles elongate, fill lumen of
vesicle with primary lens fibers
▫ End of week 7: fibers reach anterior
DEVELOPMENT OF THE RETINA vesicle wall
▪ Optic cup has two layers ▫ Secondary fibers area added to central
▫ Inner, outer layer initially separated by core
intraretinal space; obliterated in adult
▫ Outer/pigmented layer: gives rise to
pigmented layer of retina
DEVELOPMENT OF CHOROID,
SCLERA & CORNEA
▫ Inner/neural layer: gives rise to neural
▪ End of week 5: loose mesenchyme
layer of retina
surrounds eye primordium, differentiates
▪ Posterior 4/5: pars optica retinae into 2 layers
▪ Cells bordering the intraretinal space ▫ Inner layer: similar to pia mater, forms
differentiate into rods and cones highly vascularized pigmented layer,
▪ Adjacent mantle layer: gives rise to AKA choroid
neurons and supporting cells ▫ Outer layer: continuous with dura mater,
▫ Outer, inner nuclear layers, ganglion cell forms sclera
layer ▪ Anterior chamber forms on anterior aspect
▪ Surface fibrous layer contains nerve cell of the eye
axons of deeper layers ▫ Splits loose mesenchyme via
▫ Nerve fibers converge towards optic vacuolization
stalk ▫ Inner layer: iridopupillary membrane,
▫ Optic stalk develops into optic nerve sits in front of lens, iris
▪ Anterior 1/5: pars ceca retinae ▫ Outer layer: substantia propria of
▫ Pars iridica retinae: forms inner layer of cornea, continuous with sclera
iris ▪ Cornea now contains 3 layers
▫ Pars ciliaris retinae: forms ciliary body ▫ Epithelial layer derived from surface
ectoderm
260 OSMOSIS.ORG
▫ Substantia propria DEVELOPMENT OF THE OPTIC

▫ Epithelial layer bordering anterior NERVE
chamber ▪ Develops from optic stalk, which connects
▪ Posterior chamber: space between iris, lens optic cup to brain
▪ Anterior, posterior chambers filled with ▪ Initially, optic cup has ventral groove (AKA
aqueous humor produced by ciliary process choroid fissure)
of ciliary body ▫ Fissure contains hyaloid vessels
▫ Aqueous humor circulates from ▫ Nerve fibers of retina line stalk’s inner
posterior into anterior chamber through wall
pupil ▪ Week 7: choroid fissure closes
▫ In anterior chamber, fluid flows through ▫ Narrow tunnel forms inside optic stalk
canal of Schlemm (AKA scleral venous ▫ Nerve fibers fill tunnel, forming optic
sinus) at iridocorneal angle, resorbs into nerve
bloodstream
▪ Contents of optic nerve
▫ Inner layer provides neuroglia supports
DEVELOPMENT OF THE VITREOUS optic nerve fibers
BODY ▫ Hyaloid artery later transforms into
▪ Mesenchyme invades inside of optic cup central artery of retina
through choroid fissure ▪ Choroid: continuation of pia arachnoid,
▫ Forms hyaloid vessels, which supply sclera continuation of dura layer of nerve
lens during intrauterine life
▪ Invading mesenchyme also forms fibrous
network between lens, retina
▫ Interstitial spaces of network fill with
vitreous body
▪ During fetal life, hyaloid vessels eventually
disappear, replaced by hyaloid canal
OSMOSIS.ORG 261
NOTES
NOTES
ANATOMY & PHYSIOLOGY
ENDOCRINE
osms.it/endocrine-anatomy-and-physiology
ENDOCRINE GLANDS
▪ Secrete hormones directly into bloodstream
(exocrine glands use ducts)
▪ Maintain homeostasis by controlling
variables such as body temperature, fluid
balance
▫ Especially with negative feedback
mechanisms
HORMONES
▪ Can be classified as steroids/non-steroids Figure 31.1 Steroid hormones diffuse across
the target cell membrane and bind to an
Steroid hormones intracellular receptor. Peptide hormones
▪ Derived from cholesterol; produced in bind to a cell surface receptor. Both methods
adrenal glands, gonads (testes/ovaries) result in changes in gene expression.
▪ Hydrophobic/non-polar → travel through
bloodstream with transport proteins,
diffuse across target cell phospholipid HORMONE SECRETION &
membrane REGULATION
Non-steroid hormones Paracrine signaling
▪ Derived from peptides/proteins or single ▪ Effects of hormones released by nearby
amino acids cells; e.g. glucagon → activates alpha cells,
▪ Peptidic hormones are hydrophilic → bind inhibits beta cells
surface receptor proteins instead of passing
through target cell membrane Sympathetic nervous system
▪ Amino acid hormones derived from ▪ Epinephrine/norepinephrine alter secretion
tyrosine; generally hydrophilic (e.g. depending on adrenergic receptor type;
adrenaline/epinephrine and noradrenaline/ ▪ e.g. β2: activates beta cells
norepinephrine), apart from thyroid
hormones Parasympathetic nervous system
▪ Acetylcholine activates alpha cells and beta
cells via M3 receptors
262 OSMOSIS.ORG
Chapter 31 Endocrine Physiology: Endocrine Anatomy & Physiology
GLAND LOCATIONS & FUNCTIONS ▫ Hormones include antidiuretic hormone

▪ Endocrine glands scattered throughout (ADH/vasopressin), oxytocin
body ▫ ADH signals: ↑ blood osmolarity, ↓ blood
volume (ADH retains water from urine,
Hypothalamus constricts blood vessels → negative
▪ Located at base of brain feedback)
▪ Hypothalamus, brain work closely to make ▫ Oxytocin signals: childbirth (dilates
hormones that control other endocrine cervix, stimulates uterine contractions),
glands breastfeeding (contracts breast cells),
▪ Made up of several nuclei (neuron clusters) social interaction, orgasm
which secrete hormones ▪ Stimulatory pituitary hormones
▫ Thyrotropin releasing hormone (TRH):
Pituitary gland
pituitary secretes thyroid-stimulating
▪ Located just below brain; physically hormone (TSH) → thyroid produces
connected to hypothalamus by pituitary thyroid hormones
stalk (infundibulum)
▫ Corticotropin releasing hormone (CRH):
▪ Made up of anterior, posterior lobe pituitary secretes adrenocorticotropic
▪ Anterior pituitary: AKA adenohypophysis hormone (ACTH) → adrenal glands
▫ Made of glandular tissue produce cortisol
▫ Receives stimulatory, inhibitory ▫ Gonadotropin releasing hormone
hormones from hypothalamus via (GnRH): pituitary secretes
hypothalamo-hypophyseal-portal gonadotropins, e.g. follicle-stimulating
system hormone (FSH), luteinizing hormone
▪ Posterior pituitary: AKA neurohypophysis (LH) → gonads produce gametes
▫ Made of axons from hypothalamic (sperm for testes, oocytes for ovaries),
supraoptic, paraventricular nuclei sex hormones (testosterone, estrogen,
progesterone)
▫ Receives hormones directly from
hypothalamus ▫ Growth hormone releasing hormone
(GHRH): pituitary secretes growth
▫ Instead of producing own hormones,
hormone → growth of long bones,
posterior pituitary stores hormones for
tissues in body
later release
▪ Inhibitory pituitary hormones
▫ Herring bodies: axon dilations which
store hormones ▫ Growth hormone inhibiting hormone
(GHIH/somatostatin): pituitary secretes
less/no growth hormone
Figure 31.2 Endocrine glands’ location and the relationship between the hypothalamus and the
the pituitary gland’s two lobes.
OSMOSIS.ORG 263
▫ Prolactin inhibiting hormone ▪ Made of thousands of follicles which
(dopamine): pituitary secretes less/no synthesize triiodothyronine (T3), thyroxine
prolactin (no milk is produced whenever (T4)
not breastfeeding) ▫ In the cell T4 → T3
▫ T3 → ↑ basal metabolic rate
Pineal gland
▪ Parafollicular cells (C-cells) between
▪ Located behind hypothalamus, pituitary
follicles secrete calcitonin
gland
▪ Two parathyroid glands on back of
▪ Contains pinealocytes which synthesize
each thyroid lobe (four in total) secrete
melatonin
parathyroid hormone
▫ Melatonin mostly secreted during night,
▪ Calcitonin, parathyroid hormone work
regulates body’s circadian rhythm (body
similarly
clock)
▫ Control calcium, phosphate, bone
Thyroid gland metabolism
▪ Located at front of neck ▪ Regulated by blood calcium levels
▪ Left, right lobe
Figure 31.3 Pineal gland location and histological appearance of pinealocytes.
Figure 31.4 Follicular cells of the thyroid gland synthesize T3, T4; parafollicular cells secrete
calcitonin.
264 OSMOSIS.ORG
▫ Androgens: adrenals only source

of androgens in biologically-female
individuals; effects include ↑ libido, pubic
hair development, sebaceous gland
hypertrophy; minor role in biologically-
male adults
ENDOCRINE PANCREAS
▪ Located behind stomach
▪ Three sections
▫ Head, body, tail
▪ Has both endocrine, exocrine functions
Figure 31.5 The parathyroid glands are ▪ Contains hormone-producing cell clusters
found on the back of the thyroid. They ▫ Islets of Langerhans (1–2% of pancreas)
secrete parathyroid hormone. ▪ Produce hormones secreted directly into
bloodstream that regulate blood glucose
Adrenal glands Cell types

▪ Two glands situated retroperitoneally inside ▪ Alpha (ɑ) cells
renal fascia, each surrounded by fibrous ▫ 15–20% of total islet cells
capsule; sit on top of kidneys ▫ Produce glucagon
▫ Connective tissue separates them from ▫ ↓ blood glucose → glucagon secreted
kidney, renal fascia from diaphragm → hepatic glycogenolysis and
▫ One of the most vascularized tissues gluconeogenesis → glucose released
▫ Differ in shape (right shaped as pyramid, into bloodstream
left shaped as crescent moon) ▪ Beta (β) cells
▪ Outer layer (cortex) surrounding a core ▫ 65–80% of total islet cells
(medulla) ▫ Produce insulin, amylin
▪ Medulla: neuroectodermal origin; ▫ ↑ blood sugar → insulin secreted →
secretes catecholamines (e.g. adrenaline, anabolic functions: promotes glucose
noradrenaline) during “fight or flight” entry into cells, ↑ glycogen synthesis, ↓
situations lipolysis
▫ ↑ blood pressure, ↑ cardiac output, ↑ ▪ Gamma (ɣ) cells/PP cells
bronchial dilation, ↑ glycogenolysis ▫ 3–5% of total islet cells
▪ Cortex: makes up 80% of gland, ▫ Produce pancreatic polypeptide
mesodermal origin, secretes adrenocortical ▫ Secretion stimulated by meals high in
steroid hormones protein, hypoglycemia, physical activity,
▫ Three zones: zona glomerulosa (makes fasting; inhibits pancreatic exocrine
mineralocorticoids—e.g. aldosterone), (enzymes) and endocrine (insulin)
zona fasciculata (makes glucocorticoids), activity
zona reticularis (makes sex hormone ▪ Delta (δ) cells
precursors)
▫ 3–10% of total islet cells
▫ Aldosterone: regulates extracellular
▫ Produce somatostatin
fluid volume, potassium homeostasis;
involved in renin-angiotensin- ▫ Paracrine function of suppressing both
aldosterone system (RAAS); ↑ renal insulin and glucagon
water and sodium reabsorption, ↑ renal ▪ Epsilon (ε) cells
potassium excretion → ↑ blood pressure ▫ < 1% of total islet cells
▫ Cortisol: integral to stress response; ▫ Produce ghrelin
also has metabolic, anti-inflammatory, ▫ Functions in appetite stimulation
immunosuppressive, vascular effects;
regulated via hypothalamic-pituitary-
adrenal (HPA) axis
OSMOSIS.ORG 265
Figure 31.6 Location of the adrenal glands and the hormones secreted by the cortex, medulla.
Figure 31.7 The pancreas has both endocrine and exocrine functions. It has hormone-producing
clusters of cells called Islets of Langerhans.
266 OSMOSIS.ORG
OSMOSIS.ORG 267
NOTES
NOTES
PITUITARY HORMONES
GENERALLY, WHAT ARE THEY?

▪ Pituitary gland: AKA hypophyseal gland/ Thyrotropin-releasing hormone (TRH)
hypophysis ▪ Thyroid-stimulating hormone → thyroid
▪ Connected to hypothalamus via pituitary gland
stalk (infundibulum) which controls pituitary
secretory actions Prolactin (PL)
▪ Consists of two embryologically, ▪ Acts on breasts (lactogenesis)
functionally different parts that secrete ▫ Hypothalamus inhibits prolactin
different hormones production via dopamine
▫ TRH, estrogen, progesterone, oxytocin
stimulate prolactin
ANTERIOR PITUITARY
(ADENOHYPOPHYSIS)
▪ Connects to hypothalamus via blood POSTERIOR PITUITARY
vessels (hypophyseal portal system) (NEUROHYPOPHYSIS)
▪ Hypothalamus produces releasing ▪ Represents an extension of hypothalamus
hormones → pituitary secretes tropic ▪ Does not secrete its own hormones
hormones that regulate target tissues ▪ Stores, releases neurohormones
synthesized in hypothalamus
Corticotropin-releasing hormone (CRH)
▪ Adrenocorticotropic hormone (ACTH) → Vasopressin/antidiuretic hormone (ADH)
adrenal medulla ▪ Acts on kidney tubules, arterioles
Gonadotropin-releasing hormone (GnRH) Oxytocin
▪ Luteinizing hormone (LH), follicle- ▪ Acts on uterus, breasts
stimulating hormone (FSH) → ovaries,
testes
Growth hormone releasing hormone

(GHRH)
▪ Stimulates release of somatotropin/
growth hormone (GH) → various tissues
throughout body
268 OSMOSIS.ORG
Chapter 32 Endocrine Physiology: Pituitary Hormones
ADRENOCORTICOTROPIC HORMONE
(ACTH)
osms.it/adrenocorticotropic-hormone
▪ Hormone secreted by anterior pituitary STIMULATION OF ACTH RELEASE
corticotropic cells ▪ Corticotropin releasing hormone (CRH)
▪ Main action of ACTH involves stimulating secreted by hypothalamus
adrenocortical cells of zona fasciculata ▫ Stress, low blood glucose, low
of the adrenal cortex to secrete glucocorticoid levels, increased
glucocorticoids (primarily cortisol) sympathetic activity, normal diurnal
▫ Anti-inflammatory effects rhythm
▫ Increases blood glucose levels ▫ Release of ACTH demonstrates
▫ Increases fat and protein breakdown circadian rhythm affected by
suprachiasmatic nucleus → low evening
concentrations, high in morning
SYNTHESIS
▪ Pre-pro-opiomelanocortin (pre-POMC)
→ proopiomelanocortin (POMC) → ACTH RELEASE REGULATION
ACTH, gamma lipotropin, beta endorphin, ▪ ACTH release is regulated by
melanocyte-stimulating hormone hypothalamic-pituitary-adrenal axis
negative feedback
▫ Hypothalamus releases CRH → CRH
stimulates pituitary to release ACTH
→ ACTH stimulates adrenal cortex to
secrete cortisol → ↑ cortisol inhibits
hypothalamic release of CRH → ↓CRH
decreases ACTH secretion → closed
loop
ACTH SIGNALING PATHWAY

▪ ACTH binds to ACTH receptor on adrenal
cortex adrenocorticotropic cells, primarily
zona fasciculata; also expressed in skin,
both white, brown adipocytes
▪ ACTH receptor is a seven-membrane-
spanning G-coupled receptor
▪ ACTH binds to receptor → activates Gs
protein → α subunit released → activates
adenylate cyclase → ↑ cAMP → activates
protein kinase A → phosphorylation
cascade → transcription factor activation →
effects
Figure 32.1 Synthesis of ACTH in the

anterior pituitary. Corticotropin releasing
hormone (CRH) stimulates the cell to release
ACTH.
OSMOSIS.ORG 269
Figure 32.3 ACTH receptors are found on
adrenocortical cells in the zona fasciculata of
the adrenal cortex, as well as on melanocytes
in the skin.
Figure 32.2 The negative feedback loop
which regulates ACTH release.
270 OSMOSIS.ORG
GROWTH HORMONE (GH)

osms.it/growth-hormone
▪ AKA somatotropin
▪ Peptide hormone secreted by somatotropic
cells of anterior pituitary
▫ Regulates tissue growth
▪ Released in pulsatile manner every two
hours; peaks one hour after falling asleep
REGULATION OF SECRETION
Induction of GH release
▪ Hypoglycemia, ↑ estrogen, testosterone
(puberty), stress (e.g. trauma, fever),
exercise, sleep stages III, IV
Three negative feedback loops

▪ ↓ GH stimulates hypothalamus to release
GHRH → ↑ GHRH stimulates pituitary
to release GH → ↑ GH inhibits release of
GHRH → absence of GHRH inhibits GH
release → closed loop
▪ ↑ GH stimulates somatomedins Figure 32.4 The three negative feedback
production in the liver, bones, muscles → loops that regulate GH secretion, each
somatomedins inhibit GH release highlighted in a different colour. GH
▪ ↑ GH and somatomedins stimulate and somatomedin together stimulate
somatostatin production in hypothalamus somatostatin production in the hypothalamus,
→ somatostatin inhibits GH release which inhibits GH release.
GH SIGNALING PATHWAY EFFECTS OF GH

▪ Growth hormone receptor (GHR) belongs ▪ Primary effect of GH is cell metabolism
to cytokine receptor family stimulation, growth, division
▪ To activate intracellular signaling, GH must
bind to two GH receptors → dimerization Direct effects
of GHR ▪ Anti-insulin-like effects
▪ GH binds to receptor → conformational ▪ Carbohydrates: ↑ blood glucose levels
change → key tyrosine residue ▫ Stimulates gluconeogenesis,
phosphorylation → activation of tyrosine glycogenolysis in liver
kinase JAK2 → STAT5, Src family kinases, ▫ Increases tissue insulin resistance
insulin receptor substrate (IRSs) signalling
▪ Fats: ↑ fatty acids in blood
molecule activation → gene transcription,
effects ▫ Stimulates adipose tissue lipolysis
Indirect effect
▪ Insulin-like effects through insulin-like
growth factors (e.g. somatomedins like
IGF-1)
▪ Stimulates cell growth, division, and
differentiation; reduces apoptosis
OSMOSIS.ORG 271
▪ Proteins: anabolic effect
▫ Stimulates amino acid, protein uptake
▫ Stimulates protein synthesis
▫ Decreases protein breakdown
▪ Epiphyseal plates, cartilage
▫ Stimulates bone osteoblast activity,
cartilage chondrocyte activity →
increased linear growth
THYROID-STIMULATING HORMONE
(TSH)
osms.it/thyroid-hormone
▪ AKA thyrotropin TSH SIGNALING PATHWAY
▪ Glycoprotein hormone secreted by pituitary ▪ TSH binds TSH receptor primarily found on
gland thyroid gland follicular cells
▪ Main action of TSH involves stimulating ▫ Also found on adipose tissue,
thyroid gland growth, thyroid hormone fibroblasts
synthesis, release ▪ TSH receptor is integral membrane receptor
coupled with Gs protein
STIMULATION OF TSH RELEASE ▪ TSH binds to receptor → activates Gs
▪ Thyrotropin-releasing hormone (TRH) protein → α subunit released → activates
secreted by hypothalamus adenylate cyclase → ↑ cAMP → activates
▫ Low T3, T4 blood levels
▫ Decreased metabolism effects
▫ Cold stress
▫ Conditions that increase ATP demand
EFFECTS OF TSH
▪ TSH has two effects on the thyroid gland
REGULATION OF SECRETION ▫ Stimulates all the steps in thyroid
▪ TRH secreted by hypothalamus, stimulates hormone synthesis, secretion
pituitary thyrotropic cells to release TSH ▫ Trophic effect: increases growth of
▪ Thyroid hormones, specifically T3, down- thyroid gland
regulate TRH receptors on thyrotropic cells,
inhibiting TSH secretion
▪ TSH release, thyroid hormone is regulated
by negative feedback loop
▫ Hypothalamus releases TRH → TRH
stimulates pituitary to release TSH
→ TSH travels to thyroid follicle →
stimulates thyroid hormones synthesis,
secretion → thyroid hormones inhibit
both TRH, TSH release → absence
of TRH, TSH inhibits further thyroid
hormone secretion → closed loop
272 OSMOSIS.ORG
THYROID HORMONE
osms.it/thyroid-hormone
▪ Glycoprotein hormones T3 basolateral side via Na+/I- symport

(triiodothyronine), T4 (tetraiodothyronine) ▪ Iodine exits cell on apical side via
secreted by thyroid follicular epithelial cells transporter pendrin
▪ Less active form thyroid hormone (T4) is ▪ Inside follicle lumen at apical side, iodine
secreted, converted in target tissue into oxidized by enzyme thyroid peroxidase (I-
more active form (T3) → I2)
▪ I2 iodinates TG tyrosyl residues
(organification of I2), catalyzed by thyroid
SYNTHESIS OF THYROID HORMONES
peroxidase, forms monoiodotyrosine (MIT),
Six steps diiodotyrosine (DIT)
▪ Thyroglobulin (TG) synthesized in follicular ▪ On TG, two DIT molecules coupled to form
cell rough endoplasmic reticulum (RER), T4 (faster reaction); MIT coupled with DIT to
secreted into lumen (colloid) form T3 → TG now contains T3, T4, MIT, DIT
▪ Iodine from blood enters follicular cells on residues
Figure 32.5 Thyroid hormone synthesis overview. 1. Thyroglobulin (TG) is synthesized in rough
endoplasmic reticulum, secreted into colloid. 2. Iodine enters cell from blood via Na+/I- symporter.
3. Iodine exits cell into colloid via pendrin. 4. Iodine is oxidized by thyroid peroxidase, become I2
5. I2 iodinates tyrosyl residues on TG, forming monoiodotyrosine (MIT), diiodotyrosine (DIT). 6.
Two DITs combine to form T4; MIT combines with DIT to form T3.
OSMOSIS.ORG 273
THYROID HORMONE SECRETION ▪ Starvation inhibits 5’-deiodinase in target
AND TRANSPORT tissue, except in brain → lowers O2
consumption, basal metabolic rate (BMR)
Thyroid hormone secretion
▪ Thyroid hormones stored in colloid until
stimulated for secretion REGULATION OF SECRETION
▫ TSH stimulation → endocytosis of Negative feedback loop
iodinated TG by follicular epithelial cells ▪ Regulated by negative feedback loop in
→ TG transportation to basal membrane hypothalamic-pituitary-thyroid axis
→ TG fuses with lysosome → TG
▫ Thyrotropin-releasing hormone (TRH)
hydrolysis, T3, T4, MIT, DIT residue
secreted by hypothalamus, stimulates
release → T3 (10%), T4 (90%) secreted
thyrotropic cells of pituitary to release
into circulation
thyroid-stimulating hormone (TSH)
▫ Iodide from MIT, DIT residues recycled
for next synthesis Effects of TSH on thyroid gland
▪ Two effects
Transport of thyroid hormones
▫ Stimulates all steps in thyroid gland
▪ Once in circulation, most thyroid hormones
synthesis, secretion
travel bound to thyroxine-binding protein
(TBP) ▫ Trophic effect: increases thyroid gland
growth
▫ Some bound to prealbumin, albumin
▪ Small fraction travels unbound → Other regulatory factors
physiologically active forms ▪ Iodine deficiency
Activation of T4 ▪ Excessive iodine intake (Wolff–Chaikoff
effect)
▪ 90% of secreted thyroid hormone is in less
active T4 form ▫ Inhibits iodine organification
▪ T4 activated in target tissue by ▪ 5’-deiodinase deficiency (e.g. starvation)
5’-deiodinase → removes one atom of I2 → ▪ ↓ TBP synthesis (e.g. liver failure)
T4 gets converted to T3 ▫ Increases unbound (active) thyroid
hormones fraction
Figure 32.6 Thyroid hormone secretion overview. 1. TG in colloid is endocytosed into follicular
cell. 2. Lysosome fuses with vesicle; thyroid hormones are cleaved from TG.
3. Hormones are released into blood. 4. In blood, most thyroid hormones travel bound to a
protein, thyroxine-binding protein being most common.
274 OSMOSIS.ORG
▫ ↑ catecholamine, glucagon, growth

hormone activity → ↑ proteolysis,
lipolysis, gluconeogenesis
▪ Cardiovascular system
▫ ↑ β1 adrenergic receptors, Ca2+ ATPase
→ ↑ inotropic (contractility), chronotropic
(heart rate) effect → ↑ cardiac output
▪ Central nervous system (CNS)
▫ Gestational period → CNS development
▫ Adult period → ↑ brain activity, attention
span, memory
▪ Growth
▫ ↑ osteoblast, osteoclast activity → ↑
bone formation, maturation
Figure 32.7 The negative feedback loop

which regulates thyroid hormone secretion.
SIGNALING PATHWAY
▪ Thyroid hormones act on all organ systems
▪ Inside target cells, T4 converts to T3 → T3
enters nucleus, binds nuclear receptor → T3 Figure 32.8 In the target cell, T4 is converted
receptor complex binds DNA, stimulates to T3, which enters the nucleus and binds to a
transcription → translation → protein receptor. The receptor complex binds to DNA
synthesis to stimulate transcription.
▪ T3 stimulates synthesis of Na+-K+ ATPase,
Ca2+ ATPase, transport proteins, proteolytic,
lysosomal enzymes, β1 adrenergic
receptors, structural proteins
EFFECTS OF THYROID HORMONE

▪ Key hormone in regulating body
metabolism; also important for
embryological growth
▪ General effect: all tissues except brain,
spleen and gonads
▫ ↑ Na+-K+ ATPase → ↑ oxygen
consumption → ↑ basal metabolic rate
(BMR), body temperature
▪ Catabolic effect: metabolism of
macromolecules
▫ ↑ transport proteins → ↑ glucose
absorption from GI tract
OSMOSIS.ORG 275
NOTES
NOTES
ADRENAL HORMONES
SYNTHESIS OF ADRENOCORTICAL
HORMONES
osms.it/adrenocortical-hormone-synthesis
▪ Synthesized from cholesterol: carbon ▪ Different enzymes found in different layers

skeleton, 21-carbon molecules; circulation according to which hormones synthesized
supplies cholesterol which enters adrenal ▪ Cholesterol desmolase found in all layers
gland cells via endocytosis ▫ Rate-limiting step; stimulated by
▫ Some synthesized de novo → both adrenocorticotropic hormone (ACTH);
forms stored in cytoplasmic vesicles converts cholesterol to pregnolone
▪ Cytochrome p450 using O2, adrenodoxin ▪ Corticosteroid is common name for
reductase, adrenodoxin transfers H+ from steroid hormones made in cortex: include
NADPH producing energy using reduction mineralocorticoids, glucocorticoids
reactions
Figure 33.1 Three zones of adrenal cortex secrete steroid hormones under control of ACTH,
which is released by anterior pituitary. Adrenal cortex cells first convert cholesterol to
prognenolone using enzyme cholesterol desmolase. Prognenolone is then converted into
aldosterone in zona glomerulosa, cortisol in zona fasciculata, and testosterone and estrogen in
zona reticularis.
276 OSMOSIS.ORG
Chapter 33 Endocrine Physiology: Adrenal Hormones
Mineralocorticoids Androgens
▪ Synthesized in zona glomerulosa ▪ Synthesized in zona reticularis
▪ Example: aldosterone ▪ Examples: dehydroepiandrosterone
▪ Aldosterone synthase required and (DHEA), androstenedione
found only in zona glomerulosa, converts ▪ 17,20-lyase responsible for conversion of
cortisone → aldosterone glucocorticoids into androgens
▪ DHEA, androstenedione have a weak
Glucocorticoids androgenic effect
▪ Synthesized in zona fasciculata ▫ Male: converted to testosterone in
▪ Examples: cortisol, corticosterone testes
▪ 17α-hydroxylase (if deficient corticosterone ▫ Female: main source of androgens
can be formed) → 3β-hydroxysteroid ▪ Low quantity of testosterone, 17β-estradiol
dehydrogenase → 21β- and
11β-hydroxylase
Figure 33.2 Aldosterone synthesis in zona glomerulosa. Aldosterone synthase is stimulated by

hormone angiotensin II, which is produced in lungs in response to low blood pressure, volume.
Figure 33.3 Cortisol synthesis in zona fasciculata.
OSMOSIS.ORG 277
Figure 33.4 Androgen synthesis in zona reticularis.
CORTISOL
osms.it/cortisol
▪ Steroid glucocorticoid hormone secreted Major effects
by adrenal cortex; has metabolic, anti- ▪ Metabolic: ↑ blood glucose (considered
inflammatory, immunosuppressive, vascular diabetogenic hormone) by ↑ hepatic
effects glycogenolysis, ↑ lipolysis, ↑ protein
▪ Normal pulsatile secretion, approximately catabolism, ↓ cellular insulin sensitivity, ↑
10 surges in diurnal (daily) pattern appetite
▫ Concentration highest in morning, ▪ Immune: ↓ intensity of immune,
lowest in evening inflammatory responses by ↓ production
▫ Diurnal pattern: maintained by of arachidonic acid metabolites (e.g.
hypothalamic suprachiasmatic prostaglandin, thromboxane, leukotrienes),
nucleus; acts as central pacemaker for ↓ production of interleukins, interferon,
hypothalamic-pituitary-adrenal (HPA) tumor necrosis factor; ↓ T cell proliferation;
axis; adrenals maintain diurnal pattern ↓ neutrophil phagocytosis
of sensitivity to ACTH ▪ Vascular: involved in normal vascular
blood pressure maintenance; supports
Secretion regulation vascular smooth muscle responsiveness to
▪ Stress (infection, trauma, initiation of “fight catecholamine vasoconstrictive effects
or flight” response, psychological stressors), ▪ Other: ↓ connective tissue fibroblast
↑ sympathetic activity, physical activity, ↓ proliferation, ↓ bone formation, ↑ renal
blood glucose → hypothalamus stimulated blood flow, ↑ erythropoietin release, alters
to release corticotropin-releasing hormone sleep patterns
(CRH) → anterior pituitary releases
adrenocorticotropic hormone (ACTH) →
adrenal medulla secretes glucocorticoids
(primarily cortisol) → target tissues
▪ Negative feedback of cortisol to
hypothalamic-pituitary axis → ↓ cortisol
278 OSMOSIS.ORG
Chapter 33 Endocrine Physiology: Adrenal Hormones
Figure 33.5 Cortisol secretion regulation.
OSMOSIS.ORG 279
NOTES
NOTES
PANCREATIC HORMONES
GLUCAGON
osms.it/glucagon
▪ Peptide hormone secreted by pancreatic
alpha cells
▪ Important for blood glucose regulation,
along with insulin
▪ Synthesis
▫ Preproglucagon → proglucagon →
glucagon
Secretion regulated mainly by glucose

▪ ↓ glucose levels between meals or while
sleeping → ↓ insulin → glucagon secretion
stimulation → hepatic glycogenolysis,
gluconeogenesis → ↑ blood glucose levels Figure 34.1 Glucagon exerts its effects by
binding to G-protein coupled receptors on the
Other factors that regulate glucagon
membranes of liver and adipose cells.
secretion
▪ Sympathetic nervous system
▫ Adrenaline (ɑ2 receptors) EFFECTS OF GLUCAGON
▪ Parasympathetic nervous system ▪ Primary action is to increase blood glucose
▫ Acetylcholine (M3 receptors) when it falls below normal range
▪ Alanine, arginine ▪ Carbohydrates: ↑ blood glucose levels
▫ E.g. from high protein meal ▫ Stimulates glycogenolysis in liver,
▪ Cholecystokinin, somatostatin muscle
▪ Exercise ▫ Stimulates gluconeogenesis in liver,
kidney
▫ Inhibits hepatic glycolysis
GLUCAGON SIGNALING PATHWAY
▪ Fats: ↑ fatty acids, keto acid levels in blood
▪ Glucagon receptor is a heterotrimer
▫ Inhibits fatty acid synthesis, oxidation in
▫ G-protein coupled receptor that contains
liver
α, β, γ subunits
▫ Inhibits fat deposition in adipose tissue
▪ Glucagon binds to receptor → activates Gs
protein → α subunit released → activates ▫ Stimulates lipolysis
adenylate cyclase → ↑ cAMP → activates ▫ Stimulates keto acid production
effects
280 OSMOSIS.ORG
Chapter 34 Endocrine Physiology: Pancreatic Hormones
Figure 34.2 Glucagon is secreted by pancreatic alpha cells when glucose levels are low. It
increases glucose levels in the bloodstream by inducing the breakdown of storage molecules in
the liver and adipose cells.
INSULIN
osms.it/insulin
▪ Peptide hormone secreted by pancreatic SECRETION
beta cells
Secretion regulated mainly by glucose
▪ Important for blood glucose regulation
▪ Carbohydrates consumption → ↑ glucose
▪ Consists of A and B amino acid chains
→ passive diffusion into beta cells through
connected with two disulfide (-S-S-) bonds
GLUT2 transporters → stimulation of
insulin secretion
SYNTHESIS
▪ Preproinsulin → proinsulin → insulin Other factors that stimulate insulin secre-
tion
▪ During insulin synthesis, protein called
C-peptide cleaved off, secreted together ▪ ↑ fatty acid, amino acid levels in blood
with insulin in equimolar amounts within ▪ Parasympathetic nervous system
secretory vesicles → C-peptide used to ▫ Acetylcholine (M3 receptors)
measure insulin levels ▪ Sympathetic nervous system
▫ Adrenaline (β2 receptors)
▪ Growth hormone (GH), adrenal corticotropic
hormone (ACTH)
OSMOSIS.ORG 281
EFFECTS OF INSULIN
▪ The primary action of insulin is lowering
blood glucose levels when above normal
range
▪ Carbohydrates: ↓ blood glucose levels
▫ Translocates GLUT4 transporters to
muscle, adipose cell membranes →
facilitates cell uptake of glucose
▫ Activates glycogen synthesis in liver,
muscles
▫ Inhibits hepatic glycogenolysis,
gluconeogenesis
▪ Fats: ↓ fatty acids, keto acid levels in blood
▫ Inhibits fatty acids mobilization,
oxidation
▫ Stimulates fat deposition in adipose
tissue
▫ Inhibits lipolysis
▫ Inhibits keto acid formation in liver
Figure 34.3 Insulin synthesis. ▪ Proteins: anabolic effect
▫ Stimulates amino acid, protein uptake
▫ Stimulates protein synthesis
PHASES OF INSULIN RELEASE
▫ Inhibits proteolysis
▪ Two phases
▪ Other: ↓ K+ levels in blood
First phase ▫ Increases potassium uptake
▪ Involves L-type Ca2+ channels ▫ Stimulation of cell growth, gene
▪ Rapidly triggered release of preformed expression
secretory vesicles
▪ Lasts 10 minutes
Second phase
▪ Involves R-type Ca2+ channels
▪ Slow release of newly formed secretory
vesicles
▪ Lasts 2–3 hours
INSULIN SIGNALING PATHWAY

▪ Insulin receptor is a tetramer
▫ Contains two extracellular ɑ subunits
connected by disulfide bonds, two
intracellular β subunits connected to
Figure 34.4 Insulin exerts its effects by
each ɑ subunit
binding to alpha subunits of insulin receptor,
▪ Insulin binds to ɑ subunits → activates which leads to signal transduction within cell.
tyrosine kinase activity in β subunits →
β subunit autophosphorylation → insulin
receptor substrates (IRS) phosphorylation
effects
282 OSMOSIS.ORG
Chapter 34 Endocrine Physiology: Pancreatic Hormones
Figure 34.5 Insulin is secreted by pancreatic beta cells when glucose levels are high. It promotes
conversion of glucose → glycogen in liver, fatty acids → fat, and amino acids → protein.
SOMATOSTATIN
osms.it/growth-hormone-and-somatostatin
▪ Peptide hormone secreted by pancreatic EFFECTS OF SOMATOSTATIN
delta cells ▪ Inhibits secretion of insulin, glucagon
Factors that regulate somatostatin secre- ▪ Inhibits pancreatic exocrine secretion
tion ▪ Inhibits secretion of all gastrointestinal
▪ Ingestion of glucose, fatty acids, amino hormones (gastrin, cholecystokinin,
acids secretin, motilin etc.)
▪ Glucagon ▪ Decreases gastrointestinal motility, blood
flow, gastric emptying Like this book? You can download more
▪ Sympathetic nervous system from AfraTafreeh.com
▫ β-adrenergic agonists
SOMATOSTATIN SIGNALING
PATHWAY
▪ Somatostatin receptor is a G-protein
coupled receptor
▪ Somatostatin binds to receptor → activates
Gi protein → inhibits adenylate cyclase → ↓
cAMP → ↓ Ca2+ → inhibitory effect
OSMOSIS.ORG 283
NOTES
NOTES
CALCIUM & PHOSPHATE
HORMONAL REGULATION
GENERALLY, WHAT IS IT?

CALCIUM & PHOSPHATE potential, muscle contraction, hormone
HOMEOSTASIS secretion, blood coagulation
▫ Complexed calcium: Ca2+ ionically
Blood calcium level regulation
bound to other negatively-charged
▪ Normal total blood calcium: 8.5–10mg/dl molecules (e.g. oxalate, phosphate →
▪ Parathyroid hormone: ↑ calcium level electrically-neutral molecules, do not
▪ Vitamin D: ↑ calcium level partake in cellular processes)
▪ Calcitonin: ↓ calcium level ▪ Non-diffusible: cannot cross cell
membranes
Extracellular calcium ▫ Calcium bound to large negatively
▪ Diffusible: can cross cell membranes charged proteins (e.g. albumin →
▫ Free-ionized calcium (Ca2+): involved protein-albumin complex too large to
in cellular processes → neuronal action cross cell membranes → not involved in
cellular processes)
CALCITONIN
osms.it/calcitonin
CALCITONIN STRUCTURE CALCITONIN RELEASE
▪ Polypeptide hormone involved in blood ▪ Calcium-sensing receptors on C cells’
calcium regulation surface monitor blood calcium levels →
▫ Not primary calcium regulator, even if calcium drifts above normal range →
if thyroid gland removed, remaining calcitonin released
regulatory mechanisms able to maintain
calcium homeostasis CALCITONIN ACTION
▪ Produced by thyroid gland’s parafollicular ▪ Lowers blood calcium level
cells (C cells)
▪ C cells synthesize preprocalcitonin (141 Bone
amino acid polypeptide) → successive ▪ ↓ bone resorption → ↓ blood calcium
enzymatic cleavage steps produces concentration
procalcitonin → immature calcitonin (33 ▫ When attaching to bone matrix
amino acids) → mature calcitonin (32 osteoclast membranes form multiple
amino acids) → stored/readied for release in arms (ruffled border) → aids
secretory granules within C cells attachment, increases surface area
→ arms secrete acid → assists bone
breakdown
284 OSMOSIS.ORG
Chapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation
▫ Calcitonin binds to calcitonin receptor Kidneys

on basal osteoclast surface → G-protein ▪ ↓ calcium, phosphate reabsorption by
coupled receptor activation → adenylate principal cells of distal convoluted tubules
cyclase activation → adenosine
triphosphate (ATP) converted to 3’,5’-
cyclic AMP (cAMP) → ↑ cAMP levels →
↓ number of osteocyte arms formed → ↓
bone resorption
Figure 35.1 Calcitonin is made and stored in thyroid gland’s C cells.
Figure 35.2 When calcitonin binds to its receptor on an osteoclast, it reduces number of
osteoclast arms formed, decreasing bone resorption and blood calcium.
OSMOSIS.ORG 285
PARATHYROID HORMONE
osms.it/parathyroid-hormone
▪ Primary blood-calcium level regulator CA2+ CHANGES
▪ Ca2+ level changes detected by parathyroid
PARATHYROID GLANDS cell surface receptor (calcium-sensing
receptor)
▪ Hormone produced by parathyroid glands,
four pea-sized glands found posterior to ▪ Calcium-sensing receptor is G-protein
thyroid mediated receptor
▫ Parathyroid gland chief cells synthesize ▪ ↑ Ca2+ level → hormone release inhibition
preproparathyroid hormone (preproPTH) ▫ Large Ca2+ amounts bind to receptor →
(115 amino acid-long protein chain → phospholipase C activation → activated
contains biologically-active parathyroid enzyme splits inositol bisphosphate
hormone segment in N-terminal 34 (PIP2) → diacylglycerol (DAG), inositol
amino acids) triphosphate (IP3)
▫ Within chief cell endoplasmic reticulum, ▫ IP3 diffuses through cytoplasm to
protein chain cleaved by enzyme endoplasmic reticulum → binds to
peptidase (peptidase removes “pre” Ins3PR receptor on ligand-gated Ca2+
segment → proPTH → transported to channel → channel opens → calcium
Golgi apparatus) stored in endoplasmic reticulum
▫ Final processing in Golgi apparatus released into cytoplasm → ↑ intracellular
(trypsin-like enzyme cleaves off six calcium → stops binding of PTH-holding
amino acid “pro” segment → functional granules to chief cell membrane → no
parathyroid hormone (single chain 84 PTH release
amino acid polypeptide) → packaged ▪ ↓ extracellular Ca2+ levels → PTH release
into secretory vesicles → eventual facilitation
release) ▫ Little/no calcium-sensing G-protein
receptor activation → no inhibition of
PTH granule binding → PTH release
PTH SECRETION
Stimuli
▪ ↓ serum Ca2+ concentration
▪ Mild ↓ in serum magnesium (Mg2+)
concentration
▪ ↑ in serum phosphate → calcium phosphate
complex formation → calcium receptor
stimulation ↓
▪ Adrenaline
▪ Histamine
Figure 35.3 Location of the parathyroid Inhibitors
glands which produce parathyroid hormone.
▪ ↑ serum Ca2+ concentration
▪ Severe ↓ serum Mg2+ concentration
▪ Calcitriol
286 OSMOSIS.ORG
Figure 35.4 High calcium levels in blood inhibit PTH release from parathyroid cells, while low
calcium levels in blood facilitate PTH release from parathyroid cells.
Magnesium ▪ Bone breakdown → release of calcium,

▪ Involved in stimulus-secretion coupling phosphate into blood (initially forms
▪ Moderate ↓ serum Mg2+ concentration physiologically-inactive compound)
promotes action of PTH on renal mineral Kidneys
resorption
▪ PTH binds to receptors on cells of
▪ Severe hypomagnesemia (e.g. alcoholism) proximal convoluted tubules → inhibits
inhibits PTH secretion, causes PTH sodium-phosphate co-transporters on
resistance apical surface → ↓ sodium, phosphate
reabsorption → ↑ urinary phosphate
EXTRACELLULAR CALCIUM excretion
INCREASE ▪ PTH binds to receptors on principal cells
▪ PTH → ↑ extracellular calcium levels (three of distal convoluted tubules → sodium/
target organ systems) calcium channel upregulation → ↑ calcium
reabsorption from urine
Bones
▪ PTH receptors on osteoblasts Intestines
▪ PTH binding → ↑ cytokine release ▪ PTH promotes vitamin D3 (cholecalciferol)
conversion → active form
▫ Receptor activator of nuclear factor κB
ligand (RANKL) ▫ Cholecalciferol synthesized by
keratinocytes in skin epidermis when
▫ Macrophage colony-stimulating factor
exposed to UV light (also found in
(M-CSF)
foods) → cholecalciferol travels to liver,
▫ Inhibits osteoprotegerin (OPG) secretion enzyme 25-hydroxylase catalyzes
(inhibition absence → free OPG binds conversion to 25-hydroxycholecalciferol
to RANKL (decoy receptor) → prevents (calcidiol)
RANK-RANKL interaction
▫ 25-hydroxycholecalciferol travels
▫ PTH-induced cytokine release permits to kidney’s proximal tubular cells
RANK-RANKL interaction → multiple → enzyme 1-alpha-hydroxylase
macrophage precursors fuse → (upregulated by PTH) converts it to
osteoclast formation (bone breakdown)
OSMOSIS.ORG 287
1,25-dihydroxycholecalciferol (calcitriol),
AKA active vitamin D
▫ Active vitamin D travels to
gastrointestinal (GI) tract → enterocytes
of small intestine → upregulates calcium
channels → ↑ dietary calcium absorption
Figure 35.5 One way PTH increases extracellular calcium levels is by stimulating osteoclast
formation in bone.
Figure 35.6 The second way PTH increases extracellular calcium levels is by ↑ urinary
phosphate excretion and ↑ calcium reabsorption from urine.
288 OSMOSIS.ORG
Figure 35.7 The third way PTH increases extracellular calcium levels is by helping convert
cholecalciferol into vitamin D. It does so by upregulating enzyme 1α-hydroxylase.
VITAMIN D
osms.it/vitamin-D
▪ Steroid hormone (derived from cholesterol, PRECURSOR ACTIVATION
fat soluble) → gene transcription ▪ Ergocalciferol, cholecalciferol reach small
stimulation intestine lumen → packaged in small fat-
▫ Promotes new bone mineralization soluble sacs (micelles) with aid of bile salts
▫ ↑ serum Ca2+, phosphate concentration → diffuse through apical membrane of
→ ↑ available substrate concentration absorptive intestinal cells (enterocytes)
for bone mineralization ▪ Within enterocytes inactive vitamin D
precursors integrate into lipoproteins
(chylomicrons) → exit into lymphatic
VITAMIN D SOURCES system → drain into blood circulation
Intestine (hepatic portal vein) → bind to carrier
proteins (vitamin D-binding protein/
▪ Absorbs precursors (biologically inactive)
albumin) → transported to liver
▫ Vitamin D2 (ergocalciferol) is derived
▪ Hepatocytes contain 25-hydroxylase
from dietary plant sources
→ hydroxyl group added to carbon 25
▫ Vitamin D3 (cholecalciferol) is derived (C25) of ergocalciferol, cholecalciferol →
from dietary animal sources 25-hydroxycholecalciferol (calcifediol) →
Skin calcifediol (primary vitamin D circulating
form) reenters blood bound to carrier
▪ Skin keratinocyte exposure (stratum basale,
proteins
stratum spinosum) to UV light → vitamin D3
production ▫ Hepatic hydroxylation requires NADPH,
O2, Mg2+ (not cytochrome P-450)
▫ 7-dehydrocholesterol reacts with UVB
light (wavelengths between 270– ▪ Blood transports calcifediol to renal
300nm) → vitamin D3 proximal tubules → proximal tubule cell
mitochondria contain 1α-hydroxylase
→ hydroxyl added to C1 → 1,25
dihydroxycholecalciferol (calcitriol—active
vitamin D form)
OSMOSIS.ORG 289
Figure 35.8 Conversion of vitamins D2 and D3 into active vitamin D.
290 OSMOSIS.ORG
Alternative pathway Kidney

▪ Hydroxylation at C24 → biologically ▪ Stimulates Ca2+, phosphate reabsorption
inactive 24,25-dihydroxycholecalciferol
▪ Pathway choice regulated by blood calcium Intestine
level, parathyroid hormone ▪ Increases Ca2+, phosphate absorption
▫ C1 hydroxylation occurs as response to ▪ Induces vitamin D-dependent Ca2+ binding-
↓ calcium/phosphate levels protein synthesis (calbindin D-28K)
▫ 1α-hydroxylase activity ↑ through ↓ ▫ Systolic protein → binds four Ca2+ ions
plasma Ca2+ concentration, ↑ circulating ▪ Intestinal Ca2+ absorption mechanism
PTH levels, ↓ plasma phosphate ▫ Ca2+ diffusion: intestinal lumen → cell
concentration (through electrochemical gradient)
▫ C1 phosphorylation requires NADPH, ▫ Inside cell: calbindin D-28K binds Ca2+
O2, Mg2+, cytochrome P-450 pathway → Ca2+ pumped across basolateral
▫ If calcium levels sufficient, inactive membrane by Ca2+-ATPase
metabolite preferentially produced
VITAMIN D ACTIONS
Bone
▪ Acts synergistically with PTH → osteoclast
activity stimulation → bone resorption
→ old bone demineralization → ↑ Ca2+,
phosphate concentration for new bone
mineralization
Figure 35.9 Vitamin D stimulates osteoclast formation, increasing blood calcium and phosphate
concentrations.
OSMOSIS.ORG 291
Figure 35.10 Vitamin D stimulates calcium and phosphate reabsorption in kidneys.
Figure 35.11 Vitamin D stimulates calcium and phosphate absorption in the small intestine by
increasing synthesis of calbindin D-28K and sodium/phosphate cotransporters.
292 OSMOSIS.ORG
NOTES
NOTES
ANATOMY
osms.it/gastrointestinal-anatomy-physiology
▪ Alimentary/GI tract: continuous muscular ▪ Lesser omentum: double layer arises from
tube from mouth to anus lesser curvature of stomach, extends to
▪ Many digestive organs reside in abdominal, liver
pelvic cavity; covered by mesentery ▪ Greater omentum: four layers (double sheet
folds back upon itself); arises from greater
curvature of stomach, covers intestines
PERITONEUM
▪ Thin connective tissue composed of GI tract layers
mesothelium, connective tissue supporting ▪ Four basic tissue layers from esophagus to
layer, simple squamous epithelium anus
▪ Lines abdominal, pelvic cavities; binds ▪ Serosa/adventitia
organs together, holds them in place ▫ Outermost layer of intraperitoneal
▪ Contains blood vessels, lymphatics, nerves organs; also visceral peritoneum
innervating abdominal organs ▫ Primarily composed of simple squamous
▫ Parietal peritoneum: lines abdominal, epithelial cells, connective tissue
pelvic cavities ▫ Secretes slippery fluid, prevents friction
▫ Visceral peritoneum: covers organ between viscera, digestive organs
surfaces ▫ Esophagus has adventitia instead of
▫ Peritoneal cavity: potential space serosa
between parietal, visceral layers ▫ Retroperitoneal organs have serosa,
▪ Intraperitoneal organs: digestive organs; adventitia
keep mesentery during embryological ▪ Muscularis propria
development, remain in peritoneal cavity
▫ Outer longitudinal, inner circular smooth
(e.g. stomach)
muscle for involuntary contractions;
▪ Retroperitoneal organs: lose mesentery regions of thickened circular layer forms
during embryological development, lay sphincters
posterior to peritoneum (e.g. kidneys,
▫ Skeletal muscle in esophagus for
pancreas, duodenum)
voluntary swallowing
▪ Mesentery: double layer of parietal
▫ Contains myenteric plexus (between
peritoneum on dorsal peritoneal cavity,
longitudinal, circular layers of smooth
provides routes for vessels, lymphatics,
muscle)
nerves to digestive organs
▫ Myenteric plexus responsible for
Omentum peristalsis, mixing
▪ Visceral peritoneum layer covering ▪ Submucosa
stomach, intestines; contains adipose ▫ Connective tissue that binds muscularis,
tissue, many lymph nodes provides elasticity, distensibility
▫ Expands during weight gain; “fat skin” ▫ Contains Meissner’s plexus
▫ Richly vascularized, innervated
OSMOSIS.ORG 293
▪ Mucosa BLOOD CIRCULATION
▫ Innermost layer composed of epithelial ▪ Splanchnic circulation
membrane lining entire GI tract ▪ Celiac trunk: supplies stomach, liver, spleen
▫ Functions: exocrine glands secrete ▪ Superior mesenteric artery: supplies small
water, mucus, digestive enzymes, intestine
hormones; absorb digested nutrients; ▪ Inferior mesenteric artery: supplies large
provides protective surface intestine
▫ Muscularis mucosae: smooth muscle
layer responsible for mucosa movement;
contains folds to increase surface area INNERVATION
▫ Lamina propria: loose areolar connective ▪ Supplied by autonomic nervous system
tissue; contains blood, lymphatic (ANS)
vessels; contains MALT (lymphoid tissue ▪ Sympathetic component: thoracic
that protects against pathogens) splanchnic nerves → celiac plexus
▫ Epithelium: mouth, esophagus, anus ▪ Parasympathetic component: vagus nerve
composed of stratified squamous cells; ▪ Enteric division provides local control of GI
rest of GI tract simple columnar with activity; “the brain in the gut”; can function
mucus secreting cells independently of ANS
Figure 36.1 Cross section from small intestine showing the four basic tissue layers that line
gastrointestinal tract: (from the outermost) serosa/adventitia, muscularis propria, submucosa,
and mucosa.
294 OSMOSIS.ORG
Chapter 36 Gastrointestinal System: Anatomy & Physiology
STRUCTURES
ORAL (BUCCAL) CAVITY ▪ Cardiac sphincter: AKA lower esophageal
sphincter; smooth muscle at cardiac orifice
Function that prevents acidic contents of stomach
▪ Ingestion, mechanical, chemical digestion, from moving upward into esophagus
propulsion
▪ Saliva contains antibacterial properties that Histology
cleanses, protects oral cavity, teeth from ▪ Mucosa
infection ▫ Nonkeratinized stratified squamous
▪ Propulsion: swallowing (performed by epithelium (simple columnar epithelium
tongue) propels food into pharynx, starts near cardiac orifice)
propulsion through GI tract ▪ Mucosa, submucosa form longitudinal folds
▪ Mechanical digestion: via mastication by when empty
teeth, tongue ▪ Submucosa
▪ Chemical digestion: salivary amylase starts ▫ Mucus secreting glands
carbohydrate chemical breakdown ▪ Muscularis externa
Secretions ▫ Superior ⅓: skeletal muscle
▪ Chemical digestion: salivary amylase starts ▫ Middle ⅓: skeletal, smooth muscle
carbohydrate chemical breakdown; mucin, ▫ Inferior ⅓: smooth muscle
water provide lubrication ▪ Adventitia instead of serosa
▪ Lysozyme: kills some microbes
Secretions
▪ Lingual lipase: digests some lipids
▪ Mucus: lubrication, protection from gastric
acid
ESOPHAGUS
▪ Muscular tube extending from STOMACH
laryngopharynx to stomach
▪ Located in upper left abdominal cavity
▪ Esophageal hiatus: diaphragm opening quadrant
where esophagus, vagus nerve pass
▪ Contains rugae (mucosa, submucosa)
through to abdominal cavity
when stomach empty → expands to
▪ Cardiac orifice: junction of esophagus, accommodate food
stomach
Function
Function
▪ Churning, digestion, storage
▪ Propulsion/peristalsis
▪ Beginning of chemical digestion turning
▪ Epiglottis closes larynx, routes food into food into chyme to be delivered into small
esophagus intestine
▪ Lower end of esophagus contains mucous
cells to protect esophagus from stomach Regions
acid reflux ▪ Cardia: most superior area surrounding
cardiac orifice where food from esophagus
Sphincters enters stomach
▪ Upper esophageal sphincter: skeletal ▫ Defined by Z-line of gastroesophageal
muscle; regulates movement from pharynx junction
to esophagus
▫ Z-line: epithelium changes from
stratified squamous → simple columnar
OSMOSIS.ORG 295
▪ Fundus: area lying inferior to diaphragm, Secretions
upper curvature ▪ Mucous cells: neck, basal regions of glands;
▫ Food storage produce mucus that protects stomach
▪ Body: central, largest area of the stomach lining, lubricates food
▪ Pylorus: connects to duodenum via pyloric ▪ Parietal cells: gland apical region amongst
sphincter chief cells; produce HCl, intrinsic factor
▫ Controls gastric emptying, prevents ▪ Chief cells: gastric gland base; produce
backflow from duodenum into stomach pepsinogen (protein digestion)
▪ Enteroendocrine cells (ECL cells): located
Histology deep in glands; secretes histamine,
▪ Muscularis contains regular GI tract layers somatostatin, serotonin, ghrelin
with three-layered muscularis propria ▪ G-cells: gastrin
unique to stomach allowing for vigorous ▪ D-cells: somatostatin
contractions, churning
▫ Inner oblique layer
▫ Middle circular layer (contains myenteric SMALL INTESTINE
plexus) Function
▫ Outer longitudinal layer ▪ Primary organ of digestion, nutrient
Glands absorption; segmentation (localized mixing
area), peristalsis
▪ Lined with simple columnar epithelium;
forms gastric pits (tube-like opening for ▪ Absorption: food breakdown products
gastric glands) absorbed
▪ Cardia, pylorus glands mainly secrete ▪ Contains circular folds, villi, microvilli to
mucus maximize absorption surface area
▪ Fundus, body glands secrete majority of ▫ Circular folds are permanent, composed
digestive stomach secretions of mucosa, submucosa
▪ Pyloric antrum glands mainly secrete
mucus, hormones (mainly gastrin)
Figure 36.2 Stomach anatomy.
296 OSMOSIS.ORG
Innervation ▫ Suspended from posterior abdominal

▪ Relayed through celiac, superior mesenteric wall by mesentery
plexus ▫ Peyer’s patches: lymphatic tissue
▪ Sympathetic: thoracic splanchnic sections composed predominantly of
▪ Parasympathetic: vagus proliferating B lymphocytes, mostly
located in ileal lamina propria as
Blood supply protection against pathogenic bacteria;
▪ Arterial: superior mesenteric artery B lymphocytes release IgA
▪ Veins from small intestine → hepatic portal Secretions
vein → liver
▪ Brush border enzymes on microvilli
Histology complete food digestion (e.g. mucus, water,
peptidases, disaccharidases)
▪ Epithelium of villus: simple columnar
absorptive cells ▪ Pancreas, liver contribute to most small
intestine digestion
▫ Main function is absorbing nutrients
▪ Mucus secreting goblet cells in epithelium
▪ Mucosa contains pits called intestinal LARGE INTESTINE
crypts ▪ Retroperitoneal except for transverse,
▫ Crypt cells: secrete intestinal juice sigmoid parts
containing mucus ▫ Intraperitoneal transverse, sigmoid
▫ Enteroendocrine cells: within crypts, sections anchored to posterior
intraepithelial lymphocytes (T cells) abdominal wall by mesocolon
▫ Paneth cells: located deep in crypts, (mesentery)
release defensins, lysozyme to protect ▫ Connects ileum via ileocecal valve,
against pathogens sphincter
Sections Function
▪ Duodenum ▪ Digestion, absorption, propulsion,
▫ Mostly retroperitoneal defecation
▫ Curves around head of pancreas, ▪ Digestion: enteric bacteria digests
receives bile from liver via bile duct, remaining food
pancreatic secretions from pancreas via ▫ Bacteria also produce vitamin K, other B
main pancreatic duct vitamins
▫ Ampulla of vater: bulb-like point where ▪ Absorption: absorbs mainly water,
bile duct, main pancreatic duct unite, electrolytes, vitamins to concentrate, form
deliver secretions into duodenum feces
▫ Major duodenal papilla: ampulla ▪ Propulsion: propels feces towards rectum
opening into duodenum releasing bile/ ▪ Defecation: stores, eliminates feces from
pancreatic secretions body
▫ Hepatopancreatic sphincter: controls
Unique features
bile entry, pancreatic secretions
▪ Tenia coli: three longitudinal ribbons of
▫ Duodenal glands (Brunner’s) in
smooth muscle on ascending, transverse,
duodenal submucosa secrete alkaline
descending, sigmoid colons that contract to
mucus to neutralize acidic chyme
produce haustra
▪ Jejunum
▪ Haustra: small pouches/segments of large
▫ Intraperitoneal intestine created by tenia coli
▫ Suspended from posterior abdominal ▪ Epiploic appendages: small pouches of
wall by mesentery peritoneum filled with fat
▪ Ileum
▫ Intraperitoneal
▫ Joins large intestine at ileocecal valve
OSMOSIS.ORG 297
Regions Flora
▪ Cecum → ascending colon → right colic/ ▪ Large intestine contains largest bacterial
hepatic flexure → transverse colon → left ecosystem in body
colic/splenic flexure → descending colon → ▪ Function of bacteria
sigmoid colon → rectum → anal canal → ▫ Synthesize vitamins (vitamin K, some B
anus vitamins)
▫ Cecum: pouch that lies below ileocecal ▫ Ferment indigestible carbohydrates (e.g.
valve at large,small intestine junction; cellulose)
beginning of large intestine
▫ Metabolism/digestion of certain
▫ Appendix: pouch of lymphoid tissue molecules (e.g. hyaluronic acid, mucin)
(part of MALT) located in cecum, harbors
▫ Live symbiotically with host
bacteria to recolonize gut when needed
▫ Present pathogens to nearby lymphoid
▪ Anal canal has two sphincters
tissue (MALT)
▫ Internal anal sphincter: involuntary,
composed of smooth muscle Secretions
▫ External anal sphincter: voluntary, ▪ Mucus
composed of skeletal muscle
Histology
▪ Muscularis mucosae consists of inner
circular, outer longitudinal layers
▪ Large intestine mucosa: simple columnar
epithelium
▪ Anal canal: stratified squamous epithelium
▪ Does not contain folds, villi, microvilli as in
small intestine
▪ Many crypts with goblet cells
Pectinate line
▪ Divides upper ⅔ from lower ⅓ of anal canal
where many distinctions made
▪ Embryological origin
▫ Above: endoderm
Figure 36.3 Large intestine anatomy.
▫ Below: ectoderm
▪ Epithelium
▫ Above: columnar epithelium
▫ Below: stratified squamous epithelium
▪ Innervation
▫ Above: inferior hypogastric plexus
▫ Below: inferior rectal nerves
▪ Lymph drainage
▫ Above: internal iliac
▫ Below: superficial inguinal lymph nodes
▪ Vascularization
▫ Above: superior rectal artery, superior
rectal vein (drains into inferior
mesenteric vein → hepatic portal
system)
▫ Below: middle, inferior rectal arteries;
middle, inferior rectal veins
298 OSMOSIS.ORG
ACCESSORY ORGANS
▪ Gallbladder, liver, pancreas
▪ Liver
▫ Hepatocytes produce bile which
emulsifies lipid globules, aids in
absorption
▫ Stores glucose in form of glycogen
▪ Gallbladder
▫ Bile storage; releases bile into small
intestine in response to hormonal
stimulus
▪ Pancreas
▫ Exocrine function: acini secrete various
digestive enzymes; “pancreatic juice;”
e.g. secretin, cholecystokinin (CCK)
▫ Endocrine function: islets produce
glucagon, insulin to maintain normal
glucose levels; somatostatin, pancreatic Figure 36.4 Overview of gastrointestinal
polypeptide production tract, accessory organs structures.
PHYSIOLOGY
PROCESSING OF FOOD GI MUSCLE PROPERTIES
1. Ingestion ▪ Smooth muscle of GI tract acts as
2. Mechanical digestion syncytium
▫ Carried out by teeth; increases surface ▫ Muscle fibers connected by gap
area to facilitate enzymatic digestion junctions allowing electrical signals to
3. Propulsion initiate muscle contractions from one
muscle fiber to next rapidly along length
▫ Movement, mixing of food through GI
of bundle
tract, starts with swallowing
▪ Normal resting membrane potential of GI
4. Secretion
smooth muscles: -50mV to -60mV
▫ Exocrine glands secrete various
▪ Two types of electrical waves contributing
digestive juices into digestive tract
to membrane potential
lumen
5. Digestion Slow waves
▫ Complex food broken down via ▪ Generated, propagated by interstitial cells
enzymes of Cajal (pacemaker cells)
6. Absorption ▪ Slow-wave threshold: potential that must
▫ Digested nutrients absorbed by GI be reached by slow wave to propagate
mucosal cells into blood/lymph smooth muscle
7. Elimination ▪ Does not cause smooth muscle contraction
▫ Indigestible substances eliminated via ▪ Slow-wave threshold reached → L-type
anus in form of feces calcium channels activated → calcium influx
→ motility initiation
OSMOSIS.ORG 299
▪ Occur at 12 cycles/minute in duodenum, GASTROINTESTINAL MOTILITY
decreases towards colon
Gastric motility
▪ Regulated by innervation, hormones
▪ Peristaltic contractions originate in upper
▫ Excitatory stimulants (e.g. acetylcholine,
fundus, move to pyloric sphincter
substance P), inhibitory stimulants (e.g.
VIP, nitric oxide) ▪ Moves gastric chyme forward → gastric
emptying into duodenum
Spikes
Small intestinal motility
▪ True action potentials occurring
automatically when GI smooth muscle ▪ Mix chyme, digestive enzymes, pancreatic
potential becomes more positive than secretions, bile → digestion
-40mV ▪ Expose nutrients to mucosa → maximize
▪ Digestive activity controls absorption
▫ Involves regulation by autonomous ▪ Advance chyme along small intestine via
smooth muscle, intrinsic nerve plexuses, segmentation actions → ileocecal valve →
external nerves (ANS), GI hormones ileocecal sphincter → large intestine
Large intestinal motility

ENTERIC NERVOUS SYSTEM ▪ Unabsorbed small intestine material →
▪ Intrinsic nervous system of the GI system large intestine
▪ Division of ANS ▫ Contents now feces (destined for
▪ Provides major nerve supply to GI tract excretion)
controlling GI function, motility ▪ Segmental contractions (cecum, proximal
▫ Parasympathetic system activates colon) associated with haustra (sac-like
digestion segments characteristic of large intestine)
▫ Sympathetic system inhibits digestion mixes contents
▫ Also capable of self-regulation, ▪ Mass movements
autonomous function ▫ Function: move contents long distances
(e.g. transverse → sigmoid)
Receptors and plexus ▫ Occur 1–3 times daily
▪ Chemoreceptors respond to chemicals from ▫ Water absorption: fecal contents →
food in gut lumen increasingly solid (hard to mobilize)
▪ Stretch receptors respond to food ▫ Final mass movements propel contents
distending GI tract wall to rectum → stored until defecation
▪ Two plexus consist of motor neurons, ▪ Gastrocolic reflex
interneurons, sensory neurons ▫ Stomach distension → ↑ colonic motility
▫ Submucosal (Meissner’s) nerve plexus: → ↑ mass movements
innervates secretory cells → controls ▫ Afferent limb (from stomach) →
digestive secretions parasympathetic nervous system
▫ Myenteric nerve plexus: innervates mediates → efferent limb → CCK,
smooth muscle layers of muscularis → gastrin production → ↑ colonic motility
controls GI motility
▪ Segmentation, peristalsis mostly automatic
mediated by pacemaker cells, reflex arcs
Reflex mediation
▪ Short reflexes: intrinsic control (enteric
nervous system)
▪ Long reflexes: extrinsic control outside of GI
tract (e.g. CNS, autonomic nerves)
300 OSMOSIS.ORG
▪ Defecation remains tonically contracted (striated

▫ Rectum 25% full → defecation urge skeletal muscle under voluntary control)
▫ Rectum fills with feces → rectal wall → when appropriate, external anal
distends → stretch receptors send sphincter relaxed voluntarily → rectal
afferent signals to spinal cord → to smooth muscle contracts → ↑ pressure
brain (awareness of need to defecate) → Valsalva maneuver (expire against
+ afferent signals to myenteric plexus closed glottis) → ↑ intra-abdominal
→ peristaltic waves → move feces pressure → ↑ defecation pressure →
forward → internal anal sphincter feces forced out through anal canal
relaxes → external anal sphincter
OSMOSIS.ORG 301
NOTES
NOTES
GASTROINTESTINAL FUNCTION
ENTERIC NERVOUS SYSTEM

osms.it/enteric-nervous-system-and-slow-waves
▪ Intrinsic component of gastrointestinal PARASYMPATHETIC INNERVATION
(GI) innervation that can function without ▪ Parasympathetic ganglia located within
extrinsic innervation myenteric, submucosal plexuses
▪ Communicates with sympathetic nervous ▪ Parasympathetic preganglionic,
system, parasympathetics postganglionic neurons either cholinergic
▪ Ganglia located in myenteric, submucosal (release acetylcholine) or peptidergic
plexuses (release substance P/vasoactive intestinal
▫ Myenteric/Auerbach’s plexus: located peptide)
between longitudinal, circular smooth ▪ Vagus nerve innervates upper GI
muscle layers; GI movement function ▫ Upper ⅓ of esophagus, stomach, small
▫ Submucosal/Meissner’s plexus: located intestine, ascending, proximal transverse
in submucosa; function in GI secretions, colon
blood flow ▫ Consists of 75% afferent, 25% efferent
▪ Neurons of extrinsic system release fibers
neurocrines ▫ Vagovagal reflexes: reflexes in which
▫ Neurochemicals consisting of both afferent, efferent limbs originate
neurotransmitters, neuromodulators from vagus nerve
▪ Extrinsic branch of GI innervation
▫ Sympathetic, parasympathetic divisions
Figure 37.1 Locations of the myenteric (Auerbach’s) and submucosal (Meissner’s) plexuses
within the four layers of the gastrointestinal tract. The myenteric plexus is located between the
circular and longitudinal smooth muscle layers, which produce different movements in the GI
tract.
302 OSMOSIS.ORG
Chapter 37 Gastrointestinal Physiology: Gastrointestinal Function
▪ Pelvic nerves innervate lower GI

▫ Distal transverse colon, descending,
sigmoid colon
Figure 37.3 Sympathetic preganglionic

neurons synapse outside the GI tract, in the
four ganglia shown above.
Figure 37.2 The vagus nerve provides

parasympathetic innervation from the upper ▪ Sympathetic via fibers from celiac/superior
esophagus to the proximal transverse colon. mesenteric ganglia → ↓ contractions
The pelvic nerve provides innervation from ▪ Two forms of contractions; coordinated by
the distal transverse colon to the rectum. enteric nervous system
Innervation
SYMPATHETIC INNERVATION ▪ Parasympathetic via vagus nerve (CN X)
▪ Sympathetic preganglionic neurons ▫ ↑ contractions; most nerves cholinergic,
synapse in ganglia outside GI tract some release neurocrines (e.g.
▫ Celiac, superior mesenteric, inferior peptidergic)
mesenteric, hypogastric ganglia ▪ Motilin
▪ Sympathetic postganglionic neurons ▫ Secreted by endocrinocytes in proximal
either synapse on ganglia in myenteric/ small intestine, regulate contractions
submucosal plexuses or directly innervate ▪ Vasoactive intestinal peptide (VIP)
target organs ▫ Induces smooth muscle relaxation (e.g.
▪ Sympathetic preganglionic neurons are sphincters); induces water secretion into
cholinergic; sympathetic postganglionic pancreatic juice, bile; inhibits gastric acid
neurons are adrenergic (release secretion
norepinephrine) ▪ Enkephalins
▫ Inhibitory modulators in myenteric,
MECHANISMS submucosal plexuses
▪ Slow waves Segmental contractions (↓ diameter)
▫ Duodenum: 12 waves/minute ▪ Mix, expose chyme to secretions, enzymes
▫ Ileum: 9 waves/minute ▪ Contraction → splits chyme → both orad,
▪ Migrating myoelectric complexes every 90 caudad directions → relaxation → merging
minutes clears any remaining chyme of chyme → repeated
OSMOSIS.ORG 303
▪ No forward/propulsive movement along
small intestine
Peristaltic/longitudinal contractions (↓
length)
▪ Move chyme down GI tract
▪ Contraction behind bolus → proximal
portion of intestine relaxes simultaneously
→ chyme propelled in caudad direction
▪ Longitudinal, circular muscles reciprocally
innervated → do not contract together; if
circular muscle contracts → longitudinal
muscle in same segment relaxes
simultaneously
Peristalsis reflex
▪ Enterochromaffin-like (ECL) cells in
intestinal mucosa sense food bolus →
secrete serotonin (5-HT) → binds to
intrinsic primary afferent neuron receptors
→ activates peristalsis reflex → excitatory
neurotransmitters (acetylcholine, substance
P, neuropeptide Y) released behind bolus
→ ↑ circular muscle contraction → ↓
longitudinal muscle activation → segment
narrows, lengthens → in front of bolus,
circular muscle inhibitory mechanisms
(VIP, nitric oxide) activate, excitatory
pathways in longitudinal segment activate
→ segment shortens, widens → chyme
propelled forward in caudad direction
304 OSMOSIS.ORG
GASTROINTESTINAL HORMONES
osms.it/gastrointestinal-hormones
SOMATOSTATIN MOTILIN
▪ Members of G protein coupled-receptor
Function
superfamily
▪ Stimulates gastric, pancreatic enzyme
Function secretion
▪ ↓ secretion of many other hormones (e.g.
Secretion and stimulation/inhibition
gastrin, bicarbonate, digestive enzymes)
▪ Secreted by enteroendocrine M cells of
▪ ↓ nutrient absorption from gut by
proximal small intestine
prolonging gastric emptying time
▪ Secretory stimulants
▪ ↓ pancreatic secretions
▫ Duodenal alkalinization, gastric
▪ ↓ visceral blood flow
distension
Secretion and activation ▪ Inhibited by duodenal nutrients
▪ Central nervous system, pancreatic delta
cells, enteroendocrine delta cells PANCREATIC PEPTIDE (PP)
▪ Somatostatin binds receptors → activates
inhibitory G protein → inactivate adenylate Function
cyclase → ↓ cAMP production → protein ▪ ↓ gastric emptying, slows small intestine
kinase not activated → ↓ Ca2+ → inhibitory motility
effect
▪ Site of action Secretion and stimulation/inhibition
▫ Stomach, pancreas, small intestine, ▪ Secreted by endocrine cells in pancreatic
gallbladder, liver islets
▪ Secretory stimulants ▪ Secretory stimulants: intraluminal nutrients,
vagal nerve activation, hypoglycemia
▫ Glucose, arginine, leucine, glucagon,
vasoactive intestinal peptide (VIP),
cholecystokinin (CCK) PEPTIDE Y (PPY)
Function
GASTRIN ▪ Inhibits gastric acid secretion, gastric
Function motility, slows intestinal motility
▪ Induces gastric acid secretion ▪ Inhibits pancreatic exocrine secretion
Secretion and stimulation/inhibition Secretion and stimulation/inhibition

▪ Secreted by enteroendocrine G cells of ▪ Secreted by pancreatic islet alpha cells,
stomach, duodenum enteroendocrine cells
▪ Secretory stimulants ▪ Secretory stimulants
▫ Presence of acidic content, partially ▫ Ingestion of nutrition, bile acids, fatty
digested food in duodenum, vagus acids
nerve stimulation
▪ Inhibited by somatostatin
OSMOSIS.ORG 305
SECRETIN ▪ Secretory stimulants
▫ High blood glucose, glucose, arginine,
Function
leucine, glucagon, VIP, CCK
▪ ↓ acidity to improve pancreatic enzyme
function
▪ ↑ pancreatic secretion, biliary bicarbonate,
water GLUCAGON
▪ Regulates pancreatic enzyme secretion Function
▪ ↓ gastric emptying, gastrin release, gastric ▪ Counteracts insulin
acid secretion
▪ ↑ blood glucose, promotes glycogenolysis,
Secretion and stimulation/inhibition gluconeogenesis, ketogenesis
▪ Secreted by enteroendocrine S cells in ▪ Works mainly on liver
proximal small intestine
▪ Secretory stimulants
▪ Secreted by alpha cells of islet cells, L-cells
▫ Gastric acid, bile salts, peptides, fatty of intestine
acids, ethanol
INCRETINS
CHOLECYSTOKININ (CCK)
▪ Includes glucagon-like peptide-1 (GLP-1),
Function glucose-dependent insulinotropic peptide
▪ Promotes food delivery from stomach into (GIP)
small intestine Function
▪ Regulates nutrient-stimulated enzyme ▪ ↑ insulin release from pancreatic beta-cells
secretion
▪ ↑ levels of cAMP in islets leading to
▪ ↑ gallbladder contraction expansion of beta-cells
▪ ↑ enzymatic pancreatic secretion output
Secretion and stimulation/inhibition GASTRIC INHIBITORY PEPTIDE

▪ Secreted by enteroendocrine I cells (GIP)
▪ Secretory stimulants ▪ AKA glucose-dependent insulinotropic
▫ Nutrition ingestion, fatty acids, amino peptide
acids Function
▪ Weakly inhibits HCl production, stimulates
INSULIN insulin release
Function Secretion and stimulation/inhibition

▪ Major anabolic hormone ▪ Secreted by duodenal mucosa
▪ ↓ blood glucose ▪ Secretory stimulant
▪ Promotes liver, muscle glycogen storage ▫ Fatty chyme
▪ Fatty acids, triacylglycerol storage in
adipose tissue HISTAMINE
▪ Protein synthesis, glucagon suppression
Function
Secretion and stimulation/inhibition ▪ Activates parietal cells to release HCl
▪ Secreted by beta cells of pancreatic islet
cells Secretion and stimulation/inhibition
▪ Secreted by stomach mucosa
▪ Secretory stimulant
▫ Food in stomach
306 OSMOSIS.ORG
SEROTONIN GHRELIN
Function Function
▪ Stomach muscle contraction ▪ Stimulate hunger
▪ Site of action
▫ Hypothalamus lateral nucleus
▪ Secreted by stomach, duodenal mucosa
▪ Secretory stimulant Secretion and stimulation/inhibition
▫ Food in stomach ▪ Secreted by gastric cells
VASOACTIVE INTESTINAL PEPTIDE ▫ Empty stomach
(VIP) ▪ Inhibited by stomach stretching when food
present
Function
▪ Dilates intestinal capillaries
LEPTIN
▪ ↑ secretions, ↓ acid secretion
▪ Relaxes intestinal smooth muscle Function
▪ Site of action ▪ Stimulate satiety
▫ Small intestine, pancreas, stomach ▪ Site of action
▫ Ventromedial nucleus of hypothalamus
▪ Secreted by enteric neurons/ Secretion and stimulation/inhibition
parasympathetic ganglia ▪ Secreted by adipocytes
▫ Chyme, parasympathetic stimulus
ENKEPHALINS
Function
▪ Smooth muscle constriction causing ↓
fluid flow into intestines (opiates acting
on enkephalin receptors ↓ fluid flow to
intestines, cause constipation)
▪ Site of action
▫ Intestine
▪ Secreted by
▫ GI tract neurons
OSMOSIS.ORG 307
SATIETY
osms.it/satiety
▪ Hypothalamus controls appetite, satiety Insulin
▫ Ventral posteromedial nucleus (VPN) of ▪ Stimulates satiety, decreases appetite
hypothalamus: activates satiety ▪ Fluctuates throughout day
▫ Lateral hypothalamic area: activates
hunger, feeding Peptide YY (PYY)
▪ Stimulates satiety, decreases appetite
directly (via hypothalamus), indirectly (via
HORMONES inhibiting release of ghrelin)
Leptin GLP-1
▪ Stimulates satiety, decreases appetite ▪ Stimulates satiety, decreases appetite
▪ Secreted by fat cells in proportion to fat ▪ Secreted by intestinal L cells
amount in adipocytes
Ghrelin
▪ Increases appetite, hunger
▪ Secreted by gastric cells before meal
▪ Starvation, weight loss stimulates ghrelin
release
Figure 37.4 Locations of two areas in the hypothalamus that control appetite and satiety.
308 OSMOSIS.ORG
NOTES
NOTES
UPPER GASTROINTESTINAL
TRACT
CHEWING & SWALLOWING

osms.it/chewing-and-swallowing
CHEWING ▪ Involuntary component of chewing
▪ First step to process ingested food to ▫ Mouth mechanoreceptors → sensory
prepare for digestion, absorption information to brainstem → reflex
▪ Three functions oscillatory pattern to muscles of
▫ ↓ food particle size → facilitate mastication
swallowing ▪ Voluntary component
▫ Mix food with saliva → lubrication ▫ Can override reflex chewing at any time
▫ Mix food particles with amylase →
Muscles involved with mastication
begin carbohydrate digestion
▪ Temporalis muscle: fan-shaped muscle on
▪ Teeth move, masticate food into small
both sides of head
fragments, tongue functions to taste, roll
food around in oral cavity → compact into ▪ Masseter muscle: connects mandible to
small ball (bolus) zygomatic arch of temporal bone
▪ Medial pterygoid muscle: connects
Oral cavity walls mandible to medial pterygoid plate
▪ Roof: soft, hard palate ▪ Lateral pterygoid muscle: located at
▪ Floor: tongue, mylohyoid muscles condylar process
▪ Sides: cheeks ▪ All muscles of mastication innervated by
▪ Front: lips, teeth branches of trigeminal (CN V)
Figure 38.1 The structures that make up the walls of the oral cavity.
OSMOSIS.ORG 309
▪ All muscles coordinate, work together to food in mouth) → travel via vagus and
grind, mechanically break down food glossopharyngeal nerves → swallowing
▪ Tongue moves from side to side to center in medulla → sends efferent, motor
reposition food → push it between teeth information via glossopharyngeal, vagus
to be chewed, mixed with saliva → soft, nerves → directs coordinated movement
mushy bolus ready for swallowing of pharyngeal striated muscle, upper
esophagus
Three phases
▪ Oral (voluntary)
▫ Tongue presses against hard palate
→ forces bolus towards oropharynx
→ pharynx contains high density of
somatosensory receptors → activation
→ swallowing reflex initiation in medulla
▪ Pharyngeal (swallowing reflex)
▫ Soft palate, uvula moves upwards →
creates narrow passage → prevents
food reflux into nasopharynx →
epiglottis closes down over laryngeal
opening → larynx moves upwards
against epiglottis → act as seal to
prevent food entering trachea →
upper esophageal sphincter relaxes
→ food passes from pharynx to upper
esophagus → peristaltic wave initiation
→ food propelled through open upper
esophageal sphincter
▫ Breathing inhibited during this phase
▪ Esophageal (swallowing reflex/enteric
nervous system)
▫ Swallowing reflex closes upper
esophageal sphincter → food cannot
reflux back into pharynx → primary
Figure 38.2 The muscles of mastication. peristaltic wave (coordinated by
A: The temporalis and masseter muscles swallowing reflex) → propels food along
are superficial to B: the laterial and medial esophagus → if all food not cleared →
pterygoid muscles. distended esophagus → secondary
peristaltic wave is initiated by enteric
nervous system
SWALLOWING
▪ Initiated voluntarily in mouth, involuntary
thereafter
▫ AKA deglutition
▪ Pharynx has three parts
▫ Nasopharynx
▫ Oropharynx
▫ Throat
Swallowing reflex Figure 38.3 Locations of the three pharynx

▪ Somatosensory receptors near pharynx divisions and the upper esophageal sphincter.
→ detect sensory information (e.g.
310 OSMOSIS.ORG
Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract
Figure 38.4 Mastication muscles. A: The temporalis and masseter muscles are superficial to B:
the laterial and medial pterygoid muscles.
SALIVARY SECRETION
osms.it/salivary-secretion
SALIVARY GLANDS → myoepithelial cells stimulated neurally
▪ Three major salivary glands exist outside → contract → saliva ejected into mouth
oral cavity ▪ Cell types
▫ Parotid: composed of serous cells ▫ Acinar cells: produce initial isotonic
→ secrete fluid composed of ions, saliva (mixture of water, ions, enzymes,
enzymes, water mucus)
▫ Submandibular, sublingual: composed ▫ Ductal cells: modify electrolyte
of serous, mucous cells → stringy, concentrations in initial saliva to produce
viscous solution of aqueous fluid, mucin final saliva
glycoprotein for lubrication ▫ Myoepithelial cells: present in acini,
▪ Minor salivary glands (e.g. buccal) scattered intercalated ducts; contract to eject
throughout oral cavity mucosa saliva into oral cavity
▪ Each gland is paired; all produce saliva ▪ Innervation of salivary glands
which are delivered to oral cavity via ducts ▫ Saliva production stimulated by
▪ Appearance: cluster of grapes both parasympathetic (dominant),
▫ Each grape = single acinus sympathetic activation (unique feature)
▫ Blind end of branching duct system ▪ Blood supply
▪ Saliva formation is two-step process ▫ Saliva production stimulated →
▫ Acinus lined with acinar cells → unusually high blood flow
produces initial saliva → passes through ▫ When corrected for organ size, blood
intercalated duct → striated duct lined flow is ↑ 10x more than exercising
with ductal cells → modify initial saliva skeletal muscle
OSMOSIS.ORG 311
Figure 38.5 Protid glands sit in front of each ear. Submandibular glands sit under the mandible.
Sublingual glands (not pictured) are beneath the tongue, under the mouth floor.
SALIVA Saliva formation

▪ Produced by salivary glands; rate of 1L/ ▪ Initial saliva is isotonic
daily ▫ Concentrations of K+, HCO3-, Na+, Cl-
similar to plasma
Functions
▪ Final secreted saliva is hypotonic (↓
▪ Initial digestion of starches/lipids by salivary
osmolarity), when compared to plasma
enzymes
▫ ↑ K+, HCO3-, ↓ Na+, Cl-
▪ Lubricating ingested food to allow
movement through esophagus ▪ Modification of saliva by ductal cells
▪ Diluting, buffering ingested foods (which ▫ Complex transport system
may be harmful) ▪ Luminal membrane has three transporters
▪ Cleanses mouth ▫ Na+-H+ exchange
▪ Dissolves food chemicals so it can be ▫ H+-K+ exchange
tasted ▫ Cl--HCO3- exchange
▪ Basolateral membrane has two
Saliva composition transporters
▪ Water (97–99.5%) ▫ Na+-K+ ATPase
▪ Electrolytes ▫ Cl- channel
▪ Alpha-amylase: initial carbohydrates ▪ Overall action of all transporters together
digestion, like potatoes/rice
▫ Absorption of Na+, Cl- → ↓ Na+, Cl-
▪ Lingual lipase: initial lipid digestion concentration in saliva
▪ Mucus ▫ Secretion of K+, HCO3- → ↑ K+, HCO3-
▪ Immunoglobulin A concentration in saliva
▪ Kallikrein: protease enzyme; cleaves high ▫ Net absorption of solute (NaCl > KHCO3)
molecular weight kininogen → bradykinin ▪ Process of isotonic saliva → hypotonic
→ vasodilation → increased blood flow saliva
during salivary activity
▫ Ductal cells are water impermeable
▪ Lysozyme: enzyme inhibiting bacterial
▫ Due to net absorption (solutes leave
growth, prevents tooth decay
saliva, water does not travel with)
▪ Defensin: acts as local antibiotic
▪ Saliva tonicity depends on flow rates
▪ pH 6.5–7.5
▫ Depends on amount of time saliva in
▫ Usually maintained by NaHCO3 contact with ductal cells (↑ Na+, Cl-
312 OSMOSIS.ORG
absorption, ↑ K+ secretion) ▪ Parasympathetic innervation

▫ ↑ flow rate (4mL/min): composition ▫ Activity ↑ with visual stimulus of food,
parallels plasma, initial saliva produced smell, nausea, conditional reflexes (e.g.
by acinar cells Pavlov’s salivating dog)
▫ ↓ flow rate (1mL/min): most dissimilar ▫ Activity ↓ with fear, sleep, dehydration
composition to plasma ▫ Chemoreceptors, mechanoreceptors in
▫ Exception: HCO3- remains constant, oral cavity stimulated → signal carried
despite flow changes; selective via facial (CN VII), glossopharyngeal (CN
parasympathetic stimulation; ↑ flow rate IX) nerves → salivatory nucleus in brain
→ ↑ HCO3- parasympathetic stimulation stem (medulla and pons)
→ ↑ HCO3- secretion ▫ Vinegar and citric juice → strongest
chemoreceptor stimulus
Saliva secretion regulation
▫ Postganglionic neurons → release
▪ Minor salivary glands continuously acetylcholine (ACh) → bind muscarinic
secreting small amounts to keep oral cavity receptors → ↑ IP3 + intracellular Ca2+ →
moist saliva secretion
▪ When food enters → major glands ▪ Sympathetic innervation
activated → large amounts of saliva
▫ Thoracic segments T1–T3 →
produced
preganglionic nerves → synapse
▪ Two unique features
on superior cervical ganglion →
▫ Exclusive neural control by autonomic postganglionic sympathetic neurons
nervous system (other gastrointestinal release norepinephrine (NE) → bind
secretions controlled both neurally, to beta-adrenergic > alpha-adrenergic
hormonally) receptors on acinar/ductal cells →
▫ Saliva secretion ↑ by both sympathetic + stimulation of adenylyl cyclase → ↑
parasympathetic cAMP → ↑ saliva secretion
SLOW WAVES
osms.it/enteric-nervous-system-and-slow-waves
ENTERIC NERVOUS SYSTEM ▫ Myenteric nerve plexus → located

▪ AKA ‘gut brain’ between circular, longitudinal muscle
▪ Contains over 100 million neurons (more layers in muscularis externa; major
than spinal cord) controller of gastrointestinal (GI) tract
motility
▪ Intrinsic/“in-house” nerve plexuses spread
throughout GI tract like chicken wire ▪ Enteric nervous system connected to
central nervous system (CNS) via
▪ Semiautonomous enteric neurons made up
of two nerve plexuses (ganglia connected ▫ Afferent visceral fibers
by unmyelinated tracts) ▫ Sympathetic, parasympathetic branches
▫ Submucosal nerve plexus → located in ▫ Synapse with intrinsic plexus neurons
submucosa; innervates secretory cells;
controls local digestive secretions
OSMOSIS.ORG 313
Figure 38.6 The enteric nervous system is found within the walls of the entire gastrointestinal
tract. The submucosal plexus is found in the submucosa and the myenteric plexus is found
within the muscularis externa between the longitudinal and circular muscle layers.
Figure 38.7 The gastrointestinal portions of the visceral motor system.
Sympathetic division: preganglionic fibers are in the lower thoracic and upper lumbar segments
of the spinal cord, and they synapse in ganglia located near the spinal cord.
Parasympathetic division: preganglionic fibers arise from the brainstem (vagus nerve) and sacral
component of the spinal cord (pelvic nerve), and synapse in a neural plexus on or very near the
target organ.
314 OSMOSIS.ORG
SLOW WAVES Slow wave origin

▪ Unique feature of GI tract electrical activity ▪ Myenteric plexus is network of nerves,
▫ Oscillating depolarizations, located between longitudinal, circular layers
repolarization of membrane potential of in muscularis externa
GI smooth muscle cells ▪ Interstitial cells of Cajal located in myenteric
▪ Depolarization → membrane potential (Auerbach) plexus
becomes less negative → moves towards ▫ Referred to as ‘pacemaker’ cells of GI
threshold → burst of action potentials tract smooth muscle
(APs) occur on top of slow wave (plateau) ▫ Cyclic, spontaneous depolarizations,
→ contraction/smooth muscle tension repolarization occur in these cells →
→ membrane potential becomes more rapid spread to adjacent smooth muscle
negative → moves away from threshold → cells via gap junctions
repolarization → smooth muscle relaxation ▪ Pacemaker → frequency → AP rate →
Frequency coordinated smooth muscle contraction
▪ Intrinsic rate is 3–12 slow waves/minute ▪ Slow waves to contractions
▪ Not determined by hormonal/neural input, ▪ Subthreshold slow waves → can produce
however can modulate amount of APs at weak contraction
plateau → ↑/↓ contraction strength ▪ Even without AP occurrence → smooth
▪ Each part of GI tract has characteristic muscle not completely relaxed/tonically
frequency contracted
▫ Stomach → slowest (3/min), duodenum ▪ Above threshold slow waves → APs occur
→ fastest (12/min) on top of slow wave → stronger contraction
→ phasic contraction
Mechanism ▪ ↑↑ APs on top of slow wave → ↑↑ phasic
▪ Cyclic opening of Ca2+ channels → Ca2+ contraction strength
influx → depolarization ▪ Unlike skeletal muscle, where each AP
▪ Plateau phase maintained by continuous results in twitch/separate contraction,
Ca2+ influx smooth muscle APs summate into one long
▪ Opening of K+ channels → K+ outflux → contraction
repolarization
Figure 38.8 Slow wave origin and mechanism. Slow waves are generated by spontaneous
depolarization and polarization of Cajal cells, which are attached to smooth muscle cells via
gap junctions. The slow wave potentials travel through the smooth muscle cells → voltage-
gated calcium channels open → weak depolarization of smooth muscle cells → weak tonic
contractions that maintain the tone of the gastrointestinal tract.
OSMOSIS.ORG 315
Figure 38.9 Slow wave potentials from enteric nervous system + action potentials from extrinsic
nervous system → threshold potential for peristaltic contractions. Strength of contraction
is determined by number of action potentials above each slow wave; rate of contraction is
determined by the rate of the slow waves.
ESOPHAGEAL MOTILITY
osms.it/esophageal-motility
GI MOTILITY Sphincters
▪ Generally, GI motility refers to contraction, ▪ Specialized circular muscle separating
relaxation of GI walls, sphincters adjacent GI tract regions
▪ GI contractile tissue is all smooth muscle ▪ Maintain positive pressure → anterograde,
except retrograde flow prevented
▫ Pharynx ▪ Smooth muscle contraction → peristalsis
▫ Upper ⅓ esophagus of GI contents to sphincter → sphincter
▫ External anal sphincter transiently lowers pressure → relaxation →
passage of contents to adjacent organ
▪ Smooth muscle cells connected together
via gap junctions → rapid cell-to-cell ▪ Locations
transfer of action potentials → coordinated ▫ Upper esophageal sphincter: pharynx-
contractions upper esophagus
▫ Lower esophageal sphincter:
Two types of smooth muscle esophagus-stomach
▪ Circular: ↓ segment diameter ▫ Pyloric sphincter: stomach-duodenum
▪ Longitudinal: ↓ segment length ▫ Ileocecal sphincter: ileum-cecum
▪ Both contained within muscularis externa ▫ Internal and external sphincters:
layer preserves fecal continence
Two types of contractions
▪ Phasic: periodic → relaxation ESOPHAGUS
▫ Located in esophagus, small intestine
Key features
▪ Tonic: constant level of contraction, without
▪ Muscular 25cm/9.8in tube divided into
regular intervals of relaxation
three regions
▫ Located in lower esophagus, upper
▪ Cervical: connects with pharynx behind
stomach, ileocecal valve, internal anal
trachea; separated by upper esophageal
sphincter
sphincter
316 OSMOSIS.ORG
▪ Thoracic: suprasternal notch to esophageal ▪ Submucosa

hiatus in diaphragm ▫ Dense layer of connective tissue
▪ Abdominal: esophageal hiatus to containing blood vessels, lymphatics,
esophageal opening into stomach; mucus glands secreting mucus to
separated by lower esophageal sphincter lumen via ducts; contains submucosal
(Meissner) plexus
Layers ▪ Mucosa → three layers
▪ Adventitia ▫ Muscularis mucosa (outermost layer of
▫ Thick fibrous connective tissue; longitudinal muscle)
outermost ▫ Lamina propria
▪ Muscularis externa ▫ Epithelial layer
▫ Outer longitudinal, inner circular muscle
layers; myenteric plexus lies between
Figure 38.10 Regions of esophagus, associated structures.
Figure 38.11 Layers of esophageal mucosa.
OSMOSIS.ORG 317
Innervation ▪ Food bolus approaches lower esophageal
▪ Intrinsic: Vagus nerve (CN X) sphincter → opening mediated by
▪ Extrinsic: Myenteric plexus in muscularis peptidergic fibers of vagus nerve, release
externa vasoactive intestinal peptide (VIP) →
lower esophageal sphincter smooth
Function muscle relaxation → at same time, orad
▪ Esophageal motility propels food bolus region of stomach relaxes (phenomenon
from pharynx → stomach referred to as receptive relaxation) →
pressure decreases in orad stomach →
▫ Food bolus formed in oral cavity →
food bolus propelled into stomach → lower
upper esophageal sphincter opens
esophageal sphincter closes immediately,
→ bolus passes pharynx to upper
returns to high pressure resting tone →
esophagus → upper esophageal
prevents reflux
sphincter closes → primary peristaltic
contraction → series of coordinated Intrathoracic esophagus
sequential contractions → each
▪ Upper, middle esophagus located in thorax,
segment contracts → creates area of
only lower esophagus located in abdomen
high pressure behind bolus → pushed
down esophagus ▪ Intraesophageal pressure = intrathoracic
pressure which is < atmospheric pressure
▪ If not all food pushed through → distension
of esophageal wall → activation of ▪ Intraesophageal pressure < intra abdominal
mechanoreceptors in mucosal layer → pressure
afferent, sensory information to enteric ▪ This pressure difference causes two
nervous system and myenteric plexus → problems
coordination of muscle contractions above ▫ Inhibiting air from entering upper
site of distension + relaxation below it → esophagus (air will travel down pressure
secondary peristaltic wave gradient, esophagus essentially sucking
▪ Esophagus has thick muscularis externa air in); prevented by upper esophageal
compared to other parts of GI tract sphincter (always in closed resting state)
▪ Primary peristaltic wave travels ▫ Inhibiting gastric contents from entering
approximately 3cm/sec lower esophagus (reflux); prevented by
▫ Solid food takes approximately 10 lower esophageal sphincter (always in
seconds to travel from cervical region → closed resting state)
stomach ▫ Conditions where intraabdominal
▫ Liquids approximately 1–2 seconds pressure ↑↑ (e.g. pregnancy, morbid
obesity) → gastroesophageal reflux
▫ Accelerated by gravity (sitting/standing
> lying supine)
318 OSMOSIS.ORG
GASTRIC MOTILITY
osms.it/gastric-motility-and-secretions
STOMACH Layers
▪ Anatomy differentiated based on motility, ▪ Mucosa: innermost layer; modified →
stomach can be divided into orad contains various glands filled with different
(proximal), caudad (distal) cells → secrete components of gastric juice
▫ Orad region: fundus, proximal body; ▪ Submucosa: contains submucosal plexus
thin-walled → controls secretions and gastric blood
▫ Caudad region: distal body, antrum; flow, contains blood vessels
thick-walled (stronger contractions to ▪ Muscularis externa: modified
mix chyme, propel to small intestine) ▪ Serosa: outermost layer
▪ Three layers of stomach muscles that
involuntarily contract to produce peristalsis
▫ Outer longitudinal layer
▫ Middle circular layer
▫ Inner oblique layer (unique to stomach)
Innervation
▪ Extrinsic: autonomic nervous system
▪ Intrinsic: myenteric receives
parasympathetic innervation (via vagus
nerve), sympathetic innervation (via fibers
Figure 38.12 Divisions of the stomach. from celiac ganglion); submucosal plexuses
Figure 38.13 Layers of the stomach.
OSMOSIS.ORG 319
COMPONENTS OF GASTRIC threshold so APs can occur
MOTILITY ▫ 3–5/min → frequency of caudad
▪ Three components stomach contraction approximately
▪ Receptive relaxation same
▫ Relaxation of lower esophageal ▫ Slow wave frequency not influenced by
sphincter, orad stomach region to neural/hormonal input
receive food bolus from esophagus ▫ Frequency of APs, contraction force are
▪ Gastric contractions to break up bolus, mix influenced by neural/hormonal input
with gastric secretions → initiate digestion ▪ Frequency of APs, force of contraction ↑↑
▪ Gastric emptying → propelling chyme to by
small intestine ▫ Parasympathetic stimulation
▫ Gastric emptying rate hormonally ▫ Gastrin
determined → allows adequate time for ▫ Motilin
small intestine digestion/absorption ▪ Frequency of APs, force of contraction ↓↓
▫ Liquids (faster); solids (slower) by
Receptive relaxation ▫ Sympathetic stimulation
▪ Vasovagal reflex: both afferent, efferent ▫ Secretin: hormone produced by
limbs of reflex carried within vagus nerve duodenal S cells; regulates water
homeostasis, GI tract secretions
▫ Lower esophageal distension →
relaxation, opening of lower esophageal ▫ Gastric inhibitory peptide (GIP):
sphincter → mechanoreceptors hormone secreted by intestinal K cells;
detect distension → send afferent inhibits gastric acid secretion, stimulates
sensory information to CNS through insulin secretion
sensory neurons → CNS transmits ▪ Migrating myoelectric complexes
efferent information to orad stomach ▫ Periodic gastric contractions during
smooth muscle wall → postganglionic fasting
peptidergic vagal nerve fibers release ▫ Function: clear stomach of remaining
VIP → orad stomach ↓ pressure, ↑ content from last meal
volume → allows food bolus passage ▫ 90-minute intervals
▫ Vagotomy inhibits receptive relaxation ▫ Mediated by motilin
▪ Stomach can accommodate up to 1.5L of
food Gastric emptying
▪ Emptying stomach of 1.5L postmeal can
Gastric contractions take approximately three hours
▪ Thick, muscular caudad region of stomach ▪ Emptying rate closely monitored/regulated
produces strong contractions needed to to allow ample time for stomach acid
mix food with gastric secretions, digest neutralization in duodenum, digestion/
food absorption of nutrients
▪ Contraction waves begin in middle stomach ▪ Emptying speeds
body → progressively ↑ strength as food
▫ Liquids > solids
approaches pylorus
▫ Isotonic contents > hyper/hypotonic
▪ Periodically, portion of gastric contents
contents
propelled through pylorus to duodenum
▪ Solid particles must be < 1mm3;
▫ However, most gastric contents
retropulsion continues until this size
undergo retropulsion (propelled back
reached
into stomach for further mixing)
▪ Factors that ↑ gastric emptying time (slows
▪ Majority of the chyme not initially injected
gastric emptying process)
through pylorus to duodenum since
contraction wave closes pyloric sphincter ▫ ↓ pH in duodenum (presence of H+ ions);
mediated by enteric nervous system
▪ Frequency of slow waves in caudad
stomach; bringing membrane potential to ▫ H+ receptors in duodenal mucosa detect
↓ pH of intestinal contents → activate
320 OSMOSIS.ORG
interneurons in myenteric plexus → ▪ The hormone cholecystokinin (CCK)

relay info to gastric smooth muscle → secreted from duodenal I cells when fatty
↑ gastric emptying time/slows gastric acids present in duodenum → slows gastric
emptying process → allows time to emptying ( ↑ gastric emptying time) →
neutralize acid by pancreatic HCO3-. allow adequate time for fat to be digested/
▫ ↑ fatty acids (highly fatty meal) absorbed
GASTRIC SECRETION
osms.it/gastric-motility-and-secretions
▪ Altogether gastric mucosa secretes fluid Secretory cells
referred to as ‘gastric juice’ ▪ Found in gastric glands
▪ Four major components ▪ Mucous neck cells
▫ HCl ▫ Scattered around neck, basally
▫ Pepsinogen ▫ Produce thin watery mucus (different
▫ Intrinsic factor (needed for vitamin B12 from mucous cells of surface epithelium)
absorption in ileum) ▪ Parietal (oxyntic) cells
▫ Mucus (protects gastric mucosa from ▫ Found more apically; scattered around
corrosive acids, lubricates) chief cells
▪ Oxyntic glands ▫ Produce HCl, intrinsic factor
▫ Found in body of stomach ▪ Chief cells
▫ Empty secretions via ducts into lumen of ▫ Found basally
stomach ▫ Produce pepsinogen (inactive form of
▫ Opening of duct in gastric mucosa pepsin); activated by HCl
referred to as pits, lined by epithelial ▫ Also produce lipases (15% of GI
cells superficially lipolysis)
▪ Enteroendocrine cells
▫ Found deep in gland
▫ Release various chemical messengers
directly into lamina propria (e.g.
histamine, serotonin act via paracrine
mechanism, somatostatin acts via
paracrine/hormone mechanism)
▪ G cells
▫ Secrete gastrin → bloodstream → ↑ HCl
secretion by parietal cells, ↑ pepsinogen
secretion by chief cells + ↑ contraction of
stomach muscles
▪ Pyloric glands found in antrum of stomach
▫ Similar configuration to oxyntic glands
but with deeper pits
▫ Mucous neck cells secrete mucus,
HCO3-, pepsinogen → pyloric ducts
▫ G cells secrete gastrin → circulation
OSMOSIS.ORG 321
Figure 38.14 Location of secretory cells within gastric glands and in the stomach, as well as
secretory products.
Mucosal barrier ▪ Basolateral membrane has two

▪ Stomach is harshest, most corrosive transporters
environment in entire GI tract ▫ Na+-K+ ATPase
▫ Due to HCl, protein-digesting enzymes ▫ Cl--HCO3- exchanger
▪ To combat these conditions ▪ Basolateral membrane cells contain
▫ Thick bicarbonate-rich mucus carbonic anhydrase
▫ Tight junctions joining epithelial cells ▫ CO2 + H2O → H2CO3 → H+ + HCO3-
together (prevents gastric juice leakage) ▫ H+ then secreted with Cl- into lumen of
▫ Undifferentiated stem cells → shed and stomach
replace damaged epithelial mucosal ▫ HCO3- is absorbed into blood → ‘alkaline
cells tide’ (↑ blood pH in gastric venous blood
after meal)
HCl secretion and mechanism
▪ Overall net HCl secretion, net HCO3-
▪ Parietal cells → HCl secretion → gastric absorption
content pH 1–2
▪ Functions to convert inactive pepsinogen HCl secretion modulation
(secreted by chief cells) → active pepsin ▪ Gastrin (secreted into systemic circulation
→ protein digestion; also functions to kill by gastric antral G cells)
ingested bacteria ▫ Reaches parietal cells via endocrine
▪ Apical membrane of gastric gland has two mechanism
transporters ▫ Binds to CCKB receptors of parietal cells
▫ H+-K+ ATPase: H+ secreted into stomach (affinity for gastrin = CCK)
lumen; primary active process (H+ ▫ Stimulates H+ secretion via IP3/Ca2+
and K+ flow against electrochemical second messenger mechanism
gradient); site of action by proton pump ▫ Triggers for gastrin secretion: stomach
inhibitors (e.g. omeprazole) distension, small peptides, amino acids
▫ Cl- channel: Cl- follows H+ into lumen; in stomach, vagus nerve stimulation
passive process ▫ Can indirectly stimulate H+ secretion
by ↑ histamine release from
endochromaffin-like (ECL) cells
322 OSMOSIS.ORG
▪ Histamine ▫ Will not block indirect vagal effects on

▫ Released from ECL cells in gastric gastrin secretion since neurotransmitter
mucosa is gastrin-releasing peptide (GRP), not
▫ Paracrine diffusion mechanism to ACh
nearby parietal cells ▫ Can indirectly stimulate H+ secretion by
▫ Binds to H2 receptors coupled to G2 ↑ histamine release from ECL cells
protein → stimulation of adenylyl ▪ Rate of H+ secretion is regulated by
cyclase → ↑ cAMP → activation of individual actions of gastrin, histamine,
protein kinase A → ↑ secretion of H+ by ACh or by the combination of them via
parietal cells potentiation (ability of two or more stimuli
▫ Site of action of the H2 blockers (e.g. to interact together to produce a greater
cimetidine) combined response than sum of individual
effects)
▪ ACh
▫ Released by vagus nerve (directly Cephalic phase of gastric secretion
innervate parietal cells) ▪ 30% of total HCl secretion
▫ ACh directly binds to parietal cell M3 ▪ Stimuli: smell and taste of food, chewing,
receptors → activation of phospholipase swallowing, conditional reflexes in
C → releases diacylglycerol (DAG) and anticipation of eating (ex. Pavlov’s dog)
IP3 from membrane phospholipids → ▪ Two physiological mechanisms
↑ intracellular Ca2+ → Ca2+ and DAG
▫ Direct vagal stimulation of parietal cells
→ activate protein kinases → ↑ H+
secretion by parietal cells ▫ Indirect vagal stimulation of parietal cells
▫ Site of action of antimuscarinics (e.g. via gastrin
atropine); atropine does not block HCl Gastric phase of gastric secretion
secretion completely
▪ 60% of total HCl secretion
▫ Will block direct vagal effects on parietal
▪ Stimuli: gastric distension, amino acid/small
cells
peptide presence
Figure 38.15 Mechanism of HCl secretion by parietal cells in the stomach’s gastric glands.
Dotted lines indicate passive diffusion, whereas solid lines indicate active transport.
OSMOSIS.ORG 323
▪ Four physiological mechanisms
▫ Distension → direct vagal stimulation
▫ Distension → indirect vagal stimulation
(via gastrin)
▫ Antral distension → local gastrin release
reflex
▫ Amino acids/small peptides → G cells →
gastrin release
▪ Caffeine, alcohol are also HCl secretion
stimulants
Intestinal phase of gastric secretion

▪ 10% of total HCl secretion
▪ Mediated by protein digestion products
Inhibition of HCl secretion

▪ First major factor is ↓ pH of gastric contents
▫ Gastrin secretion inhibited by low pH
▫ Chyme moved to small intestine → no
longer requirement of pepsinogen →
pepsin
▪ Second major factor is somatostatin
▫ Secreted by D cells in stomach
▫ Inhibits H+ secretion from parietal cells
▫ Direct mechanism: somatostatin →
binds to receptor on parietal cell coupled
with Gi protein → ↓ adenylyl cyclase →
↓ cAMP → ↓ H+ secretion
▫ Indirect mechanism: somatostatin
inhibits ECL, G cell release of histamine,
gastrin, respectively
▪ Prostaglandins (e.g. prostaglandin E2) also
inhibit histamine’s stimulatory action on
H+ secretion via Gi protein → ↓ adenylyl
cyclase pathway
324 OSMOSIS.ORG
NOTES
NOTES
DIGESTION & ABSORPTION
DIGESTION & ABSORPTION ▫ Cranial nerves (mainly Vagus) activate
▪ Digestion: breakdown of large food muscles of pharynx, esophagus
molecules into monomers for absorption in ▫ Soft palate rises, closes nasopharynx,
gastrointestinal (GI) tract epiglottis covers larynx, upper
▪ Chemical digestion accomplished by esophageal sphincter relaxes →
enzymes secreted into alimentary canal by peristalsis moves food through pharynx,
glands esophagus → gastroesophageal
sphincter relaxes allowing food to enter
Mechanical digestion
▪ Mastication Two absorption pathways
▫ Mouth ingests food, begins mechanical, ▪ Cellular pathway: substance crosses apical/
chemical digestion (mastication, luminal membrane to enter intestinal
salivation), initiates propulsion by epithelial cell, then crosses basolateral
swallowing membrane to enter into blood
▫ Partly voluntary, partly reflexive (e.g. ▪ Paracellular pathway: move across tight
stretch reflexes, pressure inputs) junctions between intestinal epithelial cells
to enter blood
Deglutition (swallowing) ▪ Absorptive surface maximized by villi,
▪ Movement of food from mouth to stomach microvilli, folds (folds of Kerckring) in small
▪ Buccal phase: voluntary intestine
▫ Occurs in mouth ▫ Most digestion occurs in duodenum,
▫ Tongue pushes against hard palate least amount of digestion occurs in
forcing food bolus into oropharynx ileum (as reflected by length of villi -
longest villi in duodenum, shortest in
▪ Pharyngeal-esophageal phase: involuntary
ileum)
▫ Controlled by brainstem swallowing
▫ Brush border: surface of microvilli
center
containing digestive enzymes
OSMOSIS.ORG 325
HYDRATION
osms.it/hydration
▪ Total body water DEHYDRATION
▫ Intracellular fluid (inside cells) + ▪ Occurs when water loss > water intake
extracellular fluid (outside cells—e.g. ▪ Causes
blood, interstitium) ▫ Vigorous exercise, decreased oral intake,
▪ Water functions dry air, vomiting, diarrhea, excessive
▫ Bodily secretions, digestion, sweating, inability to swallow, diuretics
detoxification (urination), ▪ Symptoms
thermoregulation (sweating) ▫ Thirst, dry mouth/lips, nausea, fatigue,
▪ Total body water balanced by intake, lightheadedness, darkened/decreased
elimination urine
▪ High risk groups
Water intake
▫ Children: lower stores of water, ↑
▪ Water ingested in fluid/food form
surface area to body mass, thirst
▫ 80% → fluid; 20% → food sensors not fully developed, depend on
▪ Bloodstream absorption in small, large caregivers
intestines ▫ Elderly: decreased thirst sensation,
Water loss medication, chronic diseases affecting
kidneys
▪ Breathing; sweating; urinating, defecating
CARBOHYDRATES & SUGARS

osms.it/carbohydrates-and-sugars
DIGESTION 1,4-glycosidic bonds in starch yielding
disaccharides
Mouth
▫ Intestinal brush border enzymes: digest
▪ Begins carbohydrate digestion oligosaccharides, disaccharides →
▪ Enzyme: salivary alpha amylase lactose, maltose, sucrose → galactose,
▫ Starts starch digestion → dextrins, glucose, fructose; e.g. dextrinase,
maltose, maltotriose maltase, glucoamylase, lactase, sucrase
Stomach
▪ Salivary amylase inactivated
ABSORPTION
▪ Primary site of absorption: small intestine
▪ Relatively no breakdown of starch
Pathway of absorption
Small intestine
▪ Glucose, galactose: absorbed into
▪ Majority of carbohydrate digestion
enterocytes via sodium ion cotransport
▪ Enzymes include (secondary active transport) → GLUT2
▫ Pancreatic amylase: digests starch transporter extrudes glucose, galactose
→ disaccharides; hydrolyzes interior across basolateral membrane into blood
326 OSMOSIS.ORG
Chapter 39 Gastrointestinal Physiology: Digestion & Absorption
▫ Sodium-glucose cotransporter (SGLT1): in apical membrane → GLUT2 transporter

moves glucose inside enterocytes extrudes fructose across basolateral
against electrochemical gradient using membrane into blood; fructose absorption
ATP created from sodium gradient cannot occur against electrochemical
created by sodium-potassium ATPase gradient
on the basolateral membrane ▪ Monosaccharides leave epithelial cells via
▪ Fructose: absorbed into enterocytes via facilitated diffusion → enter villi capillaries
facilitated diffusion by GLUT5 transporter → hepatic portal vein → liver
Figure 39.1 Overview of the actions of some of the enzymes involved in carbohydrate digestion.
PROTEINS
osms.it/proteins
▪ Proteins can be absorbed in the form of (pepsin, trypsin, chymotrypsin)
amino acids, dipeptides, or tripeptides (as ▫ Exopeptidases: hydrolyze individual
opposed to carbohydrates) individual amino acids from carboxyl
end (carboxypeptidases A, B)
DIGESTION Small intestine
▪ Proteins → large polypeptides → smaller ▪ Pancreatic, intestinal brush border enzymes
polypeptides/peptides → individual amino continue digestion
acids/dipeptides/tripeptides
▪ Pancreatic enzymes
Stomach ▫ Zymogens: trypsinogen,
▪ Gastric pepsin (with HCl): digests proteins chymotrypsinogen,
→ large polypeptides procarboxypeptidase A, B
▫ Protein digestion starts with gastric ▫ Active forms: trypsin, chymotrypsin,
pepsin carboxypeptidase
▫ Secreted by chief cells, activated by low ▫ Enterokinase activates trypsinogen
pH → trypsin → trypsin autocatalyzes
▪ Proteases (endopeptidases, exopeptidases) itself, activates additional pancreatic
zymogens
▫ Endopeptidases: trypsin, chymotrypsin,
pepsin; hydrolyze interior peptide bonds
OSMOSIS.ORG 327
▫ Digest large polypeptides → small ▪ Dipeptides, tripeptides: absorbed into
polypeptides/peptides enterocytes via cotransport with protons →
▪ Intestinal brush border enzymes broken down into amino acids/transcytosis
▫ Dipeptidase, aminopeptidase,
carboxypeptidase NUCLEIC ACID DIGESTION &
▫ Digest small polypeptides/peptides → ABSORPTION
amino acids/dipeptides/tripeptides ▪ Nucleic acids → pentose sugars, nitrogen-
containing bases, phosphate ions
ABSORPTION ▪ Site of digestion: small intestine only
▪ Site of absorption: small intestine ▪ Enzymes
▫ Pancreatic ribonuclease,
Pathway of absorption deoxyribonucleases
▪ Amino acids: absorbed via cotransport with ▫ Intestinal brush border enzymes
sodium ions or facilitated diffusion out of (nucleosidases, phosphatases)
epithelial cells → enter villi capillaries → ▪ Site of absorption: small intestine
hepatic portal vein → liver
▪ Absorption pathway: active transport into
▫ Four separate transporters one each for enterocytes by membrane carriers → villi
neutral, acidic, basic amino acid capillaries → hepatic portal vein → liver
FATS
osms.it/fats
▪ Unemulsified triglycerides →
monoglycerides/diglycerides, fatty acids
▪ Site of digestion: mouth, stomach, small
intestine
▪ Lipid digestion begins with lingual, gastric
lipases hydrolyzing triglycerides → glycerol,
fatty acids
▫ CCK slows gastric emptying, allowing
adequate time for pancreatic enzymes
to work
▪ Pancreatic enzymes (pancreatic lipase,
cholesterol ester hydrolase, phospholipase
A2), colipase finish digestion in small
intestine
▫ Bile salts, lysolecithin surround, emulsify
dietary lipids to create large surface area
for pancreatic enzymes
▫ Pancreatic lipase secreted as active
enzyme, hydrolyzes triglyceride →
monoglyceride + 2 fatty acids
▫ Colipase (secreted as inactive
procolipase, activated by trypsin) binds Figure 39.2 Fats are comprised of glycerol
to pancreatic lipase protecting it from backbone and one or more fatty acid chains.
being inactivated by bile salts A few examples of fats shown above.
328 OSMOSIS.ORG
▫ Cholesterol ester hydrolase (secreted as Pathway of absorption

active enzyme) hydrolyzes cholesterol ▪ Fatty acids, monoglycerides absorbed via
ester → free cholesterol, fatty acids; ▫ Diffusion
hydrolyzes triglycerides → glycerol
▫ Fatty acids, monoglycerides leave
▫ Phospholipase A2 (secreted as micelles → enter epithelial cells →
proenzyme, activated by trypsin) triglyceride formation → chylomicrons
hydrolyzes phospholipids → lysolecithin, formation (fat globules plus surface
fatty acids apoproteins) → chylomicrons enter
▪ Final products of lipid digestion: lacteals → lymph in lacteal transports
monoglycerides, cholesterol, glycerol, fatty chylomicrons into systemic circulation
acids, lysolecithin ▪ Apoproteins are essential for absorption of
▫ Since products are hydrophobic (except chylomicrons (specifically Apo B)
glycerol),must be solubilized in micelles ▪ Short chain fatty acids diffuse into villi
before transport to enterocyte apical capillaries → hepatic portal vein → liver
membrane for absorption
▫ Micelles: products of lipid digestion
surrounded by bile salts
▪ Site of absorption: small intestine
Figure 39.3 Overview of the fat absorption pathway.

1. Fatty acids and monoglycerides leave micelles and
2. enter epithelial cells.
3. They form triglycerides.
4. Chylomicrons containing the fats are then formed.
5. The chylomicrons enter lacteals, and
6. are transported into systemic circulation.
OSMOSIS.ORG 329
VITAMINS
osms.it/vitamins
▪ With the exception of vitamin K, which is calcium binding protein → promotes
produced by intestinal bacteria, vitamins calcium absorption from small intestine
are not synthesized in body therefore must ▪ Decreased by: oxalic acid, tannins,
be attained by diet magnesium, phosphorus, phytates
▪ Increased by: acidic conditions in intestine,
Fat soluble (Vitamins A, D, E, K)
vitamin D, estrogen, lactose
▪ Location: small intestine
▪ Location: small intestine (primarily
▪ Mechanism: incorporated into micelles duodenum)
along with products of lipid digestion,
▪ Mechanism: vitamin D-dependent calcium
absorbed into enterocytes
binding protein
Water-soluble (B vitamins, vitamin C,
Absorption of iron
biotin, folic acid, nicotinic acid, pantothenic
acid) ▪ Location: small intestine
▪ Location: ileum ▪ Mechanism: ferric state (Fe3+) reduced
▪ Mechanism: cotransport with sodium → to ferrous state (Fe2+) → binds
(need intrinsic factor) except vitamin B12 apoferritin in enterocytes → transported
(cobalamin) across basolateral membrane → binds to
transferrin in blood → transferrin carries to
▪ Vitamin B12
liver
▫ Requires intrinsic factor
▫ Pathway: ingestion → stomach acidity The absorptive state: hormones
releases B12 from its food carrier ▪ Digested nutrients enter blood stream
proteins → free vitamin B12 binds to from intestines → blood glucose rises →
haptocorrin (R proteins) secreted by stimulation of pancreatic insulin release →
salivary glands (protects B12 from acid body cells increase glucose uptake reducing
degradation) → pancreatic proteases blood glucose concentration back to normal
degrade R proteins in duodenum → ▪ Hepatocytes
B12 binds to intrinsic factors (secreted ▫ Excess glucose → glycogen for storage
by gastric parietal cells) to protect it via glucose-6-phosphate intermediate
from pancreatic enzymes → intrinsic
▫ Amino acids → ketone bodies
factor-B12 complex resistant to
(converted to acetyl CoA if needed later)
degradation from pancreatic enzymes
→ absorbed in ileum ▪ Myocytes
▫ Excess glucose → glycogen for storage
Absorption of calcium via glucose-6-phosphate intermediate
▪ Active form of vitamin D, ▫ Amino acids → actin, myosin → muscle
1,25-dihydroxycholecalciferol, required for fibers
calcium absorption ▪ Adipocytes store excess lipids increasing
▪ Dietary vitamin D3 (cholecalciferol) is fat reserves
inactive
▪ Cholecalciferol → 25-hydroxycholecalciferol
(inactive) in liver →
1,25-dihydroxycholecalciferol in kidney
by 1alpha-hydroxylase → synthesizes
calbindin D-28K (vitamin D-dependent
330 OSMOSIS.ORG
INTESTINAL FLUID BALANCE

osms.it/intestinal-fluid-balance
▪ Along with nutrient digestion, GI tract re- ▪ H+ secreted into lumen + HCO3- secreted
absorbs large amounts of fluid, electrolytes into lumen (via Cl--HCO3- exchanger;
(Na+, Cl-, HCO3-, K+) not absorbed into blood) → Cl--HCO3-
▪ Small, large intestine together absorb exchanger, Na+-H+ exchanger → net NaCl
approximately 9L/2.38 gallons daily movement into cell → net NaCl absorption
▫ Diet → 2L/0.44 gallons; pancreatic, Colon
biliary, intestinal secretions → 7L/1.85
▪ Apical membrane contains Na+, K+ channels
gallons
▫ Approximately 100–200mL /0.03–0.06 ▪ Net Na+ absorption + K+ secretion
gallons) excreted in feces ▪ Aldosterone induces Na+ channel synthesis
▫ Absorptive mechanisms disrupted → → ↑ Na+ absorption, secondary to K+
diarrhea (enormous potential body- secretion
water, electrolyte loss ) Fluid, electrolyte secretion
Villi ▪ Epithelial cells lining crypts of small
▪ Line intestinal epithelial cells intestine → secrete fluid, electrolytes
(mucus, lubricating fluids assisting in
▫ First step: solute absorbed; second step:
mixing, digestion) → must also be absorbed
water follows
more distally
▫ Fluid absorbed = isosmotic (water,
▪ Electrolyte, fluid secretion route
solute absorption: parallel proportions)
▫ Small intestine: paracellular route →
▫ Similar to renal proximal tubule
“leaky” tight junctions (↓ resistance)
▫ Absorptive mechanisms vary by
▫ Colon: cellular route → “tight” tight
intestinal part
junctions (↑ resistance)
Jejunum ▪ Electrolyte, fluid secretion mechanism
▪ Major site of Na+ absorption ▫ Apical membrane: Cl- channel
▫ Enters epithelial cell → Na+-dependent ▫ Basolateral membrane: Na+-K+-2Cl-
coupled transporters on apical cotransporter (similar to thick ascending
membrane (Na+-monosaccharide loop of Henle)
cotransporters (Na+-glucose/ ▫ Na+, K+, Cl- ions move into cells from
Na+-galactose), Na+-amino acid blood → Cl- diffuses into lumen via
cotransporters, Na+-H+ exchanger) Cl- channel on apical membrane → Na+
▫ Translocates across basolateral follows Cl- passively, paracellularly →
membrane via Na+-K+ ATPase H2O secretion follows NaCl secretion
▫ H+ source (for Na+-H+ exchanger) = ▫ Apical Cl- channels closed in resting
intracellular CO2 + H2O → carbonic state → opens after various hormones/
anhydrase converts to H+, HCO3- → H+ neurotransmitters (ACh, VIP) bind
secreted into lumen → blood absorbs ▫ Bind to basolateral receptor → activate
HCO3- (“alkaline tide”) adenylyl cyclase → ↑ cAMP in crypt cells
→ cAMP opens Cl- channels
Ileum
▫ Adenylyl cyclase can be maximally
▪ Same transporters as jejunum + Cl--HCO3- activated in cholera → severe, life-
exchanger on apical membrane threatening diarrhea
▪ Cl- transporter in basolateral membrane
OSMOSIS.ORG 331
NOTES
NOTES
LIVER, GALL BLADDER, &
PANCREAS
BILE SECRETION &

ENTEROHEPATIC CIRCULATION
osms.it/bile-secretion-enterohepatic-circulation
SYNTHESIS OF BILE, BILIRUBIN
▪ Hemoglobin from old red blood cells
taken up by macrophages → biliverdin
→ unconjugated bilirubin → released
into plasma, combines with albumin →
unconjugated bilirubin absorbed into
hepatic cells, released from albumin →
liver conjugates unconjugated bilirubin
→ conjugated bilirubin excreted from
hepatocytes into intestines → some
conjugated bilirubin converted by bacteria
into urobilinogen (soluble) → some
urobilinogen reabsorbed through intestinal
mucosa back into blood → re-excreted by
liver back into gut/excreted by kidneys into
urine → urobilinogen becomes urobilin →
stercobilin in feces
RECYCLING OF BILE
▪ Bile transported from ileum into portal
blood after digestion → portal blood
delivers bile salts to liver → liver extracts
bile salts from portal blood, adds to hepatic
bile salt/acid pool → bile returned to
gallbladder
▪ Some bile excreted into feces as stercobilin
▪ Only excreted bile needs to be replaced
Figure 40.1 Bile synthesis to excretion/
recycling pathway.
332 OSMOSIS.ORG
Chapter 40 Gastrointestinal Physiology: Liver, Gall Bladder, & Pancreas
LIVER ANATOMY & PHYSIOLOGY

osms.it/liver-anatomy-physiology
LIVER ANATOMY Four lobes
▪ Right lobe (largest)
Functions
▪ Left lobe
▪ Bile production, storage (e.g. glycogen),
detoxification, nutrient interconversion, ▪ Caudate lobe
synthesis (e.g. albumin, clotting factors), ▪ Quadrate lobe
phagocytosis (Kupffer cells)
Blood supply
Location ▪ 75% from nutrient rich, oxygen poor portal
▪ Located in right upper quadrant (RUQ) vein
under diaphragm, almost entirely within rib ▪ 25% from nutrient poor, oxygen rich
cage hepatic artery
▫ Largest internal organ ▪ Enterohepatic circulation gives liver first
▪ Covered by visceral peritoneum access to nutrients, toxins, medications
▫ Except superior-most region (bare area), from gut
contacts inferior surface of diaphragm Liver lobule
▪ Falciform ligament: mesentery separates ▪ Functional unit of liver
right, left lobes; suspends liver from
▫ Hexagonal liver lobule made of
diaphragm, anterior abdominal wall
hepatocytes
▪ Round ligament/ligamentum teres: inferior
▪ Each liver lobule surrounded by six portal
to falciform ligament, remnant of fetal
triads on each point withlobes central vein
umbilical vein
in center
Figure 40.2 Superior and inferior view of liver.
OSMOSIS.ORG 333
Major fuels
▪ Glucose, fructose, galactose (after meal);
fatty acids (after fasting)
▫ Amino acids can also be used
▫ Long-chain fatty acids: major source of
fuel during prolonged fasting
Cell types
▪ Hepatocytes
▫ Function: carry out most metabolic
pathways
▫ Majority cell type in liver
▫ Contain large amounts of rough, smooth
Figure 40.3 Liver lobule. endoplasmic reticulum (ER), Golgi
bodies, peroxisomes, mitochondria
▪ Endothelial cells
▪ Portal triad
▫ Location: sinusoidal lining
▫ Portal venule + portal arteriole + bile
▫ Function: release growth factors; secrete
duct
cytokines, endocytose ligands
Sinusoids ▫ Contain fenestrations → free diffusion
▪ Mixing of portal vein, hepatic arterial blood of blood, nutrients between sinusoids,
hepatocytes
▪ Lined with leaky endothelial cells
▪ Kupffer cells
▪ Pathway of blood flow
▫ Location: sinusoidal lining
▫ Blood from hepatic portal vein, artery →
sinusoids → central vein → hepatic vein ▫ Function: macrophages specific to liver
→ inferior vena cava protect against gut-derived pathogens,
release cytokines, secrete mediators
Bile of inflammatory response, remove
▪ Produced by hepatocytes, excreted into bile damaged erythrocytes from circulation
ducts ▪ Stellate (Ito) cells
▪ Composed of bile salts, bile pigments, ▫ Location: scattered amongst
cholesterol, triglycerides, phospholipids hepatocytes
▫ Primary bile salts: cholic, ▫ Function: primary vitamin A storage
chenodeoxycholic acids (cholesterol site; regulate contractility of sinusoids;
derivatives) control turnover of extracellular matrix,
▫ Function: emulsify fat (break into smaller hepatic connective tissue
pieces to maximize surface area for ▫ Responsible for tissue cirrhosis
digestion); facilitate fat, cholesterol ▪ Pit cells (liver-associated lymphocytes)
absorption ▫ Function: natural killer cells specific to
▫ Bile salts conserved via enterohepatic liver
circulation
▫ Main bile pigment is bilirubin (waste
GALLBLADDER ANATOMY
product of hemoglobin from broken
down erythrocytes), stercobilin gives ▪ Muscular sac
feces dark color ▫ Stores, concentrates bile produced by
▪ Bile flow liver
▫ Parallel, opposite direction flow of blood ▪ Located under inferior surface of right liver
lobe
▫ Canaliculi → bile ducts → fusion of
multiple bile ducts to form common ▪ Inner mucosa (with rugae) → allows
hepatic duct → fusion with cystic duct expansion
draining gallbladder → bile duct → ▪ Smooth muscle layer → allows contraction
ampulla of vater
334 OSMOSIS.ORG
to occur in response to cholecystokinin Acinar gland

(produced by duodenum) → bile released ▪ Exocrine gland
into small intestine ▪ Acinar cells
▫ Also contracts in response to vagal ▫ Contain zymogen granules full of
stimulation proenzymes for digestion
▪ Flow of bile ▪ Stimulated by secretin, cholecystokinin
▫ Cystic duct → common bile duct → (from duodenum), vagus nerve
ampulla of vater → duodenum ▪ Secretes digestive enzymes into duodenum
▫ Amylase, lipase, nuclease secreted as
active enzymes
▫ Proteases (trypsinogen,
chymotrypsinogen,
procarboxypeptidase) secreted in
zymogen form, must be cleaved to be
activated
Figure 40.4 Gallbladder.
PANCREAS ANATOMY Figure 40.6 Acinar gland.

▪ Located retroperitoneal posterior to
stomach, duodenum
Islets of Langerhans
Four regions
▪ Endocrine gland
▫ Head: right side nestled into curve of
▪ Responsible for glucose homeostasis
duodenum
▫ Beta cells → insulin
▫ Neck: thin portion between head, body
▫ Alpha cells → glucagon
▫ Body: tapered left side
▫ Delta cells → somatostatin → inhibits
▫ Tail: ends near spleen
insulin, glucagon secretion
Ducts
▪ Main pancreatic duct: located centrally,
fuses with bile duct to drain into duodenum
▪ Accessory pancreatic duct: smaller duct;
empties directly into duodenum
▪ Ductal cells: responsible for aqueous
secretions (water, HCO3-, sodium)
▫ Secretion of bicarbonate ions neutralizes
acidic chyme entering duodenum,
provides optimal pH for activation of
digestive enzymes
Figure 40.5 Pancreatic location relative to
stomach and duodenum.
OSMOSIS.ORG 335
LIVER PHYSIOLOGY Amino acid metabolism/protein synthesis
and regulation
Efficient exchange of compounds between
▪ Liver produces plasma proteins (mainly
sinusoidal blood, hepatocytes
albumin), coagulation factors, metal-binding
▪ Fenestrated endothelial cells proteins (transferrin, ceruloplasmin), lipid
▪ Lack of basement membrane between transporters (apoproteins), protease
endothelial cells, hepatocytes inhibitors (antitrypsin), glycoproteins,
▪ Slow blood flow proteoglycans
▪ Can convert amino acids into glucose, fatty
Biotransformation of xenobiotics acids, ketone bodies
▪ Principal site for processing xenobiotics, ▪ Sugars produced by liver O-linked
toxins
▪ Phase I reactions: oxidation, reduction, Formation of ketone bodies
hydroxylation, hydrolysis ▪ Liver
▫ Introduces reactive functional groups to ▫ Only organ that can produce ketone
increase compound polarity bodies
▪ Phase II reactions: conjugation, sulfation, ▪ Cannot use ketone bodies for energy
glucuronidation, methylation ▪ Ketone bodies formed when glucose levels
▪ Detoxification: xenobiotic → phase I low, high rates of fatty acid oxidation
reaction → primary metabolite → phase ▪ Ketone bodies major fuel source for central
II reaction → secondary metabolite → nervous system (CNS) under starvation
excretion
▪ Cytochrome P450 system: major Cholesterol and triacylglycerol synthesis
xenobiotic metabolizer in body; oxidizes ▪ Liver synthesizes very low-density
substrates, adds oxygen to structures lipoprotein (VLDL) to be secreted into blood
▫ First pass effect for pharmaceuticals ▪ Food plentiful → liver activates synthesis
of fatty acid, triacylglycerol, cholesterol →
Regulation and maintenance of blood glu- reduces hepatic cholesterol synthesis
cose levels
▪ Also sends excess dietary cholesterol to
▪ ↑ blood glucose: → secretion of insulin by peripheral tissue
pancreas → ↑ uptake of glucose, amino
acids by cells; inhibition of glycolysis, Nucleotide biosynthesis
activation of glycogen synthesis, ▪ Liver can synthesize, salvage nucleotides
inhibition of gluconeogenesis, inhibition for use by other cells
of glycogenolysis, inhibition of fatty acid ▪ Salvage pathway
oxidation → ↓ blood glucose
▫ Liver converts free bases to nucleotides
▪ ↓ blood glucose: ↑ breakdown of glycogen for secretion into circulation as needed
→ secretion of glucagon, activation of by peripheral tissues
glycolysis, inhibition of glycogen synthesis,
activation of gluconeogenesis, activation Lipid metabolism
of glycogenolysis, activation of fatty acid ▪ Long-chain fatty acids
oxidation → ↑ blood glucose
▫ Liver’s major fuel source during fasting
Elimination of ammonia via urea cycle ▫ Triacylglycerols from adipose tissue →
▪ Liver fatty acids bound to albumin → liver →
activated via fatty Acyl-coenzyme A
▫ Main organ responsible for eliminating
(acyl-CoA) synthetases → fatty-acyl-
ammonia via urea cycle
CoA → fatty-acyl-carnitine → carnitine
▪ Ammonia transported to liver on glutamine, crosses inner mitochondrial membrane
alanine → converted by liver into urea for → fatty-acyl-carnitine → carnitine, fatty-
excretion in urine acyl-CoA → beta oxidation
▫ Enzymes in beta oxidation, fatty-acid
activation specific for length of fatty acid
carbon chains
336 OSMOSIS.ORG
▪ Medium-chain-length fatty-acid oxidation ▫ Oxidized by peroxisomes to octanoyl-

▫ 4–12 carbons Coa
▫ Liver, kidney is site of oxidation ▫ Generates hydrogen peroxide instead of
▫ Activating enzyme is medium-chain- flavin adenine dinucleotide (FADH2), in
length fatty acid-activating enzyme contrast to mitochondrial beta-oxidation
(MMFAE) ▪ Long-chain fatty acids
▫ Oxidation begins with medium-chain- ▫ 12–20 carbons
length acyl-CoA dehydrogenase ▫ Most common type of lipid used for
▪ Very-long-chain fatty-acid oxidation oxidation by liver
▫ > 20 carbons
PANCREATIC SECRETION
osms.it/pancreatic-secretion
FLOW RATE, COMPOSITION OF Neural stimuli
PANCREATIC JUICE ▪ Parasympathetic stimulation by vagus
nerve stimulates secretion
High flow rate
▫ Bile from gallbladder, pancreatic juice
▪ High HCO3- concentration, low Cl-
concentration Bile salt
Low flow rate ▪ Major stimulus for more bile secretion via
stimulation of secretin release
▪ High Cl- concentration, low HCO3-
concentration
ACTIVATION OF PANCREATIC
PROTEASES
REGULATION OF BILE, PANCREATIC
SECRETION ▪ Enteropeptidase cleaves, activates
trypsinogen to trypsin → trypsin activates
▪ Hormones, neural stimuli regulate secretion
chymotrypsinogen into chymotrypsin,
of bile, pancreatic juice into duodenum
procarboxypeptidase into carboxypeptidase
Hormones
▪ Secretin
▫ Released by intestinal cells in response
to acidic chyme; stimulates secretion of
bile, pancreatic juice
▪ Cholecystokinin (CCK)
▫ Major stimulus for gallbladder to release
bile into duodenum; stimulates secretion
of enzyme-rich pancreatic juice
OSMOSIS.ORG 337
NOTES
NOTES
POPULATION GENETICS
MENDELIAN GENETICS &

PUNNETT SQUARES
osms.it/mendelian-genetics-punnett-squares
▪ Genetics: science of inheritance ▪ Law of dominance: alleles can be
▪ Parental generation (“P”) → 1st filial dominant/recessive
generation (“F1”) → 2nd filial generation ▫ Dominant traits appear when ≥ one
(“F2”) dominant allele is present
▪ Homozygous: male, female alleles are same ▪ Law of independent assortment: separate
▪ Heterozygous: male, female alleles differ genes assort independently
▪ Phenotype: observable trait from genotype ▫ Genetic linkage: proximity of genes on
chromosome can cause joint assortment
Mendel’s laws
▪ Law of segregation: alleles segregate, Punnett square
offspring acquire one allele from each ▪ Table showing possible combinations of
parent genotypes
Figure 41.1 2x2 Punnett squares showing the allele combinations for one gene: flower color
in pea plants. The parent plants are homozygous for the flower color trait. When they are
crossbred (first Punnett square), each offspring in the F1 generation gets one dominant allele (P)
and one recessive allele (p). The dominant P allele masks the recessive p allele, so all the flowers
appear violet. When any two of the heterozygous F1 generation plants are bred (second Punnett
square), the three plants in the F2 generation with at least one P allele have a violet flower
phenotype and the one plant with the homozygous pp genotype has a white flower phenotype.
338 OSMOSIS.ORG
Chapter 41 Genetics: Population Genetics
Figure 41.2 4x4 Punnett square showing the allele combinations for two genes: seed color (Y
= yellow, y = green) and texture (R = round, r = wrinkly). One parent (P) plant is homozygous
dominant (YYRR; yellow, round seeds), the second is homozygous recessive (yyrr; green,
wrinkled seeds). When these plants are crossbred, all the F1 generation plants have the
genotype YyRr and the phenotype of yellow, round seeds. When the F1 generation plants are
bred (Punnett square), there are four possible combinations of the alleles for each parent: YR, Yr,
yR, and yr. We can expect the F2 generation to have four phenotypes: yellow and round (≥ one
Y and ≥ one R), yellow and wrinkled (≥ one Y and two r), green and round (two y and ≥ one R),
green and wrinkled (yyrr). They appear in the ratio 9:3:3:1.
INDEPENDENT ASSORTMENT OF
GENES & LINKAGE
osms.it/independent-assortment-and-linkage
▪ Independent assortment: separate genes ▪ Linked genes have < 50% chance of
assort independently occurring on different gametes
▫ Apart from in genetic linkage ▫ Parental gametes: linked genes
▫ Genetic linkage: proximity of genes on inherited together
chromosome can cause joint assortment ▫ Recombinant gametes: linked genes
▪ Crossing-over: in prophase 1 of meiosis, between which crossing-over has
genes can be exchanged between adjacent occurred
chromosomes
▫ Homozygous genes can occur on
different gametes
▫ Even repetitions of crossing-over can
reverse this effect
OSMOSIS.ORG 339
Figure 41.3 Red chromosome from female parent originally carried all dominant alleles for genes
A, B, C; blue chromosome from male parent originally carried all recessive alleles for genes A, B,
C. If crossing over occurs between the ends of the two chromosomes, dominant allele C from
female parent ends up in the chromosome from male parent, vice versa.
Figure 41.4 Any two genes on different chromosomes always have a 50% chance of going
through crossing over in meiosis and showing up in the same gamete. The same is true for two
genes very far apart on the same chromosome, because ending up in the same or a different
gamete depends on whether there are an odd or even number of crossing over events.
340 OSMOSIS.ORG
Figure 41.5 It is unlikely for a cut to occur in the small space between linked genes, which is
why the chance of them crossing over and ending up in different gametes is < 50%. When
linked genes are inherited together, the gametes are called “parental” because they carry
same the alleles as the original chromosomes. When crossing over occurs, they are called
“recombinant.”
INHERITANCE PATTERNS
osms.it/inheritance-patterns
Dominant vs. recessive inheritance patterns ▪ Mitochondrial inheritance: mutation on
▪ Dominant inheritance: mutation affects egg’s mitochondrial DNA
dominant allele → one copy causes disease
Autosomal inheritance
▪ Recessive inheritance: mutation affects
▪ Autosomal dominant inheritance (e.g.
recessive allele → two copies cause
Huntington’s disease)
disease
▫ Dominant homozygotes (RR),
Autosomal vs. sexual vs. mitochondrial heterozygotes (Rr) have disease
patterns ▫ Recessive homozygotes (rr) unaffected
▪ Autosomal inheritance: mutation affects ▫ Disease too severe in homozygotes →
somatic chromosome don’t reproduce
▪ Sexual inheritance: mutation affects sex
chromosome; X-linked/Y-linked
OSMOSIS.ORG 341
Figure 41.6 Autosomal dominant inheritance. Figure 41.8 Autosomal recessive inheritance.
Punnett square demonstrating probabilities When one affected and one unaffected
of healthy and disease genotypes in offspring individual reproduce, all offspring are carriers.
when a heterozygous dominant individual
(Dd) reproduces with a healthy individual
(dd). Sex-linked inheritance
▪ Males have one allele for genes on X, Y
chromosomes (hemizygous)
▪ Autosomal recessive inheritance (e.g. cystic ▪ Females have two alleles for genes on X
fibrosis) chromosomes (homozygous/heterozygous)
▫ Only recessive homozygotes have ▪ X-linked dominant inheritance (e.g. fragile X
disease syndrome)
▫ Heterozygotes carriers ▫ Dominant hemizygotes, dominant
▫ Tendency to skip generation homozygotes, heterozygotes have
▫ Children of consanguineous unions: ↑ disease
likelihood of disease ▫ Males reproducing with healthy females
have 100% chance to pass onto female
children, 0% chance to pass onto male
children
▫ Females reproducing with healthy males
have 50% chance to pass onto children
of both sexes
▪ X-linked recessive inheritance (e.g.
hemophilia)
▫ Recessive homozygotes, recessive
hemizygotes have disease;
heterozygotes are carriers
▫ Males reproducing with healthy females
have 100% chance of female children
being carriers, 0% chance of passing
disease onto male children
▫ Heterozygous females reproducing
Figure 41.7 Autosomal recessive inheritance.
with healthy males have 50% chance
Punnett square demonstrating probabilities
of female children being carriers, 50%
of healthy, disease, and carrier genotypes
chance of passing disease onto male
in the offspring when two healthy carriers
children
reproduce.
▪ Y-linked inheritance (e.g. baldness)
▪ Only male heterozygotes have disease
342 OSMOSIS.ORG
▪ Always passed from biologically-male

parent to biologically-male child
Mitochondrial inheritance
▪ Mitochondrial inheritance (e.g. DAD, AKA
diabetes mellitus and deafness)
▫ Males, females can develop disease
▫ Only females can pass disease to
offspring
Figure 41.9 Punnett squares demonstrating the inheritance patterns for fragile X syndrome, an
X-linked dominant disease, with different combinations of parental genotypes.
Figure 41.10 Punnett squares demonstrating the inheritance patterns for hemophilia, an X-linked
recessive disease, with different combinations of parental genotypes.
OSMOSIS.ORG 343
EVOLUTION & NATURAL
SELECTION
osms.it/evolution-natural-selection
Evolution traits
▪ Process by which populations change over ▫ Some individuals survive, reproduce
time ▫ Some traits → ↑ survival, reproduction
▫ Population: group of organisms within (AKA fitness)
species that live in same place ▫ → more offspring with these traits (AKA
▫ Species: group of organisms with similar differential reproduction)
characteristics, ability to breed ▪ Conclusion
Natural selection ▫ Population slowly changes over time
to favor useful traits (e.g. ↑ survival,
▪ Premises
reproduction)
▫ Individuals in species have different
▪ Artificial selection = selective breeding
HARDY—WEINBERG EQUILIBRIUM
osms.it/hardy-weinberg_equilibrium
▪ Population’s genetic traits remain same ▪ Given probability p of dominant allele A,
from one generation to next in absence of probability q of recessive allele a
evolutionary changes (e.g. natural selection, ▫p+q=1
mutation, genetic drift) ▫ prob(AA) = p2
▫ Natural selection causes population to ▫ prob(aa) = q2
favor useful traits
▫ prob(Aa) = 2pq
▫ Mutation causes new traits to arise
▪ q can be calculated from phenotype
▫ Genetic drift causes trait prominence to
▫ Square root of frequency of recessive
shift by chance (AKA sampling error)
phenotype
▫ → frequency of other phenotypes can
be calculated
344 OSMOSIS.ORG
EPIGENETICS
osms.it/epigenetics
▪ Mechanisms to selectively activate/silence ▫ 2-3 methyl groups → tightens histone
genes without modifying nucleotide tails → ↓ access for transcription factors
sequence → ↓ gene transcription
▪ Direct DNA modification
Histone modification
▫ Usually occurs in long sequences of
▪ Acetylation
cytosine,guanine nucleotides (AKA CpG)
▫ Removes positive charge → less
▫ Cytosine residues undergo methylation,
attraction to negative DNA phosphates
silencing gene expression
→ ↑ gene transcription
▪ Modifications occur throughout lifetime
▪ Methylation
▪ Affected by environmental factors (e.g.
▫ One methyl group → loosens histone
drug usage, diet, exercise)
tails → ↑ access for transcription factors
→ ↑ gene transcription ▪ Changes are reversible
LAC OPERON
osms.it/lac-operon
▪ Collection of genes in E. coli, other bacteria
that code for proteins required to transport,
metabolize lactose
▪ Includes structural genes like lacZ, lacY,
lacA as well as regulatory genes like
promoter, operator
▫ lacZ: β-galactosidase (AKA lactase)
▫ lacY: β-galactosidase permease
▫ lacA: β-galactosidase transacetylase
▫ Promoter: start transcription Figure 41.11 The lac operon. β-galactosidase
▫ Operator: prevent transcription with breaks down lactose into glucose and
repressor (coded by lacI) galactose; β-galactosidase permease allows
lactose to enter the cell; β-galactosidase
▪ Glucose, lactose concentrations can be
transacetylase’s function is not clearly
used to regulate lac operon expression
understood.
▫ ↑ glucose → repressor stays bound to
operator, blocking RNA polymerase
▫ ↑ glucose → catabolite activator protein
inhibits transcription
▫ ↓ glucose → repressor falls off
▫ ↓ glucose → catabolite activator protein
stimulates transcription
OSMOSIS.ORG 345
GENE REGULATION
osms.it/gene-regulation
▪ Natural regulation of gene expression ▪ Post-transcriptional regulation
▪ Occurs at transcription/post-transcription/ ▫ Splicing: spliceosomes remove introns
translation level (AKA non-coding sequences) from RNA
▪ Transcriptional regulation → resulting mRNA codes for proteins
▫ Epigenetics: chemical modifications more effectively
activate/silence genes without ▫ Capping: 5’ end of RNA capped
modifying nucleotide sequence (e.g. by with protective 7-methyl-guanine
methylation/acetylation of histones) → exonucleases unable to cleave off
▫ Activators: bind to DNA enhancer nucleotides
→ facilitate binding of general ▫ Editing: proteins convert certain
transcription factors, recruit histone nucleotides (e.g. ADAR: adenosine →
acetyltransferases inosine; CDAR: cytosine → uracil) to
▫ Repressors: bind to DNA silencer → create sequence variation
prevent RNA polymerase from binding ▪ Translation regulation
to promoter, recruit histone deacetylases ▫ Mainly occurs during initiation
▫ Regulatory proteins (AKA initiation)
factors must bind before ribosome can
begin translation
▫ Conditions like starvation, stress inhibit
initiation factors to save energy
Figure 41.12 An activator looping DNA in the

nucleus.
Figure 41.14 Illustration depicting the action

of spliceosomes.
Figure 41.13 A repressor protein in the

nucleus binding the DNA sequence called the
silencer, which is on the same DNA strand as
the gene.
346 OSMOSIS.ORG
GEL ELECTROPHORESIS &

GENETIC TESTING
osms.it/gel-electrophoresis-genetic-testing
▪ Method of separating, analyzing
macromolecules (e.g. DNA, RNA, proteins),
their fragments based on size, charge
Apparatus
▪ Clear box filled with gel, often agarose
▫ Small depressions (AKA “wells”) at one
end
▫ Sample macromolecules placed
separately in wells
▪ Power source connected to gel
Premise
▪ Current applied → macromolecule
fragments move through gel
▪ Charge of fragments determines
▫ Direction: opposites attract
▫ Speed: greater magnitude → faster
▪ Fragment size also determines speed
▫ Gel contains small pores; smaller size →
faster
▪ Fast-moving fragments travel further over
given period → production of multiple
bands (one per fragment)
Applications
▪ DNA analysis (e.g. genetic fingerprinting)
▫ DNA chopped up with restriction
enzymes (e.g. EcoRI cuts at GAATTC)
▫ Fragments poured into wells, current
applied Figure 41.15 Identifying DNA mutations
using EcoRI. A mutation in a single nucleotide
▫ Fragments move towards positive
from A to G in the EcoRI binding site prevents
terminal, form bands at isoelectric point
the enzyme from binding and cutting at that
▪ Identifying DNA mutations location. Now, in gel electrophoresis, there
▫ Mutation → restriction enzymes create will be only three lines (instead of four) and
different fragments → bands change one fragment will be longer, indicating that
▫ Smaller fragments → bands are further the DNA contains a mutation.
apart
▫ More abundant fragments → bands
(thicker, brighter)
▪ Other applications: estimation of molecule
size, macromolecule separation
OSMOSIS.ORG 347
POLYMERASE CHAIN REACTION
osms.it/polymerase-chain-reaction
▪ Technique used to amplify desired DNA Process
segment ▪ Denaturation: sample heated to
▪ Based on DNA melting, enzyme-driven 96°C/205°F → bonds between DNA
DNA replication strands separate, forming two template
▪ Takes place in thermal cycler strands
▪ Four essential components ▪ Annealing: sample cooled to 55°C/131°F
▫ Template DNA: strand to be replicated → primers bind to template strands
▫ Nucleotides: building blocks of DNA ▪ Extension: sample heated to 72°C/162°F
→ Taq polymerase synthesizes complete
▫ Primers: short complementary DNA
complementary DNA strands, starting from
strands to the 3’ end of each strand
end of each primer
▫ DNA polymerase: enzyme that
synthesizes DNA from nucleotides (e.g. Applications
Taq polymerase) ▪ Cloning DNA into plasmids, replicating
DNA for analysis (e.g. research and
practice)
348 OSMOSIS.ORG
NOTES
NOTES
TRANSCRIPTION, TRANSLATION,
& REPLICATION
DNA STRUCTURE
osms.it/DNA-structure
DNA (DEOXYRIBONUCLEIC ACID) ▪ Pyrimidines: cytosine (C), thymine (T) for
▪ Two polynucleotide chains (double helix DNA, uracil (U) for RNA
shape) ▫ Mnemonic: CUT the PYE
Nucleotides
▪ 5-carbon sugar, phosphate group, MNEMONIC: CUT the PYE
nitrogenous base Pyrimidines
Sugar Cytosine
▪ Deoxyribose in DNA, ribose in RNA Uracil
Thymine
Nucleobases The
▪ Purines: adenine (A), guanine (G) PYrimidinEs
▫ Pure silver: purines (pure), adenine,
guanine (AG)
Figure 42.1 Nucleotides consist of a phosphate group, 5-carbon sugar (deoxyribose for DNA)
and a nitrogenous base. The base can be a purine, which has two rings (adenine, guanine), or a
pyrimidine, which has one ring (cytosine, guanine).
OSMOSIS.ORG 349
Nucleotide binding and bonding DNA structure and packing
▪ Nucleotides bind using sugar, phosphate ▪ Strands coil around each other once every
groups (phosphate group on 5th carbon 10 base pairs → major, minor grooves
of sugar binds covalently to 3rd carbon of ▪ In order to be packed tightly, DNA wrapped
sugar) → sugar-phosphate backbone around histones (positive charge attracts to
▪ Nucleotides form hydrogen bonds with negative charge of phosphate backbone) →
bases on opposing strand nucleosomes
▫ Complementary base pairing: A pairs ▪ Nucleosomes further packed as chromatin
with T/U (two hydrogen bonds), C pairs fibers
with G (three hydrogen bonds) ▫ Euchromatin: loosely packed (genes
frequently used)
▫ Heterochromatin: densely packed
(genes rarely used)
Figure 42.2 Nucleotide binding: phosphate group on 5th carbon of sugar on one nucleotide
(called 5 prime carbon) binds covalently to 3rd carbon of sugar on another nucleotide (called
3 prime carbon. This gives each DNA strand a sugar-phosphate backbone and a direction
(5’ to 3’ and 3’ to 5’). Nucleotide bonding: nucleotide bases form hydrogen bonds with the
complementary base on the opposing strand, A with T (U in RNA) and C with G.
Figure 42.3 Major and minor grooves: larger/ Figure 42.4 DNA wraps around histone
smaller spaces between DNA strands where proteins to form nucleosomes, which pack
proteins can bind to regulate functions. tighter again to form chromatin fibers.
350 OSMOSIS.ORG
Chapter 42 Genetics: Transcription, Translation, & Replication
DNA REPLICATION
osms.it/DNA-replication
▪ Occurs in S phase of cell cycle (before cell DNA CLONING
division) ▪ Technique used to duplicate segment of
▪ 46 chromosomes duplicated → each DNA within host organism
daughter cell gets genetic material ▪ Uses “plasmids”: genetic structures outside
▪ DNA replication semiconservative → each of chromosomes, replicate independently
strand of double helix template
Process
▪ Extract desired DNA segment using
PROCESS specific restriction enzymes
Initiation ▪ Paste segment into plasmid with DNA
▪ Pre-replication complex seeks origin of ligase → “recombinant DNA”
replication, DNA helicase splits strands → ▪ Insert plasmid into host organism (e.g. E.
replication fork coli), encouraging uptake with shock (e.g.
▫ Single-stranded DNA binding proteins heat)
improve stability of lone strands ▪ Identify bacteria carrying plasmid with
▫ DNA topoisomerase prevents antibiotics (plasmids given antibiotic
overwinding of later DNA resistance gene)
▪ Leave bacteria to replicate DNA segment,
Elongation mass-manufacture protein(s)
▪ RNA primase creates multiple RNA primers
→ randomly bind → DNA polymerase Applications
adds complementary nucleotides in 3’, 5’ ▪ Producing biopharmaceuticals (e.g. insulin),
direction gene therapy (e.g. cystic fibrosis)
▫ Forms single leading strand
▫ Forms single lagging strand by
attaching (with DNA ligase) multiple
Okazaki fragments
Termination
▪ DNA polymerase leaves strand at telomere
(TTAGGG nucleotide sequences)
▪ Hayflick limit: maximum number of times
cell’s DNA can be replicated
▫ Due to repeated shortening of telomeres
during termination step
OSMOSIS.ORG 351
Figure 42.5 Three steps of DNA replication: initiation, elongation, and termination. DNA
replication results in two sets of identical DNA, each containing one old strand and one new one.
352 OSMOSIS.ORG
Figure 42.6 DNA cloning. Restriction enzyme (in this case, EcoRI) cleaves a known sequence
surrounding a target gene and a plasmid, creating pieces with sticky ends. When DNA ligase is
added, these pieces form recombinant DNA (plasmid containing target gene), as well as a gene
for antibiotic resistance. A host, in this case E. coli, is combined with recombinant plasmids and
subjected to a stressor so that some bacteria take up plasmid. Bacteria are allowed to replicate
on plate containing antibiotic, so that only ones that have taken up plasmid can survive. These
bacteria produce desired protein from target gene in plasmid.
OSMOSIS.ORG 353
TRANSCRIPTION
osms.it/transcription
▪ First step in creating protein from gene ▪ Hydrogen bonds reform on nucleotides
▪ Gene read, copied on individual messenger (already transcribed)
RNA (mRNA) ▪ Termination sequences contains two
complementary sequences → resulting
mRNA binds with itself forming hairpin
PROCESS loop
▪ DNA unpacked from chromatin, undergoes
▪ RNA polymerase detaches, DNA closes
dehelicization
back up
▪ Promoter region identifies starting point for
▪ Polyadenylate polymerase adds 7-methyl
transcription (e.g. TATA box)
guanosine cap to 5’, polyadenine tail to 3’
▪ RNA polymerase shears hydrogen bonds end of mRNA
between two strands → transcription
▪ Spliceosomes remove introns (don’t code
bubble
proteins) to leave behind exons (do code
▪ RNA polymerase follows template strand to proteins)
assemble mRNA molecule (complementary
▪ Resulting mRNA processed by ribosome to
to template strand)
create desired protein (translation)
Figure 42.7 Transcription. 1: DNA unpackaging, dehelicization; promoter region identified (TATA
box); RNA polymerase shears hydrogen bonds between strands → transcription bubble. 2:
RNA polymerase assembles mRNA strand complementary to template strand. Hydrogen bonds
reform between DNA nucleotides already transcribed. 3: Termination sequence causes mRNA to
form hairpin loop, detach. 4: Cap and tail added, introns spliced out.
354 OSMOSIS.ORG
Figure 42.8 One strand of DNA is called the coding strand and the other is called the template
strand. They have complementary nucleotide sequences. RNA polymerase builds an mRNA
molecule by reading the template strand and adding complementary nucleotides. Therefore, the
mRNA will have the same sequence and directionality as the coding strand, only with U instead
of T.
TRANSLATION
osms.it/translation
▪ Second step in creating protein from gene ▪ Binds to ribosome on aminoacyl/peptidyl/
▪ Ribosomes assemble protein from mRNA exit site
template produced in transcription ▫ Aminoacyl: binds transfer RNA (tRNA)
with complementary mRNA codon
PROCESS ▫ Peptidyl: holds tRNA with polypeptide
▪ mRNA floats out of nucleus through pore ▫ Exit: holds tRNA after amino acid
released
▪ Initiation: ribosome grabs mRNA, finds
start codon (e.g. AUG)
▪ Elongation: ribosome moves along mRNA,
producing specific amino acid for each
codon
▪ Termination: ribosome reaches stop codon,
releases polypeptide (e.g. UGA)
TRANSFER RNA (tRNA)

▪ Finds, carries amino acids to ribosome
▪ Three-letter coding sequence
(complementary to mRNA) Figure 42.9 Ribosome binding sites.
OSMOSIS.ORG 355
Figure 42.10 One strand of DNA is called the coding strand and the other is called the template
strand. They have complementary nucleotide sequences. RNA polymerase builds an mRNA
molecule by reading the template strand and adding complementary nucleotides. Therefore, the
mRNA will have the same sequence and directionality as the coding strand, only with U instead
of T.
Figure 42.11 Translation extending an existing polypeptide chain.

1: tRNA with amino acid and codon complementary to that of mRNA binds at ribosome A site.
2: Peptide bond forms between amino acid on new tRNA and tRNA in P site holding
polypeptide chain, polypeptide chain is transferred to tRNA in A site.
3: Everything moves by one site. A site is now open for a new tRNA.
356 OSMOSIS.ORG
CELL CYCLE
osms.it/cell-cycle
▪ Sequence of events between formation, ▪ Terminates with G1 checkpoint
division of somatic cell ▫ Cells with damaged DNA → G0 phase/
▪ Two phases apoptosis
▫ Interphase: preparatory phase; cell
performs basic functions, replicates Synthesis (S) phase
DNA ▪ DNA replicated (identical chromatids
▫ Mitosis: cellular division created)
Gap/Growth 2 (G2) phase

G0 (G-ZERO) PHASE ▪ Organelles duplicated
▪ Cells function but not dividing/preparing to ▪ Terminates with G2 checkpoint
divide
▪ Considered outside cell cycle MITOSIS (M) PHASE
▪ Cell divides into two daughter cells
INTERPHASE
▪ Three subphases: G1, S, G2 phases
Gap/Growth 1 (G1) phase

▪ Longest phase
▪ Cell grows while organelles function as
usual
Figure 42.12 Cell cycle summary.
OSMOSIS.ORG 357
MITOSIS & MEIOSIS
osms.it/mitosis-and-meiosis
▪ Two processes of cell division
MITOSIS
▪ Division of cell into two identical daughter
cells
▪ Part of cell cycle
▪ Consists of prophase, metaphase,
anaphase, telophase
Prophase
▪ Chromatin fibers condense
▪ Centrioles align chromosomes between
centrosomes
Metaphase
▪ Prometaphase: nuclear membrane,
nucleolus disintegrate
▪ Metaphase: chromosomes align along
metaphase plate, spindle fibers attach to
kinetochores
Anaphase
▪ Centrosomes pull on spindle fibers to
separate chromatids
Telophase
▪ New nuclear envelopes form
MEIOSIS
▪ Division of cell into four haploid daughter
cells
▪ Consists of
▫ Meiosis I: prophase I, metaphase I,
anaphase I, telophase I
▫ Meiosis II: prophase II, metaphase II,
anaphase II, telophase II
Meiosis I
▪ Prophase I
▫ Leptotene: 46 chromosomes condense,
nuclear membrane disintegrates
▫ Zygotene: chromosomes find
homologues, bind, forming tetrads (AKA Figure 42.13 Stages of mitosis: division of
synapsis) one cell into two identical daughter cells.
358 OSMOSIS.ORG
▫ Pachytene: homologous chromosomes Meiosis II

exchange genetic material (AKA ▪ Meiosis II progresses exactly as mitosis
crossing-over) ▫ Two haploid cells → four haploid cells
▫ Diplotene: homologous chromosomes ▫ Same phase names
uncoil, slide toward ends (AKA
chiasmata)
▫ Diakinesis: terminalization completed
▪ Metaphase I
▫ Tetrads migrate to metaphase plate
▪ Anaphase I
▫ Tetrads split up
▫ Chromosomes pulled to each pole by
spindle fibers
▫ Diploid cell → haploid cell
▪ Telophase I
▫ Cleavage furrow appears, cytokinesis
occurs
▪ Followed by interphase without
chromosome duplication in S phase Figure 42.15 Meiosis produces haploid
daughter cells with 23 chromosomes each.
Figure 42.14 Steps of meiosis I, prophase I.
OSMOSIS.ORG 359
GENETIC MUTATIONS & REPAIR
osms.it/DNA-mutations
osms.it/DNA-damage-and-repair
DNA MUTATIONS ▪ Multiples of three → nonframeshift
▪ Alterations in nucleotide (A, T, G, C) mutation
sequence of ≥ one gene ▫ Reading frame displaced by entire
▫ Affect somatic cells (AKA non- codon → remaining amino acids
reproductive cells), gametes → germline unchanged → similar resulting protein
mutations ▪ Frameshift mutation: resulting protein
▫ Arise spontaneously/due to mutagens abnormally long/short, most likely
nonfunctional
SMALL-SCALE MUTATIONS
▪ Single gene LARGE-SCALE MUTATIONS
▪ Substitutions: nucleotide replaced by ▪ Often occur due to errors in gamete
another formation
▪ May result in Abnormal number of chromosomes
▫ Silent mutation: same amino acid ▪ Aneuploidy
▫ Missense mutation: different amino acid ▫ Additional chromosomes (e.g. Down
(e.g. sickle cell disease) syndrome)
▫ Nonsense mutation: stop codon ▫ Missing chromosomes (e.g. Turner’s
syndrome)
INSERTIONS & DELETIONS ▪ Polyploidy
▪ Nucleotide added/removed from sequence ▫ Increased number of chromosomes per
set (e.g. triploidy)
Figure 42.16 Small-scale mutations include: substitutions, deletions, and insertions. They may
have a small or large effect on protein function depending on how the new nucleotide affects the
translation of the codon sequence into amino acids.
360 OSMOSIS.ORG
Structurally abnormal ▪ Inversion: part of chromosome breaks off,

▪ Movement of sections of chromosomes reattaches
▪ Deletion: part of chromosome goes missing ▪ Translocation: parts of two chromosomes
(e.g. cri du chat syndrome) switched
▪ Duplication: part of chromosome duplicated
Figure 42.17 Aneuploidy and polyploidy are types of large-scale mutations which result in an
abnormal number of chromosomes.
Figure 42.18 Illustration of types of structural abnormalities.
OSMOSIS.ORG 361
DNA DAMAGE ▫ Exonucleases remove damaged
▪ DNA damaged by endogenous, exogenous segment
(environmental) factors ▫ DNA polymerase rebuilds segment
▪ If damaged DNA cannot be fixed → ▫ DNA ligase glues new segment
multiple paths
▫ Senescence: stops dividing Double stranded breaks
▫ Apoptosis: programmed cell death ▪ May be due to ionizing radiation
▫ Uncontrolled cell division: develops into Repair mechanisms
tumor ▪ Non-homologous end joining
▪ If damaged DNA can be fixed → G0 phase ▫ DNA protein kinase binds to each end
Single strand damage of the broken DNA → artemis cuts off
rough ends → ends are rejoined with
▪ Causes
DNA ligase
▫ Endogenous (errors in DNA replication)
▪ Homologous end joining
▫ Exogenous (harmful chemical/physical
▫ MRN protein complex binds to each
agents)
end and removes affected nucleotides
▪ Repaired with mismatch/base excision/ → DNA polymerase copies genetic
nucleotide excision repair information from sister chromatid
▫ Endonucleases cleave damaged
segment
Figure 42.19 Repair of a mismatched nucleotide on a newly synthesized DNA strand. 1:

Endonucleases cleave either side of damaged segment; 2: Exonucleases remove damaged
segment; 3: DNA polymerase rebuilds segment; 4: DNA ligase connects new segment to strand.
362 OSMOSIS.ORG
Figure 42.20 Two repair mechanisms for double-stranded breaks: non-homologous end joining
and homologous recombination.
OSMOSIS.ORG 363
NOTES
NOTES
BLOOD COMPONENTS &
FUNCTION
BLOOD COMPONENTS
osms.it/blood-components
BLOOD COMPONENT SEPARATION BUFFY COAT
▪ Blood components separate by density in ▪ Comprises < 1% of total blood volume
centrifuge ▪ Contains platelets, leukocytes
▫ Heaviest layer: erythrocytes ▪ Platelets clump together → seal damaged
▫ Middle layer: buffy coat blood vessels
▫ Lightest layer: plasma ▪ Leukocytes ward off pathogens, destroy
cancer cells, neutralize toxins
ERYTHROCYTES
▪ Comprise 45% (hematocrit) of total blood PLASMA
volume ▪ Comprises 55% of total blood volume
▪ Carry O2 to tissues; bring CO2 to lungs ▪ No cells: 90% water + proteins,
▪ Biconcave discs (depressed center) electrolytes, gases
▫ Fit through vessels, ↑ surface area (for ▪ Albumin: maintains oncotic pressure, acts
gas exchange) as transport protein
▪ No organelles ▪ Globulins: antibodies, transport proteins
▫ ↑ space for hemoglobins ▪ Fibrinogen: involved in clot formation (helps
platelets attach)
▪ Electrolytes: include sodium, potassium,
calcium, chloride, carbonate
Figure 43.1 Blood components and their relative proportions.
364 OSMOSIS.ORG
Chapter 43 Hematology: Blood Components & Function
PLATELET PLUG FORMATION

(PRIMARY HEMOSTASIS)
osms.it/platelet-plug-formation-primary-hemostasis
▪ Hemostasis: blood-loss prevention 3. Adhesion
▪ First two hemostasis steps: platelets ▪ GP1B surface proteins on platelets bind to
clump, form plug around injury site in five Von Willebrand factor
steps
4. Activation
PLATELET PLUG FORMATION ▪ Platelet changes shape (forms arms to
STEPS grab other platelets), releases more von
Willebrand factor, serotonin, calcium, ADP,
1. Endothelial injury
thromboxane A2 (positive feedback loop)
▪ Nerves, smooth muscle cells detect injury
▪ ADP, thromboxane A2 result in GPIIB/IIIA
▪ Trigger reflexive contraction of vessel expression
(vascular spasm) → ↓ blood flow, loss
▪ Secretion of nitric oxide, prostaglandins 5. Aggregation
stop; secretion of endothelin begins → ▪ GPIIB/IIIA binds to fibrinogen, links platelets
further contraction → platelet plug
2. Exposure
▪ Damage to endothelial cells exposes
collagen
▪ Damaged cells release Von Willebrand
factor (binds to collagen)
Figure 43.2 Layers of an arterial wall.
OSMOSIS.ORG 365
Figure 43.3 Platelet plug formation steps.
366 OSMOSIS.ORG
COAGULATION (SECONDARY
HEMOSTASIS)
osms.it/coagulation-secondary-hemostasis
▪ Last two hemostasis steps: clotting factors 4. Factor IXa + factor VIIIa (binds to Von
activate fibrin, build fibrin mesh around Willebrand factor) + calcium → enter the
platelet plug common pathway
▪ Begins with either extrinsic/intrinsic
pathway; factor X activation → coagulation COMMON PATHWAY
cascade (common pathway)
1. Factor X is cleaved → factor Xa
2. Factor Xa cleaves factor V → factor Va
EXTRINSIC PATHWAY 3. Factor Xa + factor Va + calcium →
1.Trauma damages blood vessel, exposes prothrombinase complex
cells under endothelial layer ▫ Prothrombin (factor II) → thrombin
▫ Tissue factor (factor III) embedded in (factor IIa)
membrane 4. Thrombin activates platelets, cofactors (V,
2.Factor VII in blood binds to tissue factor, VIII, IX); cleaves fibrinogen, stabilizing factor
calcium → VIIa-TF complex (→ factor XIIIa + calcium → cross-links in
mesh)
INTRINSIC PATHWAY
1.Circulating factor XII contacts negatively COAGULATION TESTS
charged phosphates on platelets/ ▪ Prothrombin time (PT): tests extrinsic
subendothelial collagen → factor XIIa pathway
2.Factor XIIa cleaves factor XI → factor XIa ▪ Activated partial thromboplastin time
3.Factor XIa + calcium cleaves factor IX → (aPTT): tests intrinsic pathway
factor IXa
ROLE OF VITAMIN K IN
COAGULATION
osms.it/vitamin-k-in-coagulation
▪ Vitamin K regulates blood coagulation non-functional forms of II, VII, IX, X into
▫ Converts coagulation factors into functional forms
mature forms ▫ Adds chemical group made of one
▪ 12 coagulation factors: (I–XIII, no factor VI); carbon, two hydrogens, one oxygen to
factors II, VII, IX, X require vitamin K glutamic acid residues on proteins
▪ Quinone reductase reduces vitamin K ▪ After carboxylation step, vitamin K (as
quinone (dietary form) into vitamin K vitamin K epoxide) is converted back into
hydroquinone vitamin K quinone via epoxide reductase
▪ Vitamin K hydroquinone donates electrons ▪ Coagulation factors appear in all
to γ-glutamyl carboxylase, converting coagulation pathways
OSMOSIS.ORG 367
Figure 43.4 Coagulation steps, including the intrinsic, extrinsic, and common pathways.
368 OSMOSIS.ORG
Figure 43.5 Vitamin K cycle. A single molecule of Vitamin K can be reused many times.
ANTICOAGULATION, CLOT
RETRACTION & FIBRINOLYSIS
osms.it/clot-retraction-and-fibrinolysis
ANTICOAGULATION
▪ Occurs during primary, secondary
hemostasis; regulates clot formation
▪ Prevents clots from growing too large →
block blood flow, form emboli
▪ Regulation starts with thrombin (factor II)
▫ Multiple pro-coagulative functions
▫ Proteins C, S bind thrombomodulin-
thrombin → cleaves, inactivates factors
V, VIII
▫ Antithrombin III binds thrombin/factor X
→ inactivates both (plus factors VII, IX,
XI, XII with lower affinity)
▪ Other factors prevent platelets adhering
during primary hemostasis
▫ Nitric oxide, prostacyclin → ↓
thromboxane A2
Figure 43.6 Proteins involved in

anticoagulation. Thrombomodulin is found
on the surface of intact epithelial cells lining
blood vessels.
OSMOSIS.ORG 369
CLOT RETRACTION FIBRINOLYSIS
▪ Occurs one hour after primary, secondary ▪ Occurs two days after primary, secondary
hemostasis hemostasis; degrades clot
▫ Contracts clot ▪ Plasminogen → plasmin (via tissue
▪ Platelets in clot express integrin αIIBβ3 → plasminogen activator)
binds to fibrin expressing actin, myosin → ▪ Plasmin proteases fibrin → clot dissolves
lamellipodia contract, fibrin mesh tightens
closing wood
BLOOD GROUPS & TRANSFUSIONS

osms.it/blood-groups-and-transfusions
BLOOD TRANSFUSIONS ▪ Immune system produces antibodies
▪ Blood transfusion: person receives blood/ against absent glycoproteins
elements of blood (usually through ▪ Type AB: no antibodies → universal
intravenous infusion) recipients
▫ Homologous transfusion: anonymous ▪ Type O: no antigens → universal donors
donor
▫ Autologous transfusion: self-donor (e.g. Rh system
in planned surgery) ▪ Determined by presence of Rh protein
▪ Blood is mixed with calcium oxalate to ▫ Rh positive; Rh negative
prevent coagulation, refrigerated/frozen for ▪ Rh+ can receive blood from either group
storage ▪ Rh- can only receive Rh- blood
BLOOD TYPING CROSS MATCHING

▪ Transfusion blood types not compatible → ▪ Test to confirm donor’s blood is safe for
autoimmune reaction (hemolytic transfusion recipient
reaction) ▪ Recipient serum is mixed with donor blood
▪ Two classification systems (based on ▫ Agglutination reaction: cannot receive
presence/absence of proteins)
▫ ABO system
▫ Rh system
ABO system
▪ Determined by type of glycoproteins found
on red blood cells (RBCs)
▫ Type A; type B; type A & B; type O
(neither)
370 OSMOSIS.ORG
Figure 43.7 Blood types are reported as ABO group and Rh + or -. When both classification
systems are combined, there are eight possible blood types: A+, A-, B+, B-, AB+, AB-, O+, O-.
OSMOSIS.ORG 371
NOTES
NOTES
IMMUNE SYSTEM
INTRODUCTION TO THE
IMMUNE SYSTEM
osms.it/immune-system-introduction
▪ Includes organs, tissues, cells, molecules CELLS OF THE IMMUNE SYSTEM
▪ Protects from microorganisms, removes
Leukocytes (white blood cells)
toxins, promotes inflammation, destroys
tumor cells ▪ Formed by hematopoiesis in bone marrow
▪ Two branches ▫ Starts with multipotent hematopoietic
stem cells
▫ Innate, adaptive
▫ Cells develop into myeloid/lymphoid
progenitor cells
INNATE IMMUNE RESPONSE ▪ Myeloid cells: contribute to innate response
▪ Nonspecific cells: phagocytes, natural killer ▫ Neutrophils: phagocytes, granulocytes,
(NK) cells; no immunologic memory polymorphonuclear cells (nucleus
▪ “Feverishly” fast (minutes to hours) segmented into 3–5 lobes); stain light
pink/reddish-purple; most numerous
Noncellular components
leukocyte
▪ Physical, chemical barriers (e.g. lysozymes
▫ Eosinophils: phagocytes, granulocytes,
in tears, cilia in airways)
polymorphonuclear cells (nucleus
▪ Inflammation: stops spread of infection, usually bilobed); stain pink with eosin;
promotes healing larger cells fight parasites
▫ Four cardinal signs: redness, heat, ▫ Basophils: nonphagocytes,
swelling, pain granulocytes, polymorphonuclear cells
▪ Complement system: cascade of proteins; (nucleus bilobed/segmented); stain blue-
triggers inflammation, kills pathogens by purple with hematoxylin; aid in fighting
cytolysis, tags cells for destruction parasites; granules contain histamine,
heparin; involved in inflammatory
ADAPTIVE IMMUNE RESPONSE response; least numerous leukocyte
▪ Highly specific cells; immunologic memory, ▫ Mast cells: nonphagocytes,
need priming granulocytes; involved in inflammatory
response
▪ Significantly slower, esp. initially (weeks)
▫ Monocytes: phagocytes, antigen-
▪ Clonal expansions: cells replicate
presenting cells; release cytokines to
▪ Clonal deletion: cells die off after immune recruit other cells; only circulate in blood;
response; some survive as memory cells differentiate into macrophages/dendritic
cells
▫ Dendritic cells: phagocytes, antigen-
presenting cells; release cytokines to
recruit other cells; circulate in lymph,
372 OSMOSIS.ORG
Chapter 44 Immunology: Immune System
blood, tissue; consume large proteins ▫ B cells: contribute to adaptive response;

in interstitial fluid; break bloodborne complete development in bone marrow;
pathogens into small amino acid chains bind to specific antigens (antigen
→ move to lymph node → present presentation not needed); capable of
antigens to T cells phagocytosis, antigen presentation; load
▫ Macrophages: phagocytes, antigen- antigens on major histocompatibility
presenting cells; release cytokines to complex (MHC) II, display to T cells;
recruit other cells; stay in connective T-cell activation → B cells mature into
tissue, lymphoid organs; not in blood plasma cells; secrete lots of antibodies/
▪ Lymphoid cells: contribute to the adaptive immunoglobulins (B cell receptors in
response (except NK cells) secreted-form, mark pathogens for
destruction → “humoral immunity”)
▫ NK cells: contribute to innate response;
complete development in bone marrow; ▫ T cells: contribute to adaptive
large, contain granules; primarily target response; complete development in
infected, cancer cells; kill target cells thymus; responsible for cell-mediated
with cytotoxic granules (punch holes immunity; bind to specific antigens
in target cell membranes by binding (antigen presentation needed); naive
to phospholipids → enter cell, trigger T cells primed by antigen presenting
apoptosis, programmed cell death) cells (usually dendritic cells); generally
categorized into CD4+, CD8+ T cells;
CD4+ (helper) T cells secrete cytokines
to coordinate immune response,
only see antigens on MHC II; CD8+
(cytotoxic) T cells kill target cells, cells
with antigens on MHC I
Figure 44.1 Family tree of immune system cells.
OSMOSIS.ORG 373
CLASSIFICATION OF IMMUNE Granulocytes
CELLS ▪ Contain granules in cytoplasm
Phagocytes ▪ All cells (except mast cells)
polymorphonuclear
▪ Reach around pathogens with cytoplasm,
swallowing whole (phagosome) Antigen-presenting cells
▪ Destroy some pathogens with cytoplasmic ▪ Present antigens to T cells
granules (phagosomes fuse with granules
→ phagolysosomes; pH in vesicle drops
killing pathogens)
▪ Continue to swallow pathogens before
oxidative burst → produces highly reactive
oxygen (e.g. H2O2; destroys proteins,
nucleic acids, killing pathogens, phagocyte)
Figure 44.3 Antigen-presenting cell

(depicted here as dendritic cell) presenting an
antigen to a T cell.
Figure 44.2 Phagocyte activities.
374 OSMOSIS.ORG
Chapter 44 Immunology: Immune System
VACCINES
osms.it/vaccines
▪ Generate protective adaptive immune INACTIVATED VACCINES
response against microbes by exposure ▪ Pathogen killed using heat/formalin
to nonpathogenic forms/components of ▪ Response humoral/antibody-mediated; no
microbes cellular immunity → ↓ response
▫ Differs from passive immunity (body ▪ Hepatitis A; polio; rabies; influenza
creates own antibodies)
▪ Administration: intramuscularly,
intradermally, intranasally, subcutaneously, SUBUNIT VACCINES
orally ▪ Contain immunogenic portions of
▪ Immunoglobulin response depends on pathogens (polysaccharides/proteins)
route, type of vaccine ▪ Combination of proteins from different
▫ Intramuscular vaccinations → IgG pathogens → conjugate subunit vaccines
▫ Rotavirus vaccine (oral) → IgA ▪ Polysaccharide vaccines
▪ Four main types of vaccines ▫ T cell independent (only respond to
protein antigens)
▫ Live attenuated, inactivated (whole cell
vaccines) ▫ Not effective in children < two years old
▫ Subunit, toxoid (fractionated vaccines) ▫ Memory B cells never formed →
repeated doses needed
▫ Haemophilus influenzae type B;
LIVE ATTENUATED VACCINES hepatitis B; HPV; Bordetella pertussis
▪ Attenuated → pathogen weakened (but still (pertussis); Streptococcus pneumoniae;
replicates) Neisseria meningitidis; Varicella zoster
▪ Measles, mumps, rubella, varicella (MMRV);
rotavirus; smallpox; yellow fever
OSMOSIS.ORG 375
TOXOID VACCINES
▪ Against specific toxins (main cause of
illness)
▪ Toxoid fixed/inactivated using formalin
▪ Often combined with subunit vaccines
▪ Tetanus, diphtheria, and pertussis (TDaP),
diphtheria, tetanus, and pertussis (DTap)
vaccine
CONTRAINDICATIONS
▪ Moderate/severe infection
▪ Allergy to eggs/previous vaccines
▪ Guillain–Barré syndrome (vaccines against
influenza, DTaP)
▪ Weakened immune system
▫ Pregnant (live attenuated vaccines)
376 OSMOSIS.ORG
NOTES
NOTES
B & T CELLS
ANTIBODY CLASSES
osms.it/antibody-classes
▪ B cell receptor, major component of ▪ Main immunoglobulin in mucosal sites;
humoral immunity sometimes occurs as dimer (valence: 4)
▪ Heavy, light chain; fragment antigen- ▪ Two forms
binding region; constant region (Fc) ▫ IgA1, IgA2 (differ in constant regions)
▪ B cell develops into plasma cell → B cell
receptor secreted as antibody Immunoglobulin E (IgE)
▪ Antibodies: monomers, polymers ▪ Monomer (valence: 2)
▫ Valence: number of antigen-binding ▪ Production primarily induced by interleukin
fragments 4 (IL-4)
▪ Triggers granule release from mast cells,
eosinophils, basophils
FIVE TYPES
▪ Responds to nonpathogenic targets (e.g.
▪ Coded by heavy chain genes peanuts) → allergies
Immunoglobulin M (IgM) Immunoglobulin D (IgD)
▪ 1st antibody response ▪ Monomer (valence: 2)
▪ Monomer as B cell receptor (valence: 2) ▪ Found alongside IgM antibodies, signals
▪ Pentamer as antibody held together by maturation of B cells
joining (J) chain (valence: 10)
▪ Works against carbohydrate, lipid antigens
▪ Most effective at activating complement
pathway
Immunoglobulin G (IgG)
▪ Monomer (valence: 2)
▪ Four subclasses
▫ IgG1, IgG2, IgG3, IgG4 (differ in
constant regions)
▪ Serves as opsonin
▪ Activates classical complement pathway
Immunoglobulin A (IgA)
▪ Monomer (valence: 2)
Figure 45.1 B cell receptor components.
▪ Serves as opsonin (eosinophils, neutrophils,
some macrophages)
OSMOSIS.ORG 377
Figure 45.2 Summary of the five classes of antibodies. IgM and IgD can act as B cell receptors.
B CELL ACTIVATION &

DIFFERENTIATION
osms.it/b-cell-activation-and-differentiation
▪ Developing B cell receptor expresses μ DIFFERENTIATION
heavy chain → B cell receptors IgM ▪ B cells stimulated by cluster of
▪ Alternative splicing → IgM, IgD expressed differentiation 21 (CD21)/complement
on surface → mature, naive B cell receptor Type II (CR2) (receptor for C3d
explores lymphatic system → B cells enter complement fragment)
paracortical region of lymph nodes, migrate ▪ Activated B cells differentiate into plasma
to cortical region → form primary follicle cells, secrete antibodies
▫ Plasma cells initially secrete IgM, remain
ACTIVATION mainly in bone marrow, safeguard
▪ On activation (antigen-binding), B cell against future encounters with same
forms germinal center → secondary antigen
lymphoid follicle Activated CD4+ T cell → class switching
▪ Cross-linkage of two B cell receptors → Ig- ▪ B cells: antigen-presenting cells; present
alpha, Ig-beta, CD19 cluster antigens on major histocompatibility
▫ Blk, Fyn, Lyn phosphorylate tyrosine complex (MHC) class II to helper T cells
residues on immunoreceptor tyrosine ▪ CD40 ligand on T cell binds to CD40 on B
based activation motif (ITAM) units cell → cytokines instruct B cell on type of
→ transcription factors nuclear antibody to produce (by activation-induced
factor kappa-light-chain-enhancer of cytidine deaminase)
activated B cells (NF-kB), nuclear factor
▫ IL-4, IL-5 → IgE
of activated T cells (NFAT) → gene
expression of cytokines, upregulation of ▫ Interferon (IFN) gamma → IgG
antiapoptotic cell surface markers
378 OSMOSIS.ORG
Chapter 45 Immunology: B & T Cells
▪ Activation-induced deaminase removes

constant regions during differentiation to
leave desired antibody region
Figure 45.3 Mature, naive B cells form a primary follicle in the cortical region of a lymph node.
When the B cell binds an antigen, it activates and forms a germinal center. The follicle is now
called a secondary lymphoid follicle.
Figure 45.4 Series of events following antigen binding that lead to B cell activation. Ig-alpha, Ig-
beta, and CD19 are intracellular side chains of the B cell receptors that cluster when two B cell
receptors are cross-linked by an antigen.
OSMOSIS.ORG 379
Figure 45.5 Complement fragment C3d can bind an antigen and then be bound by molecule
CD21/CR2 on a B cell. B cells can also be activated when they have a B cell receptor that is
bound to an antigen, and a CD21 that’s bound to an antigen.
Figure 45.6 B cell differentiation. 1: B cell presents an antigen to a CD4+ T cell. 2: If the T cell
activates, it expresses CD40L on its surface, which binds to CD40 on the B cell. 3: CD40L and
CD40 binding causes the B cell to express a cytokine receptor and the T cell to release cytokines.
The type of cytokine determines what type of antibody the B cell will produce.
380 OSMOSIS.ORG
B CELL DEVELOPMENT
osms.it/b-cell-development
▪ Lymphopoiesis: development of diverse Early pro-B cell
set of lymphocytes with unique antigen ▪ Common lymphoid progenitor cell
receptors expresses recombination activating gene
(RAG) 1, RAG2 → early pro-B cell
CREATION OF SUITABLE RECEPTOR Late pro-B cell
▪ B cell receptor contains two chains ▪ Heavy chain D, J gene segments spliced
▫ Heavy, light together (allelic exclusion: 1st chromosome
▪ Antigen-binding site made of variable (V), to complete splicing suppresses 2nd) → late
diversity (D), joining (J) protein segments pro-B cell
coded by genes of same name
▫ Heavy chain: all three segments Large pre-B cell
▫ Light chain: V, J segments ▪ Late pro-B-cell attaches D-J gene segment
to V gene segment via V(D)J recombinase
→ binding site (heavy chain) recombined
with mu gene → large pre-B cell
▫ Mu gene codes for IgM constant region
protein
Small pre-B cell

▪ Functionality of heavy chain tested by
binding to surrogate light chain (VpreB,
lambda 5) → if successful, cells proliferate
→ small pre-B cell
Immature B cell
▪ Light chain rearranged → functionality of
light chain tested by autoimmune regulator
(AIRE), identifies self-reactive cells by
expressing bodily antigens in lymphoid
organs → immature B cell
▪ Central tolerance/negative selection:
elimination of self-reactive cells
Figure 45.7 Antigen binding site on heavy ▫ Strong binding to self-antigen → cell
chain is composed of V, D, and J segments, undergoes apoptosis
while antigen binding site on light chain has ▫ Intermediate binding to self-antigen →
only V and J segments. light chain repeatedly rearranged with
kappa gene on 1st, 2nd chromosomes,
lambda gene 1st, 2nd chromosomes
STAGES OF DEVELOPMENT ▫ Failure to eliminate self-reactive cells →
▪ Six stages: common lymphoid progenitor autoimmunity
cell → early pro-B cell → late pro-B cell ▪ Immature B cells finally undergo alternative
→ large pre-B cell → small pre-B cell → splicing on constant region → IgD constant
immature B cell region replaces IgM constant region → cells
released into blood
OSMOSIS.ORG 381
Figure 45.8 B cell development stages and the changes that move them to the next stage.
382 OSMOSIS.ORG
CELL MEDIATED IMMUNITY OF

CD4 CELLS
osms.it/cell-mediated-immunity-CD4-cells
▪ CD4 cells = T helper cells (support other → transcription factors signal transducer
immune cells) and activator of transcription 1 (STAT1),
▪ T cells initially naive STAT2
▪ In response to antigen, T cell primed → T helper Type II
effector T cell
▪ Fights parasites
▫ Two signals: antigen (MHC molecule on
▪ Eosinophils, basophils, mast cells → IL-4,
antigen-presenting cell), costimulation
IL-4, IL-10 → transcription factors STAT6,
(CD28 binds to B7 on antigen-
GATA-binding protein 3 (GATA3)
presenting cells)
▪ Activated T helper cell → IL-2 → up- T helper Type XVII
regulates IL-2 alpha receptor ▪ Fights fungal, bacterial infections
▪ T helper cell binds to IL-2 (autocrine ▪ Fungi, bacteria → IL1, IL6, IL23,
stimulation) → clonal expansion transforming growth factor (TGF)β →
transcription factors ROR-γ, STAT3
FOUR TYPES OF T HELPER CELL
T follicular helper (Tfh)
▪ Depends on cytokines in environment
▪ Establishes memory B cells
T helper Type I (Th1) ▪ Antigen-presenting cells → IL6, IL21, IL27
▪ Fights intracellular infections → transcription factors B cell lymphoma
▪ Macrophages → IL-12, natural killer (NK) protein 5 (BCL-5), cMaf
cells → IFN-γ, infected cells → IFNα, IFNβ
Figure 45.9 T helper cells require two signals to be primed and become effector T cells:
presentation of an antigen and binding of CD28 on T cell to B7 on antigen-presenting cell.
OSMOSIS.ORG 383
CELL MEDIATED IMMUNITY OF
NATURAL KILLER & CD8 CELLS
osms.it/cell-mediated-immunity-NK-CD8-cells
NATURAL KILLER (NK) CELLS CD8 CELLS
▪ Identify target cells; deliver perforin, ▪ CD8 cells = cytotoxic T cells
granzymes ▪ T cells initially naive
▪ Part of innate response → no need for ▪ In response to antigen, T cell primed →
specific antigen effector T cell
▪ Activation receptors recognize surface ▫ Two signals: antigen (MHC molecule on
molecules on infected cells; inhibitory antigen-presenting cell), costimulation
receptors recognize molecules (e.g. native (CD28 binds to B7 on antigen-
MHC class I molecules) presenting cells)
▪ Also activated by antibody-dependent cell- ▪ Activated T helper cell → IL-2 → up-
mediated cytotoxicity regulates IL-2 alpha receptor
▫ IgG binds to virally-infected cell → ▪ T helper cell binds to IL-2 (autocrine
CD16 on NK binds to antibody stimulation) → clonal expansion
▪ Needs to see antigen in context of MHC I to
kill cell (doesn’t need CD28)
▪ Binds nonspecifically to multiple cells with
adhesion molecules → fails to bind to MHC
I → disengages
▪ If antigen binds, cytoskeletal rearrangement
→ forms supramolecular activation cluster
(SMAC)
▫ Includes central SMAC (cSMAC) for
antigen recognition, peripheral SMAC
(pSMAC)
▪ Cytotoxic cell releases granules with
perforin, granzymes (caspases →
apoptosis)
Figure 45.10 NK cells recognize cell surface

molecules like MHC I to determine whether or
not to kill a cell. They can also kill via ADCC.
In this process, the NK cell is stimulated
by binding to the constant chain of an IgG
antibody attached to a virally infected cell.
384 OSMOSIS.ORG
Figure 45.11 CD8 cells weakly bind a variety of cells with adhesion molecules. However, they
only destroy cells with antigens on their MHC I molecules that allow the CD8 cells to bind tightly.
CYTOKINES
osms.it/cytokines
▪ Proteins secreted by all types of cells to messenger RNA (mRNA), inhibit protein
communicate (bind to receptors, trigger synthesis, express MHC
response) ▪ Type II
▫ Interferon-gamma → promotes anti-
FIVE TYPES viral state, activates macrophages, CD4+
helper T-cells
Interleukins (ILs)
▪ Act as communication between leukocytes, Colony stimulating factors (CSFs)
nonleukocytes ▪ Bind to surface receptors on hematopoietic
▪ Promote development, differentiation of T, stem cells → proliferation, differentiation
B cells
Transforming growth factors (TGFs)
▪ Mostly synthesized by helper T cells
▪ Control proliferation, differentiation of cells
Tumor necrosis factors (TNFs)
▪ Bind to cell receptors, cause cells to die MAIN FUNCTIONAL RESPONSES
(induce apoptosis)
▪ Heavily involved in inflammatory response Pro-inflammatory
(up-regulate expression of adhesion ▪ Enhance innate, adaptive immune
molecules, increase vascular permeability, responses
induce fever) ▪ IL-1, IL-12, IL-18, TNF, IFN-γ
Interferons (IFNs) Parasite/allergy

▪ Type I ▪ Help immune system handle large
▫ Produced by virally infected cells → parasites, induce allergic responses
affect surrounding cells: degrade ▪ IL-4, IL-5, IL-10, IL13
OSMOSIS.ORG 385
Regulatory stimulating factor (GM-CSF), macrophage
▪ Immunosuppressive colony-stimulating factor (M-CSF), IL-7
▪ IL-10, TGF-β Chemotactic
Growth and differentiation ▪ Help cells move towards site of
▪ Replenish immune cells inflammation
▪ Granulocyte-macrophage colony- ▪ IL-17, IL-8
MHC CLASS I & MHC CLASS II

MOLECULES
osms.it/MHC-class-I-MHC-class-II
▪ Major histocompatibility complex (MHC), Structure
AKA “human leukocyte antigen” ▪ Contains alpha, beta-2-microglobulin
▫ Cell surface proteins, present antigens chains
to T cells ▪ Alpha chain: peptide binding groove,
transmembrane region
MHC CLASS I ▫ Binding groove binds peptides 8–10
▪ Found on all nucleated cells, presents amino acids long; hydrophobic peptide
antigens from inside residues ↔ hydrophilic groove amino
acids
▪ Bound by CD8 molecules on cytotoxic T
cells ▪ Three extracellular domains: alpha-1,
alpha-2, alpha-3
▪ Includes HLA-A, HLA-B, HLA-C
Figure 45.12 Structure of an MHC class I molecule.
386 OSMOSIS.ORG
Function move peptide chains to endoplasmic

▪ Allows immune cells to sample cellular reticulum
proteins (via endogenous pathway of ▫ TAP loads peptide onto MHC class I
antigen presentation) using tapasin
▫ Marked protein sent to proteasome ▫ MHC class I loaded into exocytic vesicle,
▫ Proteasome degrades protein → short sent to cell surface
peptide chains ▫ Cytotoxic T cells, NK cells interact with
▫ Transporters of antigenic peptides (TAP) peptide (if necessary)
Figure 45.13 Endogenous pathway of antigen presentation.
MHC CLASS II presentation)

▪ Found on antigen-presenting cells, ▫ Antigen-presenting cell ingests antigen
presents antigens from outside → endosome
▪ Bound by CD4 molecules on helper T cells ▫ Lysosome + endosome →
▪ Includes HLA-DP, HLA-DQ, HLA-DR phagolysosome; degrades protein →
short peptide chains
Structure ▫ MHC class II binding groove
▪ Contains alpha, beta chains filled temporarily with invariant
▫ Both penetrate cell membrane chain (degrades during vesicular
▫ Binding groove binds peptides 14–20 transportation)
amino acids long ▫ Vesicle fuses with phagolysosome
▫ MHC class II binds peptide, sent to cell
Function surface
▪ Engulfs, destroys pathogens; presents ▫ CD4+ helper T cells interact with peptide
antigens to CD4+ T helper cells (via (if necessary)
exogenous pathway of antigen
OSMOSIS.ORG 387
Figure 45.14 MHC class II molecule structure.
Figure 45.15 Exogenous pathway of antigen presentation.
388 OSMOSIS.ORG
SOMATIC HYPERMUTATION &

AFFINITY MATURATION
osms.it/somatic-hypermutation-affinity-maturation
SOMATIC HYPERMUTATION ▫ Base excision: uracil-DNA glycosylase
▪ Intentional mutation of antibody genes to removes uracil from uridine → next
create new antigen specificities → stronger, round of replication, random nucleotide
more specific response to antigen inserted → mutations
▪ Occurs in activated B cells (germinal ▪ Only some mutations increase affinity
centers, spleen) ▫ Low affinity B cells die naturally with
▪ CD40L on T cell binds to CD40 on B cell → time
cytokines instruct B cell to produce specific ▫ High affinity B cells live on (affinity
type of antibody maturation)
▪ Activation-induced cytidine deaminase
(AID) turns cytidine into uridine (not usually AFFINITY MATURATION
found in DNA) → mismatch/base excision
▪ Process by which B cells increase affinity
repair to remove uridine
for antigen during an immune response
▫ Mismatch repair proteins MSH2, MSH6
▪ Somatic hypermutation, clonal selection
use nucleases to remove uridine; DNA
(only high affinity cells activated → only
polymerase replaces nucleotides →
high affinity cells replicate)
mutations
Figure 45.16 Somatic hypermutation only occurs in B cells which express enzyme AID. AID
makes small mutations directly in antigen binding site of B cell receptor, which get expressed in
daughter cells of a rapidly proliferating cell. These changes in the variable region change affinity
(strength) that B cell receptor has for its antigen. As antigen becomes limited, B cells with lowest
affinity will die off first, so only B cells with strongest affinity for their antigen remain.
OSMOSIS.ORG 389
T CELL ACTIVATION
osms.it/t-cell-activation
▪ Priming: T cell begins differentiation when ▫ Zeta-chain-associated protein kinase 70
exposed to antigen (ZAP-70) phosphorylates LAT, SLP-76
▫ Two signals: antigen (MHC molecule on → activation of transcription factors
antigen-presenting cell), costimulation NF-kB, NFAT → gene expression of
(CD28 binds to B7 on antigen- cytokines, upregulation of antiapoptotic
presenting cells) cell surface markers
▪ Signal sent to nucleus by CD3 peptide ▪ Activated T cell → IL-2 → up-regulates IL-2
chains alpha receptor
▫ Lymphocyte-specific protein tyrosine ▪ T helper cell binds to IL-2 (autocrine
kinase (LCK) phosphorylates tyrosine stimulation) → clonal expansion
residues on immunoreceptor tyrosine
based activation motif (ITAM) units
Figure 45.17 Summary of T cell activation. T cells need two signals to activate: first, presentation
of its antigen by MHC class I (cytotoxic C cells) or class II (helper T cells), and costimulation,
which is when CD28 and B7 bind. In helper T cells, this triggers a series of steps that lead to
upregulation of the IL-2 alpha receptor and production of IL-2 for itself, causing clonal expansion,
and CD8 T cells.
390 OSMOSIS.ORG
T CELL DEVELOPMENT
osms.it/t-cell-development
▪ Lymphopoiesis: hematopoietic stem cell STAGES OF REARRANGEMENT
→ common lymphoid progenitor cell → ▪ Tracked by CD3, CD4, CD8 cell surface
immature B cell (bone marrow) markers
Double negative/DN stage

CREATION OF SUITABLE RECEPTOR
▪ Common lymphoid progenitor initially CD3-,
▪ T cell receptor contains two chains: alpha, CD4-, CD8- (double negative/DN stage;
beta broken down into DN1, DN2, DN3, DN4)
▫ Alpha: comparable to B cell’s light chain ▫ DN1 cell expresses RAG1, RAG2 →
▫ Beta: comparable to B cell’s heavy chain DN2 cell
▪ Antigen-binding site: V, D, J protein ▫ Beta chain D, J gene segments spliced
segments coded by genes of same name together (allelic exclusion) → DN3 cell
▫ Beta chain: all three segments ▫ V gene segment combines with DJ
▫ Alpha chain: V, J segments gene segment by V(D)J recombinase →
V-D-J gene segment bound to μ gene
segment → DN4 cell
▫ Functionality of beta chain tested by
binding to invariant pre-T alpha chain →
if successful, cells proliferate
Double positive/DP stage

▪ Daughter cells express CD3, CD4, CD8
(double positive/DP stage)
Single positive/SP stage

▪ Central tolerance: eliminates potentially
self-reactive cells by positive, negative
selection
▫ Self-reactive cell elimination failure →
autoimmunity
▪ Positive selection
▫ T cells recognize/bind to self-MHC
molecules
▫ Binding failure → apoptosis
▪ Negative selection
▫ Autoimmune regulator gene (AIRE):
allows primary lymphoid organs to
express antigens normally found
throughout body; aids in testing self-
reactivity
▫ Excessively strong binding to self-
antigens → apoptosis
Figure 45.18 Structure of T cell receptor.
Different combinations of V, D, and J
segments provide T cell receptors with a
wide variety of antigen specificities.
OSMOSIS.ORG 391
Figure 45.19 T cell development summary.
392 OSMOSIS.ORG
▪ DP cells recognize self-MHC but do not

recognize self-antigen presented in MHC
molecule → downregulate either CD4/CD8
receptor → further development into single
positive (SP) cell
▫ Strong binding to MHC → CD4
downregulated → SP CD8+ T cell
▫ Weak binding to MHC → CD8
downregulated → SP CD4+ T cell
VDJ REARRANGEMENT
osms.it/VDJ-rearrangement
▪ Mechanism used to generate range of B, T HEAVY/BETA CHAIN
cell receptors REARRANGEMENT
▪ Antigen-binding sites: V, D, J protein ▪ Recombination signal sequence
segments coded by genes of same name ▫ Heptamer 5’-CACAGTC-3’,
▫ Each cell inherits multiple V, D, J 12, 23 nucleotides, nonamer
segments → randomly recombine → 5’-ACAAAAACC-3’
recombinational inaccuracy, random ▫ DNA loops to bring together two
assortment of two chains (heavy/ recombination signal sequences
beta chain rearranged first) → new ▫ RAG1, RAG2 cut DNA at recombination
specificities signal sequence
▪ V(D)J rearrangement only affects V region ▫ Recombinases (e.g. ku, artemis)
(creates variability in hypervariable regions) reattach, recombine DNA
▪ Error-prone process
▫ Cut end placed onto terminal
deoxynucleotide transferase (TdT)
to add random nucleotides → alters
antigen specificity
▪ Functionality of heavy chain tested →
random assortment of chain
LIGHT CHAIN REARRANGEMENT

▪ Rearranged into kappa/lambda light chain
(kappa rearranged before lambda)
Figure 45.20 Locations of hypervariable

regions on BCRs and TCRs affected by V(D)J
rearrangement.
OSMOSIS.ORG 393
Figure 45.21 Summary of the process by which B and T cell receptors are made.
394 OSMOSIS.ORG
NOTES
NOTES
CONTRACTION OF THE IMMUNE
RESPONSE
ANERGY, EXHAUSTION, &

CLONAL DELETION
osms.it/contracting-immune-response
CLONAL ANERGY
▪ Functional unresponsiveness to self
antigens
▪ Lymphocytes can bind to antigens, without
costimulation
▪ T cells: costimulation involves CD28
binding to B7 on antigen-presenting cells
(APCs)
▫ T regulatory cells reduce B7 expression
on antigen presenting cells
▫ Later in immune response, T cells begin
to express cytotoxic T-lymphocyte
associated protein 4 (CTLA-4) → binds
to B7
Figure 46.2 T cells express much more

CTLA-4 later in immune response. B7 binds
to CTLA-4 more strongly than it does to
CD28 and inhibits T cell → T cell inactivation.
CLONAL EXHAUSTION
▪ Later in immune response, T cells begin to
express program death 1 (PD-1)
▪ Program death ligand 1 (PD-L1) on
antigen-presenting cells bind to PD-1 → T
cells shut down
CLONAL DELETION
▪ Recognition of self antigens → T cell
apoptosis (programmed cell death)
Figure 46.1 T regulatory cells reduce ▪ Later in immune response, T cells express
costimulation by releasing cytokines that Fas
reduce B7 expression on antigen-presenting ▪ Fas ligands on CD8+ T cells, NK cells bind
cells (APCs). to Fas → activate enzymes called caspases
→ apoptosis
OSMOSIS.ORG 395
Figure 46.3 Clonal deletion. T cells express
Fas → bind to Fas ligand on CD8+ T cell/NK
cell → caspases activated → apoptosis.
B & T CELL MEMORY

osms.it/B-and-T-cell-memory
▪ Ability of B, T cells to “remember” particular MEMORY B CELLS
antigen ▪ Only B cells that have undergone class
▫ B, T cells multiply when receptors detect switching become memory B cells
particular antigen ▫ Memory response limited to peptide
▫ After immune response mounted, antigens (not lipids/carbohydrates)—
excess cells undergo apoptosis follicular T helper cells needed for
▫ Memory B, T cells contain same class-switching only respond to peptide
receptors after immune response antigens
▪ Immunologic memory → secondary ▫ Memory B cells don’t produce IgM/IgD
(anamnestic) response ▪ Live up to 10 years in lymph nodes
▫ Primary response: naive B, T cells ▪ Often differentiate into IgG-producing
require activation before response to plasma cells when reactivated
pathogen → high pathogen burden ▪ Due to somatic hypermutation, IgG created
(response can take days, weeks) late in immune response typically has
▫ Secondary response: memory B, T higher affinity than IgM created early
cells, antibodies needed to respond to in immune response → IgG binds to Fc
pathogen already exist → low pathogen gamma receptor II on IgM-producing B
burden (response occurs right away) cells, prevents differentiation into plasma
cells → ↓ IgM production, ↑ IgG production
396 OSMOSIS.ORG
Chapter 46 Immunology: Contraction of the Immune Response
Figure 46.4 B cells are activated through interactions with other immune cells. Step 1a: follicular
dendritic cell traps antigens and 1b: sends out stimulatory cytokines. Step 2: the B cell presents
the antigen to a follicular T helper cell. Step 3a: the follicular T helper cell expresses CD40L on its
surface and produces IL-21. 3b: together, they induce the B cell to undergo class switching (shift
from expressing a B cell receptor with IgM and IgD to expressing IgG, IgE, or IgA. 3c: some of
these B cells become memory B cells.
OSMOSIS.ORG 397
Figure 46.5 Process by which higher affinity IgG production is favored over lower affinity IgM
production. Memory B cells differentiate into high affinity IgG-producing plasma cells. IgG binds
to Fc gamma receptor II on newly activated B cells, which produce low affinity IgM. This prevents
them from differentiating into low affinity IgM-producing plasma cells, allowing the proportion of
high affinity IgG in the response to be greater.
MEMORY T CELLS cytotoxic cells, binding to, destroying target

▪ Cell surface ligand CD45 used to identify T cells)
cells ▪ IL-7 receptors replaced with IL-2 receptors
▫ Naive T cells express CD45A during activation → cells die shortly after
▫ Memory T cells express CD45O immune response
Effector memory T cells Central memory T cells

▪ Move around body looking for pathogens ▪ Live up to 25 years
▪ Respond as primary response (for CD4+ ▪ Remain in lymphoid tissues
helper cells, secreting cytokines; for CD8+ ▪ High levels of IL-7 receptors maintained →
cells live on after immune response
398 OSMOSIS.ORG
Chapter 46 Immunology: Contraction of the Immune Response
Figure 46.6 The two types of memory T cells (effector memory T cells and central memory T
cells) and their functions.
CONTRACTING THE IMMUNE

RESPONSE
osms.it/contracting-immune-response
▪ Immune response termination B CELLS
▪ Peripheral tolerance to self antigens limits ▪ Similar mechanisms to T cells
immune response (preventing autoimmune ▪ Later in immune response, reduced
disease) presence of antigens, T cells prevent B cell
▪ Mechanisms directed primarily at T cells; activation → anergy
includes use of T regulatory cells, clonal ▪ Surplus IgG binds to Fcγr II on B cells →
anergy, exhaustion, deletion prevent differentiation into plasma cells
T REGULATORY CELLS
▪ Inhibit antigen-presenting cells by releasing
specific molecules (e.g. indoleamine 2,3
dioxygenase)
▪ Release cytokines (e.g. IL-10, TGF-beta) →
antigen-presenting cells express inhibitory
ligand (e.g. PD-L1)
▪ Express high levels of IL-2, adenosine
receptors (competing with other T cells)
OSMOSIS.ORG 399
NOTES
NOTES
INNATE IMMUNITY
INNATE IMMUNE SYSTEM

osms.it/innate-immune-system
▪ Comprises immune system along with ▪ Phagocyte kills pathogen (post-
adaptive immunity identification)
▪ Includes barriers to repel pathogens ▫ Phagosome binds with lysosome, forms
▫ Chemical barriers: lysozyme (tears), low phagolysosome
stomach pH ▫ Specific phagolysosome granules
▫ Physical barriers: epithelium (skin/gut), (proteases, hydrolases) kill internal
cilia lining airways microorganisms while decreasing pH
▫ Azurophilic granules (hydrolases,
Key features oxidative enzymes) activate in acidic
▪ Nonspecific cells do not distinguish environment → more microorganisms
invaders killed
▪ Response occurs within minutes–hours ▫ Nicotinamide adenine dinucleotide
▪ No memory phosphate (NADPH) oxidases oxidize
▫ Always responds to pathogen in same oxygen molecules → superoxide ion
manner creation
▫ Superoxide dismutase converts
Human microbiome superoxide into hydrogen peroxide,
▪ Included in innate immunity killing remaining microorganisms
▪ Bacteria, fungi, viruses in/on humans
Signalling PRRs response to pathogens
▪ May affect host response in own way
▪ Large amount of pathogens enter →
signalling pattern recognition receptors also
RESPONSE TO PATHOGENS activated
▪ Signalling PRRs → phagocytes to release
Phagocyte response to pathogens
cytokines
▪ Phagocytes eat, kill pathogens
▪ Toll-like receptors (TLRs) especially
▪ Phagocyte consumes pathogen important in signalling PRRs
▫ Phagocytic pattern recognition ▫ PAMP activation → TLRs activate
receptors (PRRs) on phagocyte identify transcription factor NF-κB →
pathogen-associated molecular patterns proinflammatory cytokines (e.g. TNFα,
(PAMPs) on pathogens (e.g. bacterial- IL-1β, IL-6) secreted → vasodilation,
wall components) fever, recruiting leukocytes
▫ Phagocyte swallows pathogen, traps it ▫ Intracellular pathogens: interferon
in phagosome alpha, beta may be secreted (prevents
pathogen multiplication)
400 OSMOSIS.ORG
Chapter 47 Immunology: Innate Immunity
Figure 47.1 Overview of the phagocyte response to pathogens.

1. The phagocyte’s pattern recognition receptors (PRRs) identify pathogen-associated molecular
patterns (PAMPs) on the pathogen.
2. The pathogen is phagocytosed and trapped in a phagosome, which then
3. binds with lysosomes, forming a phagolysosome.
3a. Specific granules from the lysosomes act first to kill pathogens and decrease pH.
3b. After the pH is sufficiently lowered, azurophilic granules are activated and kill more
pathogens.
4. NADPH oxidases oxidize oxygen molecules to create superoxide ions. The ions are then
converted by superoxide dismutase into hydrogen peroxide, which kill the remaining pathogens.
OSMOSIS.ORG 401
COMPLEMENT SYSTEM
osms.it/complement-system
▪ Collection of plasma proteins called ▫ C1r cleaves C1s (activating C1
complement proteins molecule) → C1 cleaves C4 into C4a,
▪ Produced in liver, collectively destroy C4b → C4b binds to pathogen
pathogens ▫ C1 also cleaves C2 into C2a, C2b →
C2a joins C4b on pathogen → C4b2a
(C3 convertase) formed
COMPLEMENT SYSTEM PATHWAYS
▫ C3 convertase cleaves C3 into C3a, C3b
▪ Acts follow one of three pathways
▫ C3b binds to pathogen near C4b2a/
▫ Classical, alternative, lectin
C3 convertase, creates C5 convertase
Classical pathway (C4b2a3b)
▪ Features C1–C9 proteins ▫ C5 convertase cleaves C5 into C5a, C5b
▪ C1 ▫ C5b binds to C6, C7, C8, many C9s →
forms membrane attack complex (MAC)
▫ Component proteins C1q, C1r, C1s
→ penetrates pathogen cell membrane
(latter two—serine proteases)
▪ C1 consists of six C1q proteins
▫ Binds to six antibody-antigen
complexes
▪ Calcium ties together C1
▫ Lack of calcium → lack of C1
Alternative pathway
▪ Factor B, factor D proteins
▪ C3 cleaved spontaneously (small amounts)
▪ Pathway steps
▫ C3b binds to pathogen → factor B binds
to pathogen
▫ Factor D cleaves factor B → forms Ba,
Bb → C3bBb formed (C3 convertase)
▫ Follows classical pathway
▪ Constant activation prevention
Figure 47.2 Structure of a C1 protein. ▫ C1-inhibitor protein dissociates C3bBb
Each of the six C1q proteins can bind to an
antibody-antigen complex. Calcium ties the Lectin pathway
protein together. ▪ Features mannose-binding lectin protein
(binds to bacterial mannose)
▪ Pathway steps
▪ Proteins inactive until “cleaved” (portion of
▫ Mannose-binding lectin protein
protein breaks off)
acts similar to C1 → cleaves C4, C2
▪ Pathway steps to eventually establish C4b2a (C3
▫ C1q proteins bind to Fc portion of convertase)
antibody when bound to antigen ▫ Follows classical pathway
▫ Two C1q proteins bind → C1 changes
shapes (conformational change)
exposing C1r, C1s
402 OSMOSIS.ORG
Chapter 47 Immunology: Innate Immunity
Figure 47.3 Overview of the classical complement pathway.

1. C1q binds to an antibody-antigen complex.
2. When two C1q proteins are bound, C1 undergoes a conformational change, exposing C1r
and C1s. C1r then cleaves C1s to activate C1.
3. C1 cleaves C4 and C2.
4. C4 and C2 bind to the surface of the pathogen, forming C3 convertase.
5. C3 convertase cleaves C3.
6. C3b binds to the pathogen near the C3 convertase, forming C5 convertase.
7. C5 convertase cleaves C5.
8. C5b joins C6, C7, C8, and then multiple C9s to form the membrane attack complex,
penetrating the pathogen cell membrane.
OSMOSIS.ORG 403
Figure 47.5 Overview of the lectin pathway.
Mannose-binding lectin protein binds to
mannose on the pathogen, then cleaves
C4 and C2. The rest follows the classical
pathway (from step 4 in earlier figure).
OTHER COMPLEMENT PROTEIN

ROLES
▪ In addition to MAC-formation
Figure 47.4 Overview of the alternative
complement pathway. 1. Small amounts of ▫ C3b: opsonin → opsonizes pathogens,
C3 are cleaved spontaneously. 2. C3b and coats them with molecules, encourages
factor B bind to the pathogen. 3. Factor D phagocytosis
cleaves factor B. 4. C3b and Bb form a C3 ▫ C5a, C3a: chemotaxins → recruit
convertase and cleave more C3 proteins. neutrophils, eosinophils, monocytes,
The rest follows the classical pathway (from macrophages
step 6 in previous figure). 5. C1-inhibitor ▫ C5a, C3a: anaphylatoxins → cause
constantly prevents activation of this basophil, mast cell degranulation,
pathway by dissociating C3bBb. releases proinflammatory molecules
Figure 47.6 Other roles of complement proteins. C3b acts as an opsonin; it coats pathogens to
facilitate phagocytosis. C5a and C3a act as chemotaxins; they recruit neutrophils, eosinophils,
monocytes, and macrophages. C5a and C3a also act as anaphylatoxins; they cause basophils
and mast cells to degranulate.
404 OSMOSIS.ORG
NOTES
NOTES
BONES, JOINTS, & CARTILAGE
SKELETAL SYSTEM ANATOMY &

PHYSIOLOGY
osms.it/skeletal-system-anatomy-physiology
SKELETAL BASICS TYPES OF BONES
▪ 206 bones in skeleton
Long bones
▪ Separated into axial, appendicular skeleton
▪ Length > width
Axial skeleton ▪ Humerus, radius, ulna (in arms);
▪ Vertical axis of body; 80 bones (22 in skull, metacarpals, phalanges (hands, fingers);
33 vertebrae, 24 ribs, 1 sternum) femur, tibia, fibula (legs); metatarsals,
phalanges (feet, toes)
Appendicular skeleton ▪ Primarily responsible for height
▪ Supports limbs; pectoral girdle (clavicles,
scapulae) holds humeri, pelvic girdle (hip Short bones
bones) holds femora; 126 bones (4 in ▪ Similar length, width
shoulders, 6 arms, 54 hands, 2 hips, 8 legs, ▪ Carpal bones (in wrists); tarsal bones
52 feet) (ankles)
▪ Support hands, feet
Figure 48.1 Overview of skeleton.
OSMOSIS.ORG 405
Flat bones
▪ Thin, sometimes curved
▪ Skull bones; scapulae, sternum, ribs
▪ Protect vital organs
Sesamoid bones
▪ Embedded in tendons, shaped like giant
sesame seeds
▪ Pisiform bone (in wrists); patella (knees)
▪ Support, protect, give additional leverage to
tendons
Irregular bones
▪ Facial bones; mandible; vertebrae; sacrum,
coccyx
SURFACE FEATURES OF BONES Figure 48.2 Types of bones.
Sites of muscle, ligament attachment

▪ Tubercle, tuberosity: small bumps on bone, STRUCTURE OF BONE
serve as attachment sites for muscles; large
tubercle → tuberosity; deltoid tuberosity (on Cortical/compact bone
humerus) ▪ Surrounded by periosteum
▪ Process: bony prominence; xiphoid process ▪ Contains pipe-like structures called osteons
(sternum) ▪ Osteons contain hollow centers (Haversian
▪ Crest: narrow ridge; iliac crest (ilium) canals) for nerves, blood cells; connected
laterally by Volkmann’s canals
Projections ▪ Osteon walls made of bone matrix (type I
▪ Part of joints collagen reinforced with hydroxyapatite),
▪ Condyle: rounded, articular projection; produced by osteoblast cells
lateral, medial condyles (femur); epicondyle ▪ Some osteoblasts get trapped in bone
→ raised portion on/above condyle (lateral, matrix → mature into osteocytes → repair
medial epicondyles) old/broken bone
▪ Ramus: arm-like section; mandibular ramus ▪ Osteoclast cells secrete enzymes → break
(mandible) down bone matrix → release calcium,
phosphate into blood
Openings, passageways, depressions
▪ Foramen: holes in bone, allow blood Trabecular/spongy bone
vessels/nerves through; foramen magnum ▪ Similar material to cortical bone
(in occipital bone of skull) ▪ Looser structure; branching rods called
▪ Canal/meatus: tunnels, allow blood vessels/ trabeculae
nerves through; optic canal (sphenoid ▪ Contains bone marrow, consists of
bone); external auditory meatus (temporal hematopoietic stem cells (“red marrow”),
bone of ear) adipocytes/fat cells (“yellow marrow”)
▪ Sinuses, cavities: empty spaces within/ ▫ Appendicular bones often contain red
between bones; nasal cavity, paranasal marrow at tips, yellow marrow in hollow
sinuses medullary cavity (center)
▪ Fossa: depressions where other structures ▫ Axial bones mostly red marrow
rest; hypophyseal fossa (sphenoid bone)
406 OSMOSIS.ORG
Chapter 48 Musculoskeletal Physiology: Bones, Joints, & Cartilage
Figure 48.3 Bone cross-section showing structure which consists of cortical bone and spongy
bone. Spongy bone contains two types of bone marrow, each made up of a different kind of cell.
CARTILAGE
osms.it/cartilage
WHAT IS CARTILAGE? ▪ Extracellular matrix: protein fibers
▪ Strong, flexible connective tissue (collagen for strength; elastin for flexibility)
▫ Comprises part of nose, ears suspended in viscous gel (water,
proteoglycan aggregates)
▫ Provides cushioning between joints
▫ Chondrocytes: chondroblasts trapped in
▫ Supports/connects body parts (e.g.
lacunae (small holes) of matrix; maintain,
costal cartilage connects ribs to
repair extracellular matrix
sternum)
▫ Proteoglycan aggregates:
▪ Perichondrium: connective tissue that
hyaluronan (long chain of hyaluronic
wraps around cartilage
acid molecules) with hundreds of
▫ Outer layer contains fibrous connective proteoglycans (proteins + long chains
tissue, blood vessels of glycosaminoglycan sugars—GAGS)
▫ Inner layer contains chondroblasts → branching off
secrete proteins that make extracellular
matrix
OSMOSIS.ORG 407
Figure 48.4 Cross-section through cartilage showing its histological structure. Perichondrium
wraps around extracellular matrix. Chondroblasts originally in perichondrium become
chondrocytes as they become trapped in the extracellular matrix.
TYPES
▪ Three main cartilage types
Elastic cartilage
▪ Least common type
▪ ↑ chondrocyte density; ↓ protein fiber
density (mostly loose elastin fibers, some
type II collagen fibers)
▪ Softest, most flexible cartilage
▪ Ear pinnae, throat epiglottis
Hyaline cartilage
▪ Most common type
▪ Medium chondrocyte density; medium
protein fiber density (mostly type II collagen Figure 48.5 Proteoglycan aggregate, found
fibers, some loose elastin fibers) in viscous gel of the extracellular matrix.
▪ Stronger, but less flexible cartilage; ↓
friction surface
▪ Embryonic skeleton (eventually replaced
by bone); nose; larynx walls; tracheal,
costal cartilages; growth plates; articular
cartilages
Fibrocartilage
▪ ↓ chondrocyte density; ↑ protein fiber
density (mostly type I collagen fibers)
▪ Most tensile strength; resistant to
compression, stretching; ↓ flexible
▪ Meniscus of knee, spinal intervertebral
discs
408 OSMOSIS.ORG
Figure 48.6 Histology, characteristics of the three main cartilage types.
GROWTH PATTERNS
▪ Two cartilage growth patterns
▪ Both growth patterns present in growing
bones of children, teenagers (e.g. femur)
▫ Chondrocytes in growth plate →
interstitial growth → cartilage lengthens
→ osteoblasts turn cartilage into bone
▫ Articular cartilage on tips of bone
experience both appositional, interstitial
growth
Appositional growth
▪ Chondroblasts secrete new matrix on
existing surfaces → cartilage expands,
widens
Interstitial growth
▪ Chondrocytes secrete new matrix within
cartilage → cartilage grows in length
Figure 48.7 The two cartilage growth

patterns. Both types of growth occur in
articular cartilage. In the growth plate, only
interstitial growth occurs.
OSMOSIS.ORG 409
BONE REMODELING & REPAIR
osms.it/bone-remodeling-repair
BONE REPAIR (Howship’s lacunae), hydrochloric acid
▪ Old bone removed/resorbed (broken down) → dissolves hydroxyapatite into soluble
before new tissue replaces it calcium, phosphate
1. Osteoblasts sense microcracks, secrete 4. Osteoblasts secrete osteoprotegerin
receptor activator of nuclear factor κβ → deactivates RANKL, slows down
ligand (RANKL) osteoclast activity (before osteoclast
2. RANKL binds to RANK receptors on apoptosis), osteoid seam (mostly
monocytes → causes them to fuse, form collagen) → fill in Howship’s lacunae
multinucleated osteoclast cells 5. Calcium, phosphate deposit on seam
3. Osteoclasts secrete lysosomal enzymes forming hydroxyapatite
(mostly collagenase) → digest collagen 6. Some osteoblasts get trapped within
in bone matrix → create surface holes lacunae → turn into osteocytes
Figure 48.8 Summary of bone repair.
410 OSMOSIS.ORG
REMODELING FACTORS
▪ Hormonal
▫ Parathyroid hormone enhances bone
resorption
▫ Calcitonin inhibits bone resorption
▫ Vitamin D (→ ↓ calcitonin) enhances
bone resorption
▪ Mechanical (physical stress)
▫ Wolff’s law: bones that bear more
weight remodel more
FIBROUS, CARTILAGE, &

SYNOVIAL JOINTS
osms.it/fibrous-cartilage-synovial-joints
TYPES Three main categories (based on location)
▪ Classification based on movement of three ▪ Sutures: junctions between adjacent skull
main groups bones; Sharpey’s fibers connect bones;
▫ Fibrous joints: no movement fixed (non-fused in babies → partially
▫ Cartilaginous joints: some movement movable)
▫ Synovial joints: freely movable ▪ Gomphoses: peg-and-socket joints for
teeth; periodontal ligaments connect roots
of teeth to sockets; slightly movable
FIBROUS JOINTS ▪ Syndesmoses: remaining fibrous joints;
▪ Synarthrosis/fixed joints connected by interosseous membrane (e.g.
▪ Bones are connected by ligaments between radius, ulna); slightly movable
Figure 48.9 Three main categories of fibrous joints.
OSMOSIS.ORG 411
CARTILAGINOUS JOINTS
▪ Hyaline cartilage connects bones, stretches
to allow some movement
▪ Synchondrosis: costochondral joint, where
cartilage attaches rib to sternum; growth
plates between bone diaphysis, epiphysis
▪ Symphysis: symphysis pubis in pelvic bone
(fibrous cartilage)
▫ ↑ strength, ↓ flexibility
SYNOVIAL JOINTS
▪ Joint capsule connects bones
▫ Composed of outer fibrous capsule, Figure 48.10 The two categories of
inner synovial membrane cartilaginous joints (with examples).
▫ Filled with synovial fluid: lubricates joint,
absorbs shock; made of hyaluronic acid,
lubricin, proteinases, collagenases
▫ Articular cartilage covers tips of bones
(same function)
▪ Allow for abduction, adduction, rotation
about axis
Six main categories (based on structure,

movement)
▪ Hinge joints: allow movement only in one
axis (e.g. between humerus, ulna)
▪ Pivot joints: allow for rotation (e.g. between
head of radius, groove of ulna) Figure 48.11 Synovial joint cross-section
▪ Plane (gliding) joints: allow flat bones to showing joint capsule.
glide across one another (e.g. in carpal,
tarsal bones)
▪ Ball and socket joints: allow all movements
(e.g. shoulder joint)
▪ Condyloid (ellipsoid) joints: allow
most movements, but not rotation (e.g.
metacarpophalangeal, metatarsophalangeal
joints)
▪ Saddle joints: allow most movements, with
limited rotation (e.g. carpometacarpal joint)
412 OSMOSIS.ORG
Figure 48.12 The six categories of synovial joints (with examples). Joints circled in green.
OSMOSIS.ORG 413
NOTES
NOTES
MUSCLES
MUSCULAR SYSTEM ANATOMY &

PHYSIOLOGY
osms.it/muscle-anatomy-physiology
▪ Three types of muscle cell/tissue ▪ Combine at end to form tendons
▫ Skeletal, cardiac, smooth ▫ Origin attaches to stationary bone;
▪ Differ in location, innervation, cell structure insertion attaches to moving bone
▫ All cells excitable, extensible, elastic
Myocytes
▪ Long cylindrical cells with multiple nuclei
SKELETAL MUSCLE ▪ Cell membrane → sarcolemma
▪ Attaches to bone/skin; mostly voluntary; ▪ Cytoplasm → sarcoplasm
maintains posture, stabilizes joints, ▫ Contains smooth endoplasmic reticulum
generates heat → sarcoplasmic reticulum (stores
▪ Most muscles consist of belly (contracts), calcium)
tendons ▪ Transverse tubules (T tubules) project from
Connective tissue sarcolemma to center of muscle
▪ Layers of connective tissue separate ▪ Long filaments called myofibrils fill
muscle belly sarcoplasm, contain thin actin filaments,
thick myosin filaments (arranged into
▫ Epimysium: wrapped around muscle
sarcomeres)
▫ Perimysium: wrapped around fascicles
in muscle Motor signals
▫ Endomysium: wrapped around muscle ▪ Brain’s motor signals control skeletal
fibers/cells (e.g. myocytes in fascicles) system
▪ Motor neurons release acetylcholine
receptors onto sarcolemma → rapid
ion shifts across sarcolemma, down T
tubules → calcium enters myocyte →
sarcoplasmic reticulum releases calcium
into sarcoplasm → actin, myosin bind →
sarcomeres contract → myocyte contracts
→ sarcoplasmic reticulum grabs calcium →
muscle relaxes
Figure 49.1 Cross section of skeletal muscle

illustrating connective tissue layers, fascicles,
muscle fibers.
414 OSMOSIS.ORG
Chapter 49 Musculoskeletal Physiology: Muscles
Figure 49.2 Composition of a myocyte.
CARDIAC MUSCLE Thick and thin filaments

▪ Involuntary, striated muscle; found only in ▪ Like skeletal muscle, cardiac myofibrils
heart walls contain sarcomeres bounded by Z bands
▪ Shorter than skeletal muscle; branched and ▫ Z bands: perpendicular to myofibril,
interconnected attached to thin filaments
▪ 1–2 central nuclei per fiber ▫ Thick filaments lie between Z bands
▪ Numerous mitochondria provide resistance ▫ All proteins involved are globular
to fatigue ▪ Thick, thin filaments slide over each other
▪ Pacemaker cells demonstrate automaticity; → contraction
generate action potentials
Thick filaments
Intercalated discs ▪ Myosin: tail with two heads
▪ Composed of gap junctions and ▫ Each head has ATPase, actin binding
desmosomes sites
▫ Gap junctions: areas of low resistance,
allows fast signal propagation between Thin filaments
cardiomyocytes (coordinated contraction ▪ Actin: globular/G-actin polymerizes into a
of cells) strand of filamentous/F-actin
▫ Desmosomes: anchor the cells together; ▫ Two F-actins twist into strand with
keeps cells from pulling apart during myosin binding site
contraction ▪ Tropomyosin: site blocker, prevents
▫ Allows heart to work as a unit contraction by disabling attachment of
(functional syncytium; syn = together, myosin to actin
citos = cell) ▪ Troponin: molecule composed of three
subunits:
T tubules/transverse tubules
▫ C: Ca2+ binding → stops troponin
▪ Invaginate from sarcolemma inhibition of actin
▪ Also serve faster propagation ▫ I: Inhibitory → inhibits ATPase
▫ Help conduct signal deeper into cell, ▫ T: → relaxed state attachment of
enabling more synchronized contraction troponin complex to actin; myocardial
▫ Run along Z bands, communicate with infarction marker in blood
sarcoplasmic reticulum ( Ca2+ storage)
OSMOSIS.ORG 415
Endomysium (intercellular connective SMOOTH MUSCLE
tissue) ▪ Often found in hollow organs (e.g.
▪ Contains capillaries, nerves intestines, bladder, uterus, blood vessels);
▪ Provides support, elasticity; separates cells involuntary muscle
▪ Maintained by fibroblasts ▪ Smooth muscle cells fusiform, only one
nucleus
▪ No T tubules; invaginations called caveolae
▪ Thin, thick myofilaments; no sarcomeres →
“smooth” appearance
Figure 49.3 Appearance of myosin and actin filaments.
Figure 49.4 Z bands are the boundaries Figure 49.5 Features of smooth muscle cells.
between sarcomeres in skeletal and cardiac
muscles.
416 OSMOSIS.ORG
OSMOSIS.ORG 417
Figure 49.6 An illustration of the three types of muscle: skeletal, cardiac, and smooth.
SLOW TWITCH & FAST TWITCH

MUSCLE FIBERS
osms.it/slow-fast-twitch-muscle-fibers
▪ Each action potential generates brief FAST OXIDATIVE FIBERS
muscle contraction (AKA twitch) ▪ AKA Type IIa fibers
▪ Twitches overlap to create longer, smooth ▪ Have aerobic respiration pathway for
muscle contractions metabolizing glucose
▪ Larger than slow fibers → stronger
Skeletal muscle fibers
contractions
▪ Slow twitch (AKA slow oxidative)
▪ ↑ blood vessels, ↑ myoglobin → red color
▪ Fast twitch (AKA fast oxidative, fast
▫ AKA “fast red muscle fibers”
glycolytic)
▪ ↑↑ mitochondria supports aerobic
▪ Slow twitch fibers → slow-functioning
respiration
ATPases → slower individual twitches
▪ Generate lots of ATP, use more; ↑ glycogen
▪ Fast twitch fibers → fast-functioning
storage
ATPases → longer individual twitches
▪ Fatigue quickly
SLOW OXIDATIVE FIBERS

▪ AKA Type I fibers
FAST GLYCOLYTIC FIBERS
▪ AKA Type IIx fibers
▪ Have aerobic respiration pathway for
metabolizing glucose ▪ Have anaerobic respiration pathway for
metabolizing glucose
▪ Relatively small → weakest contractions
▪ Largest fibers → stronger contractions
▪ ↑ blood vessels, ↑ myoglobin → red color
▪ ↓ blood vessels, ↓ myoglobin → white color
▫ AKA “slow red muscle fibers”
▫ AKA “white muscle fibers”
▪ ↑↑ mitochondria supports aerobic
respiration ▪ ↓ mitochondria
▪ Generate lots of ATP, use little; ↓ glycogen ▪ Generate little ATP, use lots; ↑↑ glycogen
storage storage
▪ Sustain muscle ability for long time ▪ Fatigue fastest
418 OSMOSIS.ORG
SLIDING FILAMENT MODEL OF

MUSCLE CONTRACTION
osms.it/sliding-filament-model
MECHANISM OF MUSCLE
CONTRACTION AFTER POWER
STROKE
▪ Thick myosin filaments pull thin actin
filaments towards M-line → sarcomere
shortens; A-band of the muscle does not
change, but H-, I-bands shorten
▪ At max contraction, almost complete
overlap of thick, thin filaments; H-, I- bands
almost completely gone
FACTORS DETERMINING
CONTRACTION FORCE
Size of muscle fibers
▪ Larger muscle fibers → ↑ filaments → ↑
cross-bridges → stronger contraction
Number of active muscle fibers

▪ ↑ muscle fibers → stronger contraction
Frequency of stimulation (force-frequency

relationship)
▪ ↑ frequency of stimulation → ↑ calcium Figure 49.7 The changes that occur when
ions flow from sarcoplasmic reticulum into muscle contracts.
sarcoplasm → ↑ bind to troponin regulatory
proteins on actin filaments → ↑ myosin
binding → stronger contraction
Length of sarcomere
▪ AKA length-tension relationship
▪ Longer sarcomere → stronger contraction;
directly proportional
Velocity of muscle shortening

▪ AKA force-velocity relationship
▪ Slower contraction → stronger contraction
OSMOSIS.ORG 419
ATP & MUSCLE CONTRACTION
osms.it/ATP-and-muscle-contraction
MUSCLE TONE
▪ Force applied to muscles at rest
MUSCLE TENSION
▪ Pulling force when muscles act
MUSCLE CONTRACTION
▪ Action potential travels along
sarcolemma, reaches T-tubule, stimulating
dihydropyridine (DHP) receptors
▪ DHP receptor stimulation opens ryanodine
receptors
▫ AKA calcium channels
▪ Calcium from sarcoplasmic reticulum flows
into sarcoplasm, binds to C-subunits of
troponin regulatory proteins
▪ Troponin changes shape, moving
tropomyosin out of the way, allowing actin
to be bound by myosin head’s cross-bridge
formation
▪ Energy cocks myosin head backwards →
high-energy position
▪ Myosin head can then launch towards
M-line, pulling actin filament with it
▫ AKA power stroke
▪ Action potential ends → calcium ions
pumped back into sarcoplasmic reticulum
→ C-subunit of troponin no longer bound
→ troponin, tropomyosin cover back up
actin’s active sites → no myosin binding
(cross-bridge detaches) → muscle relaxes
ISOTONIC VS. ISOMETRIC

CONTRACTIONS
Figure 49.8 Muscle contraction.
▪ Isotonic: muscle length changes but tension
1: Part of myosin head is an ATPase; it
stays same
cleaves ATP into ADP and phosphate ion.
▪ Isometric: muscle length stays same but 2: Myosin head uses this energy to tip back
tension increases into its high-energy position.
3: Myosin head binds to active site on actin,
SAITO SAYS HI triggering release of stored energy in myosin
head.
4: Power stroke (myosin head launches,
pulling actin with it).
420 OSMOSIS.ORG
NEUROMUSCULAR JUNCTION &

MOTOR UNIT
osms.it/neuromuscular-junction-motor-unit
NEUROMUSCULAR JUNCTION ▪ Positive charge builds up inside muscle
▪ Where axon terminal meets muscle fiber fiber → creates end plate potential
▪ Presynaptic membrane ▫ AKA depolarization
▫ Membrane of axon terminal ▪ Resting potential of membrane: -100mV
▪ Postsynaptic membrane → -60mV
▫ AKA motor end plate ▪ Voltage-gated sodium channels open up →
more sodium ions flow in, generating action
▫ Membrane of skeletal muscle fiber
potential in muscle fiber
▪ Synaptic cleft
▫ Gap between membranes
ACTION POTENTIAL CESSATION IN
MUSCLE FIBER
▪ Action potential in axon stops → voltage-
gated calcium channels close → influx
of calcium ions to axon terminal stops
→ synaptic vesicles stop fusing with
membrane
▪ Remaining acetylcholine in cleft degraded
by acetylcholinesterase into choline, acetate
→ choline taken back into axon terminal
→ acetylcholine transferase makes new
acetylcholine → acetate diffuses away
Figure 49.9 Illustration of the neuromuscular MOTOR UNITS

junction. ▪ One lower motor neuron, fibers it
innervates form single motor unit
▪ On average, one lower motor neuron
ACTION POTENTIAL GENERATION innervates 150 skeletal muscle fibers
IN MUSCLE FIBER
▪ More precise muscles → smaller motor
▪ Action potentials in axon terminal
units; e.g. 10–15 muscle fibers per neuron
stimulate voltage-gated calcium channels
in eye
in presynaptic membrane → extracellular
calcium ions flow into the axon terminal ▪ Less precise muscles → larger motor units
(e.g. ≤ 2000 muscle fibers per neuron in
▪ Calcium binds to acetylcholine-containing
bicep)
vesicles in axon terminal → vesicles fuse
with presynaptic membrane, acetylcholine
released into synaptic cleft
▪ Two acetylcholine molecules bind to one
ligand gated ion channel
▫ AKA nicotinic receptor
▫ On motor end plate → sodium ions flow
into muscle
OSMOSIS.ORG 421
Figure 49.10 Action potential generation in muscle fiber. Influx of sodium ions leads to buildup
of positive charge inside muscle fiber. Action potential generated → muscle fiber contracts.
Figure 49.11 Action potential cessation in muscle fiber. Action potential in axons stops →
voltage-gated calcium channels close → influx of calcium stops → synaptic vesicles stop fusing
with membrane.
422 OSMOSIS.ORG
NOTES
NOTES
NERVOUS SYSTEM
osms.it/nervous-system-anatomy-physiology
THE NERVOUS SYSTEM ▫ Efferent divided into somatic (voluntary),
▪ Network of brain, spinal cords, nerves autonomic (involuntary) nervous
▪ Sensory/afferent, integrative, motor/efferent systems
functions ▫ Autonomic nervous system comprised
of sympathetic, parasympathetic
Sensory/afferent nervous systems
▪ Receptors monitor external, internal ▪ Sensory receptors: structure at nerve
environment ending; detects physical, environmental
▫ Conscious stimuli (e.g. vision, hearing, stimulus; e.g. pain, temperature
touch) ▪ Ganglia/ganglion (plural/singular):
▫ Unconscious stimuli (e.g. pH, blood collection of neuron cell bodies outside CNS
pressure) ▪ Plexuses/plexus (plural/singular): network
of nerves outside CNS
Integrative
▪ Sensory/afferent input received by central
nervous system → information processed
→ interpreted → response initiated
Motor/efferent
▪ Brings motor information from central
nervous system to periphery
▪ Controls actions of effector organs (e.g.
muscles, glands)
ORGANIZATION OF THE NERVOUS

SYSTEM
Central nervous system (CNS)
▪ Brain, spinal cord
Peripheral nervous system (PNS)

▪ Nerves connect PNS with CNS Figure 50.1 Organization of the nervous
▪ Includes 12 pairs of cranial nerves, 31 pairs system.
of spinal nerves
▪ Efferent (motor), afferent (sensory) divisions
OSMOSIS.ORG 423
CELLS OF THE NERVOUS SYSTEM: ▪ Neuron’s conducting region; forms
NEURON synapses with dendrites
▪ Specialized, excitable cell; receives, ▪ Each neuron has only one axon
transmits signals, AKA action potentials ▫ May be as long as 1m/3ft
▪ Very long longevity; can last a lifetime with ▫ Nerve fiber: one long axon
adequate nutrition ▪ Axon collaterals: axon branches
▪ Amitotic, except olfactory epithelium, some ▪ Carries action potential from cell body to
areas of hippocampus target cell (e.g. other neurons)
▪ High metabolic rate; require steady supply ▪ Lacks rough ER, golgi apparatuses
of oxygen, glucose
▪ Cytoplasm contains numerous
▫ Oxygen deprivation → death within microtubules/microfilaments
minutes
▫ Site of materials migration between cell
Cell body/soma body, axon terminus
▪ Contains endoplasmic reticulum (ER: ▪ May be insulated with myelin sheath
chromatophilic substance, Nissl bodies), ▪ Axolemma: plasma membrane of axon
Golgi apparatus, mitochondria, neurofibrils, ▫ Responsible for maintaining neuron’s
microtubules, pigments (e.g. melanin, membrane potential via ion channels
lipofuscin); surrounds nucleus ▪ Axon terminals: ends of axons, release
▪ Site of protein synthesis, processing neurotransmitters
▪ Clusters of axons
Dendrite
▫ In PNS: nerves
▪ Short processes, project from cell body
▫ In CNS: tracts
▪ Receive information from adjacent neurons,
contain receptors Myelin sheath
▪ Brings information to cell body via graded ▪ Only axons are myelinated
potentials
▪ Functions
▪ One neuron may have numerous dendrites
▫ Protects fibers; ↑ transmission speed
Axon ▪ Produced by oligodendrocytes in CNS, by
▪ Projection from specialized region of cell Schwann cells in PNS
body, AKA axon hillock ▪ Nodes of Ranvier: gaps in myelin where
▫ Axon hillock: site of action potential action potential jumps from one node to
generation next
Figure 50.2 Structure of a neuron.
424 OSMOSIS.ORG
Chapter 50 Neurology: Anatomy & Physiology
▫ Saltatory conduction → ↑ speed of PNS NEUROGLIA

propagation
Satellite cells
▪ Gray matter: CNS regions containing nerve
cell bodies, unmyelinated axons ▪ Similar function as astrocytes
▪ White matter: CNS regions containing Schwann cells, AKA neurolemmocytes
myelinated axons
▪ Form myelin sheath
Structural and functional classification ▪ Involved in regeneration of damaged
▪ Unipolar neurons peripheral nerve fibers
▫ One process, divides into two branches
▫ Mostly function in PNS as first-order
sensory neurons; conduct impulses
along afferent pathways
▪ Bipolar neurons
▫ Two processes (axon, dendrite) on
opposite sides of cell body
▫ Sensory neurons found in special sense
organs (e.g. olfactory mucosa, retina)
▪ Multipolar neurons
▫ ≥ three processes: one axon, rest are
dendrites
▫ Primary functions: interneurons within
CNS; motor neurons (conduct impulses
along efferent pathways)
Figure 50.3 Coronal cross-section of the
brain showing gray matter and white matter.
CNS GLIAL CELLS (NEUROGLIA)
Astrocytes
▪ Most abundant; multiple functions
▫ Provide structural, metabolic support for
neurons
▫ Determine capillary permeability
(essential for blood-brain barrier via
formation of tight junctions)
▫ Control chemical environment (clean
up spilled neurotransmitters, potassium
ions)
Microglial cells
▪ Protective role
▪ Phagocytize microbes, debris
Oligodendrocytes
▪ Forms myelin sheath
Ependymal cells
▪ Line cavities of brain, spinal cord
▪ Form partially permeable barrier between
cerebrospinal fluid (CSF), tissue
▪ Cilia assist in CSF circulation
Figure 50.4 Structures of unipolar, bipolar,
and multipolar neurons.
OSMOSIS.ORG 425
Figure 50.5 Glial cells of the CNS and PNS.
SYNAPSES Electrical synapse

▪ Junction point from one neuron to next ▪ Open channels conduct electricity via
▪ Presynaptic neuron: conducts impulse gap junctions composed of connexons
toward synapse (protein channels); connecting cytoplasm of
▪ Postsynaptic neuron: conducts impulse adjacent neurons
away from synapse ▪ Rapid, unidirectional or bidirectional
transmission
Chemical synapse ▪ Examples
▪ Most common type of synapse ▫ Cardiac muscles (promote synchronized
▪ Information exchanged unidirectionally activity)
via neurotransmitters (e.g. serotonin, ▫ Hypothalamic hormone-secreting
glutamate, glycine, epinephrine, GABA, neurons (creates burst of hormone
histamine) release)
▪ Action potential spreads along presynaptic
neuron → depolarizes presynaptic neuron
→ voltage-gated calcium channels open SPINAL CORD
→ trigger release of neurotransmitter in ▪ Long, tubular bundle of nervous tissue;
vesicles via exocytosis → neurotransmitter protected by bony vertebral column,
binds to postsynaptic membrane receptor meninges, CSF
→ generation of action potential → ▪ Central canal continuous with fourth
excitation/inhibition (depending on ventricle; carries CSF through spinal cord
neurotransmitter) ▪ Extends from brainstem to lumbar region
▪ Neurotransmitter removed from synaptic ▫ Information travels up spinal cord via
cleft by diffusion, degradation, cellular afferent (sensory) fibers, down via
uptake efferent (motor) fibers
426 OSMOSIS.ORG
▪ White matter: afferent, efferent fibers

▪ Gray matter: cell bodies
▪ Cell bodies arranged in three columns, AKA
horns
▫ Anterior (ventral) horns: receive
information from brain’s motor cortex
→ send it to skeletal muscles → trigger
voluntary movement
▫ Posterior (dorsal) horns: take sensory
information → send it to brain’s sensory
cortex
▫ Lateral horns: help regulate processes
like urination, digestion, heart rate
(mostly sympathetic activity)
▪ 31 pairs of nerves
▫ Nerve pairs: 8 cervical, 12 thoracic, 5
lumbar, 5 sacral, 1 coccygeal
▫ Cauda equina: nerve roots at end of
vertebral canal
▪ Nerves arising from spinal column
innervate specific bodily regions
▫ Each spinal nerve (except C1) provides
cutaneous sensory perception
▫ Dermatome: section of skin supplied by Figure 50.6 Cross-section of the spinal cord
pair of spinal nerves showing its structure.
STRUCTURES OF THE BRAIN

breathing (pneumotaxic center), relay
Brainstem: medulla, pons, midbrain information between cerebellum,
▪ Posterior part of brain continuous with cerebral hemispheres
spinal cord ▪ Midbrain (mesencephalon)
▪ Responsible for basic life-sustaining body ▫ Participates in vision, hearing,
functions; e.g. breathing, blood pressure, motor control, sleep-wake cycle,
consciousness, swallowing consciousness
▪ 10/12 cranial nerves (cranial nerves III-XII) ▪ Reticular formation (RF) scattered
arise in brainstem throughout brainstem
▪ Medulla ▫ Responsible for consciousness;
▫ Vasomotor (cardiovascular) center, maintaining posture, general muscle
respiratory center, swallowing/coughing/ tone, major visceral functions;
vomiting centers interpretation, processing of noxious
stimuli
▫ All ascending sensory, descending
motor tracts connecting spinal cord with Cerebellum
other parts of brain ▪ AKA “little brain”
▫ Pyramids on anterior surface of medulla: ▪ Responsible for coordinating, planning,
descending corticospinal tracts cross executing movements; balance, posture,
(decussate) to opposite side spatial perception
▪ Pons ▪ Integrates sensory information; fine-tunes
▫ Controls facial expressions, sensations motor activity (e.g. learned motor skills),
▫ Controls body equilibrium, posture stores it as muscle memory
▫ Works with medulla to regulate
OSMOSIS.ORG 427
Figure 50.7 Sagittal section of the brain showing the brainstem, which includes the midbrain,
pons, and medulla.
Diencephalon ▫ Premotor cortex: orientation of body

▪ Thalamus ▫ Supplementary motor area: planning
▫ Relay station for sensory, motor sequence of movement
information going to/from cerebral ▪ Parietal
cortex, brainstem, spinal cord; screens ▫ Somatosensory processing
insignificant information ▫ Has homunculus pattern similar to
▪ Hypothalamus motor cortex
▫ Major homeostatic control system ▪ Temporal
▫ Links nervous system to endocrine ▫ Functions in hearing, olfaction, visual
system via pituitary gland recognition
▫ Thermostatic control of body ▪ Occipital
temperature ▫ Responsible for analyzing, interpreting
▫ Along with limbic system, participates visual information
in emotions such as anger, emotional
response to pain, sexual arousal-related Cerebral cortex
behaviors ▪ Gray matter (cell bodies, dendrites) on
▫ Regulates circadian rhythms outer surface of cerebrum: information
▫ Plays role in regulating eating, drinking; processing
contains thirst center, which senses ▫ Motor association area: determines
osmotic pressure of extracellular fluid appropriate movements for specific
▪ Pineal gland tasks
▫ Produces melatonin ▫ Primary somatosensory: receives
sensory input; somatosensory
Cerebrum association area provides discrete
▪ Divided into right, left hemispheres interpretation
▪ Separated by corpus callosum: connects ▪ Language processing
left side to right side ▫ Broca’s area: generation of spoken word
▪ Contain folds (gyri): increase surface area (moving muscles to speak)
▪ Sulci: grooves between gyri ▫ Wernicke’s area: comprehension of
▪ Four lobes: frontal, parietal, temporal, speech
occipital ▪ White matter: axons; carry information to
▪ Frontal other parts of brain
▫ Primary motor cortex: voluntary
movement (motor homunculus)
428 OSMOSIS.ORG
Figure 50.8 Sagittal section of the brain showing the diencephalon, which includes the
thalamus, hypothalamus, and pituitary gland.
Figure 50.9 The structure of the cerebrum and cerebellum. The cerebrum contains gyri (which
are the folds) and sulci (which are the grooves between the folds).
Figure 50.10 The four lobes of the cerebrum and some of their functions.
OSMOSIS.ORG 429
Figure 50.11 The structures of the basal ganglia.
Basal nuclei (ganglia) Flow of CSF through ventricles

▪ Gray matter deep within brain; deep nuclei ▪ CSF produced by choroid plexus in lateral,
of cerebral hemispheres third, fourth ventricles → lateral ventricle
▪ Contains caudate nucleus, globus pallidus, → through interventricular foramen to third
putamen nucleus ventricle → through cerebral aqueduct to
▪ Mainly responsible for regulating fourth ventricle → through lateral, median
movement, tone, motor control apertures to subarachnoid space (some
CSF enters central canal of spinal cord) →
superior sagittal sinus, venous circulation
VENTRICLES & CSF
Ventricles MENINGES
▪ Four interconnected spaces filled with CSF
Anatomy
▪ Two lateral ventricles: located in frontal
▪ Made up of three layers
lobes, extend posteriorly into parietal lobes
▪ From superficial to deep: dura mater,
▪ Interventricular foramen (foramen of
arachnoid mater, pia mater
Munro): connects lateral ventricles to each
other, to third ventricle ▪ Dura mater: tough, inflexible layer
▪ Third ventricle: lies between thalamic ▫ Separates brain into compartments,
bodies, surrounded by hypothalamus forms sinuses for major veins of brain
▪ Cerebral aqueduct (aqueduct of Sylvius): ▫ Falx cerebri: separates right, left major
connects third, fourth ventricles veins of brain
▪ Fourth ventricle: located between ▫ Falx cerebelli: separates right, left lobes
cerebellum, pons of cerebellum
▪ Two lateral apertures (foramina of ▫ Tentorium cerebelli: separates right, left
Luschka), one medial aperture (foramen lobes
of Magendie): connect fourth ventricle to ▪ Arachnoid mater: middle layer that projects
subarachnoid space into sinuses (arachnoid villi)
▫ Subarachnoid space: lies between
CSF arachnoid, pia mater
▪ CSF similar in composition to blood with ▫ Contains CSF
most proteins removed ▫ Contains all blood vessels, cranial nerve
▪ Made by ependymal cells of choroid of brain
plexuses ▪ Pia mater: innermost layer
▪ Circulates throughout ventricles, central ▫ Adheres to brain
canal; also covers brain, meninges
▫ Fuses with empyema, forming choroid
▪ Protects brain (brain “floats” in cushioning plexus, which produce CSF
fluid), provides nutrients to tissues in CNS
430 OSMOSIS.ORG
Figure 50.12 Ventricular system of the brain.
Figure 50.13 The meninges: three tissue layers which protect the brain and spinal cord.
AUTONOMIC NERVOUS SYSTEM Sympathetic

▪ Involuntary branch of PNS ▪ “Fight or flight” functions: activated when
▪ Extends from CNS to target organ via individual exposed to stressful situation
two-neuron chain; interact at autonomic ▪ Originates in thoracic, lumbar region of
ganglion spinal cord (T1-L2)
▫ Preganglionic fiber: synapses with cell ▪ Preganglionic axon length: short
body of second neuron ▪ Postganglionic axon length: long
▫ Postganglionic fiber: innervates effector ▪ Neurotransmitters, receptors
organ ▫ Preganglionic fibers release
▪ Both systems are active; one dominates acetylcholine → binds to nicotinic
other depending on situation receptor in postganglionic neuron →
▪ Dual innervation of organs by both releases norepinephrine → binds to
sympathetic and parasympathetic divisions alpha/beta receptors on effector organs
▫ Exceptions: most arterioles, veins, sweat → releases acetylcholine → binds to
glands only innervated by sympathetic muscarinic receptors on sweat glands
nerve fibers ▫ Preganglionic fibers release
acetylcholine → binds to nicotinic
receptor on adrenal medulla →
epinephrine released → binds to alpha/
beta receptors on effector organs
OSMOSIS.ORG 431
Parasympathetic ▫ Sympathetic: beta-2 receptors → ciliary
▪ “Rest and digest” functions: conserves, muscle relaxation for far vision; alpha-
stores energy; maintains “housekeeping” 1 → radial muscle contraction → pupil
functions dilation
▪ Originates in craniosacral areas of spinal ▫ Parasympathetic: M receptors → ciliary
cord (CN III, VII, IX, X; S2-S4) muscle contraction for near vision +
▪ Preganglionic axon length: long sphincter muscle constriction → pupil
constriction
▪ Postganglionic axon length: short
▪ GI tract
▪ Neurotransmitters, receptors
▫ Sympathetic: alpha-2, beta-2 receptors
▫ Preganglionic fiber releases
→ GI tract smooth muscle wall
acetylcholine → binds to nicotinic
relaxation, ↓ GI motility; alpha-1 → ↑
receptor in postganglionic neuron
sphincter tone
→ releases acetylcholine → binds to
muscarinic receptor on effector organ ▫ Parasympathetic: M receptors → ↑ GI
smooth muscle wall contraction and
Enteric nervous system (GI) motility, ↓ sphincter tone; ↑ gastric
▪ “Second brain:” autonomous function secretion
independently from autonomic nervous ▪ Bladder
system ▫ Sympathetic: beta-2 receptors →
▪ Neurons collected into two ganglia detrusor muscle relaxation, urinary
▫ Myenteric (Auerbach’s), Meissner’s sphincter contraction
plexus ▫ Parasympathetic: M receptors →
▪ Coordinates peristalsis, GI tract secretions detrusor muscle contraction, urinary
sphincter relaxation
Sympathetic vs. parasympathetic effects on ▪ Liver
organs ▫ Sympathetic: beta-2, alpha-1 receptors
▪ Some organs only innervated by → gluconeogenesis, glycogenolysis
sympathetic division, but many innervated ▫ Parasympathetic: no direct effect
by both sympathetic, parasympathetic
▪ Adrenals
divisions → work cooperatively to regulate
normal function ▫ Sympathetic: nicotinic receptors →
release of epinephrine, norepinephrine
▪ Heart
▫ Parasympathetic: no direct effect
▫ Sympathetic: beta-1 receptors → ↑
heart rate, contractility → ↑ cardiac
output
▫ Parasympathetic: muscarinic (M)
receptors → ↓ heart rate, contractility
(atria only) → ↓ cardiac output
▪ Vascular smooth muscle
▫ Sympathetic: skin/splanchnic alpha-
1 receptors → constriction; skeletal
muscle vascular beta-2 receptors →
dilation; skeletal muscle vascular alpha-
1 receptors → constriction
▫ Parasympathetic: no direct effect
▪ Bronchial tree
▫ Sympathetic: beta-2 receptors →
dilation
▫ Parasympathetic: M receptors →
constriction
▪ Eye
432 OSMOSIS.ORG
NEURON ACTION POTENTIAL

osms.it/neuron-action-potential
▪ Electric signals sent down axons ▫ Sodium channel becomes inactivated
▪ Generated by rapid rising, falling of (absolute refractory period)
membrane potential ▫ Voltage-gated potassium channels then
▪ Resting membrane potential (approx. act → potassium flows out
-65mV) determined by intra, extracellular ▫ Sodium/potassium pump moves
ion concentrations sodium out of cell, potassium in →
▫ Ion channels open → depolarization of hyperpolarization
neuron (net influx of positive charge/ ▫ Sodium channels remain closed but can
excitatory postsynaptic potential) be activated (relative refractory period);
▫ Depolarization to approx. -55mV → hyperpolarization → stronger stimulus
voltage-gated sodium channels open at needed
axon hillock → sodium rushes into cell ▪ In myelinated areas, electrical force of
→ action potential (neuron is positively moving ions pushes subsequent ions along
charged to approx. +40mV) (saltatory conduction)
Figure 50.14 Graphical summary of the voltage changes that occur during a neuron action
potential and the accompanying states of voltage-gated sodium and potassium channels. The
action potential is initiated by a net influx of excitatory postsynaptic potentials (EPSPs). Not
shown above are sodium/potassium pumps, which help to maintain the resting membrane
potential, as well as help to return to that resting potential through repolarization.
OSMOSIS.ORG 433
Figure 50.15 Saltatory conduction through myelinated areas of an axon increases the speed of
signal conduction down the axon.

OF THE EYE
osms.it/eye-anatomy-physiology
ANATOMY OF THE EYE ▪ Compound tubuloacinar structure, contains
serous cells producing watery serous
Conjunctiva secretions, AKA tears
▪ Mucous membrane rich with lymphatic ▪ Innervated by parasympathetic fibers from
channels facial nerve (CN VII)
▪ Portions ▪ Lacrimal secretions contain lysosomes,
▫ Palpebral conjunctiva: lines interior of antibodies, mucus to moisten, protect eye
eyelid adhered to tarsus surface
▫ Bulbar conjunctiva: lines surface of the ▪ Pathway of tears
eye; nonkeratinized stratified squamous ▫ Produced in lacrimal gland → blinking
epithelium causes spread of tears across eyeball
▪ Functions → lacrimal canaliculi via lacrimal puncta
▫ Protects cornea from friction via mucus → lacrimal sac → nasolacrimal duct →
production empties into inferior nasal meatus inside
▫ Contributes to immune surveillance by nasal cavity
preventing microbes from entering eye
Lacrimal apparatus
CHAMBERS & FLUIDS
▪ Anterior, posterior segments separated by
▪ Consists of lacrimal gland, draining ducts
lens
Lacrimal gland
Posterior segment
▪ Paired, almond-shaped exocrine glands
▪ Largest segment
located at upper lateral portion of each orbit
▪ Filled with gel-like vitreous humor
434 OSMOSIS.ORG
▫ Transmits light Aqueous humor

▫ Holds neural layer of retina against ▪ Continually produced by ciliary processes
retinal pigmented layer ▪ Composed of filtered plasma
▫ Maintains shape of eyeball ▪ Transports needed metabolites to avascular
▫ Contributes to intraocular pressure cornea, lens; removes metabolic wastes
▪ Pathway of flow: enters posterior chamber
Anterior segment → passes through pupil → anterior
▪ Divided into anterior and posterior chamber → trabecular network → scleral
chambers venous sinus (canal of Schlemm) → venous
▪ Filled with aqueous humor blood
▫ Small amount diffuses into vitreous
Anterior chamber
humor
▪ Larger chamber
▫ Intraocular pressure primarily depends
▪ Bounded by cornea anteriorly, trabecular on balance between production and
meshwork laterally, iris posteriorly drainage
Posterior chamber
▪ Smaller chamber; irregularly shaped; size LAYERS OF EYE WALL
changes during accommodation ▪ Divided into fibrous layer, vascular layer,
▪ Bounded by iris anteriorly, lens posteriorly innermost layer (retina)
▪ Base formed by the ciliary processes ▫ Superficial → deep
Figure 50.16 Three eye chambers. Anterior and posterior chambers are filled with aqueous
humor. Vitreous chamber is filled with vitreous humor.
Figure 50.17 The three layers of the eye.
OSMOSIS.ORG 435
Fibrous layer distance vision, dim light, sympathetic
▪ Sclera activation to dilate pupil)
▫ “White” of eye ▪ Ciliary body
▫ Composed mainly of collagen, elastic ▫ Ciliary muscles: smooth muscles that
fibers control shape of lens
▫ Attachment point for extrinsic eye ▫ Ciliary processes: secrete aqueous
muscles humor
▫ Continuous with cornea, dura mater of ▫ Ciliary zonule/suspensory ligament:
brain fibers extending from ciliary processes
▪ Limbus to lens (secures lens in place)
▫ Intersection between sclera, cornea
▪ Cornea
▫ Anterior, transparent avascular portion
of fibrous layer
▫ Makes up major refractive surface of eye
▫ Layers: anterior → posterior
▪ Corneal (sub) layers
▫ Stratified squamous epithelium: derived
from neural crest cells
▫ Bowman layer: acellular; serves as
barrier, protecting underlying stroma
from malignant cells in epithelium
▫ Stroma: transparent due to lack of blood
vessels, lymphatics
▫ Descemet membrane: basement layer
separating epithelium from Bowman
layer; protective function; epithelial stem
cells located in this layer Figure 50.18 The iris is composed of two
smooth muscle layers, the dilator pupillae and
▪ Simple squamous epithelium: AKA corneal
the sphincter pupillae.
endothelium; contains sodium pumps to
pump water out of cornea, preserving its
clarity
Vascular layer
▪ AKA uvea
▪ Choroid, iris, ciliary body
▪ Pigmented middle layer
▪ Choroid
▫ Richly vascularized
▫ Contains melanocytes to absorb light
▫ Discontinued by optic nerve posteriorly
▪ Iris
▫ Visible colored portion surrounding pupil
(central opening in iris; allows light to
enter eye)
▫ Composed of two smooth muscle
layers: sphincter pupillae (contracts
during close vision, bright light,
parasympathetic activation to constrict
pupil), dilator pupillae (contracts during Figure 50.19 Components of the ciliary body.
436 OSMOSIS.ORG
Retina ▪ Optic disc

▪ Innermost layer ▫ Spot where optic nerve (CN II) exits eye
▫ Further divided into outer pigmented ▫ AKA “blind spot”
layer, inner neural layer ▫ Not noticeable since each blind spot is
▪ Sub-layers: superficial → deep compensated by other eye
▫ Pigment cell → photoreceptor → outer ▪ Macula lutea
nuclear → outer plexiform → inner ▫ Area of greatest visual acuity
nuclear → inner plexiform → ganglion ▫ Contains mainly cones
cell → optic nerve layer
▫ Only portion of eye with enough cone
Retina: outer pigmented layer density to allow detailed color vision,
hard focus
▪ Pigmented epithelial cells absorb light,
store vitamin A for photoreceptor cells to ▫ Lateral to blind spots
use ▪ Fovea centralis
▪ Function: photoreceptor maintenance ▫ Center of macula lutea
▫ Contains only cones
Retina: inner neural layer
▫ Region of greatest visual acuity in
▪ Extends anteriorly to ciliary body macula
▪ Three types of neurons: photoreceptors, ▪ Optic nerve
bipolar cells, ganglion cells
▫ Composed of retinal ganglion cell axons
▫ Night-vision photoreceptors (rods):
▫ Exits retina via optic disc
dim-light, non-color vision; more
numerous, more sensitive to light than ▪ Optic chiasm
cones; not present on fovea; do not ▫ X-shaped structure where optic nerves
create sharp, clear images/low acuity meet
▫ Day-vision photoreceptors (cones): ▫ Axons from nasal retina cross over to
bright-light, color vision; present on opposite sides → optic tracts
fovea; high resolution/high acuity ▪ Optic tract
▫ Bipolar cells: synapse with ganglion ▫ Synapses with cells in lateral geniculate
cells nucleus in both sides of thalamus
▫ Ganglion cells: where action potentials
are generated; leave eye as optic nerve
Figure 50.20 Components of the neural layer of the eye.
OSMOSIS.ORG 437
▫ Sharpens contrasts, enhances depth EXTRAOCULAR MUSCLES
perception ▪ Orbicularis oculi
▫ Optic radiations sent to primary visual ▫ Circular muscle that encircles eye
cortex, AKA occipital lobe ▫ Closes eyelid when contracted
▪ Levator palpebrae superioris
VASCULAR SUPPLY ▫ Located inside eyelid
▪ Choroidal vessels supply external ⅓ of eye ▫ Raises eyelid
▪ Retinal central artery and central vein ▪ Extrinsic eye muscles
supply internal ⅔ of the eye ▫ Control eye movement
▫ Originate from walls of orbit (common
tendinous/annular ring), insert onto
surface of eye
Figure 50.21 Lateral view of the left eye showing the extraocular muscles. Not shown:
orbicularis oculi.
438 OSMOSIS.ORG
PHYSIOLOGY OF VISION: → no action potentials carried along optic

PHOTORECEPTION & nerve to brain
PHOTOTRANSDUCTION
▪ Photoreceptors, ganglion cells, bipolar cells Focusing light on retina
generate excitatory (EPSPs), inhibitory ▪ Light → cornea → aqueous humor → lens
postsynaptic potentials (IPSPs) instead of → vitreous humor → neural layer of retina
action potentials ▫ Excites photoreceptors of pigmented
▪ Light hits retina, 11-cis retinal converted layer → photoreception, AKA conversion
to all-trans retinal → production of of light into electrical impulses
metarhodopsin II → activation of transducin ▪ Light bent three times:
→ activation of phosphodiesterase, ▫ Entering cornea, AKA major refractive
converting cGMP to 5-GMP → ↓ step; entering lens; exiting lens
cGMP → closure of sodium channels ▫ Refractive power of cornea is constant,
→ hyperpolarization of photoreceptor whereas lens’ refractive power can be
membrane → ↓ glutamate release changed
(excitatory neurotransmitter) from
photoreceptors → either inhibition or Distant vision
excitation ▪ Normal resting status of human eye: preset
▫ Depends on which type of glutamate for distant vision
receptor activated ▪ Ciliary muscles relaxed → ciliary zonule
fibers taut → lens is flat (lowest refractive
Glutamate receptors
power) → parallel rays focus on retina
▪ Ionotropic receptor: excitatory/depolarizing
▪ Sympathetic activation causes ciliary
▫ ↓ excitatory glutamate response → muscle relaxation, pupillary dilation
hyperpolarization of bipolar, horizontal
▪ Far point of vision: distance beyond which
cells → inhibition
no accommodation/change in lens shape
▪ Metabotropic receptor: inhibitory/ required for focusing
hyperpolarizing
▫ ↓ inhibitory glutamate response → Near vision
depolarization of bipolar, horizontal cells ▪ Involves accommodation, pupillary
→ excitation constriction, convergence
▪ Establish on-off patterns of visual fields ▪ Lens accommodation
▫ Ciliary muscles contract → ciliary zonule
LIGHT VS. DARKNESS fibers relaxed → lens becomes spherical
(increases refractory power of lens)
Light ▫ Parasympathetic activation → ciliary
▪ Photoreceptors hyperpolarize → ↓ muscle contraction
glutamate release ▪ Pupil constriction
▫ Glutamate: inhibitory ▫ Mediated by sphincter pupillae muscles
▪ → Lack of IPSPs causes bipolar cells to of iris
depolarize, release neurotransmitter onto ▫ Parasympathetic activation
ganglion cells → ganglion cells propagates ▫ ↑ depth of focus
EPSPs → action potential transmitted to
▪ Convergence of eyes
brain via optic nerve
▫ Eyes rotate medially as object moves
Darkness closer
▪ Photoreceptors depolarize → increased ▫ Mediated by extrinsic eye muscles via
glutamate release → glutamate causes oculomotor nerve (CN III)
IPSPs → IPSPs cause bipolar cells
to hyperpolarize, inhibits release of Visual field
neurotransmitters onto ganglion cells → ▪ Everything seen by single eye
ganglion cells do not propagate EPSPs ▫ Overlap → central “binocular” visual
field
OSMOSIS.ORG 439
▪ Split into two parts ▪ Information from left visual fields of both
▫ Nasal visual field: projected onto eyes travel to right half of brain, vice versa
temporal retina, axons stay on that side ▫ Cause: axons from nasal retina crossing
of brain over
▫ Temporal visual field: projected onto ▪ Some nerve fibers synapse at superior
nasal retina, axons cross to opposite colliculi instead of lateral geniculate body,
side of brain at optic chiasm ascend to midbrain

OF THE EAR
osms.it/ear-anatomy-physiology
EXTERNAL EAR ANATOMY ▪ Incus/“anvil”: connects malleus, stapes
▪ Stapes/“stirrup”: footplate inserts onto oval
Pinna/auricle
window; connects middle, inner ear
▪ Composed of elastic cartilage covered with
▪ Stapedius, tensor tympani: two skeletal
thick skin
muscles attached to auditory ossicles;
▪ Function protect ears from prolonged, loud noises;
▫ Captures sound waves, guides them not brief explosive, noise (e.g. gunshot)
into auditory canal
Oval window
External auditory meatus ▪ Membrane-covered opening connecting
▪ AKA auditory canal middle, inner ear; transforms vibrations into
▪ Contains ceruminous glands fluid waves
▫ Secretes cerumen (ear wax); with small
Round window
hairs, traps foreign objects
▪ Membrane-covered opening relieves
▪ Function
pressure created by fluid waves
▫ Guides sound waves to tympanic
membrane Mastoid antrum
▪ Canal in posterior wall of tympanic cavity,
Tympanic membrane
communicates with mastoid air cells
▪ AKA eardrum
▪ Thin, connective tissue membrane covered Pharyngotympanic/eustachian tube
by skin (external), mucous membrane ▪ Canal links middle ear, nasopharynx
(internal) ▪ Swallowing/yawning opens tube to
▪ Separates external, middle ear equalize middle ear cavity, atmospheric air
▪ Vibrates when hit by sound waves → pressure
vibrates ossicles ▪ Pathogens may travel through tube → otitis
media
MIDDLE EAR ANATOMY
INNER EAR ANATOMY
Auditory ossicles
▪ Bony labyrinth: system of channels/cavities,
▪ Linked by synovial joints in chain; transmit houses membranous labyrinth, fluid filled
vibration of tympanic membrane to oval
▪ Three semicircular canals: rotational
window
acceleration in three planes of movement
▪ Malleus/“hammer”: connected to tympanic (lateral, superior, posterior)
membrane, incus
440 OSMOSIS.ORG
Figure 50.22 Parts of the ear with parts of the middle, inner ear.
OSMOSIS.ORG 441
Cochlea ▪ Cochlear nerve (part of cranial nerve VIII)
▪ Spiral bony chamber, coils around central carries information from basilar membrane
axis to brain; cell bodies in spiral ganglia
▪ Contains organ of Corti: site of auditory Three chambers (scalae)
transduction
▪ Scala vestibuli
▪ Two receptors
▫ Superior chamber superior to cochlea;
▫ Inner hair cells: mechanoreceptors with with vestibule next to oval window
protruding cilia; arranged in single rows
▫ Filled with perilymph: similar to
embedded in basilar membrane
cerebrospinal fluid (CSF), extracellular
▫ Outer hair cells: mechanoreceptors with fluid
protruding cilia; arranged in parallel
▫ Conducts sound vibrations for hearing,
rows; more numerous; body embedded
proprioception
in basilar membrane
▪ Scala media
▪ All hair cell cilia attached to tectorial
membrane above ▫ Middle chamber
▫ Cochlear duct
Basilar membrane ▫ Filled with endolymph
▪ Narrow, thick near oval window/base; wide, ▪ Scala tympani
thin near cochlea (apex)
▫ Inferior chamber in cochlea
▪ Function
▫ Attaches to round window
▫ Sound reception
▫ Filled with perilymph
Figure 50.23 Anatomy of the cochlea and organ of Corti.
442 OSMOSIS.ORG
AUDITORY SYSTEM auditory cortex located at transverse gyrus

of Heschl in temporal lobe
Pathway of sound waves
▪ Accessory auditory nuclei
▪ Sound waves travel through external ear →
▪ Superior olivary nucleus: sound localization;
vibrate tympanic membrane
integration, interpretation of sound received
▪ Tympanic membrane vibrates ossicles → in both ears at slightly different times
ossicles amplify sound → stapes vibrates
oval window
▪ Perilymph in scala vestibuli moves → VESTIBULAR SYSTEM
pressure waves travel through perilymph ▪ Sensory information from vestibular system
towards helicotrema → cochlear duct → → generates visual images for retina →
vibrates basilar membrane posture adjustments to maintain balance
▪ Hair cells bend by shearing force, cilia ▪ Vestibular organ located within temporal
pushes against tectorial membrane → bone adjacent to cochlea; three semicircular
cilia bend in one direction → ↑ potassium canals, otolith organs (utricle, saccule)
conduction → depolarization (cilia bends
Semicircular ducts
in other direction → ↓ potassium →
hyperpolarization) → action potential ▪ Function
generated in cochlear nerve → sends ▫ Rotational/angular acceleration to
signals to brain maintain balance
▪ Sounds waves > 20Hz ▪ Three canals at right angles to one another
▫ Pressure waves → cochlear duct → in each plane of space (anterior, posterior,
perilymph of scala tympani → cochlear lateral)
duct → vibrates basilar membrane → ▪ Filled with endolymph: similar to
sound waves converted to electrical intracellular fluid (↑ potassium; ↓ sodium)
signal → hearing sensation ▪ Ampulla: dilated portion at one end;
▪ ↑ intensity of sound = ↑ distal membrane contains hair cells, protrudes into gelatinous
displaced in vibratory motion substance, cupula
▪ Hair cells: tonic rate of electrical firing
Amplification of sound waves
▫ Fire constantly when head not moving
▪ Pressure exerted on oval window >
▪ Head rotation → endolymph deflects hair
pressure exerted on tympanic membrane
cells in certain direction in semicircular
(due to smaller size of oval window)
canals → change in baseline electrical firing
▪ Ossicles rate → propagation down vestibular nerve
→ brainstem
Frequency mapping (tonotopic map)
▪ Sound frequencies displace basilar Otolith organs: utricle, saccule
membrane at different locations ▪ Function
▪ Base (short, stiff fibers): 20,000Hz; ▫ Linear acceleration
nearest to stapes, responds best to high
▪ Contain
frequencies
▫ Hair cells with calcium carbonate
▪ Apex (long, floppy fibers): 20Hz; responds
crystals
best to low frequencies
▫ Maculae (balance receptor, responds to
Central connections changes in head position)
▪ Hair cell receptors in organ of Corti → ▪ Moving head in any direction → gravity
primary cell bodies located in spiral/auditory deflects calcium carbonate crystals,
ganglion (bipolar cells in spiral of cochlea) attached hair cells → stereocilia
→ axon carries signal → dorsal, ventral bends toward/away from kinocilium
cochlear nuclei in pons → secondary axons → depolarization/hyperpolarization
project via lateral lemniscus → inferior respectively → excitation/inhibition
colliculus in midbrain → medial geniculate respectively
nucleus in thalamus → projects to primary ▪ Head upright: macula horizontal, saccule
vertical
OSMOSIS.ORG 443
▪ Tilting head forward/laterally: ipsilateral (superior, inferior, lateral) → secondary
utricle excited sensory axons project to five areas in
▪ Tilting head backward/medially: ipsilateral central nervous system (CNS)
utricle inhibited ▪ Spinal cord via medial, lateral
▪ Forward movement of head: saccule vestibulospinal tracts
excited ▪ Cerebellum via vermis, flocculonodular lobe
▪ Lateral, medial movement of head: saccule ▪ Extraocular muscles via medial longitudinal
excited fasciculus (MLF), CN nuclei III, IV, VI
▪ Reticular formation in medulla (vomiting
Pathway of signal centrally center)
▪ Hair cells receptor → propagation of signal ▪ Medial geniculate body/cortex: provides
→ vestibular/Scarpa’s ganglion (primary orientation of body in space
sensory cell bodies of vestibular system;
bipolar cell type) → vestibular nuclei in pons
Figure 50.24 The semicircular canals measure rotational/angular acceleration to maintain

balance. Movement of endolymph displaces hair cells in the ampulla. Hair cells then transmit this
information as an electrical signal along the vestibular branch of CN VIII to the brain.
Figure 50.25 The otolith organs, the utricle and saccule, measure linear acceleration using
balance receptors in the macula.
444 OSMOSIS.ORG
NOTES
NOTES
AUTONOMIC NERVOUS SYSTEM
▪ Part of peripheral nervous system ▪ Preganglionic neurons → preganglionic

(PNS); regulates basic visceral processes fibers → synapse with autonomic ganglia
necessary to homeostasis (postganglionic neurons) → postganglionic
▪ Autonomic nervous system (ANS) affects fibers → target organ
visceral organs, glands, involuntary muscles
→ regulates heart rate, respiration rate, Preganglionic neurons
digestion, urination, salivation, sexual ▪ General visceral efferent (GVE) neurons
arousal, etc. ▪ Located in central nervous system (CNS)
▪ Divided into two systems (spinal cord)
▫ Sympathetic, parasympathetic ▪ Release acetylcholine (ACh)
▪ Unlike somatic nervous system, in ANS Postganglionic neurons
▫ Neurotransmitters synthesized, stored, ▪ GVE, general visceral afferent (GVA)
released in varicosities (analogous to neurons
presynaptic nerve terminals in somatic
▪ Located outside central nervous system
nervous system)
▪ Release acetylcholine/norepinephrine/
▫ Target organ’s tissue can be innervated
neuropeptides
by multiple postganglionic neurons
▫ Postsynaptic receptors widely scattered Autonomic ganglia
on target organ ▪ Contain neuron cell body clusters
(postganglionic neurons)
NEURONS ▪ Synapse points between preganglionic
▪ Two neuron types in both sympathetic, fibers, postganglionic fibers
parasympathetic systems
▫ Preganglionic, postganglionic
SYMPATHETIC NERVOUS SYSTEM

osms.it/sympathetic-nervous-system
▪ ANS component; controls visceral functions Postganglionic neurons
requiring fast response (i.e. “fight or flight”) ▪ Located close to spinal cord
▪ Ganglia close to spinal cord → short ▫ Paravertebral ganglia (cervical, thoracic,
preganglionic fibers, long postganglionic rostral lumbar, caudal lumbar, pelvic
fibers ganglia)
▫ Prevertebral ganglia (celiac, aorticorenal,
Preganglionic neurons
superior mesenteric, inferior mesenteric
▪ Located: thoracolumbar spinal cord’s ganglion)
intermediate horn (T1–L2)
▫ Chromaffin cells of adrenal medulla
▪ Cholinergic neurons → release ACh (modified sympathetic ganglion)
OSMOSIS.ORG 445
▪ Either adrenergic/cholinergic Sympathetic nervous system effects
▫ Adrenergic neurons → release ▪ Cardiovascular: ↑ heart rate, ↑ cardiac
norepinephrine/epinephrine (adrenal output, vasoconstriction
medulla) ▪ Respiratory: bronchodilation
▫ Cholinergic → release ACh ▪ Gastrointestinal: ↓ motility, ↓ secretions
▪ Effector organ receptors: ɑ1, ɑ2, β1, β2, β3 ▪ Genitourinary: ↓ bladder’s detrusor muscle
activity, ejaculation
▪ Metabolic: ↑ gluconeogenesis
▪ Glands: ↓ salivation, ↑ sweating
▪ Pupils: mydriasis
Figure 51.1 Neurons originating in the hypothalamus synapse with sympathetic pre-ganglionic
cells bodies in spinal cord nuclei. Some pre-ganglionic neurons synapse in the paravertebral
ganglia of the sympathetic chain; others synapse in the pre-vertebral ganglia.
Figure 51.2 Sympathetic preganglionic neurons release acetylcholine, which bind to nicotinic
receptors on postganglionic neurons. Postganglionic neurons release catecholamines, which are
received by adrenergic receptors on target organs.
446 OSMOSIS.ORG
Chapter 51 Neurology: Autonomic Nervous System
PARASYMPATHETIC NERVOUS
SYSTEM
osms.it/parasympathetic-nervous-system
▪ ANS component controls visceral functions ▪ Mostly cholinergic, but some non-
not requiring fast response (i.e. “rest and adrenergic, non-cholinergic → release
digest”) neuropeptides
▪ Ganglia close to target organ → long ▪ Effector organ receptors are muscarinic
preganglionic fibers, short postganglionic
fibers Parasympathetic nervous system effects
▪ Cardiovascular: ↓ heart rate, ↓ cardiac
Preganglionic neurons output
▪ Located in brainstem (nuclei of cranial ▪ Respiratory: bronchoconstriction
nerves II, VII, IX, X), sacral spinal cord (S2– ▪ Gastrointestinal: ↑ motility, ↑ secretions
S4)
▪ Genitourinary: ↑ bladder’s detrusor muscle
▪ Cholinergic neurons → release ACh activity, erection
Postganglionic neurons ▪ Metabolic: ↓ glycogenesis
▪ Located close to target organs ▪ Glands: ↑ salivation
▫ Ciliary ganglion (cranial nerve III) ▪ Pupils: miosis
▫ Submandibular ganglion (cranial nerve
VII)
▫ Otic ganglion (cranial nerve IX)
▫ Near/inside target organ (cranial nerve
X, sacral nerves)
Figure 51.3 Neurons originating in the hypothalamus synapse with parasympathetic pre-
ganglionic cells bodies in brainstem, spinal cord at levels S2, S3, and S4. Pre-ganglionic neurons
synapse in cranial ganglia and near/in target organ.
OSMOSIS.ORG 447
Figure 51.4 Summary of parasympathetic components of cranial nerves III (oculomotor), VII
(facial), and IX (glossopharyngeal).
Figure 51.5 Parasympathetic preganglionic neurons release acetylcholine, which binds to

nicotinic receptors on the post-ganglionic neuron. The post-ganglionic neuron also releases
acetylcholine, which binds to muscarinic (G-protein coupled) receptors on target organs.
448 OSMOSIS.ORG
OSMOSIS.ORG 449
ADRENERGIC RECEPTORS
osms.it/adrenergic-receptors
▪ Metabotropic receptors: respond β2 adrenergic receptors (stimulatory effect)
to catecholamines (norepinephrine, ▪ Skeletal muscle blood vessels →
epinephrine) vasodilation
▪ Located on sympathetic effector ▪ Bronchioles → relaxation
organs → stimulated → sympathetic/ ▪ Pancreas → ↑ secretion
sympathomimetic response
▪ Liver → ↑ glycogenolysis, ↑
▪ Types gluconeogenesis
▫ ɑ, β adrenergic receptors: ɑ1, ɑ2, β1, β2,
β3 β3 adrenergic receptors (stimulatory
effects)
ɑ1 Adrenergic receptors (stimulatory ▪ Adipose tissue → lipolysis, thermogenesis
effect)
▪ Detrusor muscle → relaxation
▪ Gastrointestinal tract blood vessels, skin
blood vessels → vasoconstriction Adrenergic receptor mechanism
▪ Bladder, gastrointestinal (GI) tract ▪ Catecholamines binding → Gq (stimulatory)
sphincters → contraction or Gi (inhibitory) protein activation
▪ Radial (dilator) muscle of iris → contraction → second messenger cascade → ↑
▪ Pancreas → ↓ secretion phospholipase C or ↓ adenylate cyclase →
▪ Liver → ↑ glycogenolysis effect
▪ ɑ1 adrenergic receptors
ɑ2 Adrenergic receptors (inhibitory effect) ▫ Gq protein activation → second
▪ Presynaptic nerve terminals messenger cascade → ↑ phospholipase
(autoreceptors) → presynaptic inhibition of C → ↑ IP3, DAG, Ca2+ → stimulatory
neurotransmitter release effect
▪ Postganglionic parasympathetic nerve ▪ ɑ2 adrenergic receptors
terminals in GI tract (heteroreceptors) → ↓ ▫ Gi protein activation → ↓ adenylate
insulin secretion cyclase → ↓ cAMP → inhibitory effect
▪ ↓ platelet aggregation ▪ β1 adrenergic receptors
β1 Adrenergic receptors (stimulatory ▫ Gs protein activation → ↑ adenylate
cyclase → ↑ cAMP → stimulatory effect
effect)
▪ β1 adrenergic receptors
▪ Heart
▫ Sinoatrial (SA) node → ↑ heart rate ▫ Gs protein activation → ↑ adenylate
(positive chronotropic effect) cyclase → ↑ cAMP → stimulatory effect
▫ Atrioventricular (AV) node → ↑
conduction (positive dromotropic effect) CATECHOLAMINES
▫ Ventricular muscle → ↑ contractility ▪ Neurotransmitters synthesized, released by
(positive inotropic effect) adrenergic neurons
▪ Salivary glands → ↓ salivation ▪ Include epinephrine (adrenaline),
▪ Adipose tissue → lipolysis norepinephrine (noradrenaline), dopamine
▪ Kidney → ↑ renin secretion
450 OSMOSIS.ORG
Synthesis ▪ Epinephrine
▪ Tyrosine → L-dopa; catalyzed by tyrosine ▫ MAO: dihydroxymandelic acid
hydroxylase ▫ COMT: metanephrine
▪ L-dopa → dopamine; catalyzed by dopa ▫ Both: 3-methoxy-4-hydroxymandelic
decarboxylase acid (VMA)
▪ Dopamine → norepinephrine; catalyzed by ▪ Dopamine
β hydroxylase ▫ MAO: dihydroxyphenylacetic acid
▪ Norepinephrine → epinephrine; ▫ COMT: 3-methoxytyramine
catalyzed by phenylethanolamine-N-
▫ Both: homovanillic acid (HVA)
methyltransferase (PNMT); only in adrenal
medulla Adrenergic transmission
Degradation ▪ Present in
▪ All catecholamines can be degraded ▫ Most postganglionic sympathetic
by deamination by monoamine oxidase neurons (norepinephrine)
(MAO)/methylation by catechol-O- ▫ Adrenal medulla’s chromaffin cells
methyltransferase (COMT)/both (epinephrine)
▪ Norepinephrine ▫ Ventral tegmental area, substantia nigra
▫ MAO: dihydroxymandelic acid (dopamine)
▫ COMT: normetanephrine
▫ Both: 3-methoxy-4-hydroxymandelic
acid (VMA)
Figure 51.6 Types of adrenergic receptors, the G-proteins with which they can be coupled, and
the catecholamines that bind with them.
OSMOSIS.ORG 451
CHOLINERGIC RECEPTORS
osms.it/cholinergic-receptors
▪ Receptors respond to neurotransmitter ▪ Mechanism
acetylcholine ▫ Acetylcholine binding → Gq (stimulatory)
▪ Located on parasympathetic effector or Gi (inhibitory) protein activation
organs, CNS → stimulated → → second messenger cascade → ↑
parasympathetic/parasympathomimetic phospholipase C/↓ adenylate cyclase →
response stimulatory/inhibitory effect
▫ M1, M3, M5 → Gq protein activation → ↑
Nicotinic receptors phospholipase C → ↑ IP3, DAG, Ca2+ →
▪ Ionotropic receptors stimulatory effect
▪ Type: location ▫ M4 → Gi protein activation → ↓
▫ Nm: neuromuscular junction (non adenylate cyclase → ↓ cAMP →
autonomic) inhibitory effect
▫ Nn: autonomic ganglia and adrenal ▫ M2 → Gi protein activation → K+ channel
medulla activation → inhibitory effect
▪ Mechanism
▫ Acetylcholine binding → Na+, K+ ACETYLCHOLINE (ACh)
diffusion → depolarization → voltage ▪ Neurotransmitter synthesized, released by
Na+ channel activation → action cholinergic neurons
potential → stimulatory effect
▪ Synthesis
Muscarinic receptors ▫ Acetyl CoA + choline → acetylcholine;
▪ Metabotropic receptors (G-protein coupled catalyzed by choline acetyltransferase
receptors) ▪ Degradation
▪ Located in CNS, all parasympathetic ▫ Acetylcholine → acetylcholine CoA +
effector organs, some sympathetic effector choline; catalyzed by cholinesterase
organs ▪ Cholinergic transmission is present in
▪ Type: location ▫ Basal ganglia, hippocampus, cerebral
▫ M1: autonomic ganglia, exocrine glands, cortex
CNS ▫ All neuromuscular junctions
▫ M2: heart, sweat glands, CNS ▫ All preganglionic neurons (both
▫ M3: smooth muscle (blood vessels, parasympathetic, sympathetic neurons)
lungs), glands, eyes, CNS ▫ All postganglionic parasympathetic
▫ M4: CNS, sweat glands neurons
▫ M5: CNS ▫ Some postganglionic sympathetic
neurons (sweat glands)
452 OSMOSIS.ORG
Figure 51.7 Types of muscarinic receptors and the G-proteins with which they can be coupled.
Figure 51.8 Mechanism of action of receptors coupled with Gq protein. The type of adrenergic
receptor that couples with Gq protein is the alpha 1 receptor. The types of cholinergic muscarinic
receptors that couple with Gq protein are the M1, M3, and M5 receptors.
OSMOSIS.ORG 453
Figure 51.9 Mechanism of action of receptors coupled with Gs protein. The type of adrenergic
receptor that couples with Gs protein is the beta receptor. The type of cholinergic muscarinic
receptor that couples with Gs protein is the M3 receptor.
Figure 51.10 Mechanism of action of receptors coupled with Gi protein. The type of adrenergic
receptor that couples with Gi protein is the alpha 2 receptor. The types of cholinergic muscarinic
receptors that couple with Gi protein are the M2 and M4 receptors.
454 OSMOSIS.ORG
NOTES
NOTES
BLOOD BRAIN BARRIER & CSF
BLOOD BRAIN BARRIER (BBB)

osms.it/blood-brain_barrier
▪ Selective barrier separating blood, BBB PERMEABILITY
interstitial liquid in central nervous system ▪ May change due to inflammation,
(CNS) irradiation, tumors
▪ Molecular transport keeps harmful ▪ Permeant molecules (lipid-soluble
substances out, allows metabolic waste molecules)
products to diffuse from brain → plasma ▫ Steroid hormones; oxygen; carbon
▪ Formed by dioxide; water; glucose, essential amino
▫ Tight junctions between endothelial acids; certain electrolytes
cells of brain capillaries ▪ Impermeant molecules
▫ Astrocyte projection (“feet”) supporting, ▫ Non-essential amino acids; waste
maintaining structure products; microbes, toxins; proteins;
▫ Basal (basement) membrane certain electrolytes (e.g. potassium);
▪ Passive transport: no energy needed (e.g. water-soluble drugs
passive diffusion of lipid-soluble molecules)
▪ Active transport: energy needed (e.g. BBB IN CIRCUMVENTRICULAR
facilitated diffusion of glucose, amino acids) ORGANS
▪ Primary function: CNS homeostasis ▪ Absent in circumventricular organs →
▫ Providing selective nutrient passage connection between CNS, blood
▫ Controlling fluid movement ▪ Includes sensory, secretory organs
▫ Protecting from toxins, microbes
Sensory organs
▪ Sense plasma molecules, coordinate
response to them
▫ Area postrema/vomiting center (senses
harmful substances in blood → vomiting
reflex)
▫ Subfornical organ
▫ Vascular organ of lamina terminalis
Figure 52.1 Components of the blood brain
barrier. Secretory organs
▪ Receive stimuli, secrete substances directly
in plasma
▫ Posterior pituitary gland
▫ Median eminence of hypothalamus
▫ Pineal gland
OSMOSIS.ORG 455
Figure 52.2 Sensory and secretory circumventricular organs.
CEREBROSPINAL FLUID (CSF)

osms.it/cerebrospinal-fluid
▪ Body fluid found within CNS CHARACTERISTICS
▪ Fills, circulates through ▪ Quantity: 125mL in total
▫ Ventricular system (lateral ventricles, ▪ Color: limpid
third ventricle, fourth ventricle, central ▪ Pressure: range from 8–15mmHg (supine)
canal of spinal cord) to 16–24mmHg (sitting)
▫ Subarachnoid space surrounding brain, ▪ pH: 7.33
spinal cord ▪ Protein content: 35mg/dL (< serum)
▪ Glucose: 60mg/dL (< serum)
CIRCULATION ▪ Electrolytes (mEq/L)
▪ Lateral ventricles → interventricular ▫ Sodium: 138
foramina → third ventricle → cerebral ▫ Potassium: 2.8
aqueduct → fourth ventricle → lateral,
▫ Calcium: 2.1
median apertures → subarachnoid space,
cisterns (some enters spinal column) → ▫ Magnesium: 2.0
arachnoid granulations (arachnoid mater ▫ Chloride: 119 (> serum)
outpouching) → venous system circulation ▪ Sampled by lumbar puncture
▪ Kept in motion by cilia of ependymal cells ▫ Lumbar cistern puncture at end of spinal
lining ventricle system cord; between second, third lumbar
vertebrae (L2–L3)
PRODUCTION
▪ Mostly produced by choroid plexuses FUNCTIONS
▫ Network of capillaries, modified ▪ CNS protection
ependymal cells in ventricles ▫ Trauma → absorbs mechanical energy
▫ Also functions as blood-CSF barrier ▫ Own weight → provides buoyancy
▪ Rate ▫ Ischemia → decreases quantity, relieves
▫ 500mL/day intracranial pressure
▪ Regulated by ▫ Toxic metabolites → clears them out
▫ Hormones, blood pressure, autonomic ▪ Transportation medium for chemical
nervous system signals, nutrients
456 OSMOSIS.ORG
Chapter 52 Neurology: Blood Brain Barrier & CSF
Figure 52.3 Ventricular system of the brain through which CSF flows.
Figure 52.4 CSF circulation. CSF is produced by the choroid plexuses of the ventricles and is
reabsorbed through the arachnoid granulations.
OSMOSIS.ORG 457
NOTES
NOTES
BRAIN FUNCTIONS
WHAT ARE BRAIN FUNCTIONS? Theta waves (4–7Hz)
▪ Normal brain functions: continuous ▪ Irregular waves
neuronal electrical activity ▪ Often appear in children, may appear in
▪ Measured by electroencephalogram (EEG) conscious, alert-stage adults
for research, diagnostics
▫ Electrodes on scalp record brain activity Delta waves (<4Hz)
(measure voltage differences between ▪ ↑ amplitude waves
cortical regions) ▪ Often appear during deep sleep stages,
anesthesia
BRAIN WAVES ▪ In awake adults, may indicate brain damage
▪ Brain wave activity altered by mental state
▫ Slower brain waves: prominent during
relaxation
▫ Higher brain waves: prominent during
wakefulness/alertness
▫ Extreme ↑/↓ frequencies: suggest
damaged cerebral cortex
▪ Spontaneous brain waves controlled by
autonomic nervous system, continue to
appear during unconsciousness, coma (if
some brain, body functions continue)
▫ Lack of spontaneous brain waves
(i.e. “flat EEG” without peaks/troughs)
suggests brain death
▪ Four characteristic EEG brain wave
patterns: different consciousness/sleep
stages
▫ Appearance: continuous peaks/troughs
▫ Wave frequency: number of peaks/
second (hertz (Hz))
▫ Wave amplitude/intensity: indicates
synchronicity of many neurons
Alpha waves (8–13Hz)

▪ Low amplitude, rhythmic, regular, Figure 53.1 Four types of brain waves. From
synchronous waves top to bottom: alpha waves (awake but
▪ Appear during relaxed consciousness relaxed), beta waves (awake and alert), theta
states waves (common in children), delta waves
(deep sleep).
Beta waves (14–30Hz)
▪ Rhythmic, but ↑ frequency, ↓ regularity
compared to alpha waves
▪ Appear during alert consciousness states
458 OSMOSIS.ORG
Chapter 53 Neurology: Brain Functions
SLEEP
osms.it/sleep
WHAT IS SLEEP? important for learning, cognitive
▪ Naturally recurring partially-unconscious performance
state (inhibited response to external stimuli)
▫ Coma: unconscious state (no response SLEEP PATTERNS
to external stimuli) ▪ Hypothalamus controls sleep cycle timing
▪ Depressed cortical, continued brain stem ▫ Retina directly connected to
activity → continued autonomic nervous hypothalamus, controls pineal gland
system functions (e.g. controlling heart rate, (produces melatonin)
respiration, blood pressure)
▫ Decreasing light → melatonin release →
▪ Alternating stages based on EEG patterns sleepiness
▪ Alternating sleep/wake cycles = body’s
SLEEP STAGES natural circadian rhythm
▪ Young/middle-aged adults: sleep starts in
Non-rapid eye movement (NREM) sleep
4-stage NREM sleep → alternating REM,
▪ Little/no eye movement, thought-like brain NREM cycles
activity, less voluntary muscle inhibition
▪ REM occurs approximately every 90
▪ Stage 1 minutes; each cycle ↑ time
▫ Immediately after falling asleep ▫ First REM: 5–10 minutes
▫ EEG: irregular waveforms: slow ▫ Last REM: 20–50 minutes
frequencies, ↑ amplitudes
▫ Early in the night: deep sleep → awake
▪ Stage 2 periods (SWS sleep dominant)
▫ First 30–45 minutes of sleep; occurs ▫ Later in the night: REM sleep dominant
with deeper sleep
▪ Sleep patterns change over lifetime; ↑ age =
▫ EEG: theta waves present ↓ sleep needs
▪ Stages 3/4 ▫ Infants: 16 hours
▫ Slow-wave sleep (SWS) ▫ Adults: 7.5–8.5 hours
▫ 90 minutes into sleep ▫ ↑ age = ↑ length of each sleep cycle
▫ EEG: activity slows down progressively ▫ Children spend more time in SWS than
▫ Decreased heart rate, blood pressure adults
▫ Important for restorative functions
Rapid eye movement (REM) sleep

▪ Characterized by irregular brain waves →
alpha waves (typically seen when awake)
▪ ↑ heart rate, blood pressure, respiratory
rate; ↓ gastrointestinal function
▫ Paradoxical sleep: although most body
function activity increases/mimics
wakefulness, individual is asleep
▪ Brain oxygen use: REM sleep > awake
▪ Spinal cord interneurons inhibit motor Figure 53.2 Hypongram illustrating
neurons → temporary skeletal muscle progression through one sleep cycle. W =
paralysis wakefulness, R = REM sleep, N1 = stage 1
▪ Most dreaming occurs NREM, N2 = stage 2 NREM, N3 = stage 3
▪ Associated with memory consolidation; NREM.
OSMOSIS.ORG 459
CONSCIOUSNESS
osms.it/consciousness
WHAT IS CONSCIOUSNESS? CONSCIOUSNESS STAGES
▪ Awake, responsive state; simultaneous ▪ Alertness: information processing, physical
cerebral cortex electrical activity arousal
▪ Associated with stimuli perception, ▪ Sleep: partially unconscious state (reduced
voluntary movement control, high mental sensory activity)
processing levels ▪ Dreaming: mental experiences during sleep
▪ Superimposed by different neuron activities ▪ Altered: hypnosis, meditation, drug-
▫ E.g. same neurons involved in cognition, induced, brain diseases, age → brain wave
motor control activity changes
▪ Holistic, interconnected (e.g. memories can
be triggered by smells, locations, people,
etc.)
▪ Clinically, consciousness used to assess
response (range: conscious → coma)
▪ Commonly assessed based on response to
stimuli (movements, sounds, touch, etc.)
LEARNING
osms.it/learning
WHAT IS LEARNING? exploring, interacting with world
▪ Respond to stimulus → acquire new/adjust ▪ Begins at birth, ends at death
existing knowledge/skills/information/ ▪ Can occur in different forms
behaviors ▪ Affected by internal, external factors
▪ Influenced by single/repeated events ▫ External: genetics, environment
▪ Active process ▫ Internal: attention, attitude, goals,
▫ Absorb knowledge by experiencing, values, behavior, emotions
ATTENTION
osms.it/attention
WHAT IS ATTENTION? ▪ Limited by capacity, duration
▪ Behavioral, cognitive process ▪ Involves allocating processing resources
▫ Selective concentration on information (e.g. while multitasking)
▪ Attention placed on subset of all perceived ▪ Integral component of cognitive system for
stimuli (e.g. one person in a crowd) environmental responses
460 OSMOSIS.ORG
MEMORY
osms.it/memory
WHAT IS ATTENTION? ▪ Long-term memory (LTM)
▪ Information storage, retrieval ▫ Vast information amounts stored,
▫ Important for learning, behavior, recalled on demand
consciousness ▫ Short-term → long-term memory
transfer influenced by emotional
states; repetition; new, old information
MEMORY STAGES
association; automatic memory
▪ Sensory memory
▫ Visual, auditory memory
▫ Generally lasts 1 second without
MEMORY TYPES
rehearsal, but recalled information very ▪ Declarative (explicit/fact) memory
detailed ▫ Explicit information learned, requires
▪ Short-term memory (STM) (AKA working conscious recall
memory) ▪ Non-declarative memory
▫ Generally fades over 30 seconds ▫ Procedural (skills) memory; motor
without rehearsal memory; emotional memory;
▫ Limited capacity conditioned responses from repetition,
experience
▪ Working memory
▫ Information kept in consciousness for
manipulation, integration
LANGUAGE
osms.it/language
WHAT IS LANGUAGE? BRAIN'S LANGUAGE PROCESSING
▪ System that communicates ideas, feelings ▪ Processed in dominant left hemisphere,
through words especially Broca's area, Wernicke's area
(connected by arcuate fasciculus)
COMPONENTS OF LANGUAGE ▫ Broca’s area: controls speech’s motor
functions
▪ Phonology: language’s auditory sound
▫ Wernicke’s area: language
▪ Morphology: word structure
comprehension
▪ Semantics: word meaning
▪ Non-dominant right hemisphere:
▪ Syntax: words combined into sentences body language (language’s nonverbal
▪ Pragmatics: language depends on context, component)
pre-existing knowledge, audience ▪ Aphasia: inability to produce/comprehend
language
OSMOSIS.ORG 461
Figure 53.3 Lateral view of the left side
of the brain showing the locations of
Wernicke and Broca’s areas. These areas are
responsible for language comprehension and
production, respectively.
EMOTION
osms.it/emotion
WHAT IS EMOTION? EMOTIONAL RESPONSE
▪ Conscious experience involving mental ▪ Physiological response: arousal → heart
activity, pleasure/displeasure levels rate, body temperature, blood pressure
▪ Associated with mood, motivation, behavior changes
▪ Involves experience, processing, behavior, ▪ Behavioral response: facial expressions,
psychological changes, behavioral changes body language
▪ Cognitive response: interpretation depends
on past experience
STRESS
osms.it/stress
WHAT IS STRESS? STRESSORS
▪ Body’s physical, mental, emotional ▪ Biological elements, external stimuli, causal
response to change requiring adaptation events
▪ Positive stress (eustress): motivation, ▫ Environment: uncomfortable
alertness temperature, loud noises
▪ Negative stress (distress): decreased ▫ Daily events: losing keys, forgetting
performance, anxiety items
▪ Stress level severity: dependent on ▫ Work/academic events: assignments,
individual’s skills, abilities, coping time management
mechanisms ▫ Social events: family-, friend-, society-
related demands
462 OSMOSIS.ORG
▫ Chemical/biological: diet, alcohol, drugs

▫ Psychological: pressure, lack of control,
unpredictability, frustration, conflict
STRESS RESPONSES
▪ Physiological
▫ Alarm stage: initial reaction activates
sympathetic nervous system (to
maintain body functions enabling
response)
▫ Resistance stage: continuous hormone
release (e.g. cortisol to maintain blood
sugar levels; epinephrine to stimulate
sympathetic nervous system) to
continue engaging body
▫ Exhaustion stage: body unable to
maintain increased sympathetic nervous
system activity
▪ Emotional
▫ Individual may feel irritable, tense,
helpless
▫ May affect concentration, memory
▪ Behavioral
▫ Individual may withdraw, abuse
substances, become aggressive, suicidal
▫ Chronic stress may lead to mental
health disorders
OSMOSIS.ORG 463
NOTES
NOTES
MOTOR NERVOUS SYSTEM
MOTOR CORTEX
osms.it/motor-cortex
MOTOR CORTEX BASICS movement
▪ Cerebral cortex region dedicated to
voluntary movement planning, control, Primary motor cortex (area four)
execution ▪ Topographically organized into motor
▪ Location: posterior precentral gyrus, homunculus
anterior to central sulcus ▪ Origin of programmed motor neuron
activation patterns → movement execution
▪ Upper motor neurons in motor cortex
THREE INTERCONNECTED become excited → transmit to brain
REGIONS stem, spinal cord → activate lower motor
Premotor cortex neurons → coordinated appropriate muscle
contraction (voluntary movement)
▪ Movement preparation, sensory guidance
▪ Emphasis on control of proximal, trunk
muscles MOTOR ACTIVATION PATTERN
▪ Supplementary motor, premotor cortices
Supplementary motor cortex develop motor plan (specific muscles
▪ Internally generates movement planning to contract, extent, sequence) → upper
sequences motor neurons in primary motor cortex →
▪ Programs complex motor sequences descending nerve tracts → lower motor
▫ Active during mental movement neurons in spinal cord
rehearsal (even without physical ▪ Basal ganglia, cerebellum provide
execution) additional fine tuning of motor output
▪ Coordinates two sides of body, bilateral
Figure 54.1 The three regions of the motor cortex.
464 OSMOSIS.ORG
Chapter 54 Neurology: Motor Nervous System
MOTOR NEURONS & MUSCLE

SPINDLES
osms.it/motor-neurons-and-muscle-spindles
MOTOR NEURONS Intrafusal fibers
▪ Innervated by γ motor neurons
Motor unit
▫ Small myelinated neurons that don’t
▪ Single motor neuron, muscle fibers it
directly innervate muscle
innervates
▫ Innervate intrafusal fibers → keep
▪ All muscle fibers in motor unit are same
muscle spindles tight → allows for
fiber type (slow vs. fast twitch)
accurate detection of degree of stretch
▪ Fine control: few muscle fibers per neuron
▪ Too small to generate significant force
(e.g. eye muscles)
▪ Encapsulated in sheaths → form muscle
▪ Coarse control: thousands of muscle fibers
spindles
per neuron (e.g. postural muscles)
▫ Run parallel to extrafusal fibers
▪ Motor neuron pool: motor neuron collection
innervating muscle fibers in same muscle ▫ Abundant in muscles used for fine
movements
Force of contraction ▫ Spindle-shaped organs composed of
▪ Graded action; determined by number of intrafusal muscle fibers
motor units recruited ▫ Innervated by sensory, motor nerve
▪ Small motor neurons: innervate few muscle fibers
fibers (generate relatively small amounts ▫ Attached to connective tissue
of force) → low threshold to activation →
typically fire first Intrafusal muscle spindle types
▪ Large motor neurons: innervate many ▪ Both subtypes present in every spindle
muscle fibers (generate relatively large ▪ Nuclear bag fibers
amounts of force) → require large action ▫ Larger, nuclei accumulate in central
potentials to activate → typically fire last “bag” region
▪ Size principle: more motor units recruited ▪ Nuclear chain fibers
→ larger motor neurons involved → greater ▫ Smaller, nuclei arranged in rows
tension developed (chains), more common
MUSCLE SPINDLE FIBERS MUSCLE SPINDLES INNERVATION

Extrafusal fibers Sensory (afferent) nerves
▪ Majority of skeletal muscle ▪ Group Ia afferent nerves
▪ Innervated by α motor neurons ▫ Innervates central region of both
▫ Large, myelinated multipolar (one axon, intrafusal muscle spindle subtypes
many dendrites) neurons that innervate ▫ Relatively large nerves → fast
extrafusal muscle fibers of skeletal conduction velocity
muscles
▫ Form primary endings in spiral-shaped
▫ Directly responsible for muscle terminal around central region of muscle
contraction spindle fibers
▫ Generate force
OSMOSIS.ORG 465
Figure 54.2 Muscles are composed of muscle fibers bundles with extrafusal muscle fibers on
the outside and intrafusal fibers on the inside. There are two intrafusal fiber subtypes: nuclear
bag fibers and nuclear chain fibers, determined by the nuclei arrangement within.
▪ Group II afferent nerves ▫ Muscle stretch → extrafusal muscle

▫ Primarily innervate nuclear chain fibers fibers lengthen, parallel intrafusal fibers
▫ Intermediate diameter → intermediate stretch
conduction velocity ▫ Increased length of intrafusal fibers
▫ Form secondary endings on nuclear detected by sensory afferent fibers
chain fibers (primarily) innervating them; increase in length
of intrafusal fibers activates group Ia,
Motor (efferent) nerves group II sensory afferent fibers (group Ia
▪ Two types afferent fibers detect velocity of length
▫ Dynamic γ motor neurons → synapse change; group II afferent fibers detect
on nuclear bag fibers → “plate endings” length of muscle fibers)
▫ Static γ motor neurons → synapse ▫ Activation of group Ia afferent fibers
on nuclear chain fibers → form “trail stimulates α motor neurons in spinal
endings” → spread out over longer cord → innervation of extrafusal fibers in
distances same muscle → muscle contraction →
original stretch is opposed when reflex
causes muscle to contract
MUSCLE SPINDLES FUNCTION ▫ γ motor neurons coactivated with
▪ Stretch receptors α motor neurons → muscle spindle
▪ Extrafusal muscle fibers contract/stretch remains sensitive to muscle length
→ muscle spindles correct for changes in changes (even during contraction)
muscle length → return muscle to resting
length after shortening/lengthening
466 OSMOSIS.ORG
MOTOR NEURONS CLASSIFICATION ▫ Innervate specialized intrafusal

▪ α motor neurons muscle fibers (part of muscle spindles
▫ Innervate extrafusal skeletal muscle that sense muscle length) → adjust
fibers → contraction sensitivity of muscle spindles → ensures
appropriate response as extrafusal
▪ V motor neurons
fibers contract
▫ Smaller, slower
▪ α, γ motor neurons are co-activated →
▫ Regulate sensitivity of intrafusal muscle muscle spindles remain sensitive to muscle
fibers length changes as muscle contracts
Figure 54.3 Stretch reflex when extensor muscles are stretched. Type Ia sensory neurons
synapse with α motor neurons of extensor muscles, causing extensor muscle contraction. Type
II sensory neurons synapse with an interneuron, which inhibits the α motor neurons to the flexor
muscles → flexor muscles relax. These actions together oppose the original stretch.
Figure 54.4 Coactivation of lower motor neurons and gamma motor neurons by upper motor
neurons ensures that muscle spindle remains sensitive to muscle length changes (even during
contraction).
OSMOSIS.ORG 467
PYRAMIDAL & EXTRAPYRAMIDAL
TRACTS
osms.it/pyramidal-and-extrapyramidal-tracts
▪ Motor neurons descend from cerebral ▫ Forms at level of medullary pyramids
cortex (cortical motor areas, associated → 10% of corticospinal tract fibers do
modulatory areas), brainstem via pyramidal, not decussate → forms anterior tract;
extrapyramidal tracts eventually decussate at spinal level they
innervate
PYRAMIDAL TRACTS ▪ Damage → upper motor neuron syndrome
▪ Pass through medullary pyramids → Corticobulbar tract
descend onto lower motor neurons in spinal ▪ Conducts impulses from brain → cranial
cord nerves
Corticospinal tract ▪ Primary motor cortex: projects through
▪ Forms efferent nerve fibers of upper motor corona radiata, genu of internal capsule/
neurons → conduct impulses from brain to some fibers through posterior limb of
spinal cord internal capsule → midbrain
▪ Cortical motor areas (primary motor ▪ Midbrain: internal capsule becomes
cortex, premotor cortex, supplementary cerebral peduncles, ventral white matter
motor areas), modulating sensory areas of cerebral peduncles form crus cerebri
(somatosensory cortex, parietal lobe, → middle third of crus cerebri forms
cingulate gyrus) → posterior limb of internal corticobulbar (and corticospinal fibres)
capsule → cerebral peduncle (base of → corticobulbar fibers exit brainstem at
midbrain) → pons → medulla → spinal appropriate level to synapse on lower
cord → synapse directly onto alpha motor motor neurons of cranial nerves
neurons → control voluntary movement ▪ Controls facial, neck muscles (expression,
▪ Forms two tracts based on where fibers mastication, swallowing)
cross over (decussate) to opposite side of ▪ Only nerves controlling muscles of lower
body in medulla oblongata (decussation → face decussate
muscles controlled by contralateral side of ▪ Damage: unilateral → only involves lower
brain) face; bilateral → pseudobulbar palsy
▫ Lateral corticospinal tract, anterior (inability to control facial muscles)
corticospinal tract ▫ Pseudobulbar palsy signs, symptoms:
▪ Lateral corticospinal tract: responsible for slow, indistinct speech; dysphagia;
fine-motor movement of upper, lower limbs small/stiff/spastic tongue; brisk jaw jerk,
▫ Forms at level of medullary pyramids labile affect with/without evidence of
→ 90% of corticospinal tract fibers upper motor lesion also affecting limbs
decussate → lateral corticospinal tract
▪ Anterior corticospinal tract: responsible
for gross, postural movement of trunk,
proximal musculature
468 OSMOSIS.ORG
Figure 54.5 Upper motor neuron pathway in corticospinal tract. Lateral corticospinal tract fibers
decussate in medulla, while anterior corticospinal tract fibers decussate at the level of the lower
motor neuron (which they synapse with).
OSMOSIS.ORG 469
Figure 54.6 Pathway of upper motor neurons in corticobulbar tract. The fibers that decussate
do so at the cranial nerve level (which they synapse with). Cranial nerve lower motor neurons
that receive upper motor neuron branches from both ipsilateral, contralateral sides include: CN V,
XI, and portion of VII (that innervates muscles of the face’s upper half). Cranial nerves that only
receive upper motor neuron signals from the contralateral side include: CN XII and the part of VII
that controls muscles of the face’slower half.
EXTRAPYRAMIDAL TRACTS Rubrospinal tract

▪ Motor neurons from motor cortex that don’t ▪ Originates in red nucleus of midbrain,
pass through pyramids of medulla; tracts projects to motor neurons in lateral spinal
run through pons, medulla, target lower cord (runs adjacent to lateral corticospinal
motor neurons in spinal cord tract), terminates in cervical spinal cord
▪ Control reflexes, locomotion, complex ▪ Mediates voluntary movement (primarily
movements, posture upper limbs)
▪ Modulated by nigrostriatal pathway, basal ▪ Activates flexor muscles
ganglia, cerebellum, vestibular nuclei, ▪ Inhibits extensor muscles
sensory areas of cerebral cortex ▪ Can assume function of corticospinal tract if
▪ Extrapyramidal tract damage: various types corticospinal tract is injured
of dyskinesias (involuntary movement ▪ Damage: temporary slowness of movement
disorders)
470 OSMOSIS.ORG
Lateral vestibulospinal tract

▪ Originates in lateral vestibular nucleus
(Deiters nucleus), projects to ipsilateral
motor neurons in spinal cord
▪ Activates extensors; inhibits flexors
▪ Maintains upright balance, posture through
action on muscles of trunk, legs
▪ Receives input from cerebellum
Reticulospinal tract
▪ Coordinates automatic locomotion, posture
movements
▪ Facilitates, inhibits voluntary movement
▪ Mediates autonomic function
▪ Modulates pain
▪ Damage at/just below level of red nucleus
▫ Decerebration: unopposed extension of
head, limbs
▪ Pontine (medial) reticulospinal tract:
originates in nuclei of pons, projects to
ventromedial spinal cord; activates anti-
gravity extensor muscles
▪ Medullary (lateral) reticulospinal tract:
originates in medullary reticular formation, Figure 54.7 Rubrospinal tract.
projects to spinal cord; inhibits excitatory
axial extensors
Tectospinal tract (colliculospinal tract)

▪ Originates in superior colliculus, projects to
cervical spinal cord
▪ Controls neck muscles: mediates reflex,
postural movements of head in response to
visual, auditory stimuli
Figure 54.8 Lateral vestibulospinal tract.
OSMOSIS.ORG 471
Figure 54.9 Pontine and medullary reticulospinal tracts.
472 OSMOSIS.ORG
OSMOSIS.ORG 473
CEREBELLUM
osms.it/cerebellum
CEREBELLUM
▪ Location: posterior fossa below occipital
lobe
▪ Connected to brain stem by three cerebellar
peduncles containing afferent, efferent
fibers
▪ Regulates movement, posture: controls
movement synergy (rate, range, force,
direction)
Figure 54.12 Cerebellum divisions from

anterior, lateral views. The vermis is
the narrow ridge separating the two
hemispheres, fissures separate the lobes.
FUNCTIONAL DIVISIONS
Vestibulocerebellum
Figure 54.10 Cerebellum location relative to
▪ Anatomical components: flocculonodular
brain and skull.
lobe (plus immediately adjacent vermis)
▪ Vestibular input: balance, eye movement
Spinocerebellum
▪ Anatomical components: vermis,
intermediate parts of hemispheres
▪ Spinal cord input (proprioception):
regulation of movement synergy
Pontocerebellum
▪ Anatomical components: lateral part of
cerebellar hemispheres
▪ Cerebral input (via pontine nuclei): controls
Figure 54.11 Superior, middle, inferior planning, movement initiation
peduncles attach cerebellum to brain stem.
474 OSMOSIS.ORG
▪ Granular layer
▫ Innermost layer: contains granule cells,
Golgi II cells, glomeruli
▫ Excitatory mossy fibers from pontine
nuclei enter granular layer, deep
cerebellar nuclei; in glomeruli axons
of mossy fibers from spinocerebellar,
pontocerebellar tracts synapse on
dendrites of granules, Golgi type II cells
Figure 54.13 Functional cerebellum divisions Cerebellar cortex output

(anterior view). ▪ Purkinje cell axons → always inhibitory
(GABAergic)
▪ Purkinje cells axons project topographically
CEREBELLAR CORTEX to deep cerebellar nuclei, lateral vestibular
nuclei
Three layers
▪ Regulates movement synergy
▪ Molecular layer
▫ Outermost layer: contains outer stellate
cells, basket cells, dendrites of Purkinje,
Golgi II cells, axons of granule cells
▫ Two inhibitory interneuron types:
stellate cells, basket cells (inhibit
Purkinje cells, basket cells, outer stellate
cells, Golgi type II cells)
▪ Purkinje cell layer
▫ Middle layer: contains Purkinje cells
▫ Primary integrative neurons of cerebellar
cortex
▫ Provides sole output of cerebellar cortex Figure 54.15 Deep cerebellar and vestibular
nuclei, to which Purkinje cells project. The
▫ Exclusively inhibitory output onto deep
lateral vestibular nuclei are in the medulla.
cerebellar neurons, vestibular nuclei of
brainstem
Figure 54.14 The three layers of the cerebellar cortex, from superficial to deep.
OSMOSIS.ORG 475
Excitatory input to cerebellar cortex interneurons (basket, stellate, Golgi II)
▪ Arises from two systems: climbing fibers, ▪ Excitatory projection from cerebellar cortex
mossy fiber system (both project to deep → activates secondary circuits → modulate
cerebellar nuclei) output of cerebellar nuclei via Purkinje cells
▪ Climbing fibers: originate in inferior olive of
medulla, project directly to Purkinje cells in Cerebellar interneurons
1:1 ratio ▪ Modulate Purkinje cell output
▫ Single action potential → multiple ▪ All cerebellar interneurons are inhibitory
excitatory bursts of descending (except granule cells)
amplitude (complex spikes) in Purkinje ▫ Granule cells offer excitatory input for
dendrites basket cells, stellate cells, Golgi II cells,
▫ Modulate Purkinje cell response to Purkinje cells
mossy fiber input ▫ Basket, stellate cells inhibit Purkinje cells
▫ May be involved in cerebellar learning (parallel fibers)
▪ Mossy fiber system: majority of cerebellar ▫ Golgi II cells inhibit granule cells →
input reduce excitatory effect on Purkinje cells
▫ Vestibulocerebellar, spinocerebellar
pontocerebellar afferents LESION DISORDERS
▫ Project to granule cells (excitatory ▪ Lesions → lack of voluntary coordination
interneurons) → found in synapse of muscle movements, limbs, posture, gait
collections which form glomeruli → (ataxia)
axons from granule cells ascend to
molecular layer → bifurcate → form General signs and symptoms
parallel fibers ▪ Lack of coordination → errors in fine
▫ Parallel fibers synapse with many movement control
Purkinje cell dendrites → excitation ▪ Delayed onset of movement/poor execution
beams across Purkinje cell row of sequences
▫ Each Purkinje cell’s dendritic tree may ▪ Overshoot target, stop before reaching
receive input from up to 250, 000 ▪ Dysdiadochokinesia: unable to perform
parallel fibers (contrast with climbing rapid alternating movements
fiber input to Purkinje dendrites → 1:1) ▪ Intention tremor: tremor perpendicular to
▫ Mossy fiber input produces single action direction of voluntary movement, increases
potential (AKA simple spikes) near end of movement
▫ Parallel fibers also synapse on cerebellar
Figure 54.16 Projection destinations for climbing and mossy fibers.
476 OSMOSIS.ORG
▪ Rebound phenomenon: inability to stop ▫ Midline (vermis): truncal, gait ataxia

movement ▫ Lateral (hemispheric): limb ataxia,
dysmetria, dysdiadochokinesia, intention
Specific signs and symptoms
tremor, dysarthria, hypotonia
▪ According to affected portion of cerebellum
▫ Posterior (flocculonodular lobe):
nystagmus, poor postural control, gait
dysfunction
BASAL GANGLIA: DIRECT

& INDIRECT PATHWAY OF
MOVEMENT
osms.it/basal-ganglia-direct-indirect-pathways
BASAL GANGLIA ▪ Function: influence motor cortex via
▪ Collection of subcortical nuclei pathways through thalamus
▪ Consists of globus pallidus, striatum ▫ Aid in planning, execution of smooth
(caudate nucleus, putamen, amygdala) movements; contribute to affective,
▪ Associated nuclei: ventral anterior, ventral cognitive function
lateral nuclei of thalamus; subthalamic
nucleus of diencephalon; substantia nigra
of midbrain
Figure 54.17 Location of basal ganglia and associated structures in coronal slice of the brain.
OSMOSIS.ORG 477
COMPLEX AFFERENT & EFFERENT BASAL GANGLIA DISEASES
PATHWAYS
Parkinson’s disease
▪ Excitatory pathways use glutamate as
neurotransmitter ▪ Cellular damage → cells of pars compacta
of substantia nigra degenerate → reduce
▪ Inhibitory pathways use GABA
inhibition via indirect pathway, reduce
(γ-aminobutyric acid) as neurotransmitter
excitation via direct pathway
▪ Almost all cerebral cortex areas project
▪ Initial accumulation in olfactory bulb,
topographically onto striatum, input from
medulla oblongata, pontine tegmentum;
motor cortex → striatum → thalamus
early non-motor symptoms (loss of smell,
→ back to the cortex via indirect/direct
sleep disturbances, autonomic dysfunction)
pathways
▪ Progression: affects midbrain, basal
▪ Outputs of indirect, direct pathways from
forebrain, neocortex, typical Parkinson’s
basal ganglia to motor cortex are opposed,
symptoms (resting tremor; movement
balanced
slowness, delay; shuffling gait)
▫ Disturbance of output → upsets balance
▪ Treatment: aim to ↑ dopamine level in brain/
of motor control → activity increases/
mimic its action with dopaminergic drugs
decreases
▫ L-DOPA (dopamine precursor) →
▪ Back-and-forth connection between
remaining dopamine neurons produce,
striatum, pars compacta of substantia nigra
secrete more dopamine
are dopaminergic
▫ Dopamine agonists (e.g. bromocriptine)
▫ Dopaminergic pathway is inhibitory
→ bind to postsynaptic dopaminergic
via D2 receptors on indirect pathway;
receptors
excitatory effect via D1 receptors on
direct pathway ▫ MAO-B inhibitors → impede dopamine
breakdown
Direct pathway (excitatory)
Huntington’s disease
▪ Striatum → inhibits → internal segment of
globus pallidus, pars reticulata of substantia ▪ Hereditary disorder caused by destruction
nigra (structures that would inhibit of striatal, cortical cholinergic neurons,
otherwise excitatory structures) inhibitory GABAergic neurons
▪ Substantia nigra → inhibitory input to ▪ Presents with chorea (writhing
thalamus movements), dementia
▪ Thalamus → excitatory input to motor ▪ No known cure
cortex
▪ Overall input is excitatory
Indirect pathway (inhibitory)

▪ Striatum → inhibits → external segment of
globus pallidus → inhibits → subthalamic
nucleus
▪ Subthalamic nucleus projects excitatory
input to internal segment of globus pallidus
→ internal segment of globus pallidus, pars
reticulata of substantia nigra → inhibits →
thalamus
▪ Thalamus → excitatory input to motor
cortex
▪ Overall input of indirect pathway is
inhibitory
478 OSMOSIS.ORG
Figure 54.18 Direct pathway. Cerebral cortex sends excitatory projections to striatum → sends
inhibitory projections to internal globus pallidus → sends inhibitory projections to thalamus.
When striatum inhibits internal globus pallidus, internal globus pallidus can’t inhibit thalamus →
thalamus is free to send excitatory signals to motor cortex.
Figure 54.19 Indirect pathway. Cerebral cortex sends excitatory projections to striatum → sends
inhibitory projections to external globus pallidus → sends inhibitory projections to subthalamic
nucleus. When striatum inhibits external globus pallidus, external globus pallidus can’t inhibit
subthalamic nucleus → subthalamic nucleus is free to send excitatory signals to internal globus
pallidus. Internal globus pallidus inhibits thalamus, preventing it from sending excitatory signals
to the motor cortex.
OSMOSIS.ORG 479
SPINAL CORD REFLEXES
osms.it/spinal-cord-reflexes
Intrinsic reflex ▪ Motor neuron: conducts efferent impulse
▪ Involuntary, unlearned, rapid, predictable from integration center to effector
response to stimulus ▪ Effector: muscle fiber/gland that responds
▫ Prevents need for conscious thought to efferent impulse (contracts/secretes)
about all actions (e.g. staying upright,
withdrawing from pain, controlling CLASSIFICATION
visceral reactions)
▫ Subject to modification if necessary Somatic
▪ Activates skeletal muscle
Acquired reflex
▪ Voluntary; occasionally non-voluntary
▪ Acquired after sufficient repetition (e.g. (reflexes)
complex sequence of reactions that occur
while driving a car) Autonomic (visceral)
▫ Process is automatic, but had to be ▪ Activates visceral organ effectors
learned initially ▫ Smooth muscle: involuntary; forms
walls of hollow organs, glands, blood
REFLEX ARC COMPONENTS vessels, tracts of respiratory, urinary,
reproductive systems
▪ Receptor: detects stimulus
▫ Cardiac muscle: involuntary; forms heart
▪ Sensory neuron: transmits afferent impulse
walls
to central nervous system (CNS)
▪ Integration center: processes information,
dictates response
▫ Simple reflex arcs: single synapse
between sensory neuron, motor neurons
(monosynaptic reflex)
▫ Complex reflex arcs: multiple
synapses with chains of interneurons
(polysynaptic reflex)
480 OSMOSIS.ORG
NOTES
NOTES
SENSORY NERVOUS SYSTEM
SENSORY RECEPTOR FUNCTION

osms.it/sensory-receptor-function
▪ 1st order neurons carry information from voltage gated channels open → triggers
somatosensory receptors action potential
▫ Pseudounipolar: no separate dendrites, ▫ To prevent multiple neurons firing,
axons neurons have inhibitory interneurons,
▫ Single axon splits into central branch, AKA lateral inhibition
peripheral branch ▫ Stimulus strength, duration determined
▫ Peripheral branch goes from cell body in by frequency of nerve firing
dorsal root ganglia to receptive field on ▪ Adaption: fewer signals sent in response to
peripheral tissue same stimulus over time
▫ Small receptive field = ↑ resolution ▫ Fast adapting/phasic: high sensitivity;
▫ Large receptive field = ↓ resolution falls off quickly
▫ Ion channels open, close in response to ▫ Slow adapting/tonic: constant sensitivity
stimulus → membrane depolarizes →
Figure 55.1 Features of 1st order neurons and lateral inhibition. Interneurons suppress activity of
the neurons next to one that has received a stimulus (lateral inhibition) → pin points stimulus by
defining its boundaries.
OSMOSIS.ORG 481
SOMATOSENSORY PATHWAYS
osms.it/somatosensory-pathways
▪ Somatic senses: touch, proprioception, funiculus of spinal cord
pain, temperature ▫ Via cuneate fascicle for arms, chest
▪ Types of somatosensory fibers ▫ Via gracilis fascicle for trunk, legs
▫ Non-myelinated fibers (type C): ▪ 1st, 2nd order neurons synapse in medulla
slowest; sense burning pain, hot ▫ 1st synapse
temperature
▪ 2nd order neurons run to medial lemniscus,
▫ Small myelinated fibers (type Aδ): decussate; run through pons, midbrain to
faster; sense sharp pain, gross touch, the thalamus
cold temperature
▪ 2nd, 3rd order neurons synapse in thalamus
▫ Large myelinated fibers (type A-α; A-β):
▫ 2nd synapse
fastest; sense proprioception, vibration,
fine touch ▪ 3 order neurons run to sensory cortex in
rd
parietal lobe
▪ 3rd, 4th order neurons synapse in sensory
SOMATOSENSORY PATHWAYS cortex
▪ Carry somatosensory input up spinal cord ▫ 3rd synapse
to brain
▪ Some 1st order neurons synapse with
▪ Consist of 4-neuron relay interneurons at posterior horn
▫ 1st order neuron/afferent sensory ▫ Axons run to anterior horn, synapse
neuron: has sensory receptors, converts directly with motor neuron
stimuli into impulse
▫ Important for reflexes
▫ 2nd order neuron: cell body in spinal cord
or brainstem, synapses with 3rd-order
neuron
▫ 3rd order neuron: cell body in thalamus,
sends signal to somatosensory cortex
▫ 4th order neuron/cortical neuron: cell
body in sensory cortex
▪ Includes medial lemniscal/posterior
pathway, spinothalamic/anterolateral
pathway
MEDIAL LEMNISCAL PATHWAY

▪ Carries information about fine touch,
proprioception
▪ Large myelinated fibers of 1st order neurons
run to spinal cord
Figure 55.2 The two somatosensory
▪ Neurons run through posterior/dorsal pathways.
482 OSMOSIS.ORG
Chapter 55 Neurology: Sensory Nervous System
Figure 55.3 The medial lemniscal pathway carries information about fine touch and
proprioception. It includes three synapses between four neurons.
▪ 1st, 2nd order neurons synapse in posterior

horn of spinal cord/1st synapse
▫ Small myelinated fibers: enter through
dorsal root, bend upwards, travel
through two vertebral segments
▫ Non-myelinated fibers: follow same
pathway but synapse with interneurons
first, AKA before reaching posterior horn
▪ 2nd order neurons decussate, cross to
anterior horn through central canal
▪ Neurons then carried through one of two
tracts to thalamus
▫ Lateral tract: carries information for
pain, pressure, temperature through
Figure 55.4 Reflex pathway occurs at the
lateral funiculus
level of the spinal cord: 1st order neuron
synapses with an interneuron, which ▫ Anterior tract: carries information for
synapses with a motor neuron. crude touch through anterior funiculus
▪ 2nd, 3rd order neurons synapse in
thalamus/2nd synapse
SPINOTHALAMIC PATHWAY ▪ 3rd order neurons run to sensory cortex in
▪ Carries information about pain, parietal lobe
temperature, crude touch ▪ 3rd, 4th order neurons synapse in sensory
▪ Small/non-myelinated fibers of 1st order cortex/3rd synapse
neurons run to spinal cord
▫ Small myelinated fibers: sharp pain, cold
temperature
▫ Non-myelinated fibers: hot temperature,
burning pain, crude touch
OSMOSIS.ORG 483
Figure 55.5 The spinothalamic pathway carries information about pain, temperature, and crude
touch. It includes three synapses between four neurons. The 1st order C fibers synapse with an
interneuron, which then synapses with the 2nd order neuron.
SOMATOSENSORY RECEPTORS
osms.it/somatosensory-receptors
▪ Perceive general somatic senses ▪ Fast adapting; small receptive fields
▪ Include mechanoreceptors, AKA both
Merkel (tactile) discs
mechanosensors and proprioceptors,
thermoreceptors, nociceptors ▪ Sensitive to pressure
▪ Non-encapsulated; located in epidermis of
hairless skin
MECHANOSENSORS
▪ Slow adapting; small receptive fields
▪ Used for touch; several types
Ruffini (bulbous) corpuscles
Meissner/tactile corpuscles
▪ Sensitive to skin stretching
▪ Sensitive to light touch
▪ Encapsulated; located in dermis of all skin
▪ Encapsulated; located in dermis of hairless
▪ Slow adapting; big receptive fields
skin
484 OSMOSIS.ORG
Pacinian (lamellar) corpuscles ▪ Located throughout perimysium, AKA

▪ Sensitive to vibration connective tissue around muscle cells
▪ Encapsulated; located deep in dermis/ Golgi tendon organ
subcutaneous tissue of all skin
▪ Detect when tendon stretched
▪ Fast adapting; big receptive fields
▪ Located in tendons close to muscle
insertion
PROPRIOCEPTORS
▪ Used for proprioception; several types Joint receptors
▪ Detect joint position, motion
Muscle spindle ▪ Located in joint
▪ Detect when muscle stretched
Figure 55.6 The four types of mechanosensors. Only Pacinian and Ruffini corpuscles are
present in all kinds of skin (hairless and hairy).
Figure 55.7 The three types of proprioceptors.
OSMOSIS.ORG 485
THERMORECEPTORS NOCICEPTORS
▪ Used for temperature ▪ Used for pain; several types
▪ Transient receptor potential channels ▫ Thermals: sense extremely cold/hot
mediate sensations temperatures
▫ Transduction of heat involves TRPV ▫ Mechanical: sense excess pressure/
channels; activated at 32–48°C/90– deformation
118°F ▫ Polymodal: Sense combination of both
▫ Transduction of cold involves TRPM8;
activated at 10–40°C/ 50–104°F
▪ At extremely cold/hot temperatures,
nociceptors take over
PHOTORECEPTION
osms.it/photoreception
▪ Process by which rods, cones convert light ▪ 10 retina layers; numbered from deepest
waves into electrical signals outwards
▪ Photoreceptors: modified neurons, AKA ▫ Pigment epithelium
rods/cones ▫ Photoreceptor
▫ Have outer segment: detects light ▫ Outer limiting membrane
▫ Inner segment: cell body ▫ Outer nuclear
▫ Synaptic terminal: connects to ▫ Outer plexiform
interneurons ▫ Inner nuclear
▪ Photoreceptors located in retina ▫ Inner plexiform
▫ Ganglion cell
▫ Nerve fiber
▫ Inner limiting membrane
Figure 55.8 The two types of photoreceptors (rods and cones) and their main features.
486 OSMOSIS.ORG
Figure 55.9 Retina = light-sensitive neural layer of tissue at back of eye, composed of 10 layers.
Axons of ganglion cells exit eye through optic disc, form optic nerve (CN II).
OPTIC PATHWAYS
osms.it/optic-pathways-and-visual-fields
▪ Visual phototransduction: light waves on

retina → electrical signals
▪ Rods, cones send electrical signal through
optic nerve (cranial nerve II)
▫ Exits via the optic disc on the retina
▪ Optic nerves meet at optic chiasm
▪ Axons from nasal retina cross over to
opposite sides → optic tract (synapses with
cells in lateral geniculate nucleus in both
sides of thalamus) → primary visual cortex/
occipital lobe
VISUAL FIELD
▪ Everything seen by single eye
▪ Split into two parts
▫ Nasal visual field: projected onto Figure 55.10 The nasal portion of the eye’s
temporal retina, axons stays on that side visual field is projected onto the temporal
of brain retina, and the temporal portion of the eye’s
▫ Temporal visual field: projected onto visual field is projected onto the nasal retina.
nasal retina, axons cross to opposite Axons from the nasal retina cross to the
side of brain at optic chiasm opposite side of the brain at the optic chiasm
▪ Information from left visual fields of both so that all the information from the left and
eyes goes to right half of brain, vice versa right visual fields stay together.
▫ Due to axons from nasal retina crossing
over
OSMOSIS.ORG 487
Figure 55.11 Visual field projections onto the retinas and the primary optic pathway, which
carries information from the retina to the primary visual cortex in the occipital lobe of the brain.
488 OSMOSIS.ORG
AUDITORY TRANSDUCTION &

PATHWAYS
osms.it/auditory-transduction-and-pathways
▪ Process by which ear converts sound ▫ Contains endolymph
waves into electrical pulses ▫ Above is scala vestibuli, below is scala
tympani
OUTER EAR ▪ Cochlear duct, scala vestibuli, scala tympani
▪ Amplifies sound, directs sound waves communicate through helicotrema
▫ Pinna → external auditory canal → ▪ Oval window amplifies, transfers sounds
eardrum vibrates waves to scala vestibuli → perilymph →
helicotrema → cochlear duct → displaces
basilar membrane towards scala tympani
MIDDLE EAR ▫ Higher frequencies: early membrane
▪ Transmits airborne sound waves to inner ▫ Lower frequencies: late membrane
ear
▫ Malleus (attached to eardrum) → incus
→ stapes → oval window → cochlea/ ORGAN OF CORTI
inner ear ▪ Stimulated by vibration of basilar
membrane
▪ Made up of mechanosensory/hair cells
COCHLEA
▪ Project out 30–300 stereocilia, AKA
▪ Coils around the modiolus/bone
sensory organelles
▪ Base is contiguous with middle ear through
▫ Tips of stereocilia embedded in tectorial
vestibule
membrane
▪ Has bony outer shell
▪ Inner hair cells closer to medialis
▫ Contains perilymph
▫ Innervated by sensory nerve fibers
▪ Cochlear duct is inside bony shell
Figure 55.12 Anatomy of the ear.
OSMOSIS.ORG 489
▪ Outer hair cells closer to spiral ligament ▪ Potassium flows in → membrane
▫ Innervated by motor nerve fibers depolarizes → voltage-gated calcium
▫ Changes stiffness of membrane to channels open → glutamate vesicles
adjust auditory signal released into synaptic space → sends
electrical impulse to auditory cortex, AKA
▪ Vibration of basilar membrane pushes
Brodmann’s areas 41 and 42, via auditory
organ of Corti, hair cells against tectorial
nerve
membrane
▪ Pressure on basilar membrane allows
protein filaments/tip links to reach, open
potassium channels
Figure 55.13 Anatomy of the cochlea.
Figure 55.14 Anatomy of the organ of Corti.
490 OSMOSIS.ORG
Figure 55.15 Electrical impulse production via organ of Corti hair cells.
VESTIBULAR TRANSDUCTION
osms.it/vestibular-transduction
▪ Process by which the ear determines ▪ Tips of cilia embedded in otolithic
spatial equilibrium and converts it into membrane
electrical signals ▪ Bottom of each cell connected to sensory
▫ Signals are sent to brain via vestibular neurons
branch of vestibulocochlear nerve ▪ Striola divides hair cells into two sections
▪ Vestibular apparatus located in inner ear ▫ Receptors arranged to face striola
▫ Includes semicircular canals (dynamic ▪ Movement pushes protein filaments/tip
equilibrium), utricle, saccule (static links on cilia on one side of striola to reach,
equilibrium) open potassium channels on kinocilium
▫ Potassium flows in → membrane
STATIC EQUILIBRIUM depolarizes → voltage-gated calcium
▪ Managed by otolith organs (utricle, saccule) channels open → glutamate vesicles
are released into the synaptic space →
▫ Both contain round macula
sends electrical impulse to brain
▪ Contains balance receptors/hair cells with
stereocilia, kinocilium
OSMOSIS.ORG 491
UTRICULAR MACULA SACCULAR MACULA
▪ Horizontally oriented: detects horizontal ▪ Vertically oriented: detects vertical
movement movement
▪ Receptors arrangement: kinocilia face ▪ Receptor arrangement: kinocilia face away
towards striola from striola
Figure 55.16 Anatomy of the inner ear.
Figure 55.17 Orientation of hair cells relative to the striola in the macula and saccule.
492 OSMOSIS.ORG
DYNAMIC EQUILIBRIUM
▪ Managed by semicircular canals
▫ U-shaped ducts containing endolymph;
oriented at 90° to each other
▪ Ampulla
▫ Houses crista ampullaris
▫ Contains balance receptors/hair cells
with stereocilia, surrounded by cupula
▫ Bottom of each cell connected to
sensory neurons
▫ Axial rotation in plane of a semicircular
canal drags cupula in opposite direction Figure 55.18 Orientation of the three
due to inertia → depolarization/ semicircular canals.
hyperpolarization of hair cells → sends
electrical impulse to brain
▪ Brain uses combination of signals from
both ears to determine equilibrium
Figure 55.19 Simultaneous depolarization, hyperpolarization of hair cells in left, right ears allows
brain to determine direction of movement.
OSMOSIS.ORG 493
VESTIBULO-OCULAR REFLEX &
NYSTAGMUS
osms.it/vestibulo-ocular_reflex_nystagmus
▪ Reflex occurs in response to head EFFERENT PATHWAY
movement by the vestibular apparatus; ▪ From the right vestibular nucleus, nerves
results in eye movement in the opposite cross over to contralateral (left) abducens
direction of the head nucleus → lateral rectus muscle stimulated
▫ Stabilizes position of the eye in the line via abducens nerve/CN VI → left lateral
of sight during head movement rectus muscle contracts → left eye moves
▪ Semicircular canals within the vestibular to left
apparatus respond to rotation and angular ▪ Other fibers from left abducens act as
acceleration/deceleration of the head interneurons → travel to right oculomotor
▪ Contains hair cells (receptors) that create nucleus → left lateral, right medial rectus
action potential when stimulated muscles move eyes to left
▪ Eyes move all the way to the left →
creates physiological form of nystagmus
AFFERENT PATHWAY (involuntary back-and-forth eye movement)
▪ Sensory signals generated by hair cells → where eyes move slowly to the left, then
action potential travels along nerves → rapidly to the right
vestibular branch of the vestibulocochlear
nerve (CN VIII) → vestibular nuclei in pons
OLFACTORY TRANSDUCTION &

PATHWAYS
osms.it/olfactory-transduction-and-pathways
OLFACTION ▪ Mucus produced in Bowman’s glands
▪ Process by which nose converts smells into in connective tissue below, AKA lamina
electrical signals propria
▪ Perceived by sensory neurons in roof of
nasal cavity, AKA olfactory region OLFACTORY RECEPTOR CELLS
▪ Carried by olfactory nerve (CN I) ▪ Bipolar neurons
▪ Send dendrites to bottom of the epithelium
OLFACTORY REGION ▫ Dendrites project out as cilia
▪ Lined by olfactory epithelium ▪ Olfactory receptor proteins/G-protein
▪ Consists of olfactory receptor cells coupled receptors embedded in cilia
▫ AKA chemoreceptors; respond to ▪ Specific odorants bind onto receptors →
odorants G-olfactory protein activates → opens
▪ Supported by columnar epithelial cells calcium, sodium channels via G-protein
coupled receptor pathway
494 OSMOSIS.ORG
▪ Calcium-activated chloride channels open OLFACTORY TRACT

→ chloride ions flow out → cell membrane ▪ Lateral tract runs to ipsilateral piriform
depolarizes → neuron fires complex
▪ Neuron sends axons that join up to form ▫ Some fibers go to limbic system
olfactory nerves (collectively called CN1) ▪ Medial tract crosses to contralateral piriform
▪ CN1 passes through olfactory foramina to complex
olfactory bulb ▪ Adaption: fewer signals sent in response to
▫ Second order neurons send signals to same odorants over time
olfactory cortex via olfactory tract
Figure 55.20 Vestibulo-ocular reflex pathway at work when an individual turns their head to
the right.
OSMOSIS.ORG 495
Figure 55.21 Anatomy of the olfactory region.
Figure 55.22 The cilia of bipolar olfactory receptor cells use a G-protein coupled receptor
pathway to generate a signal.
496 OSMOSIS.ORG
Figure 55.23 Destinations of the olfactory tract.
TASTE & THE TONGUE

osms.it/taste-and-the-tongue
▪ Taste: sensation produced when
substances react with taste receptor cells,
AKA gustation
▫ Five primary tastes of bitter, salty, sour,
sweet, umami/savory
TONGUE
▪ Surface is covered by mucosa
▪ Contains both intrinsic, extrinsic muscles
▫ Intrinsic muscles: start, end within
tongue; help change shape Figure 55.24 Sulcus terminalis divides
▫ Extrinsic muscles: attach to structures tongue into posterior third and anterior two
outside tongue; help guide movement thirds.
▪ Divided by a V-shaped group, AKA sulcus
terminalis, into posterior third, an anterior
two-thirds ▪ Contain taste buds
▪ Covered with papillae ▫ More sensitive to sweet, umami
▫ Small bumps/projections
Foliate papillae
▪ On sides of tongue
TYPES OF PAPILLAE ▪ Contain taste buds
Filiform papillae ▫ More sensitive to salty, sour
▪ On anterior two-thirds
Circumvallate papillae
▪ Used for sensation of touch
▪ On back of anterior two-thirds
Fungiform papillae ▪ Contain taste buds
▪ On tip of tongue ▫ More sensitive to bitter
OSMOSIS.ORG 497
TASTE BUDS
▪ Small structures housing taste receptor
cells, basal cells that differentiate into taste
receptor cells
▪ Found on tongue as well as soft palate,
pharynx, epiglottis, larynx, upper
esophagus
TASTE RECEPTOR CELLS

▪ Used to perceive taste, AKA respond to
tastants
▪ Arranged like orange wedges with
supporting cells between
▪ Have thin, hair-like microvilli/gustatory hair
protruding out of taste pore
▪ Send signals to brain via axons
▫ Anterior two-thirds innervated by facial
nerve
▫ Posterior third, oral cavity innervated by
glossopharyngeal nerve
▫ Back of throat, esophagus innervated by
vagus nerve
Figure 55.25 The four types of papillae and
their locations on the tongue.
Figure 55.26 Anatomy of a taste bud.
498 OSMOSIS.ORG
PERCEPTION OF TASTE ▪ Complex tastes: combination of taste

▪ Chewed up particles → mix with saliva receptors
→ travel to papillae → make contact with ▪ Adaption: fewer signals sent in response to
gustatory hairs same tastants over time
▪ For salty/sour tastes ▪ Factors affecting taste
▫ Na+, H+ ions make contact with ▫ Hunger: ↑ sensitivity to sweet, salty
gustatory hair tastes
▫ Ion channels allow these ions into cell ▫ Infections, allergies: ↓ sensitivity
▫ Membrane depolarizes ▫ Age: ↓ sensitivity; because receptor cells
▫ Voltage gated channels open not replaced as quickly
▫ Extracellular calcium flows inside
▫ Neurotransmitters fuse with cell
membrane
▫ Nerves tell brain
▪ For sweet, bitter, umami tastes
▫ Tastants bind to G-protein coupled
receptors
▫ Triggers G-protein coupled pathway
▫ Calcium channels on endoplasmic
reticulum open
▫ Intracellular calcium ions flow into cell
▫ Neurotransmitters fuse with cell
membrane
▫ Nerves tell brain
Figure 55.27 The two taste perception methods.
OSMOSIS.ORG 499
NOTES
NOTES
SPINAL CORD & NERVES
BRACHIAL PLEXUS
osms.it/brachial-plexus
▪ Network of nerves innervating shoulder, TRUNKS
arm, hand (supply afferent/sensory, ▪ C5, C6 form superior trunk
efferent/motor nerve fibers); one on each ▪ C7 remains as middle trunk
side of body
▪ C8, T1 form inferior trunk
▪ Begins as five roots → combine to three
▪ Suprascapular nerve branches off from
trunks → split into six divisions (three
superior trunk
anterior, three posterior) → combine
into three cords → end in five terminal ▫ Innervates supraspinatus, infraspinatus,
branches; also preterminal (collateral) acromioclavicular, glenohumeral joints
branches
DIVISIONS
▪ Each trunk splits into anterior, posterior
division
CORDS
▪ Lateral cord
▫ Superior, middle trunk anterior divisions
▪ Posterior cord
▫ All three trunk posterior divisions
▪ Medial cord
▫ Inferior trunk anterior division
▪ Lateral pectoral nerve branches off from
Figure 56.1 Brachial plexus location in body. lateral cord
▪ Upper, middle, lower subscapular nerves
branch off from posterior cord
ROOTS ▪ Medial cutaneous nerves of arm, forearm,
▪ First four: from last four cervical nerves (C5, medial pectoral nerve branch off from
C6, C7, C8) medial cord
▪ Last one: from first thoracic nerve (T1)
▪ Long thoracic nerve (LT) branches off from
TERMINAL BRANCHES
C5, C6, C7
▪ Musculocutaneous nerve comes from
▫ Innervates serratus anterior
lateral cord
▪ Dorsal scapular (DS) nerve branches off
▫ Innervates biceps brachii, brachialis,
from C5
coracobrachialis
▫ Innervates rhomboid muscles
▪ Median nerve formed from lateral, medial
▪ Phrenic nerve contributed to by C5 cords
▫ Innervates diaphragm ▫ Innervates flexors of forearm, hand
500 OSMOSIS.ORG
Chapter 56 Neurology: Spinal Cord & Nerves
▪ Axillary, radial nerves split out from ▫ Radial nerve innervates triceps brachii,
posterior cord brachioradialis, forearm extensors
▫ Axillary nerve innervates deltoid, teres ▪ Ulnar nerve off from medial cord
minor ▫ Innervates wrist, fingers
Figure 56.2 Divisions of the brachial plexus.
Figure 56.3 Names and locations of brachial plexus’ collateral branches.
OSMOSIS.ORG 501
Figure 56.4 Contributions of the spinal nerves to the brachial plexus’ terminal branches.
Figure 56.5 A simplified diagram of the brachial plexus with mnemonics for names and order
of divisions (Remember To Drink Cold Beer) and the terminal branches (MARMU).
502 OSMOSIS.ORG
CRANIAL NERVES
osms.it/cranial-nerves
▪ 12 nerve pairs originating in brain, ▪ Includes olfactory, optic, oculomotor,
brainstem trochlear, trigeminal, abducens, facial,
▫ Supply body (primarily head, neck) with vestibulocochlear, glossopharyngeal, vagus,
motor, sensory information accessory, hypoglossal nerves
Figure 56.6 The cranial nerves originate from the brain (including brainstem).
MNEMONIC: MNEMONIC:
Cranial Nerve Names Cranial Nerve Functions
On (S = sensory, M = motor)
Old Some
Olympus Say
Towering Marry
Top, Money
A But
Fine My
Victorian Brother
Gentleman Says
Viewed Big
A Brains
Hawk Matter
More
OSMOSIS.ORG 503
I - OLFACTORY NERVE (SENSORY) midbrain, follows oculomotor nerve through
▪ Function: smell superior orbital fissure
▪ Arises from primary olfactory cortex ▪ Innervates superior oblique muscles
(temporal lobe) (abducts, depresses, internally rotates
▪ Neurons form olfactory tracts → run to eyeball)
olfactory bulb (above cribriform plate of
ethmoid bone) V - TRIGEMINAL NERVE
▪ Receives information from sensory nerve (SENSORY/MOTOR)
fibers (axons from nasal cavity’s olfactory ▪ Function: facial movement, chewing,
neurons) which synapse with olfactory temperature, touch, pain
bulb’s neurons ▪ Emerges from pons; travels to trigeminal
ganglion
II - OPTIC NERVES (SENSORY) ▪ Splits into ophthalmic, maxillary,
▪ Function: vision mandibular nerves
▪ Emerge from eye retinas ▫ Opthalmic nerve exits through superior
▪ Pass through optic canal, unite at optic orbital fissure, gives sensory innervation
chiasm (partial decussation occurs) → optic to upper eyelid, nose, forehead, scalp
nerve fibers form optic tracts → synapse at ▫ Maxillary nerve exits through foramen
different nuclei rotundum, gives sensory innervation to
▫ Suprachiasmatic nucleus in maxilla, nasal cavity, palate, cheeks’ skin
hypothalamus (regulates sleep-wake ▫ Mandibular nerve exits through foramen
cycle) ovale, gives sensory innervation to
▫ Pretectal nucleus in midbrain (regulates tongue (not taste buds), lower lip, lower
eye reflexes) teeth, chin, temporal scalp. Gives motor
innervation to chewing muscles
▫ Lateral geniculate nucleus in thalamus
(thalamic fibers form optic radiations,
run to occipital visual cortex → VI - ABDUCENS NERVE (MOTOR)
determines sight) ▪ Function: eyeball movement
▪ Emerges from pons; runs through superior
III - OCULOMOTOR NERVE (MOTOR) orbital fissure
▪ Function: eye movement ▪ Innervates lateral rectus muscle (abducts
▪ Arises from ventral midbrain; runs through eye)
superior orbital fissure to eye
▪ Splits into superior, inferior branch VII - FACIAL NERVE (SENSORY/
▫ Superior branch innervates levator MOTOR)
palpebrae superioris (raises upper ▪ Function: taste, saliva, tears, facial
eyelid), superior rectus (elevates eye) movement (i.e. facial expressions)
▫ Inferior branch innervates inferior ▪ Emerges from pons; enters temporal bone
oblique (abducts eyeball), inferior through internal acoustic meatus
rectus (depresses, adducts eyeball), ▪ Runs within bone to geniculate ganglion
medial rectus (adducts eyeball) ▪ Splits into greater petrosal nerve, stapedius
with proprioception; controls pupil nerve, chorda tympani
constriction (sphincter pupillae), visual
▫ Greater petrosal nerve provides
focusing (ciliaris) via ciliary ganglion
autonomic fibers to lacrimal, nasal,
palatine, pharyngeal glands
IV - TROCHLEAR NERVE ▫ Stapedius nerve sends motor fibers to
(PRIMARILY MOTOR/SOME middle ear’s stapedius
SENSORY) ▫ Chorda tympani gives sensory
▪ Function: eyeball movement innervation to taste buds of tongue’s
▪ Arises from dorsal midbrain; runs around anterior two thirds
504 OSMOSIS.ORG
▪ Remaining nerve exits skull through ▪ Brings in sensory information from

stylomastoid foramen thoracic, abdominal organs; aortic arch’s
▪ Splits again into temporal, zygomatic, baroreceptors; chemoreceptors in carotid,
buccal, mandibular, cervical branches aortic bodies; epiglottis’ taste buds
(innervating forehead, nose, cheeks, around
eyes/lips, chin) XI - ACCESSORY NERVE
▪ Function: swallowing; head, shoulder
VIII - VESTIBULOCOCHLEAR movement
NERVE (SENSORY) ▪ Considered vagus nerve accessory
▪ Function: hearing, equilibrium ▪ Forms from rootlets emerging from spinal
▪ Emerges from pons; runs through internal cord; enters skull via foramen magnum,
acoustic meatus emerges from medulla, runs through jugular
▪ Splits into cochlear, vestibular nerves foramen
▫ Cochlear nerve supplies cochlea’s ▪ Innervates trapezius, sternocleidomastoid
hearing receptors muscles (head, neck movement); carries
▫ Vestibular nerve supplies vestibule’s sensory proprioceptive information from
equilibrium receptors larynx, pharynx
IX - GLOSSOPHARYNGEAL NERVE XII - HYPOGLOSSAL NERVE

(SENSORY/MOTOR) ▪ Function: tongue movement, speech,
▪ Function: swallowing, monitoring blood swallowing
pressure/oxygen/carbon dioxide ▪ Arises from medulla; runs through
▪ Arises from medulla; runs through jugular hypoglossal foramen
foramen ▪ Sends motor fibers to tongue muscles,
▪ Innervates tongue, pharynx carries sensory proprioceptive information
▪ Sends motor fibers to stylopharyngeus
(elevates pharynx in swallowing),
parasympathetic motor fibers to parotid
salivary glands, sensory fibers to tongue’s
posterior third
▪ Conveys information from carotid bodies’
chemoreceptors (blood oxygen, carbon
dioxide levels), carotid sinus’ baroreceptors
(blood pressure)
X - VAGUS NERVE (SENSORY/

MOTOR)
▪ Function: smooth muscle control, digestive
enzyme secretion
▪ Arises from medulla; runs through jugular
foramen
▪ Dips down into thorax, abdomen Figure 56.7 CN I: olfactory nerve.
▪ Sends somatic motor innervation
to pharynx, larynx (swallowing),
parasympathetic fibers to heart, lungs,
abdominal organs (heart rate, breathing,
digestion)
OSMOSIS.ORG 505
Figure 56.8 CN II: optic nerve.
Figure 56.9 CN III: oculomotor nerve.
Figure 56.10 CN IV: trochlear nerve and CN VI: abducens nerve. Together, CN III, IV, and VI
control eye movement.
506 OSMOSIS.ORG
Figure 56.11 CN V: trigeminal nerve. The three branches include the ophthalmic nerve (V1),
maxillary nerve (V2), and mandibular nerve (V3).
Figure 56.12 CN VII: facial nerve, including the intracranial and extracranial branches.
Figure 56.13 CN VIII: vestibulocochlear nerve, which splits into the vestibular and cochlear
nerves once it passes through the internal acoustic meatus.
OSMOSIS.ORG 507
Figure 56.14 CN IX: glossopharyngeal nerve has sensory and motor functions.
Figure 56.15 CN X: vagus nerve also has sensory and motor functions.
Figure 56.16 CN XI: accessory nerve enters the skull through foramen magnum, then exits again
through the jugular foramen. It innervates the trapezius and sternocleidomastoid muscles.
508 OSMOSIS.ORG
Figure 56.17 CN XII: hypoglossal nerve innervates the tongue and has both motor and sensory
function.
OSMOSIS.ORG 509
NOTES
NOTES
RENAL ANATOMY & PHYSIOLOGY

osms.it/renal-anat-phys
RENAL SYSTEM ▪ Renal capsule (inner)
▪ Two kidneys ▫ Dense connective tissue
▫ Filter the blood from harmful substances ▫ Gives kidney shape
▫ Regulate blood pH, volume, pressure,
osmolality
▫ Produce hormones
▪ Located between T12, L3 vertebrae;
partially protected by ribs 11, 12; behind
peritoneal membrane (retroperitoneal)
▪ Right kidney slightly lower due to larger
portion of the liver on right side
▪ Filter 150 liters of blood everyday; receive
¼ of cardiac output from renal arteries
(from aorta)
▫ Renal arteries divide → segmental
Figure 57.1 Kidney placement in relation to
arteries → interlobar arteries (between
ribs and vertebrae.
renal columns) → arcuate arteries (cover
bases of renal pyramids) → cortical
radiate arteries (supply the cortex) →
afferent arterioles (supply nephrons)
MORPHOLOGY
Renal hilum
▪ Indentation in the middle of each kidney
▪ Entry/exit point for ureter, arteries, veins,
lymphatics, nerves
Surrounding tissue (three layers)

▪ Renal fascia (outer)
▫ Dense connective tissue
▫ Anchors kidney
Figure 57.2 Arterial bloodflow in the kidney.
▪ Adipose capsule (middle)
▫ Fatty tissue
▫ Protects kidney from trauma
510 OSMOSIS.ORG
Chapter 57 Renal Physiology: Anatomy & Physiology
Renal cortex (outer portion)

▪ Outer cortical zone
▪ Inner juxtamedullary zone
▪ Renal columns project into the kidney,
separating medulla
Renal medulla (inner portion)

▪ 10-18 renal pyramids with pointy ends
(renal papilla/nipples) towards center of
kidney
▪ Renal lobes: renal pyramids including
cortex above them
▪ Renal papilla → minor calyces → major
calyces → renal pelvis → ureter
Figure 57.3 Transverse cross-section

showing retroperitoneal position of kidneys,
surrounding tissue layers.
Figure 57.4 Cross-section through kidney showing renal medulla, renal cortex, and urine flow
through kidney.
Nephron ▫ Epithelium comprises podocytes

▪ Functional unit of kidney (about one million wrapped around basement membrane;
in each kidney) gaps called filtration slits allow small
▪ Composed of renal corpuscle, renal tubule solutes through but block large proteins,
red blood cells
▪ Blood filtration starts in renal corpuscle
▫ Blood leaving glomerulus enters efferent
▫ Includes glomerulus, a tuft of capillaries
arteriole → divides into peritubular
supplied by afferent arteriole, and
capillaries → these reunite into cortical
Bowman’s capsule
radiate veins → arcuate veins →
▫ Blood flows into glomerulus → water, interlobar veins → renal veins → inferior
solutes (e.g. sodium) pass through vena cava
capillary endothelium → through
basement membrane → through
epithelium → into Bowman’s space
(becoming filtrate)
OSMOSIS.ORG 511
Figure 57.5 Nephron anatomy.
▪ Filtrate from Bowman’s capsule enters ▪ Blood pressure, glomerular filtration rate
renal tubule regulated by juxtaglomerular complex
▫ Made up of proximal convoluted tubule, ▫ Located between distal convoluted
descending/ascending limbs of nephron tubule and afferent arteriole
loop (loop of Henle), distal convoluted ▫ Contains three types of cells: macula
tubule, collection ducts (which send densa, extraglomerular mesangial,
urine to minor calyces) juxtaglomerular (granular) cells
▫ Filtrate is further filtered by passing
water, solutes between filtrate, blood in
peritubular capillaries
Figure 57.6 Blood flow through nephron and venial bloodflow in kidney.
512 OSMOSIS.ORG
Chapter 57 Renal Physiology: Anatomy & Physiology
▫ Macula densa cells in distal convoluted

tubule sense ↓ sodium/blood pressure
→ juxtaglomerular cells secrete renin
→ ↑ sodium reabsorption, constricting
blood vessels → ↑ blood pressure via
the renin–angiotensin–aldosterone
system (RAAS)
▪ Urine from renal tubules enters minor
calyces → major calyces → renal pelvis →
ureter
Bladder
▪ Bladder receives urine from ureter
▫ Urine enters at ureterovesical junctions
▫ Muscular walls fold into rugae as
bladder empties Figure 57.7 Cross-section through renal
▪ Bladder wall contains multiple layers capsule showing juxtaglomerular complex.
▫ Transitional epithelium: allows bladder
to distend while maintaining a barrier
▫ Detrusor muscle: helps with bladder
contraction
▫ Fibrous adventitia: holds bladder loosely
in place
▪ Located in front of rectum in biologically-
male individuals; in front of vagina,
uterus, and rectum in biologically-female
individuals
▪ Holds 750mL of urine
▫ Biologically-female individuals: slightly
less due to crowding from uterus
▪ Contains smooth triangular region (trigone Figure 57.8 Bladder anatomy.
region) on bladder floor
▫ Bounded by two ureterovesical
junctions and internal urethral orifice
▫ Highly sensitive to expansion → signals
brain as bladder fills
Figure 57.9 Sagittal cross-section showing placement of bladder in relation to other organs.
OSMOSIS.ORG 513
Figure 57.10 Coronal cross-section through bladder showing urethra anatomy.
Urethra Urination
▪ Drains urine from bladder ▪ Involves close coordination between
▪ Structured differently in biologically male nervous system and bladder muscles
and female people ▪ Bladder volume of > 300–400mL, sends
▫ Starts at internal urethral orifice signals to micturition center in spinal
▫ Male: passes through prostate (prostatic cord (located at S2 and S3) → micturition
urethra), deep peritoneum (intermediate reflex causes contraction of bladder and
urethra), penis (spongy urethra); also relaxation of both sphincters
used during ejaculation (semen enters ▫ Pontine storage center in pons of brain
via seminal vesicles) can be activated to stop micturition
▫ Female: passes through perineal floor reflex
of pelvis, exits between labia minora ▫ Pontine micturition center can be
(above vaginal opening but below activated to allow micturition reflex
clitoris)
▫ Detrusor muscle thickens at internal
urethral orifice forming internal sphincter
(involuntary control; controlled by
autonomic nervous system; keeps
urethra closed when bladder isn’t full)
▫ External sphincter is located at level of
urogenital diaphragm in floor of pelvis
(voluntary control; can be used to stop
urination with kegel exercises)
Figure 57.11 Signal pathways of micturition

reflex.
514 OSMOSIS.ORG
NOTES
NOTES
ACID-BASE PHYSIOLOGY
ACID-BASE MAP &

COMPENSATORY MECHANISMS
osms.it/acid-base_map_and_ compensatory_mechanisms
ACID-BASE MAP COMPENSATORY MECHANISMS

▪ Main physiologic pH factors ▪ Simple acid-base disorder
▫ HCO3−, CO2 ▫ Single problem changing pH
▪ Acid-base map ▪ Mixed acid-base disorder
▫ HCO3− concentration (x-axis)/CO2 partial ▫ Multiple problems compounding/
pressure (y-axis) diagram cancelling out
▪ Henderson–Hasselbalch equation
Multiple compensatory mechanisms
▫ pH = 6.1+log ([HCO3-]/0.03PCO2)
▪ Respiratory acidosis
▫ PCO2 is partial pressure of CO2
▫ Kidneys retain more HCO3−
▪ Diagonal lines
▪ Respiratory alkalosis
▫ Drawn where each point on graph has
same pH (isohydric lines) ▫ Kidneys excrete more HCO3−
▪ Drawing lines for pH = 7.35, pH = 7.45 ▪ Metabolic acidosis
▫ Comprises area where all HCO3−, CO2 ▫ Lungs blow off CO2 (deeper, more
frequent breaths)
combinations correspond to “normal”
pH ▪ Metabolic alkalosis
▫ Lungs retain CO2 (shallower, less
pH out of normal range frequent breaths)
▪ One of two ways
▫ Acidosis: pH ↓ 7.35, enters top-left
portion of map
▫ Alkalosis: pH ↑ 7.45, enters bottom-
right portion of map
▪ One of two reasons
▫ Respiratory: PCO2 too ↑/↓
▫ Metabolic: [HCO3−] too ↑/↓
OSMOSIS.ORG 515
Figure 58.1 An acid-base map shows the relationship between pH, bicarbonate concentration,
and partial pressure of carbon dioxide in respiratory and metabolic acidosis or alkalosis, and how
these values are adjusted when there is renal or respiratory compensation. The accompanying
tables depict the changes in PCO2, [HCO3-, and pH associated with respiratory/metabolic
acidosis/alkalosis.
BUFFERING & HENDERSON-

HASSELBALCH EQUATION
osms.it/buffering_&_henderson-hasselbalch_equation
BUFFERING more H+ ions created, resists pH change

▪ Buffers: pH change-resisting solutions ▪ Strong acid added to acidic buffer
▪ Can comprise ▫ H+ ions would ↓ pH
▫ Acidic buffer: weak acid, conjugate base ▫ Shifts acid equilibrium in opposite
▫ Basic buffer: weak base, conjugate acid direction → conjugate base reacts with
H+ ions → resists pH change
equilibrium formation (e.g. HA ⇄ H+ + A or
▪ Weak acids, bases do not dissociate fully →
B + H2O ⇄ BH+ + OH-)

▪ Strong acid added to basic buffer
▫ H+ ions would ↓ pH, also reacts with
▫ Le Chatelier’s principle: equilibriums excess OH- ions
move forward/backward, balance ▫ OH- loss ions shifts base’s equilibrium →
products/reactants’ gain/loss ↑ OH ion creation → resists pH change
▪ Strong base added to basic buffer
Resisting pH change
▫ OH- ions would react with H+ ions to ↑
▪ Acidic, basic buffers resist all pH changes
pH
▪ Strong base added to acidic buffer
▫ Shifts base’s equilibrium in opposite
▫ OH- ions react with H+ ions → ↑ pH direction → conjugate acid reacting with
▫ H+ ion loss shifts acid’s equilibrium → OH- ions → resists pH change
516 OSMOSIS.ORG
Chapter 58 Renal Physiology: Acid base
HENDERSON-HASSELBALCH ▫ Solving for H+ → [H+] = K([HA]/[A-])

EQUATION ▫ Negative log of both sides → pH = pK +
▪ Henderson–Hasselbalch equation log([A-]/[HA])
determines buffer’s pH ▪ Note
▫ pH = pK + log([A-]/[HA]) ▫ If [A-] = [HA], then pH = pK
▪ This is derived
▫ Weak acid equilibrium: equilibrium
constant K → K = [H+][A-]/[HA]
PHYSIOLOGIC pH & BUFFERS

osms.it/physiologic-pH-and-buffers
PHYSIOLOGIC pH
▫ H2O + CO2 ⇄ H2CO3 ⇄ H+ + HCO3-
▪ Equilibrium reaction
▪ Measures balance between acids, bases in
body ▪ Excess
▪ pH: -log[H+] ▫ CO2 blown off by lungs
▫ [H+]: hydrogen ion concentration ▫ HCO3- eliminated by kidneys
▪ Ideal: [H+] = 40 x 10-9 Eq/L = 40 nEq/L →
pH = 7.4 (slightly alkaline) Phosphate buffer system (extracellular)
▫ Acidemia: pH < 7.4 ▪ Acidic buffer: dihydrogen phosphate
▫ Alkalemia: pH > 7.4 (H2PO4- )
▪ ↑ [H+] → ↓ pH (negative sign in equation) ▪ Conjugate base: monohydrogen phosphate
(HPO42-)
▪ pH, [H+] has logarithmic (not linear)
▫ H2PO4- ⇄ H+ + HPO42-
relationship ▪ Equilibrium reaction
PHYSIOLOGIC BUFFERS Protein buffer system (extracellular)

▪ Physiologic buffers occur naturally in body ▪ Protein amino acids may have exposed
▪ Results in separate acidic (-COOH ⇄

▫ Maintains stable pH between 7.35–7.45 carboxyl (-COOH), amine (NH2) groups
Bicarbonate buffer system -COO- + H+ ), basic (-NH2 + H+ ⇄ -NH3+)

▪ Extracellular, most important buffers
▪ Acidic buffer: carbonic acid (H2CO3)
Intracellular buffer systems
▪ Conjugate base: bicarbonate ion (HCO3-)
▪ Hemoglobin: buffer in red blood cells
▪ Carbonic acid can be formed from H2O, CO2
(selectively binds H+ ions)
(carbonic anhydrase catalyzes reaction)
▪ Organic phosphates (e.g. ATP) can buffer
similarly
OSMOSIS.ORG 517
PLASMA ANION GAP
osms.it/plasma-anion-gap
PLASMA ANION GAP ▫ Organic anions aren’t measured →
▪ Cations, anions coexist within plasma plasma anion gap ↑
▫ To keep plasma electrically neutral sum ▫ Organic acids include lactic acid,
of cation charges must equal sum of ketoacids, oxalic acid, formic acid,
anion charges hippuric acid
▪ Not all cation, anion concentrations can be ▪ Some cases (e.g. diarrhea/renal tubular
measured acidosis)
▫ Often gap (“plasma anion gap”) ▫ Kidneys reabsorb more Cl− ions →
between measured cation charges plasma anion gap remains normal
(mainly Na+), smaller measured anion (hyperchloremic metabolic acidosis)
charges sum (mainly Cl−, HCO3- )
High gap may suggest
▪ Plasma anion gap range: 3–11 mEq/L
▪ Unmeasured anion buildup (e.g.
▫ High gap → high unmeasured anion
hyperphosphatemia, hyperalbuminemia)
number
▪ Metabolic alkalosis (high pH triggers
▫ Low gap → low unmeasured anion
albumin to release H+ ions → negative
number
charge ↑ on unmeasured albumin
▪ Unmeasured anions include anion molecules)
component of several organic acids,
negatively charged plasma proteins (e.g. Low gap may suggest
albumin) ▪ Unmeasured anion ↓ (e.g.
hypoalbuminemia)
DIAGNOSTIC TOOL ▪ Unmeasured cation ↑ (rarely)
▪ Plasma anion gap serves as useful ▫ E.g. hyperkalemia, hypercalcemia,
diagnostic tool hypermagnesemia
Metabolic acidosis
▪ Organic acids’ H+ ions convert HCO3- into
H2CO3
THE ROLE OF THE KIDNEY IN

ACID-BASE BALANCE
osms.it/kidney_and_acid-base_balance
KIDNEYS' FUNCTION ▪ Kidneys consist of nephrons

▪ Kidneys maintain acid-base balance in two ▫ Each has glomerulus (capillaries clump)
ways ▪ During filtration, plasma leaves glomerulus
▫ HCO3- reabsorption: urine into blood entering renal tubule (consists of proximal
▫ H+ secretion: blood into urine convoluted tubule, loop of Henle, distal
convoluted tubule)
518 OSMOSIS.ORG
▪ Tubules lined with brush border cells (apical ▫ Sodium/chloride bicarbonate

surface facing tubular lumen, basolateral cotransporters on basolateral surface
surface facing peritubular capillaries) snatch up HCO3- , nearby sodium/
chloride ion, moving both into blood
HCO3- reabsorption
▪ Primarily in proximal convoluted tubule H+ secretion
▫ Na+ ions exchanged for H+ ions through ▪ Primarily in proximal convoluted tubule
apical surface → bind with HCO3- → ▫ Sodium-hydrogen countertransport:
form H2CO3 H+ ions exchanged for Na+ ions through
▫ Carbonic anhydrase type 4 splits H2CO3 apical surface
into H2O, CO2 ▫ Another mechanism in distal convoluted
▫ H2O, CO2 diffuse across membrane tubule, collecting ducts involving alpha-
▫ Carbonic anhydrase type 2 recombines intercalated cells
them into H2CO3 ▫ Chemical buffers (ammonia, phosphate)
▫ H2CO3 dissolve into H+,HCO3- prevent urine pH from dropping too low
in tubules (< 4.5)
METABOLIC ACIDOSIS
osms.it/metabolic-acidosis
METABOLIC ACIDOSIS Normal anion gap
▪ HCO3 ion reduction → blood pH ↓ to <
-
▪ HCO3- lost in various ways, Cl− ↑ prevents
7.35 anion gap change (hyperchloremic
metabolic acidosis)
TYPES ▪ Possible causes
▪ Distinguished by high/normal anion gap ▫ Diarrhea, renal tubular acidosis
▫ Measured cation concentration
▫ E.g. Na+ ions, minus measured anion REGULATORY MECHANISMS
concentration (e.g. Cl−, HCO3− ions) ▪ Body has several regulatory mechanisms to
reverse ↓ pH
High anion gap
▫ H+ ions moved from blood into cells,
▪ H+ ions from organic acids convert HCO3- to exchanged for K+ ions (may cause
H2CO3 hyperkalemia); if organic anions present,
▫ ↓ HCO3− ion concentration (measured can enter cells with H+ ions → K+ ions
in anion gap), ↑ organic anion are not released
concentration (not measured) ▫ Chemoreceptors fire more in low pH
▫ Naturally-occurring organic acids: → ↑ respiratory rate, breath depth → ↑
e.g. lactic acid production (lactic ventilation, CO2 movement out of body
acidosis), ketoacid production (diabetic ▫ H+ ions excreted by kidneys → HCO3-
ketoacidosis), excessive uric, sulfur- reabsorbed (with normal renal function)
containing acid retention (chronic renal
failure)
▫ Ingestible organic acids: e.g. oxalic acid
(antifreeze), formic acid (methanol),
hippuric acid (toluene)
OSMOSIS.ORG 519
Figure 58.2 Illustration depicting the two kinds of metabolic acidosis: high anion gap (where
H+ from organic acids converts HCO3- to H2CO3), and normal anion gap (where a Cl- increase
maintains the normal anion gap).
METABOLIC ALKALOSIS
osms.it/metabolic-alkalosis
METABOLIC ALKALOSIS diuretics/severe dehydration cases
▪ HCO3 ion gain → blood pH ↑ > 7.45
- (contraction alkalosis)
▪ Hypokalemia
CAUSES ▫ Diarrhea/diuretic use, triggering renin-
angiotensin-aldosterone mechanism →
▪ Associated with direct HCO3- ion gain/
distal convoluted tubule dumps H+ ions,
loss of H+ ion loss (thus → HCO3- ion gain),
reabsorbs HCO3- ions
usually both
▪ HCO3- ion ingestion
▪ Hypokalemia
▫ E.g. excessive antacid use (NaHCO3)
▫ Metabolic alkalosis cause
▫ May also be result of other root causes
REGULATORY MECHANISMS
Excessive H+ ion loss causes ▪ Body has regulatory mechanisms to
▪ Vomiting (gastric secretions acidic) reverse ↑ pH
▫ Also causes HCO3- ion buildup in ▫ K+ ions move from blood into cells →
pancreas (would normally neutralize exchanged for H+ ions (may contribute
gastric secretions) to hypokalemia)
▪ Abnormal renal function ▫ Chemoreceptors fire less in high pH →
▫ E.g. adrenal tumors secrete aldosterone ↓ respiratory rate, breathing depth → ↓
→ distal convoluted tubule dumps H+ ventilation, CO2 retention
ions, reabsorbs HCO3- ions ▫ HCO3- ions excreted by kidneys → H+
reabsorbed (normal renal function)
Excessive HCO3- ion gain causes
▪ ↑ kidney reabsorption
▫ Volume contraction with loop/thiazide
520 OSMOSIS.ORG
Figure 58.3 Illustration summarizing the definition and causes of metabolic alkalosis.
RESPIRATORY ACIDOSIS
osms.it/respiratory-acidosis
RESPIRATORY ACIDOSIS (pneumonia); fluid buildup between
▪ CO2 gain → blood pH ↓ < 7.35 alveoli, capillary walls (pulmonary
edema) → impaired gas exchange
between alveoli, capillary
CAUSES
▪ Ventilation ↓ (frequency, breath depth) for
variety of reasons → lungs blow off too REGULATORY MECHANISMS
little CO2 ▪ Body has several regulatory mechanisms to
▫ Stroke/medication overdose/etc. → reverse pH ↓
respiratory-center abnormality in ▫ Low pH → chemoreceptors fire more
brainstem → attempted ↑ in respiratory rate,
▫ Obesity, trauma, neuromuscular breathing depth → ↑ ventilation
disorders (myasthenia gravis), etc. → ▫ H+ ions bind to basic protein molecules
respiratory muscle-contraction failure (mainly exposed hemoglobin -NH2
▫ Airway obstruction groups), although in small amounts
▫ Alveoli damage (chronic obstructive ▫ H+ ions excreted by kidneys, HCO3-
pulmonary disease); alveoli fluid buildup reabsorbed
OSMOSIS.ORG 521
RESPIRATORY ALKALOSIS
osms.it/respiratory-alkalosis
RESPIRATORY ALKALOSIS ▫ Incorrectly-set ventilator → medical
▪ CO2 loss → blood pH ↑ > 7.45 intervention
CAUSES REGULATORY MECHANISMS

▪ Ventilation ↑ (frequency, breath depth) for ▪ Body has several regulatory mechanisms to
variety of reasons → lungs blowing off too reverse pH ↑
much CO2 ▫ High pH → chemoreceptors fire less
▫ Respiratory-center abnormality in → attempted ↓ in respiratory rate,
brainstem breathing depth → ↓ ventilation
▫ Pneumonia, pulmonary embolism, etc. ▫ H+ ions released from acidic protein
→ low oxygen levels (hypoxia) molecules (mainly exposed hemoglobin
▫ Anxiety, panic attacks, sepsis, salicylates -COOH groups), although in small
overdose amounts
▫ HCO3- ions excreted by kidneys, H+ are
reabsorbed
522 OSMOSIS.ORG
NOTES
NOTES
FLUIDS IN THE BODY
BODY FLUID COMPARTMENTS

osms.it/body-fluid-compartments
GENERAL CHARACTERISTICS ▫ Negative plasma proteins are too big to
▪ Fluid divisions in body travel through pores; electroneutrality
▫ Includes intracellular fluid, extracellular is maintained by repelling small anions
fluid into interstitial fluid and attracting small
cations into plasma (Gibbs–Donnan
▪ “60-40-20 rule”
effect) → interstitial fluid has ↑ small
▫ Total body water is 60% of body weight, anion concentration (e.g. Cl-) and ↓
of which two thirds is intracellular → small cation concentration (e.g. Na+)
total intracellular fluid is 40% of body
weight, total extracellular fluid is 20% of
body weight VOLUMES OF BODY FLUID
▪ Due to macroscopic electroneutrality COMPARTMENTS
principle, fluid compartments have same ▪ Determined by administering and
concentration of positive charges as measuring concentration of substances
negative charges that are known to settle in specific
compartments (dilution method)
▫ Radiolabeled albumin for plasma
INTRACELLULAR &
(cannot pass into interstitial fluid)
EXTRACELLULAR FLUID
▫ Smaller molecules like mannitol and
▪ Large difference between intracellular fluid
inulin for interstitial fluid (cannot pass
and extracellular fluid (e.g. Na+K+ ATPases
through cell membranes)
establish high concentration of K+ inside cell
and high concentration of Na+ outside cell) ▫ Heavy water (D2O) for total body water
(knowing this and above, intracellular
Intracellular fluid fluid can be calculated too)
▪ Dissolves cations (esp. K+ and Mg2+) ▫ Measuring concentration of these
and anions (esp. proteins and organic substances in their respective body fluid
phosphates e.g. ATP) compartments allows us to calculate
Extracellular fluid
volume
(= AmountGiven
Concentration
)
▪ Includes interstitial fluid (around cells) and ▫ To account for loss of these substances
plasma (aqueous part of blood, containing in urine, subtract amount lost from
about 10% proteins e.g. albumin) amount given and use this value in
▫ Both dissolve cations (esp. Na+) and formula
anions (esp. Cl- and HCO3-)
▫ Solutes and water travel between the
interstitial fluid and plasma through
pores in endothelial cells of capillaries
OSMOSIS.ORG 523
Figure 59.1 A sample problem demonstrating how to solve for total body water, extracellular
fluid, and intracellular fluid volumes using information gained from D2O and mannitol.
524 OSMOSIS.ORG
Chapter 59 Renal Physiology: Fluids in the Body
WATER SHIFTS BETWEEN

BODY FLUID COMPARTMENTS
osms.it/water-shifts-between-body-fluid-compartments
Key features ▪ E.g. adrenal insufficiency (deficiency in

▪ Movement of water between body fluid several hormones, including aldosterone).
compartments to maintain constant Aldosterone important for sodium
osmolarity reabsorption from kidneys; ↓ aldosterone =
▪ Shifts are characterized by change in ↑ sodium loss in urine
volume and concentration of extracellular
fluid VOLUME EXPANSION
▫ ECF volume: ↑ = expansion; ↓ =
contraction Isosmotic volume expansion
▫ ECF osmolarity: ↑ = hyperosmotic; ↓ = ▪ Gain of isosmotic fluid in ECF
hyposmotic; no change = isosmotic ▪ Volume ↑ but osmolarity is constant → no
▪ Six possible combinations water shift
▪ ↑ plasma volume and arterial pressure;
↓ plasma protein concentration and
VOLUME CONTRACTION hematocrit
Isosmotic volume contraction ▪ E.g. receiving an infusion of isotonic NaCl
▪ Loss of isosmotic fluid from ECF solution
▪ Volume ↓ but osmolarity is constant → no Hyperosmotic volume expansion
water shift ▪ Gain of solutes or hyperosmotic fluid in ECF
▪ ↓ plasma volume and arterial pressure; ▪ Volume ↑ and osmolarity ↑ → water shifts
↑ plasma protein concentration and from ICF
hematocrit
▪ E.g. diarrhea ↓ plasma protein concentration and
Hyperosmotic volume contraction hematocrit
▪ Loss of hyposmotic fluid from ECF ▪ E.g. eating salty chips
▪ Volume ↓ and osmolarity ↑ → water Hyposmotic volume expansion
shifts from ICF (net effect is still volume ▪ Gain of hyposmotic fluid in ECF
contraction)
▪ Volume ↑ and osmolarity ↓ → water shifts
▪ ↓ plasma volume and arterial pressure; to ICF (net effect is still volume expansion)
↑ plasma protein concentration but
hematocrit is unchanged (since red blood
↓ plasma protein concentration but
cells lose volume too)
hematocrit is unchanged
▪ E.g. heavy sweating (sweat is hyposmotic
▪ E.g. too much antidiuretic hormone causing
relative to ECF)
excessive water reabsorption
Hyposmotic volume contraction
▪ Loss of solutes/hyperosmotic fluid from ECF
▪ Volume ↓ and osmolarity ↓ → water shifts
to ICF
▪ ↓ plasma volume and arterial pressure;
↑ plasma protein concentration and
hematocrit
OSMOSIS.ORG 525
Figure 59.2 Visualization of the types of volume contraction.
526 OSMOSIS.ORG
Figure 59.3 Visualization of the types of volume expansion.
OSMOSIS.ORG 527
RENAL CLEARANCE
osms.it/renal-clearance
▪ Rate at which kidneys clear blood plasma ▪ Free water clearance is renal clearance of
of substance pure water
▪ For substance “x”, renal clearance
U osm
[U ]x ×V
CH O = V − Posm
V
C= [ P]x
2
▫ [U]x: urine concentration of x ▫ Uosm: urine osmolarity

▫ [P]x: plasma concentration of x ▫ Posm: plasma osmolarity
▫ V: urine flow rate
▪ To measure reabsorption/secretion of
substance in kidneys, inulin can be used as
reference point
▫ Inulin is freely filtered
▫ Inulin is not reabsorbed/secreted
▪ Clearance ratio for substance x is
Cx
Cinulin
▫ = 1 → x is freely filtered, not secreted

▫ > 1 → x is freely filtered, secreted
▫ < 1 → x is not freely filtered/is
reabsorbed
528 OSMOSIS.ORG
Figure 59.4 Sample questions solving for renal clearance of a solute and free water clearance.
OSMOSIS.ORG 529
NOTES
NOTES
RENAL BLOOD FLOW
REGULATION
RENAL BLOOD FLOW REGULATION

osms.it/renal-blood-flow-regulation
▪ Blood enters kidney via renal artery, leaves ▫ Binds to angiotensin receptors along
via renal vein afferent, efferent arterioles → smooth
▫ Blood enters glomerulus via afferent muscle cells contract
arteriole, leaves via efferent arteriole ▫ Efferent arterioles more sensitive to
▪ Renal blood flow: volume of blood that angiotensin II → constrict more → blood
reaches kidneys in unit time; determined by builds up in glomerulus → GFR constant
pressure gradient (pressure in renal artery - ▫ High levels of angiotensin II → afferent
pressure in renal vein) divided by arteriolar arterioles constrict equally → ↓ GFR
resistance
Key hormones: decreasing arteriolar
▫ ↑ blood pressure → ↑ pressure in renal
resistance (increasing renal blood flow)
artery → ↑ renal blood flow
▪ Atrial natriuretic peptide
▫ ↓ arteriolar resistance → ↑ renal blood
flow ▫ Secreted by atria of heart in response to
increased cardiac workload
▪ Renal blood flow determines glomerular
filtration rate (GFR) ▫ Binds to natriuretic peptide receptors
along afferent, efferent arterioles →
▫ ↑ renal blood flow → ↑ GFR
smooth muscle cells relax
▪ Regulation of renal blood flow: increasing/
▪ Brain natriuretic peptide
decreasing arteriolar resistance
▫ Secreted by ventricles of heart in
Key hormones: increasing arteriolar response to increased cardiac workload
resistance (decreasing renal blood flow) ▫ Binds to natriuretic peptide receptors
▪ Adrenaline (epinephrine) along afferent, efferent arterioles →
▫ Secreted by adrenal gland in response smooth muscle cells relax
to sympathetic stimulation ▪ Prostaglandins (e.g. prostaglandin E2, I2)
▫ Binds to alpha-1 adrenergic receptors ▫ Produced by kidneys in response to
along afferent, efferent arterioles → sympathetic stimulation
smooth muscle cells contract ▫ Binds to prostaglandin receptors along
▪ Angiotensin II afferent, efferent arterioles → smooth
▫ Renin produced by juxtaglomerular muscle cells relax
cells in afferent arteriole → released ▫ Prevents kidney damage during
into blood, becomes angiotensin I sympathetic stimulation
in response to low blood pressure ▪ Dopamine
→ converted into angiotensin II by ▫ Synthesized in brain, kidneys
angiotensin-converting enzyme (ACE),
▫ Binds to dopaminergic along afferent,
synthesized in endothelial cells (esp. in
efferent arterioles → smooth muscle
lungs)
cells relax
530 OSMOSIS.ORG
Chapter 60 Renal Physiology: Renal Blood Flow Regulation
AUTOREGULATION OF RENAL Mechanisms for autoregulation

BLOOD FLOW ▪ Myogenic mechanism: smooth muscle cells
▪ Keeps renal blood flow, GFR constant over in arterioles automatically contract when
range of systemic blood pressures (80– stretched by high blood pressure (related to
200mmHg) increased renal blood flow)
▫ 80mmHg: smooth blood cells in ▪ Tubuloglomerular mechanism: macula
arterioles completely relaxed, renal densa cells release adenosine → increases
blood flow optimal resistance in afferent arteriole when more
▫ Systemic blood pressure increases → sodium, chloride ions detected in distal
smooth blood cells contract to maintain convoluted tubule (related to increased
optimal renal blood flow GFR, renal blood flow)
Figure 60.1 Graph displaying the relationship between systolic blood pressure and renal blood
flow. The kidneys achieve consistency between 80–200mmHg by adjusting their own arteriole
resistance.
Figure 60.2 The region where the distal convoluted tubule and the afferent arteriole are close
to one another is called the juxtaglomerular apparatus. This proximity allows adenosine from the
macula densa cells to diffuse over to the juxtaglomerular cells of the afferent arteriole, alerting
them to ↑ GFR. This increases arteriolar resistance → ↓ GFR.
OSMOSIS.ORG 531
MEASURING RENAL PLASMA FLOW
& RENAL BLOOD FLOW
osms.it/measuring-renal-plasma-blood-flow
▪ Fick principle: amount of substance in Effective renal plasma flow
blood that flows into organ = amount that ▪ Two assumptions
flows out (if organ doesn’t produce/degrade ▫ 90% of PAH leaves kidneys in urine →
that substance) 10% leaves in renal vein negligible
True renal plasma flow ▫ Concentration of PAH in renal artery =
concentration of PAH in any peripheral
▪ Add para-aminohippuric acid (PAH) to
vein
body (isn’t made in body, doesn’t affect
[PAH ]urine × Urine flow
renal function) Effective renal plasma flow =
▪ [PAH ]
▪ Fick principle: amount of PAH that flows
into kidneys through renal artery = amount ▪ Effective renal plasma flow = 90% of true
of PAH that flows out (through urine, renal renal plasma flow
veins)
Renal blood flow
▫ Inwards flow of PAH = outwards flow
Renal plasma flow
of PAH Renal blood flow =
▪ (1− hematocrit)
▫ [PAH]artery x renal plasma flow = ([PAHvein
x renal plasma flow) + ([PAHurine x urine ▫ Hematocrit: blood volume fraction
flow) occupied by red blood cells (i.e. fraction
of blood volume not plasma)
▫ Renal plasma flow x ([PAH]artery - [PAH]
vein
) = [PAH]urine x urine flow
[PAH ]urine × Urine flow
Renal plasma flow =
▫ [PAH ]artery − [PAH ]vein
▪ Measure concentration of PAH in renal
artery/vein, urine; measure urine flow
Figure 60.3 Para-aminohippuric acid (PAH) is used to measure effective renal plasma flow. It is
assumed that about 90% of PAH that enters kidneys through renal artery is excreted in urine,
and only 10% enters the renal vein → ignore this, assume that effective renal plasma flow =
90% of true renal plasma flow.
532 OSMOSIS.ORG
NOTES
NOTES
RENAL ELECTROLYTE
REGULATION
GLOMERULAR FILTRATION
osms.it/glomerular-filtration
▪ Fluid passage through glomerular filtration peritubular capillaries
barrier; approx. 125mL/min ▪ Separates blood in capillaries from
▪ Glomerular filtrate: fluid that passes Bowman's space, Bowman's capsule
through all glomerular filtration barriers ▪ Allows only water, some solutes to pass
▫ Blood minus red blood cells, plasma into Bowman’s space
proteins ▪ Three layers: endothelium, basement
▪ Anything remaining in glomerulus carried membrane, epithelium
away by efferent arteriole ▪ Juxtaglomerular apparatus: secretes renin
▪ Starling forces → glomerular filtration
Endothelium
▫ Different pressures of fluids, proteins in
glomerular capillaries, Bowman's space ▪ Comprised of glomerular capillary
endothelial cells featuring pores (AKA
▪ Most filtration occurs at beginning of
fenestrations)
glomerulus, nearer afferent arteriole
▪ Allows passage of solutes, proteins
▪ Blocks red blood cell passage
Basement membrane
▪ Gel-like layer with tiny pores
▪ Blocks plasma protein passage
▫ Due to pore size, negative membrane
charge
Epithelium
▪ Comprised of podocytes (wrap around
basement membrane)
▪ Also blocks plasma protein passage
Figure 61.1 An illustration depicting the
glomerulus and its relationship to the rest of
the nephron.
GLOMERULAR FILTRATION BARRIER

▪ Capillary walls of glomerulus
▫ Glomerulus: tuft of capillaries in
nephron’s renal corpuscle
▫ Blood enters glomerulus through Figure 61.2 The three layers of the
afferent arteriole → leaves through glomerular filtration barrier.
efferent arteriole → divides into
OSMOSIS.ORG 533
STARLING FORCES Hydrostatic blood pressure in capillary
▪ Determine fluid movement through ▪ Positive relationship
capillary wall ▪ Afferent arteriole vasoconstriction → ↓
▪ Includes hydrostatic/fluid pressures, renal blood flow
oncotic/protein pressures ▫ ↓ hydrostatic blood pressure in capillary
▪ Three Starling forces at play in glomerular (↓ GFR)
filtration barrier ▪ Afferent arteriole vasodilation → ↑ renal
▫ Hydrostatic pressure of blood in blood flow
capillary (Pgc) ▫ ↑ hydrostatic blood pressure in capillary
▫ Hydrostatic pressure of filtrate in (↑ GFR)
Bowman’s space (Pbs) ▪ Efferent arteriole vasoconstriction → ↑ fluid
▫ Oncotic pressure of proteins in capillary in glomerular capillary
(ℼgc) ▫ ↑ hydrostatic blood pressure in capillary
glomerulus: Puf = Pgc - (Pbs + ℼgc)

▪ Determines net ultrafiltration pressure of (↑ GFR)
▪ Efferent arteriole vasodilation → ↓ fluid in
▫ Net ultrafiltration pressure ↓ along each glomerular capillary
proteins remain (↑ ℼgc)

glomerular capillary—as fluid removed, ▫ ↓ hydrostatic blood pressure in capillary
(↓ GFR)
▫ At filtration equilibrium, net ultrafiltration
pressure equals 0 (no fluid filtered) Hydrostatic filtrate pressure in Bowman’s
space
▪ Negative relationship
▪ Doesn’t normally occur
▪ Urine flow blockage → urine backup (e.g.
stone lodged in ureter)
▫ ↑ hydrostatic filtrate pressure in
Bowman’s space (↓ GFR)
Oncotic protein pressure in capillary

▪ Negative relationship
▪ ↑ plasma protein concentration can ↑
oncotic protein pressure in capillary (↓ GFR)
▪ ↓ plasma protein concentration can ↓
Figure 61.3 Illustration depicting the three oncotic protein pressure in capillary (↑ GFR)
Starling forces at play in the glomerular
filtration barrier. FILTRATION FRACTION (FF)
▪ Ratio of glomerular filtration rate to renal
plasma flow
GLOMERULAR FILTRATION RATE
(GFR) ▫ FF = GFR / RPF
▪ Filtrate volume produced by all of body’s ▪ Indicates how much fluid reaching kidneys
glomeruli in one minute is filtered into renal tubules
▪ GFR = Puf × Kf where Kf is filtration
coefficient
▫ Kf: indicates capillary’s fluid permeability
▫ Fenestrations, large surface area → high
Kf for glomerular capillaries
▪ Depends on all three Starling forces
534 OSMOSIS.ORG
Chapter 61 Renal Physiology: Renal Electrolyte Regulation
PROXIMAL CONVOLUTED TUBULE

osms.it/proximal-convoluted-tubule
▪ First renal tubule segment
▪ Receives filtrate from renal corpuscle
▪ Passes filtrate to loop of Henle
▪ Lined by brush border cells
▫ Apical surface faces lumen; lined with
microvilli
▫ Basolateral surface faces interstitium
▪ Surrounded by peritubular capillaries →
reabsorption, secretion of solutes to/from
blood via interstitium Figure 61.4 The relationship between the
▪ Reabsorbs Na+, K+, Ca2+, Cl-, Mg2+ into proximal convoluted tubule's brush border
bloodstream cells and a peritubular capillary.
NA+ MOVEMENT
Natural concentration gradient from lumen
into cells
▪ Cotransporters: use this energy to
move other solutes (e.g. Na+-glucose
cotransporter)
▪ Na+/K+ ATPase: pumps 3Na+ from cell into
interstitium, 2K+ from interstitium into cell
▫ Movement against two concentration
gradients → ATP required
Figure 61.5 The Na+-glucose cotransporter
▪ Na+/H+ exchanger: pumps Na+ from cell into
uses the concentration gradient of Na+ to
cell, H+ from cell into lumen
transport glucose against its concentration
▫ Assists HCO3- reabsorption by creating gradient.
H2CO3 → H2O + CO2
Paracellular route
▪ Leaky tight junctions → some Na+
movement between cells
▫ ↓ claudin proteins → ↑ permeability
▪ Urea, water diffuse straight across cells →
interstitium
▪ Glutamine breakdown inside cell → NH4+
(cell → lumen) + HCO3- (cell → interstitium)
▪ Organic acids, some medications diffuse
directly from capillaries into lumen (e.g.
Figure 61.6 Na+/K+ ATPase and the
penicillin)
paracellular route of Na+ movement.
OSMOSIS.ORG 535
LOOP OF HENLE
osms.it/loop-of-henle
▪ Receives filtrate from proximal convoluted
tubule
▪ Passes filtrate to distal convoluted tubule
▪ Composed of descending, thin ascending,
thick ascending limbs
▪ Establishes osmotic gradient; allows
varying urine concentration
▪ Lined by epithelial cells
▫ Apical surface faces lumen
▪ Surrounded by peritubular capillaries
▫ AKA vasa recta
▫ Reabsorption, secretion of solutes to/
from blood via interstitium
Descending limb
▪ Filtrate that enters has osmolarity of
~300mOsm/L (interstitial osmolarity)
▪ Squamous epithelial cells have aquaporins Figure 61.7 Countercurrent multiplication
on both surfaces is the process of creating the concentration
▫ Water moves across cells into gradient along the loop of Henle. It uses ATP.
interstitium
▪ Osmolarity ↑ to ~1200mOsm/L at bottom
of loop
Thin ascending limb

▪ No aquaporins on thin ascending limb; Na+,
Cl- channels instead
▫ Move from lumen into interstitium along
concentration gradient
▪ Osmolarity ↓ to ~600mOsm/L at top of thin
loop
Thick ascending limb

Figure 61.8 Aquaporins transport H2O
▪ Cuboidal epithelium in thick ascending limb
out of the thin descending limb; channel
has Na-K-2Cl cotransporters
proteins transport Na+ and Cl- out of the thin
▫ Na+, K+, 2Cl- moved from lumen into ascending limb; Na-K-2Cl cotransporters and
cells using Na+ concentration gradient channels transport Na+, K+, and Cl- out of the
▪ Na /K+ ATPase works as previously
+
thick ascending limb.
▪ K+, Cl- channels → move from cell into
interstitium along concentration gradient
▪ Osmolarity ↓ to ~325mOsm/L at top of
thick loop
▪ Countercurrent multiplication: process of
creating concentration gradient along loop
536 OSMOSIS.ORG
DISTAL CONVOLUTED TUBULE

osms.it/distal-convoluted-tubule
Figure 61.9 Filtrate passes through the early Figure 61.10 Illustration of transporters
and late portions of the distal convoluted present in the early distal convoluted tubule.
tubule, then reaches the collecting duct.
Late distal convoluted tubule

▪ Receives filtrate from loop of Henle ▪ → collecting ducts
▪ Passes filtrate to collecting ducts ▪ Principal cells, α-intercalated cells
▪ Composed of early, late distal convoluted dispersed among brush border cells
tubules ▪ Aldosterone upregulates pump synthesis
▪ Lined by brush border cells ▪ Principal cells have
▫ Apical surface faces lumen; not lined ▫ K+ pumps (cell → lumen; uses ATP)
with microvilli
▫ Na+ pumps (“ENaC”; lumen → cell)
▫ Na+/K+ ATPases
▪ Surrounded by peritubular capillaries →
▪ Aquaporin 2 in principal cells allows
reabsorption, secretion of solutes to/from
for water reabsorption in response to
blood via interstitium
antidiuretic hormone
Early distal convoluted tubule ▪ α-intercalated cells have
▪ Impermeable to water ▫ H+ ATPases, H+-K+ ATPases (movement
▪ Na+: natural concentration gradient from against concentration gradients → ATP
lumen → cells required)
▪ Cotransporters use this energy to move ▫ Na+/K+ ATPases
other solutes (e.g. Na+-Cl- cotransporter)
▪ Cl- moves from cells → interstitium through
direct channels
▪ Ca2+ moves across cells → interstitium
through direct channels
▫ On basolateral surface: Na+-Ca2+
channel pumps Na+ from interstitium →
cell, Ca2+ from cell → interstitium
▪ Ca2+ reabsorption regulated by parathyroid
hormone
▫ Creates more Na+-Ca2+ channels
▪ Na+/K+ ATPase works as previously Figure 61.11 Illustration of transporters
present in the late distal convoluted tubule.
OSMOSIS.ORG 537
TF/PX RATIO & TF/PINULIN
osms.it/TF_Px-ratio-TF_Pinulin
[TF/P]x RATIO [TF/P]INULIN
▪ Refers to concentration of substance (X) in ▪ Inulin (inert substance—neither reabsorbed
tubular fluid (TF) and plasma (P) at given nor secreted) concentration throughout
point in nephron nephron helps determine how much is
reabsorbed
Helps determine substance net secretion/ ▪ Inulin concentration will ↑ as water is
absorption reabsorbed
▪ [TF/P]x = 1 ▪ Determined using this formula:
▫ X: not reabsorbed/secreted (e.g. freely 1
filtered) Fraction of filtered water reabsorbed = 1−
[TF / P]inulin
▫ X: reabsorbed in proportion to water
▫ E.g. [TF/P]glucose = 1 when glucose, water ▫ Fraction of filtered water reabsorbed =
reabsorbed equally in Bowman’s space 1 - 1/2 = 0.5 (50%)
▪ [TF/P]x < 1 ▫ [TF/P]inulin = 2 when 50% of water
▫ X: reabsorbed more than water is reabsorbed (inulin concentration
doubles)
▫ E.g. [TF/P]glucose < 1 when glucose
reabsorbed more than water along ▪ Double ratio formula determines fraction of
proximal tubule filtered load of substance in nephron at any
point
▪ [TF/P]x > 1
[TF / P]x
▫ X: reabsorbed less than water/X
secreted into tubular fluid [TF / P]inulin
▫ E.g. [TF/P]urea > 1 in presence of ▪ If [TF/P]Na+ divided by [TF/P]inulin = 0.3,
antidiuretic hormone (ADH) at collecting then 30% sodium remains in tubule, 70%
ducts (water reabsorbed, not urea) reabsorbed
538 OSMOSIS.ORG
CALCIUM HOMEOSTASIS
osms.it/calcium-homeostasis
▪ 1% Ca2+ found in intracellular fluid (ICF), Filtered load reabsorption
extracellular fluid (ECF); 99% in bones, ▪ Coupled with Na+ reabsorption in proximal
teeth tubule, loop of Henle (passively reabsorbed
▪ Functions: cell membrane permeability, via electrochemical gradient created by Na+,
blood clotting, muscle contraction water)
▪ 40% plasma Ca2+ bound to protein ▫ 67% reabsorbed by proximal tubule
▫ Unbound is physiologically active ▫ 25% reabsorbed in thick ascending limb
▫ Regulated by parathyroid hormone of loop of Henle (paracellular route); loop
(PTH) diuretics ↓ reabsorption/↑ secretion
▪ 8% reabsorbed in distal tubule
Ca2+ HANDLING ▫ Reabsorptive Ca2+ regulation site: only
nephron segment not coupled with Na+
Filtration reabsorption; PTH, thiazide diuretics
▪ Only unbound Ca2+ (60%) is filtered → ↑ Ca2+ reabsorption (hypocalciuric
action)
▪ Calculation of Ca2+ filtered load if total
plasma Ca2+ = 5mEq/L and GFR = 180L/ Excretion
day
▪ < 1%
▫ 180 X 5 X 0.6 = 540mEq/day
MAGNESIUM HOMEOSTASIS
osms.it/magnesium-homeostasis
▪ < 1% Mg2+ found in ECF; 60% in bones, Filtered load reabsorption
20% in skeletal muscle, 19% in soft tissues, ▪ 30% reabsorbed by proximal tubule
remainder found in ICF ▪ 60% reabsorbed by thick ascending limb of
▪ Functions: neuromuscular activity; loop of Henle
enzymatic reactions within cells; ATP ▫ Loop diuretics ↓ Mg2+ reabsorption (↑
production; Na+, Ca2+ transport across cell excretion)
membranes
▪ 5% reabsorbed by distal tubule
▪ 20% plasma Mg2+ bound to protein
▫ Unbound is physiologically active Excretion
▪ 5%
Mg2+ HANDLING
Filtration
▪ Only unbound Mg2+ (80%) is filtered
OSMOSIS.ORG 539
PHOSPHATE HOMEOSTASIS
osms.it/phosphate-homeostasis
▪ ICF phosphate (15%) used for DNA, ATP Filtered load reabsorption
synthesis, other metabolic processes ▪ 70% reabsorbed by proximal tubule;
▫ ECF phosphate (<0.5%) serves as buffer 15% by proximal straight tubule via
for H+ Na+-phosphate cotransporter in luminal
▫ 85% in bones membrane
▪ Excess phosphate excreted when Tm
(transport maximum) is reached
PHOSPHATE HANDLING
▪ PTH inhibits Na+-phosphate cotransporter
Filtration → ↓ phosphate Tm → phosphaturia
▪ Freely filtered across glomerular capillaries
Excretion
▪ 15%
POTASSIUM HOMEOSTASIS
osms.it/potassium-homeostasis
▪ Potassium (K+): primary intracellular cation ▪ ↑ ECF osmolarity
▫ Regulates intracellular osmolarity ▫ Osmotic gradient causes H2O
▫ Concentration gradient across cell movement out of cells → ↑ intracellular
membrane establishes resting K+ → diffusion of K+ from ICF to ECF
membrane potential, essential for (H2O brings K+ with it)
excitable cell function (e.g. myocardium) ▪ Exercise
▫ Cellular ATP stores depleted → K+
INTERNAL K+ BALANCE channels open in muscle cell membrane
→ K+ moves down concentration
▪ Difference between intracellular
▪ 𝝰-adrenergic receptor activation

gradient to ECF
K+ concentration (98% of total K+),
extracellular K+ concentration (2% of total
K+) maintained by Na+-K+ ATPase ▫ Hepatic Ca2+-dependent-K+-channel
▪ K+ shifts in/out of cells activation → K+ moves from ICF to ECF
▫ Potentially causes hypo-/hyperkalemia Inward K+ shifts
Outward K+ shifts ▪ Insulin
▪ ↓ insulin ▫ ↑ Na+-K+ ATPase activity → ↑ cellular K+
uptake
▫ ↓ Na+-K+ ATPase activity → ↓ cellular K+
uptake ▪ H+-K+ exchange in alkalosis
▪ Cell lysis ▫ ↓ blood H+ → H+ leaves cell → K+ enters
cell
▫ K+ released from ICF
▪ ↓ ECF osmolality
▪ H -K+ exchange in acidosis
+
▫ Osmotic gradient causes H2O
▫ ↑ blood H+ → H+ enters cell → K+ moves
movement into cells → ↓ ICF K+
from ICF to ECF
concentration → diffusion of K+ from
540 OSMOSIS.ORG
ECF to ICF ▪ Reabsorbed by 𝝰-intercalated cells/

▪ β2-adrenergic receptor activation secreted by principal cells
▫ ↑ Na+-K+ ATPase activity → K+ enters ▫ Dietary K+: high K+ diet—K+ enters cells
cell (via insulin) → ↑ intracellular K+ → ↑ K+
in principal cells → ↑ K+ secretion across
luminal membrane → ↑ K+ excretion; low
EXTERNAL K+ BALANCE
K+ reabsorption by 𝝰-intercalated cells
K+ diet—↓ K+ secretion by principal cell, ↑
▪ Dietary K+ intake = renal excretion of K+ via
renal mechanisms ▫ Aldosterone effects on principal
cells: presence of aldosterone/
K+ HANDLING hyperaldosteronism (↑ K+ secretion);
hypoaldosteronism (↓ K+ secretion)
Filtration ▪ Acid-base imbalance effects on principal
▪ Freely filtered across glomerular capillaries cells: alkalosis (↑ K+ secretion); acidosis (↓
K+ secretion)
Filtered load reabsorption
▪ Diuretic effects on principal cells: loop,
▪ 67% reabsorbed by proximal tubule thiazide (↑ K+ secretion); K+ sparing (inhibit
(isosmotic fluid reabsorption along with aldosterone effects → ↓ K+ secretion)
water, Na+)
▪ Luminal anions (e.g. sulfate, HCO3-) in
▪ 20% reabsorbed by thick ascending limb distal tubule, collecting duct (↑ lumen
▫ K+ reabsorbed without water electronegativity by non-reabsorbable
(impermeable to water) via Na+-K+-2Cl- anions → ↑ K+ secretion)
cotransporter
▫ K+ diffuses through K+ channels across Excretion
basolateral membrane (reabsorption)/K+ ▪ Varies from 1–110% of filtered load
diffuses into lumen (no reabsorption)
▪ Fine-tuning of K+ balance at distal tubule,
collecting duct depending on current
physiological requirements
SODIUM HOMEOSTASIS
osms.it/sodium-homeostasis
▪ Sodium (Na+): primary cation in ECF Effective arterial blood volume (EABV)
▫ Determines ECF osmolarity ▪ ECF volume with arterial system perfuses
tissue
Na+ BALANCE REGULATION ▪ Normal ECF changes → parallel EABV
changes (e.g. ↑ ECF = ↑ EABF)
▪ Na+ balance (Na+ excretion = Na+ intake)
determines ECF volume, blood volume, ▪ Edema: fluid filtered into interstitial space
blood pressure (BP) → ↑ ECF → ↓ EABV (↓ BP) → Na+ excretion
altered by kidneys (attempts to restore
▫ Positive Na+ balance: ↑ Na+ retained
normal EABF, BP)
→ ↑ Na+ in ECF → ECF expansion → ↑
blood volume, ↑ blood pressure Na+ excretion regulation (↑/↓) mechanisms
▫ Negative Na+ balance: ↑ excreted, lost in ▪ Sympathetic nervous system activity
urine → ↓ Na+ in ECF → ECF contraction
▫ Baroreceptors detect ↓ BP →
→ ↓ blood volume, ↓ blood pressure
sympathetic nervous system activation
→ afferent arteriole vasoconstriction, ↑
OSMOSIS.ORG 541
Na+ reabsorption by proximal tubule Na+ HANDLING
▪ Natriuretic hormones: respond to ↑ ECF
Filtration
volume → ↑ GFR, natriuresis (renal Na+,
water excretion) → ↓ ECF ▪ Freely filtered across glomerular capillaries
▫ Atrial natriuretic peptide (ANP): volume Filtered load reabsorption
receptors detect atrial wall stretching →
▪ 67% reabsorbed by proximal tubule
ANP secreted by cells in atria
▫ Isosmotic reabsorption of water, Na+
▫ Brain natriuretic peptide (BNP): volume
receptors in ventricles detect stretching ▫ Water reabsorption coupled with Na+
→ BNP secreted by cells in ventricles reabsorption ([TF/P]Na+ = 1)
▫ Urodilatin: synthesized in distal tubular ▪ 25% reabsorbed by thick ascending limb
cells → paracrine actions on kidney ▫ Na+ reabsorbed without water
(impermeable to water) via Na+-K+-2Cl-
▫ ↑ ECF volume → ECF dilution, ↓ ℼc
▪ Peritubular Starling forces
cotransporter
(capillary oncotic pressure); ↓ proximal ▫ Influenced by ADH, loop diuretics
tubule Na+ reabsorption ▪ 5% reabsorbed by early distal convoluted
tubule
ℼc; ↑ proximal tubule Na+ reabsorption
▫ ↓ ECF volume → ↑ ECF concentration, ↑
▫ Na+ reabsorbed without water
▪ Renin-angiotensin-aldosterone (impermeable to water) via Na+-2Cl-
system (RAAS): ↓ arterial blood cotransporter
pressure (BP) → ↓ renal perfusion → ▫ Influenced by thiazide diuretics
juxtaglomerular apparatus secretes ▪ 3% reabsorbed by late distal convoluted
renin → angiotensinogen (plasma tubule
protein) converted to angiotensin I → ▫ Influenced by aldosterone
angiotensin I converted to angiotensin II
→ adrenal cortex secretes aldosterone, Excretion
vasoconstriction → ↑ Na+, Cl-, water ▪ < 1% excreted (99% net Na+ reabsorption)
reabsorption → ↑ ECF volume, ↑ BP
Excess Na+ intake response
↓ ℼc → ↓ sympathetic activity, ↑ ANP (and

▪ → Na+ ECF distribution → ↑ ECF, ↑ EABV,
other natriuretic hormones), ↓ RAAS → ↑

Na+ excretion
▪ → ↓ ECF, ↓ EABV, ↑ ℼc → ↑ sympathetic

Decreased Na+ intake response
activity, ↓ ANP (and other natriuretic

hormones), ↑ RAAS → ↓ Na+ excretion
542 OSMOSIS.ORG
NOTES
NOTES
RENAL REABSORPTION
& SECRETION
TUBULAR REABSORPTION
& SECRETION
osms.it/tubular-reabsorption-secretion
▪ Blood chemistry balanced, urine formed Filtration with partial reabsorption
through glomerular filtration, tubular ▪ Electrolytes (e.g. sodium, bicarbonate)
reabsorption, secretion easily reabsorbed, may be partially
▫ Filtered blood continues through reabsorbed, secreted
glomerulus, substances reabsorbed/
secreted according to body’s needs Filtration with complete reabsorption
▫ Entire plasma volume filtered approx. 60 ▪ Nutritional substances (e.g. glucose, amino
times/day acids) completely reabsorbed
REABSORPTION SECRETION
▪ Retention of substances contained in ▪ Substances not reabsorbed (e.g. organic
filtrate back into peritubular capillary blood acids), secreted into tubular fluid to become
urine
Filtration only/no reabsorption
▪ Occurs with: products of metabolism (e.g.
urea, creatinine), foreign substances (e.g.
drugs)
TUBULAR REABSORPTION
OF GLUCOSE
osms.it/tubular-reabsorption-glucose
▪ Filtration rate of glucose: mass of glucose basolateral surface; peritubular
filtered through kidneys per day (depends capillaries surround tubules
on plasma glucose concentration)
▪ Kidney filtrate passes through renal tubules GLUCOSE REABSORPTION
in nephron before becoming urine
▪ Occurs primarily in proximal convoluted
▫ Tubules lined by brush border cells with tubule
apical surface (lined with microvilli),
OSMOSIS.ORG 543
gradient to move glucose against
concentration gradient
2. Glucose diffuses across basolateral
membrane into peritubular capillaries
(facilitated diffusion with GLUT1/GLUT2)
▪ Normal plasma glucose levels (< 200mg/
dL): glucose reabsorption matches filtration
▪ High plasma glucose levels (> 200mg/
dL): limited number of glucose transporter
proteins prevents reabsorption from
keeping up with filtration
▪ Higher glucose levels (> 350mg/dL):
glucose transporter proteins fully saturated,
reabsorption cannot go faster; transport
maximum (Tm)
Figure 62.1 Graph showing glucose filtration
rate as a function of plasma glucose. As the
plasma glucose concentration increases, the GLUCOSE EXCRETION
filtered load of glucose increases linearly. ▪ Excess glucose excreted in urine
▫ Threshold: plasma glucose level at
which glucose excretion starts
Two steps ▫ Splay: initial, nonlinear increase in urine
1. Glucose moves across apical membrane excretion
into brush border cells ▪ Glycosuria (glucose excreted in urine) may
▫ Glucose concentration inside cells be caused by diabetes mellitus (↓ insulin
typically higher than outside → sodium- → ↑ plasma glucose)/hormonal changes
glucose linked transporters use energy during pregnancy (↑ renal blood flow → ↑
from existing sodium concentration glucose filtration)
Figure 62.12 An illustration depicting the two steps of glucose reabsorption that occur in the
proximal convoluted tubule: transport across the apical membrane of the brush border cells,
followed by transport across the basolateral membrane of the brush border cells by GLUT1 or
GLUT2.
544 OSMOSIS.ORG
Chapter 62 Renal Physiology: Renal Reabsorption & Secretion
Figure 62.2 A graph showing glucose reabsorption and secretion rates as a function of plasma
glucose. The glucose reabsorption line plateaus because the plasma [glucose] has been reached
where all the GLUT1/GLUT2 transporters in virtually all the nephrons are occupied by glucose
molecules.
TUBULAR SECRETION OF PARA-

ANIMOHIPPURIC ACID (PAH)
osms.it/tubular-secretion-PAH
▪ Body's entire plasma volume, including
some para-aminohippuric acid (PAH),
filtered approx. 60 times/day
▫ PAH: organic acid; approx. 90% bound
to plasma proteins, cannot be filtered
▫ Filtration rate of PAH: mass of PAH
filtered through kidneys per day
(depends on plasma concentration of
unbound PAH)
▪ Kidney filtrate passes through renal tubules
in nephron before becoming urine
▫ Tubules lined by brush border cells with Figure 62.3 Graph showing PAH filtration
apical surface (lined with microvilli), rate as a function of unbound plasma PAH.
basolateral surface; peritubular
capillaries surround tubules
OSMOSIS.ORG 545
▪ No renal reabsorption of PAH ▪ Low PAH concentrations (< Tm): all PAH
▪ PAH secretion occurs primarily in proximal leaves via urine
convoluted tubule ▪ PAHentering = PAHexcreted
▫ Special carrier proteins on basolateral ▪ [PAH]R.A. x RPF = [PAH]urine x urine flow
membrane transport PAH, other organic rate (UFR)
anions directly into tubules ▫ Renal, urine concentrations of PAH both
▪ Low plasma PAH levels: PAH secretion measured in milligrams per millilitre
increases linearly with PAH concentration ▫ RPF, urine flow rate (UFR) both
▪ Higher plasma PAH levels: limited number measured in liters per minute
of carrier proteins prevents secretion from ▪ RPF = ([PAH]urine x UFR)/[PAH]R.A. (milliliters
increasing, even with increasing PAH of plasma per minute)
concentration (Tm) → some PAH left behind ▪ Some PAH may remain in renal vein →
in peritubular capillaries estimate usually accurate to 10% of true
▪ Both filtered, secreted PAH excreted in RPF
urine ▪ Renal plasma flow can be used to calculate
renal blood flow (RBF)
Using PAH to estimate renal plasma flow
(RPF) ▫ RBF = RPF/(1-Hct)
▪ Fick’s principle: PAHentering = PAHleaving ▫ Hematocrit (Hct): volume of blood
occupied by red blood cells (RBCs)
▪ PAH enters kidney via renal artery; leaves
via renal vein/urine
Figure 62.4 Graph showing PAH secretion and excretion rates as a function of plasma PAH.
546 OSMOSIS.ORG
Chapter 62 Renal Physiology: Renal Reabsorption & Secretion
UREA RECYCLING
osms.it/urea-recycling
▪ Urea: one of body’s waste products of Henle (resulting in 110% of initial urea in
(byproduct of amino acid breakdown) bottom of loop of Henle)
▪ Freely filtered across kidneys’ glomerular ▫ Occurs due to higher urea concentration
capillaries, travels through renal tubule in medullary interstitium
▪ Part of reabsorbed urea secreted back into ▪ Ascending limb of loop of Henle, early distal
loop of Henle → “urea recycling” convoluted tubule impenetrable to urea,
▫ Helps establish corticopapillary gradient water (urea levels stay same)
(reabsorbs water from kidneys back into ▪ 70% of initial urea reabsorbed into
blood) interstitium in late distal convoluted tubule,
cortical, outer medullary collecting ducts
Four steps to urea recycling (leaving behind 40% of initial urea to be
▪ 50% of urea reabsorbed by simple diffusion excreted in urine)
in proximal convoluted tubule (leaving ▫ Occurs due to antidiuretic hormone
behind 50% of initial urea), together with (ADH)-induced water reabsorption
water through aquaporins → concentration
▪ Urea from medullary interstitium secreted gradient of urea towards interstitium
back into tubule in descending limb of loop
WEAK ACIDS & BASES -

NON-IONIC DIFFUSION
osms.it/non-ionic_diffusion
▪ Many substances secreted by proximal ▪ Nonionic weak acids, bases lipid soluble,
tubule weak acids/bases able to passively diffuse back into blood
▪ Exist in uncharged (nonionic)/charged from urine
(ionized) forms; amount depends on pH of ▪ Ionized weak acids, bases not lipid soluble,
tubular fluid remain in tubular fluid to be excreted
▫ Urine with low pH: nonionic forms ▪ Excretion of unwanted substances, toxins
dominate accomplished by manipulating urine pH,
▫ Urine with higher pH: ionized forms promoting ionization
dominate
OSMOSIS.ORG 547
NOTES
NOTES
WATER REGULATION
OSMOREGULATION
osms.it/osmoregulation
▪ Regulation of body fluid solute
concentrations
▫ Concentrations measured in osmolarity
(mOsm/L)
▫ Osmole: single ion in solution
BLOOD PLASMA OSMOLARITY

▪ 290–300 mOsm/L
▪ Main components
▫ Sodium, glucose, urea
▪ Osmolarity = 2[Na+] + [Glucose]/18 +
[BUN]/2.8
▫ Glucose, blood urea nitrogen (BUN)
measured in mg/dL
HYDRATION
▪ Changes in hydration affect plasma Figure 63.1 Body response to overhydration.
osmolarity, blood pressure
▫ Osmoreceptors in supraoptic nuclei of
anterior hypothalamus detect changes
in plasma osmolarity
▫ Baroreceptors in cardiovascular system
detect changes in blood pressure
▪ Osmoreceptors, baroreceptors regulate
production of ADH in hypothalamus
Overhydration
▪ Plasma osmolarity decreases, blood
pressure increases
▪ Osmoreceptors, baroreceptors fire less,
stimulating less ADH production
▪ Less/no water reabsorbed from kidneys
Dehydration
▪ Plasma osmolarity increases, blood
pressure decreases
▪ Osmoreceptors, baroreceptors fire more, Figure 63.2 Body response to dehydration.
stimulating greater ADH production
▪ More water reabsorbed from kidneys
548 OSMOSIS.ORG
Chapter 63 Renal Physiology: Water Regulation
KIDNEY COUNTERCURRENT
MULTIPLICATION
osms.it/kidney-countercurrent-multiplication
▪ Concentration gradient (corticopapillary ▪ Single effect recurs, fluid more
gradient) established in medulla of kidney concentrated at bottom of ascending limb
→ more ions enter interstitium at bottom
TWO STEPS Two steps repeat
▪ In nephron loop of Henle ▪ Form concentration gradient of
1200mOsm/L at inner medulla,
Single effect
300mOsm/L at outer cortex
▪ Takes advantage of ascending limb being
impermeable to water
▪ Sodium, potassium, chloride ions enter COUNTERCURRENT EXCHANGE
tubule cells along ascending limb via ▪ Important process for corticopapillary
Na+K+2Cl- cotransporters on apical surface gradient
▪ Na/K ATPase pumps sodium ions through ▪ Peritubular capillaries permeable to water,
basolateral surface into interstitium in solutes
exchange for potassium ions ▪ Osmosis would destroy corticopapillary
▪ Potassium, chloride ions enter interstitium gradient if capillaries only ran along
▪ Osmosis → ions in interstitium diffuse into descending limb → peritubular capillaries
descending limb → fluid concentration run down descending limb, up ascending
limb → allow extra solutes pulled from
Flow of fluid interstitium near descending limb to
▪ Uses new fluid to distribute ions return to interstitium near ascending limb
(as corticopapillary gradient decreases)
▪ New fluid pushes existing fluid around loop
→ water diffused from capillary into
▪ Concentrated fluid (previously in interstitium returns
descending limb) enters ascending limb
Figure 63.3 To increase urine osmolarity, nephrons rely on the corticopapillary gradient. The
interstitium becomes increasingly hypertonic relative to the lumen of the tubule.
OSMOSIS.ORG 549
Figure 63.4 Single effect: ions leave ascending limb, but water can’t follow → urine osmolarity
in ascending limb decreases. Water can pass through descending limb → descending limb
equilibrates with the interstitium. Numeric values = number of mOsm/L (e.g. 300 = 300mOsm/L).
550 OSMOSIS.ORG
Figure 63.5 Flow of new fluid into the loop of Henle + single effect = corticopapillary gradient.
Numeric values = number of mOsm/L (e.g. 300 = 300mOsm/L).
OSMOSIS.ORG 551
Figure 63.6 Countercurrent exchange: peritubular capillaries run down the descending limb and
up the ascending limb to maintain the corticopapillary gradient.
ANTIDIURETIC HORMONE
osms.it/antidiuretic-hormone
▪ Peptide hormone prevents excessive urine capillaries → binds to V2 receptors
production by reabsorbing water from (AVPR2) on basolateral membrane of
kidneys principal cells (along collecting ducts of
▪ Allows body to control amount of fluid nephrons)
retention ▪ AVPR2 signals adenylyl cyclase to convert
▪ Antidiuretic hormone (ADH) production ATP to cAMP → cell produces water
triggered by osmoreceptors in supraoptic protein channels called aquaporins, opens
nuclei of anterior hypothalamus, existing aquaporins (in apical membrane) of
baroreceptors in cardiovascular system; principal cells → osmosis pulls water from
stimulated by angiotensin II lumen of ducts into interstitium, reabsorbed
▪ ADH (AKA vasopressin) also causes into circulation
smooth muscles cells in arteries to constrict
ADH PATHWAY
▪ Produced in paraventricular, supraoptic
neurons of hypothalamus → travels down
axons through infundibulum → stored in
posterior pituitary gland
▪ When needed, released into blood, travels
to kidneys
▪ In kidneys, travels through peritubular
552 OSMOSIS.ORG
Figure 63.7 The ADH pathway. Increased plasma osmolarity triggers ADH release from the
posterior pituitary. ADH acts on the principal cells of the distal convoluted tubule, collecting
ducts → ↑ aquaporins in the cell membranes → ↑ water reabsorption → ↓ plasma osmolarity.
OSMOSIS.ORG 553
Figure 63.8 ADH is produced in the paraventricular and supraoptic nuclei in the hypothalamus,
stored in Herring bodies in paraventricular and supraoptic neurons, and released into the
bloodstream from the posterior pituitary gland.
FREE WATER CLEARANCE

osms.it/free-water-clearance
▪ Free water: water without solutes ANTIDIURETIC HORMONE EFFECTS
▪ Free water clearance: rate at which kidneys ▪ High amounts of ADH → lots of free water
filter free water out of blood plasma reabsorbed, retained (negative free water
clearance) → hyperosmotic urine
PATHWAY ▪ Low amounts of ADH → little free water
reabsorbed, excreted (positive free water
▪ Free water filtered out of blood plasma in
clearance) → hypoosmotic urine
ascending limbs, distal convoluted tubules
of kidneys’ nephrons, solutes removed ▪ Free water clearance, 0: excreted urine has
same osmolarity as blood plasma
▪ Free water reabsorbed into circulation
through aquaporin protein channels in ▪ CH2O = V - (Uosm/Posm)V
collecting ducts ▫ V: urine flow rate (mL/min)
▫ Uosm: urine osmolarity
▫ Posm: plasma osmolarity
554 OSMOSIS.ORG
NOTES
NOTES
FEMALE REPRODUCTIVE
SYSTEM
ANATOMY & PHYSIOLOGY OF THE

FEMALE REPRODUCTIVE SYSTEM
osms.it/female-reproductive-system
EXTERNAL ORGANS
▪ Labia minora, labia majora, clitoris (erectile
tissue), mons pubis
▫ Vulvar vestibule: space between labia
minora; includes vaginal, urethral
opening
INTERNAL ORGANS
Ovaries (female gonads)
▪ Epithelial, follicular, granulosa, theca, oocyte
cells
▪ Secrete estrogen, progesterone Figure 8.1 External organs of the female
▪ Located superior, lateral to uterus reproductive system.
▪ Held in place by ovarian, broad, suspensory
ligaments
▫ Suspensory ligaments contain ovarian
artery, vein, nerve plexus
▪ Made up of outer cortex, inner medulla
▫ Cortex contains ovarian follicles (oocytes
surrounded by granulosa cells); medulla
contains blood vessels, nerves
Fallopian tubes (uterine tubes)

▪ Two tubes, each associated with one ovary,
on side of uterus
▪ Flattened mesothelial, epithelial, secretory,
intercalary cells
▪ Fimbriae around ovary → infundibulum →
ampulla (where fertilization most commonly
occurs) → isthmus region opens into
uterine cavity
▪ Covered by peritoneum, supported by
mesosalpinx Figure 8.2 External organs of the female
▪ Lined with smooth muscle, cilia to sweep reproductive system.
zygote towards uterus; inner mucosa
provides nutrients for oocyte
OSMOSIS.ORG 555
Uterus
▪ Located posterior to bladder, anterior to
rectum
▪ Fundus (top) → uterine body → uterine
isthmus → cervix (neck of uterus)
▫ Cervical opening to vagina: external os;
thins, dilates during childbirth
▫ Cervical opening into uterine cavity:
internal os
▪ Anchored to sacrum (uterosacral ligaments)
→ anterior body wall (round ligaments)
Figure 8.3 The locations of the ovarian, ▪ Supported by cardinal ligaments,
suspensory, and broad ligaments. mesometrium
▪ Three layers of uterine wall
▫ Perimetrium, myometrium (smooth
muscle), endometrium (highly vascular
mucosal layer)
Vagina
▪ Extends from uterus, opens into vulva
(covered by hymen in childhood)
▪ Outer muscular wall containing rugae; inner
mucous membrane of stratified squamous
epithelium
▪ Fornix (superior, domed area) connects to
sides of cervix
Figure 8.4 Outer cortex of ovary containing
follicles and inner medulla containing blood
vessels, nerves.
Figure 8.6 The three layers of the uterine

wall. External to internal: perimetrium →
myometrium → endometrium.
Figure 8.5 Features of the fallopian tubes.
556 OSMOSIS.ORG
Chapter 64 Reproductive Physiology: Female Reproductive System
Figure 64.7 Anterior view of the uterus and lateral view of the uterus in relationship to
surrounding structures.
OOGENESIS ▫ Follicle with most follicle-stimulating

hormone (FSH) receptors becomes
Fetal development dominant follicle; primary oocyte →
▪ Oogonia (primordial oocyte cell) undergo meiosis I completed, secondary oocyte
mitotic division → ↑ oogonia (diploid cells) (haploid cell with 23 chromosomes)
▪ 7 months formed
▫ Oogonia begin meiotic division, become ▪ Ovulation: dominant follicle ruptures →
primary oocytes (diploid cells) secondary oocyte released → peritoneal
cavity → pulled inside fallopian tube
Follicular development ▪ Luteal phase: follicle remains → corpus
▪ Infancy to puberty luteum (luteinized granulosa, theca cells)
▫ Primary oocyte surrounded by ▫ Luteinized granulosa cells secrete
granulosa cells form primary (primordial) inhibin → ↓ FSH → ↓ estrogen → ↓
follicle luteinizing hormone (LH)
▪ Menstrual cycle (approx. every 28 days) ▫ Luteinized theca cells: ↑ progesterone
▫ Primary follicle → secondary follicle → → dominant hormone
tertiary (Graafian) follicle
▪ Antrum (fluid-filled cavity) forms in Graafian Fertilization
follicles; granulosa cells secrete nourishing ▪ If fertilization occurs → oocyte becomes
fluid for primary oocyte mature ovum → progesterone produced
▪ Theca cells produce androstenedione (sex until placenta forms
hormone precursor) → converted into ▪ If fertilization does not occur → corpus
estradiol in granulosa cells luteum → corpus albicans
▪ Follicular phase of menstrual cycle:
Graafian follicles grow
OSMOSIS.ORG 557
558 OSMOSIS.ORG
Figure 64.8 Stages of follicular development. Stage one: primordial follicles → primary follicles,
meaning that the follicular cells surrounding the primary oocyte develop into granulosa cells.
Stage two: primary follicles → secondary follicles → teritary (Graafian) follicles. This stage
results in a few fast-growing Graafian follicles. Stage three: dominant follicle is established.
Ovulation: dominant follicle ruptures, releases secondary oocyte into fallopian tube. The
secondary oocyte stops in metaphase of meiosis II. Luteal phase: weeks 3 to 4 of menstrual
cycle. The remains of the follicle turn into the corpus luteum. If fertilization occurs, the corpus
luteum keeps making progesterone until the placenta forms. If not, the corpus luteum stops
making hormones after about ten days, becomes fibrotic → corpus albicans.
OXYTOCIN & PROLACTIN

osms.it/oxytocin-prolactin
▪ Peptide hormones involved in production, → stored in Herring bodies → released into
release of milk blood → target tissues (e.g. breasts, uterus)
OXYTOCIN PROLACTIN (PL)

▪ Essential for progression of labor, control ▪ Synthesized by lactotrophs in anterior
of postpartum bleeding, return of uterus to pituitary → target tissue (breasts)
pre-pregnancy state (involution) ▪ Synthesis inhibited by dopamine during
▪ Synthesized, secreted by hypothalamus → non-pregnant/non-breastfeeding state
travels down axons to posterior pituitary
Figure 64.9 Synthesis and secretion of oxytocin and prolactin.
OSMOSIS.ORG 559
FUNCTIONS DURING LACTATION
▪ Neuroendocrine reflex: suckling by infant at
breast → stimulates mechanoreceptors in
nipple, areola → action potential travels up
spinal cord to hypothalamus
▪ First, burst of oxytocin released from
posterior pituitary → enters bloodstream →
breasts, uterus
▫ Myoepithelial cells surrounding alveoli
in breasts contract → milk ejection from
alveolus (let-down reflex)
▫ Stimulates contractile activity of uterine
myometrium → ↓ postpartum bleeding;
promotes uterine involution Figure 64.10 Anatomy of the breast.
▪ Second, thyrotropin-releasing hormone
(TRH) from hypothalamus → PL
released from anterior pituitary →
enters bloodstream → breasts → ↑ milk
production, secretion by alveolar epithelial
cells
▪ ↑ PL inhibits release of GnRH from
hypothalamus → ↓ LH, FSH from anterior
pituitary → ↓ development of ovarian
follicles, ovulation, menstrual periods
Figure 64.11 Illustration of the neuroendocrine reflex. In response to the suckling of a baby,
oxytocin released from the posterior pituitary stimulates ejection of milk, and prolactin released
from the anterior pituitary increases milk production.
560 OSMOSIS.ORG
FUNCTIONS DURING & AFTER ▫ Positive feedback loop: ↑ uterine

LABOR contractions → fetal head pushes
▪ Oxytocin (powerful uterine muscle against cervix → neural signal travels
stimulant) produced during pregnancy, to spinal cord → hypothalamus → ↑
does not stimulate uterine contractions due oxytocin release from posterior pituitary
to → ↑ uterine contractions → cycle
▫ Rapid degradation by placental continues until delivery (baby, placenta)
oxytocinase ▪ After labor, milder contractions continue
▫ Progesterone-induced inhibition of ▫ Clamp down on placental arteries at
oxytocin receptors on myometrium placental attachment site → ↓ bleeding
▪ Estrogen-induced oxytocin receptor ▫ Gradually ↓ size of uterus (involution)
expression + ↑ myometrial sensitivity to ▫ Additional oxytocin released during
oxytocin promotes uterine contractions breastfeeding → speeds involution
during labor
MENSTRUAL CYCLE
osms.it/menstrual-cycle
▪ Menstruation (menses): shedding of uterine Day 1
functional endometrium ▪ Hypothalamus releases gonadotropin-
▪ Occurs approx. every 28 days releasing hormone (GnRH) → anterior
pituitary releases FSH, LH → one oocyte
dominates → develops within primary
follicle
▪ Primary (primordial) follicle: oocyte
surrounded by single layer of granulosa
cells (nourish oocyte)
Days 1–13
▪ Granulosa cells proliferate → follicle grows
→ develops outer layer of cells (theca layer)
→ respond to LH by producing estrogen →
mature follicle
▫ Estrogen acts on uterine endometrium
to prepare for fertilized egg →
Figure 64.12 The uterine endometrium
initiates uterine proliferative phase →
consists of a thin base layer and a functional
endometrial lining grows
layer. The functional layer is subject to the
changes (thickening and shedding) that occur ▫ Estrogen also feeds back to
during the menstrual cycle. hypothalamus, pituitary → turns off
GnRH, FSH, LH
Day 14
FOLLICULAR PHASE ▪ Brief LH surge stimulates ovulation →
▪ Ovulation (days 1–14): maturing follicles, follicle ruptures → oocyte ejected out of
proliferation of uterine mucosa, dominated follicle
by estrogen
OSMOSIS.ORG 561
LUTEAL PHASE Day 25
▪ After ovulation, empty follicle collapses ▪ If fertilization does not occur → corpus
→ turns into corpus luteum → produces luteum undergoes apoptosis →
progesterone (approx. 14 days) progesterone levels fall
▫ Endometrium becomes highly ▪ If fertilization does occur → embryonic
vascularized, glycogen-filled tissue tissue secretes human chorionic
(secretory phase) gonadotropin (hCG) → signals corpus
luteum to continue production of estrogen,
Days 15–24 progesterone to support pregnancy
▪ Egg travels through fallopian tube
PREGNANCY
osms.it/pregnancy
▪ Obstetric history (GTPAL) activity (6–8 weeks)
▫ G (gravida): number of pregnancies,
regardless of duration (including current ESTIMATED DATE OF DELIVERY
pregnancy) (EDD)
▫ T: number of term infants born ▪ Calculated from last menstrual period (LMP)
▫ P: number of preterm infants born to estimated date of delivery (EDD)
▫ A: number of spontaneous/induced ▪ Naegele’s rule: add 7 days to 1st day of
abortions LMP, subtract 3 months, add 7 days, add 1
▫ L: number of currently living children year
▫ Example: G3P1202 (3 pregnancies, 1 ▪ Ultrasonic examination
term birth, 2 preterm births, 0 abortions, ▫ Measurement of crown-to-rump length
2 living children) in first trimester
▪ Pregnancy lasts approx. 280 days (40 ▪ Measurement of fundal height estimates
weeks); divided into three trimesters pregnancy progression
▫ Symphysis: 12–14 weeks
SIGNS & SYMPTOMS ▫ Umbilicus: 20 weeks
▫ Rises above umbilicus 1 cm/week until
Presumptive
36 weeks
▪ Amenorrhea; breast fullness, tenderness;
nausea/vomiting (“morning sickness”);
urinary frequency; fatigue; fetal movement PHYSIOLOGICAL CHANGES IN THE
(16–20 weeks of gestation) REPRODUCTIVE SYSTEM
Probable Uterus
▪ Uterine enlargement; softening of uterine ▪ ↑ size, capacity due to hypertrophy,
isthmus (Hegar sign); vaginal, cervical hyperplasia, mechanical stretching
purplish-blue discoloration (Chadwick sign); ▪ 20 times larger
positive urine/serum hCG ▪ ↑ strength, distensibility, contractile
proteins, number of mitochondria
Positive
▪ ↑ volume capacity (10 mL–5 L)
▪ Auscultation of fetal heart tones (7–8
▪ Softening of uterine isthmus (Hegar’s sign)
weeks of gestation); “quickening” (fetal
movements); fetal sac visualized by
ultrasound (5–6 weeks); fetal cardiac
562 OSMOSIS.ORG
Figure 64.13 Fundal height = distance from symphysis pubis to top of uterus (fundus). Fundal
height is a good estimate of gestational age.
Cervix (sebaceous glands)

▪ Formation of mucus plug; seals ▪ Progesterone
endocervical canal ▫ ↑ alveolar-lobular development; prevents
▪ ↑ vascularity → purplish-blue color milk production during pregnancy
▪ Mild softening due to edema, hyperplasia (inhibits prolactin)
(Goodell’s sign); ↑ softening in third ▪ Estrogen
trimester ▫ ↑ growth of lactiferous ducts
▪ Secretion of colostrum begins week 16
Placenta
▪ Develops where embryo attaches to uterine
wall PHYSIOLOGICAL CHANGES IN
▪ Expands to cover 50% internal uterine OTHER BODY SYSTEMS
surface
Cardiovascular
▪ Functions as maternal-fetal organ for
▪ Mild hypertrophy
metabolic, nutrient exchange
▪ S2, S3 more easily auscultated, split
▪ Secretes estrogen, progesterone, relaxin,
exaggerated
hCG
▪ Heart displaced upward, forward, slightly
Vagina to left
▪ ↑ vascularity → bluish-purple color ▪ ↑ heart rate by 15–20 beats/minute
▪ Loosening of connective tissue → ↑ ▪ Stroke volume ↑ 30%, cardiac output (CO)
distensibility ↑ 30-50% (by term); ↓ blood pressure (BP)
▪ Leukorrhea despite ↑ CO due to progesterone-induced
▫ pH of 3.5–6.0 → protects against vasodilation; BP = CO × systemic vascular
bacterial infections resistance (SVR)
▪ Supine hypotensive syndrome caused by
Breasts gravid uterus pressing on inferior vena cava
▪ ↑ size, weight, nodularity, blood flow, (left lateral recumbent position optimal for
vascular prominence CO, uterine perfusion)
▪ Areola, nipples are a darker pigmentation ▪ Gravid uterus elevates pressure veins
due to ↑ melanocyte activity draining legs, pelvic organs → slowed
▪ ↑ activity of Montgomery’s tubercles venous return, dependent edema, varicose
veins, hemorrhoids
OSMOSIS.ORG 563
Respiratory
▪ ↑ oxygen consumption, subcostal angle,
anteroposterior diameter, tidal volume
(30–50%), minute ventilatory volume,
minute oxygen uptake
▪ Gravid uterus places upward pressure on
diaphragm → elevates approx. 4 cm
▪ Hyperventilation → mild respiratory
alkalosis (renal compensation → maternal
blood pH 7.40–7.45)
▪ Nasal congestion, epistaxis due to
estrogen-induced edema
Figure 64.14 Cardiovascular changes during Gastrointestinal

pregnancy. When lying down, uterus presses ▪ Gums bleed easily due to estrogen-induced
on inferior vena cava → less blood to right hyperemia, friability
atrium → hypotension. The uterus also ▪ Progesterone-induced smooth muscle
presses on pelvic veins → varicose veins, relaxation, delayed gastric emptying,
swelling in lower legs, ankles. ↓ peristalsis → nausea, vomiting (AKA
“morning sickness” ); constipation;
heartburn (pyrosis), esophageal reflux;
Hematologic intrahepatic cholestasis of pregnancy due
▪ ↑ blood volume (approx. 1500 mL) to ↓ gallbladder emptying time → ↑ risk of
▫ Related to sodium, water retention due cholelithias
to changes in osmoregulation, secretion ▪ ↑ saliva production (ptyalism)
of vasopressin by anterior pituitary,
renin-angiotensin-aldosterone system Urinary & renal
(RAAS) ▪ Bladder
▪ ↑ total red blood cell (RBC) volume (approx. ▫ First trimester: gravid uterus presses on
30%), with iron supplementation bladder → urinary frequency, nocturia,
▫ ↑ volume, oxygen-carrying capacity stress incontinence
needed for ↑ basal metabolic rate ▫ Second trimester: uterus occupies
(BMR), needs of uterine-placental unit abdominal space → ↓ urinary frequency
(offsets blood loss at delivery) ▫ Third trimester: presenting part
▫ Plasma > RBC volume → hemodilution, descends into pelvis → urinary
↓ hematocrit (physiologic anemia) frequency, nocturia, stress incontinence
▪ ↑ white blood cell (WBC) count (approx. ▪ ↑ glomerular filtration rate (GFR)
5,000–12,000/mm3 ) ▫ 40–50% by second trimester; ↑ urinary
▪ ↑ clotting factors (fibrin, fibrinogen): output (25%)
hypercoagulable state of pregnancy ▪ ↑ size of kidneys (1–1.5 cm)
▪ Dilation of urinary collecting system →
physiologic hydronephrosis
▪ Urinalysis
▫ Glycosuria (due to ↑ glucose load),
↑ protein excretion (due to altered
proximal tubule function + ↑ GFR)
Integumentary
▪ Hyperpigmentation (due to estrogen, ↑
melanocyte activity) → melasma (chloasma)
Figure 64.15 Pregnancy is a high volume brownish “mask of pregnancy”; linea
state. Plasma volume ↑ > RBC volume ↑ → ↓ nigra formation on abdomen; darkening of
hematocrit (physiologic anemia).
564 OSMOSIS.ORG
nipples, areolae, vulva ▪ “Diabetogenic state” of pregnancy

▪ ↑ cutaneous blood flow → ↑ heat ▫ ↑ need for glucose, insulin production →
dissipation → pregnancy “glow” hypertrophy, hyperplasia of pancreatic
▪ ↓ connective tissue strength secondary to beta cells
↑ adrenal steroid levels → stretch marks ▪ ↓ thyroid-stimulating hormone (TSH);
(striae gravidarum) in breasts, abdomen, thyroid gland enlarges; ↑ total T3, T4
thighs, inguinal area ▪ Reproductive hormones
▪ Estrogen-induced vascular permeability → ▫ hCG from placenta; estrogen,
spider nevi, angiomas, palmar erythema progesterone from corpus luteum (first,
second trimesters), placenta (second,
Musculoskeletal third trimesters)
▪ Abdominal distension + shift in center of ▫ Suppressed FSH, LH due to feedback
gravity → lordosis from estrogen, progesterone, inhibin
▪ Enlarging uterus → separation of ▫ ↓ oxytocin levels throughout pregnancy
abdominal rectus muscles (diastasis recti) → ↑ labor onset → ↑↑ second stage of
▪ ↑ progesterone, relaxin → ↑ joint mobility, labor
“waddling” gait
▫ Widening of symphysis pubis
NUTRITIONAL NEEDS
▫ Facilitates accommodation of fetus into
pelvis ▪ Recommendation of additional 300 kcal/
day, weight gain of 25–35 pounds (11.5–
▪ High bone turnover, remodeling
16 kg)
Endocrine ▫ 11 lb (5 kg): placenta, amniotic fluid,
▪ ↑ size of pituitary gland; mostly due to fetus
proliferation of lactotroph cells ▫ 2 lb (0.9 kg): uterus
▫ ↑ intrasellar pressure → ↑ risk of ▫ 4 lb (1.8 kg): ↑ blood volume
postpartum infarction (Sheehan ▫ 3 lb (1.4 kg): breast tissue
syndrome) in setting of postpartum ▫ 5–10 lb (2.3–4.5 kg): maternal reserves
hemorrhage ▪ 600 mcg folic acid/day → RBC synthesis,
▪ ↑ parathyroid hormone (meets calcium placental/fetal growth, ↓ risk of neural tube
need of developing fetal skeleton) defects
▪ Physiologic hypercortisolism ▪ 1,000–1,300 mg calcium/day supports
▫ ↑ need for estrogen, cortisol → ↑ pregnancy, lactation
glucocorticoids from adrenal glands → ▪ 60g protein daily supports tissue growth
supports fetal somatic, reproductive ▪ 27 mg iron/day supports ↑ RBCs
growth
LABOR
osms.it/labor
▪ Labor (parturition): uterine contractions PREMONITORY SIGNS
→ cervical changes → delivery of baby, ▪ Cervical changes
placenta ▫ Remodeling of cervix by enzymatic
▪ Begins at term (37–42 weeks of gestation) collagen dissolution, ↑ water content →
▪ Duration of three stages varies with softening, ↑ distensibility
gravidity (nulliparas typically longer than ▪ Cervical softening → expulsion of mucus
multiparas) plug → “bloody show” (pink-tinged mucus)
OSMOSIS.ORG 565
▪ Spontaneous rupture of amniotic Transition phase
membranes (ROM) ▪ 30 minutes–2 hours
▪ Intense contractions every 1.5–2 minutes
False labor
▪ Duration 60–90 seconds
▪ AKA Braxton-Hicks contractions
▪ Cervical dilation 7–10cm
▪ True labor: regular, increase in frequency,
duration, intensity; produce cervical ▪ Effacement 100%
changes (e.g. dilation/opening up,
effacement/getting thinner); pain begins SECOND STAGE
in lower back, radiates to abdomen, not
▪ AKA pushing stage
relieved by ambulation
▪ Begins with full dilation
▪ False labor: irregular, intermittent
contractions; no cervical changes; pain in ▪ Navigation through maternal pelvis dictated
abdomen; walking may decrease pain by 3 Ps
▫ Power, passenger, passage
FIRST STAGE OF LABOR Power

▪ Frequency, duration, intensity of uterine
Early/latent
contractions
▪ 8–12 hours
▪ Physiology of contractions
▪ Mild contractions every 5–30 minutes
▫ Stimulation of uterine myometrium
▪ Duration 30 seconds each
▫ Alpha-receptors stimulate uterine
▪ Gradually increase in frequency, intensity, contractions
duration
▫ Numerous oxytocin receptors, mostly on
▪ Cervical dilation 0–3 cm uterine fundus
▪ Effacement 0–30% ▪ Contraction steps
▪ Spontaneous ROM ▫ Wave begins in fundus, proceeds
downward to rest of uterus → muscle
Active phase
shortens in response to stimulus →
▪ 3–5 hours increment (build up) → acme (peak)
▪ Contractions every 3–5 minutes → decrement (gradual letting up) →
▪ Duration ≥ 1 minute relaxation → fetal descent, cervical
▪ Cervical dilation 3–7 cm effacement, dilation → amount of
▪ Effacement 80% pressure exerted by uterine contractions
(intrauterine pressure) measured in
▪ Progressive fetal descent
millimeters of mercury (mm Hg)
Figure 64.16 Features of the phases of the first stage of labor.
566 OSMOSIS.ORG
Passenger ▫ Gynecoid: rounded pelvic inlet,

▪ Fetal size midpelvis, outlet capacity adequate;
▫ Fetal head most critical; cephalopelvic optimal for vaginal delivery
disproportion → labor dystocia (difficult/ ▫ Android: heart-shaped pelvic inlet; ↓
obstructed) midpelvis diameters, outlet capacity;
▫ Macrosomia (birth weight ≥ 90th associated with labor dystocia
percentile for gestational age/> 4500 g) ▫ Anthropoid: oval-shaped pelvic inlet;
associated with shoulder dystocia (fetal midpelvis diameters, outlet capacity
shoulder unable to pass below maternal adequate; favorable for vaginal delivery
pubic symphysis), birth injuries ▫ Platypelloid: oval-shaped pelvic inlet,
▪ Fetal attitude: relationship of fetal parts to ↓ midpelvis diameters, outlet capacity
one another adequate; not favorable for vaginal
▫ Full flexion (chin on chest; rounded delivery
back with flexed arms, legs); smallest ▪ Cardinal movements (mechanisms of labor)
diameter of head (suboccipitobregmatic ▫ Descent:: presenting part reaches pelvic
diameter) presents at pelvic inlet inlet (engagement) before onset of labor
▪ Fetal lie: relationship of fetal cephalocaudal → degree of descent (fetal station),
axis (spinal column) to maternal relationship of presenting part to
cephalocaudal axis maternal ischial spines → fetus moves
▫ Longitudinal (ideal): fetal spine lies from pelvic inlet (-5 station) down to
along maternal ischial spines (0 station) to pelvic outlet
(+4 station) to crowning at vaginal
▫ Transverse: fetal spine perpendicular to
opening (+5 station)
maternal
▫ Flexion: fetal chin presses against chest,
▫ Oblique: fetus at slight angle
head meets resistance from pelvic floor
▪ Fetal presentation: fetal/presenting part
▫ Internal rotation: fetal shoulders
enters pelvic inlet first
internally rotate 45º; widest part of
▪ Cephalic: head first shoulders in line with widest part of
▫ Vertex (most common): optimal for pelvic inlet
easy delivery; head completely flexed ▫ Extension: fetal head passes under
onto chest → occiput (part of fetal skull symphysis pubis (+4 station), moves (+5
covered by occipital bone) is presenting station), emerges from vagina
▫ Brow: fetal head partially extended; ▫ Restitution (external rotation): head
sinciput (part of fetal skull covered externally rotates as shoulders pass
by frontal bone, anterior fontanelle to through pelvic outlet, under symphysis
orbital ridge) presenting part pubis, turns to align with back
▫ Face: fetal head hyperextended; fetal ▫ Expulsion: anterior shoulder slips under
face from forehead to chin presenting symphysis pubis, followed by posterior
part shoulder, rest of the body; marks end of
▪ Breech: head up; bottom, feet, knees second stage
present first
▫ Frank breech: hips flexed, knees
extended; bottom presents
THIRD STAGE
▪ Delivery of placenta, umbilical cord, fetal
▫ Complete breech: hips, knees flexed;
membranes; uterus contracts firmly,
bottom presents
placenta begins to separate from uterine
▫ Incomplete breech: one/both hips not wall
completely flexed; feet present
▫ Shoulder: transverse lie; shoulders
present first FOURTH STAGE
▪ Physiological adaptation to blood loss,
Passage initiation of uterine involution
▪ Route through bony pelvis
▪ Size, type of pelvis
OSMOSIS.ORG 567
Figure 64.17 Fetal attitude, lie, and presentation are all critical factors in determining the fetus’
ease of passage through the maternal pelvis.
568 OSMOSIS.ORG
Figure 64.18 Second stage cardinal movements: the fetal position changes that occur during labor.
OSMOSIS.ORG 569
BREASTFEEDING
osms.it/breastfeeding
▪ Provision of breast milk from lactating every 3 hours
breast; involves breast tissue development, ▪ If milk not removed, builds up → ↑
initiation of milk secretion lactogenesis intramammary pressure → ↓ capillary blood
▪ Pregnancy, human placental lactogen flow → glandular tissue involutes → ↓ milk
(hPL), progesterone released from placenta, production
+ PL released from anterior pituitary gland
→ stimulates growth of breast glandular
tissue → prepares epithelial cells lining
BIOCHEMICAL COMPOSITION OF
alveoli to produce milk
BREAST MILK
▫ Progesterone prevents lactation until Benefits for baby
after delivery of placenta ▪ ↑ whey to casein ratio, enzymes, hormones
▪ Delivery of baby, placenta → ↓↓ → ↑ absorption, digestion of milk
progesterone → milk synthesized in alveoli ▪ Immunoglobulins
▫ ↓ risk of infection; esp. respiratory,
INFANT SUCKLING gastrointestinal, otitis media; ↓ risk of
▪ Stimulates release of oxytocin, PL necrotizing enterocolitis in premature
infants
Oxytocin ▪ Long-chain polyunsaturated fatty acids
▪ Required for milk to be released from alveoli (PUFAs)
▪ Neuroendocrine reflex → let-down reflex ▫ Aids neural. visual development
(milk ejection) ▪ ↑ beneficial bacteria (Lactobacillus,
▫ Myoepithelial cells contract → milk Bifidobacterium) in gut microflora
ejection from alveolus → drained by ▪ Cytokines
milk-collecting ducts → transported to ▫ Anti-inflammatory properties
nipple
▪ Ideal source of nutrition for newborns,
▪ Milk ejection continues as long as infant including premature infants
continues suckling
▪ Milk composition transitions from early
▪ Other triggers for oxytocin release, let- postpartum period to mature milk to meet
down reflex infant needs
▫ Sounds/sights/smells connected to
infant (e.g. infant crying) Benefits for mother
▪ Accelerated uterine involution, ↓ risk of
PL chronic disease (e.g. diabetes Type II,
▪ Continues milk production arthritis, heart disease; cancers of breast,
▪ Amount of milk produced depends on ovaries, uterus)
amount removed at feeding (supply meets
demand) Colostrum
▪ Milk extraction facilitated by good latch ▪ Small amounts of milk produced during
of baby onto nipple, frequent emptying of second half of pregnancy
breast ▪ Thick, yellowish fluid (due to beta-
▫ Good latch: baby’s mouth wide open, carotene) rich in immune cells, antibodies,
covering areola, lips flanged out, nipple antioxidants, protein, fat-soluble vitamins,
up against roof of mouth, baby’s tongue minerals; low in fat, lactose
up against bottom of areola ▪ Protects newborn from infection; laxative
▫ Feedings every 1–2 hours at first, then effect → passage of first stool (meconium),
570 OSMOSIS.ORG
formed in fetal gastrointestinal tract ▪ Presentation: firm, tender breast; may have
▪ Helps establish healthy gut microbiome ↑ vascular markings
▪ Treatment: empty breasts (↑ breastfeeding,
Transitional milk pumping); warm shower/compresses
▪ Produced 7–10 days postpartum; thinner before feeding (enhances let-down), cool
than colostrum; light yellow color compresses after feeding; nonsteroidal
anti-inflammatory drugs (NSAIDs);
Mature milk application of cool green cabbage leaves
▪ Produces 2 weeks postpartum ▪ Prevention: frequent feedings, good latch
▪ Watery, slight bluish color; fat content to ensure emptying breast
increases during feeding
▪ Biologically complex Sore, cracked nipples
▫ Protein, fat, sugars (e.g. lactose, ▪ Cause: improper latch, positioning
oligosaccharides), vitamins, minerals, ▪ Presentation: pain; blister/bleb on nipple if
immunoglobulins, antibodies (esp. pores plugged
secretory IgA), immune cells (e.g. ▪ Treatment: cool/warm compresses; apply
macrophages, neutrophils), immune- expressed breast milk to nipple; mild
modulating factors (e.g. lactoferrin, analgesics (e.g. acetaminophen)
lysozyme, lactoperoxidase) ▪ Prevention: good breastfeeding technique
▪ Low in vitamin D; supplementation often
recommended Mastitis
▪ Continues to be produced until lactation ▪ Cause: bacterial infection
ceases ▪ Presentation: usually unilateral, localized
▪ Healthy maternal diet supports breast milk warmth, tenderness/pain, edema,
production erythema, firmness; acute onset of flu-like
symptoms (e.g. fever, fatigue)
▪ Treatment: continued breastfeeding,
CONTRAINDICATIONS & CAUTIONS NSAIDs, antibiotics
TO BREASTFEEDING
▪ Prevention: good hygiene
Contraindications
Yeast infections
▪ Certain maternal medications (e.g.
chemotherapy), illicit drugs (e.g. cannabis, ▪ Cause: Candida albicans; history of infant
heroin) oral/diaper candidal infection/maternal
vaginal candidal infection
▪ HIV infection (in high-income settings)
▪ Presentation: infant may have white
▪ Herpes zoster, herpes simplex
plaques in oral area; mother may
▫ If lesions on breast experience pain, red/sore nipples
▪ Tuberculosis ▪ Treatment: for mother, topical antifungal
▫ Until approx. 2 weeks of maternal applied after feeding; infant, nystatin
pharmacotherapy solution swabbed into oral mucosa after
feeding
Cautions
▪ Prevention: good hygiene; avoid excessive
▪ Smoking discouraged (↑ risk of SIDS, moisture by keeping breasts dry between
respiratory problems) feedings
▪ Minimize alcohol; if consumed, wait two
hours before breastfeeding
▪ Limit caffeine
BREASTFEEDING PROBLEMS
Engorgement
▪ Cause: milk accumulation in breast tissue,
vascular congestion, resulting in pain
OSMOSIS.ORG 571
MENOPAUSE
osms.it/menopause
▪ Diagnosed when menstrual cycles have Others
stopped for entire year, no identified ▪ Urinary tract dysfunction → dysuria, urinary
pathological cause urgency
▪ Caused by natural effects of ovarian ▪ Mood instability → depression, anxiety
follicular depletion during aging process ▪ Decline in cognitive function, difficulty
▪ Usually begins age 50 concentrating
▪ Preceded by perimenopause ▪ ↓ collagen content in skin → ↑ skin
▫ 4 years before final menstrual period; wrinkling
missed/irregular menstrual cycles, ▪ ↓ lean body mass
changes in bleeding patterns (heavy, ▪ Individualized approach for menopausal
prolonged, light) hormone therapy (MHT)
▫ Estrogen/estrogen + progestin helpful in
HORMONAL CHANGES some cases
▪ ↓ estrogen, progesterone → ↓ hypothalamic
inhibition → ↑ bursts of GnRH → ↑ FSH,
LH
PHYSIOLOGICAL EFFECTS OF
ESTROGEN WITHDRAWAL
Hot flashes
▪ Caused by hypothalamus-associated
thermoregulatory dysfunction → vasomotor
instability
▪ Sensation of heat (centered on chest, face
→ generalized), diaphoresis, palpitations,
anxiety
▪ Night sweats
▫ Hot flashes occur at night → trouble
sleeping
▪ Avoid triggers (e.g. hot drinks, spicy foods);
maintain cool ambient temperature; dress
in lighter clothing
▪ Stops within few years of onset
Vulvovaginal atrophy
▪ Vaginal dryness, loss of vaginal rugae →
dyspareunia
▪ Vaginal estrogen creams, lubricants helpful Figure 64.19 Hormone activity in a regular
menstrual cycle. Estrogen and progesterone
↓ protective effects from estrogen levels ↓ during menopause because the
▪ ↑ risk of cardiovascular disease ovaries run out of functional follicles → no
▪ ↓ bone marrow density → ↑ risk of theca or granulosa cells to produce more
osteoporosis, bone fractures hormones. So ↓ estrogen, progesterone → ↓
hypothalamic inhibition → ↑ bursts of GnRH
▫ ↑ vitamin D, calcium (diet, supplements)
→ ↑ FSH, LH.
helpful
572 OSMOSIS.ORG
ESTROGEN & PROGESTERONE

osms.it/estrogen-progesterone
▪ Female steroid hormones, produced mainly estrogen, progesterone
by ovaries
▫ Some estrogen produced in adrenal EFFECTS OF ESTROGEN
cortex, adipose tissue; secreted by
▪ Maturation of female reproductive organs
placenta during pregnancy
(e.g. uterus, fallopian tubes, vagina)
▫ Corpus luteum secretes estrogen,
▪ Secondary sexual characteristics (e.g.
progesterone
breast growth, fat distribution)
▪ Three types
▪ ↑ estrogen (pre-ovulation) → prepares
▫ Estradiol (most biologically active), uterine epithelium for implantation
estrone, estriol (endometrial proliferation); endometrial
secretion in collaboration with progesterone
SYNTHESIS ▪ Dominant hormone during the follicular
▪ Cholesterol → theca cells → converted to phase of ovarian cycle; follicle maturation;
pregnenolone via cholesterol desmolase → initiates ovulation via FSH, LH surge
pregnenolone converted into progesterone
Pregnancy
via 3-beta-hydroxysteroid dehydrogenase
(HSD) → released into blood → binds ▪ Secreted by placenta to support uterus;
to plasma proteins (e.g. albumin) → stimulates development of myometrium
transported to target tissues ▪ ↑ melanin-stimulating hormones →
▪ Remainder of pregnenolone converted to hyperpigmentation
17-hydroxypregnenolone → converted ▪ ↑ vascularity of upper respiratory tract;
into dehydroepiandrosterone (DHEA) → hypersecretion of mucus
finally converted into androstenedione ▪ Preparation for labor
(testosterone precursor) by 3-beta-HSD ▫ Stimulates development of myometrial
▪ Androstenedione diffuses to nearby gap junctions, promotes coordinated
granulosa cells → androstenedione contractions
converted to testosterone by 17-beta- ▫ Promotes cervical ripening
hydroxysteroid → testosterone converted ▫ ↑ uterine responsiveness to oxytocin
to 17-beta-estradiol dehydrogenase (↑ oxytocin receptors), triggering
aromatase (most biologically active type of parturition
estrogen during reproductive period)
▪ Breasts
▪ 17-beta-estradiol released into blood →
▫ Stimulates growth of duct cells
binds to sex hormone-binding globulin
(SHBG) Systemic
▫ Plasma protein, carries 17-beta- ▪ Required for closure of epiphyseal plates
estradiol to target tissues (e.g. uterus, (both sexes)
vagina, bones)
▪ Anabolic effect on bones
▪ ↓ low-density lipoprotein (LDL), ↑ high-
SECRETION density lipoproteins (HDL)
▪ Regulated by hypothalamic-pituitary- ▪ Maintains flexibility of blood vessels
ovarian axis through feedback loops ▪ Promotes skin elasticity, fat deposition
▪ At puberty, pulsatile release of GnRH from ▪ ↓ estrogen during perimenopausal/
hypothalamus → anterior pituitary secretes menopausal years → ↑ risk of
FSH, LH → ovarian follicles differentiate cardiovascular morbidity, osteoporosis,
into theca, granulosa cells → secrete sexual dysfunction
OSMOSIS.ORG 573
EFFECTS OF PROGESTERONE ▪ Breasts: ↑ alveolar-lobular development,
▪ Dominant hormone during luteal phase of prevents milk production during pregnancy
ovarian cycle (inhibits prolactin)
▪ ↑ progesterone (secretory phase of ▪ Respiratory:: ↑ sensitivity to CO2, mild
menstrual cycle) → forms decidual tissue hyperventilation, ↓ airway resistance
for implantation ▪ ↑ vasodilation
Pregnancy Systemic
▪ Maintains pregnancy: ↓ irritability of ▪ Works with estrogen to promote bone
myometrium → ↓ risk of spontaneous remodeling → ↑ bone density
abortion ▪ Promotes skin elasticity
▪ Cervis: forms mucus plug
Figure 64.20 The steps of progesterone synthesis. LH stimulates proliferation of theca cells →
cholesterol desmolase converts more cholesterol into pregnenolone.
Figure 64.21 Synthesis of androstenedione from pregnenolone. Androstenedione will be used in

the next steps to synthesize 17-beta-estradiol.
574 OSMOSIS.ORG
Figure 64.22 Synthesis of 17-beta-estradiol from androstenedione. FSH increases the activity of
aromatase. Some target tissues for 17-beta-estradiol include the uterus and vagina, bones, and
blood vessels.
OSMOSIS.ORG 575
NOTES
NOTES
MALE REPRODUCTIVE SYSTEM
ANATOMY & PHYSIOLOGY OF THE

MALE REPRODUCTIVE SYSTEM
osms.it/anatomy-physiology-male-reproductive-system
EXTERNAL ORGANS
▪ Penis, scrotum
▪ Two testes (male gonads) in scrotum
Penis
▪ Smooth muscle cells
▪ Enlarged tip (glans penis), surrounded by
loose skin (foreskin)
▪ Opens as external urethral orifice
▪ Three cylindrical bodies of erectile tissue
(vascular spaces, surrounded by smooth Figure 65.1 External and internal male
muscle) reproductive system anatomy.
▫ Corpus spongiosum, two corpora
cavernosa
▪ Arousal → smooth muscle cells relax,
blood flows into vascular spaces, corpora
cavernosa distend → veins compress,
blood doesn't drain → local engorgement
→ erection
Testes
▪ Functions: produce sperm (in seminiferous
tubules), testosterone (by Leydig cells)
▫ Descend into scrotum from abdominal
cavity (seventh month of gestation)
▫ Scrotum provides cooler environment
needed for spermatogenesis
▪ Contains epithelial, Sertoli, Leydig, sperm
cells
▪ Separated by scrotal raphe
▪ Covered by tunica albuginea
▫ Septa project towards center → 250
lobules (1–4 seminiferous tubules) Figure 65.2 Penis anatomy.
▪ Seminiferous tubules
▫ Surrounded by epithelial lining,
576 OSMOSIS.ORG
Chapter 65 Reproductive Physiology: Male Reproductive System
capillaries, Leydig cells ▪ Spermatogonium (diploid cell)

▫ Spermatogonia (primordial sperm cells) undergoes mitosis → two daughter cells
→ spermatocytes (towards lumen) → (spermatogonia)
spermatids → sperm (most central); ▫ One spermatogonia cycled back to
Sertoli cells (extend from margin to serve as spermatogonium
lumen; provide nutrients; establish ▫ Second spermatogonia continues on to
blood-testis barrier) produce sperm
▫ Tubules combine → rete testis (in ▪ Spermatogonia (diploid cell) undergoes
mediastinum testis) → efferent ducts → mitosis → primary spermatocyte
epididymis ▪ Primary spermatocyte undergoes meiosis I
→ secondary spermatocytes (haploid cells)
INTERNAL ORGANS emerge
▪ Ducts for sperm, accessory glands (seminal ▪ Secondary spermatocytes undergo meiosis
vesicles, prostate gland, bulbourethral II → spermatids (haploid)
glands) ▪ Spermatids enter lumen → cellular
Sperm
▪ Acrosome: enzymes to penetrate oocyte
(female gamete)
▪ Neck (midpiece): mitochondria for energy
▪ Tail: helps sperm swim
▪ Mature, swim in epididymis head; move
through seminiferous tubules, rete testis by
peristalsis
Spermatogenesis
▪ Begins at puberty
▪ Hypothalamus secretes gonadotropin- Figure 65.4 Sperm anatomy.
releasing hormone (GnRH) → pituitary
secretes luteinizing hormone (LH), follicle-
stimulating hormone (FSH)
▫ LH binds to Leydig cells → stimulates
testosterone production
▫ FSH binds to Sertoli cells → produces
androgen binding protein (ADP) → more
testosterone crosses blood-testis barrier
Figure 65.5 Hypothalamus secretes GnRH,

stimulates pituitary release of FSH, LH
(important to testosterone production).
Figure 65.3 Testes anatomy.
OSMOSIS.ORG 577
differentiation → acquire tail → mature sperm
▪ Regulation via feedback loops
▫ Sertoli cells secrete inhibin → negative
feedback to pituitary → ↓ FSH
▫ Leydig cells secrete testosterone →
negative feedback to pituitary → ↓ LH
Ejaculation
▪ Mature sperm exit through tail of
epididymis → vas deferens → secretions
from seminal vesicle at ampulla →
ejaculatory ducts → secretions from
prostate gland → secretions from
bulbourethral glands → empty into urethra
▪ Accessory glands secrete fluids into urethra
▫ Seminal: seminal fluid (contains fructose
for energy, prostaglandins for transport)
▫ Prostate: prostatic fluid (alkaline →
neutralizes acidic vaginal secretions)
▫ Bulbourethral: lubricant
▪ Semen (seminal fluid): final mixture of all Figure 8.6 Spermatogenesis.
fluids with spermatozoa
▪ During ejaculation, bladder sphincter
contracts (prevents urine from mixing with
semen)
Figure 65.7 Once produced, the mature sperm exit the tail of the epididymis (1) and travel
through the vas deferens (2) where they are combined with secretions of the seminal vesicles
(3) at the ampulla. The mature sperm then pass through the ejaculatory ducts and secretions of
the prostate gland (4). Finally, the bulbourethral gland (5) secretions are added and the semen is
ejaculated through the urethra.
578 OSMOSIS.ORG
Chapter 65 Reproductive Physiology: Male Reproductive System
TESTOSTERONE
osms.it/testosterone
WHAT IS TESTOSTERONE? NEGATIVE FEEDBACK
▪ Main androgenic hormone REGULATION
▪ Produced, released by Leydig cells of testes ▪ High testosterone levels → inhibits
▪ Synthesized from cholesterol in series of hypothalamus from secreting GnRH,
steps involving multiple enzymes pituitary gland from secreting LH
▪ Inactivated in liver → eliminated in urine, ▪ Sertoli cells in testes secrete glycoprotein
bile called inhibin → inhibits pituitary gland
secreting FSH
▪ Active locally on Sertoli cells (paracrine
action)
▫ Sertoli cells produce androgen-binding
protein (ABP) → keep testosterone
levels high
▫ Testosterone reinforces follicle-
stimulating hormone (FSH)
spermatogenesis stimulation
▪ Active in rest of body (endocrine action)
Circulation in bloodstream
▪ Approx. 98% bound to proteins (albumin,
sex-hormone binding globulin)
▫ Not biologically active when bound to
protein
▫ Functions as reservoir of free
testosterone
▫ Production regulated by androgens,
Figure 65.8 Testosterone production is
estrogens
regulated through a negative feedback
▪ Approximately 2% free, biologically active loop by the hormones released by the
hypothalamus and the Leydig cells.
PRODUCTION
Regulated by hypothalamic-pituitary axis MECHANISM OF ACTION
▪ Low testosterone → hypothalamic arcuate ▪ Binding on androgen receptor in cell of
nuclei secrete GnRH into hypothalamic- target tissue → androgen-receptor complex
hypophyseal portal blood → GnRH moves into nucleus → gene transcription →
arrives to anterior lobe of pituitary gland generation of new proteins → physiological
→ pituitary gland secretes FSH, LH (AKA effects
gonadotropins)
▫ LH → Leydig cells produce testosterone
EFFECTS OF ANDROGENIC
by increasing cholesterol conversion into
HORMONES TESTOSTERONE &
pregnenolone (first step of testosterone
DIHYDROTESTOSTERONE
production)
▫ FSH → spermatogenesis, Sertoli cell Testosterone
function ▪ Masculinizes internal genital tract in male
fetus; promotes descent of testes before
birth
OSMOSIS.ORG 579
▪ Puberty: muscle mass increases;
epiphyseal plates close; penis, seminal
vesicles grow; spermatogenesis; rise of
libido; secondary sexual characteristics
(thickens vocal cords, deepening voice,
male pattern of hair growth)
▪ Adulthood: maintains reproductive tract;
anabolic effect on proteins
Dihydrotestosterone (DHT)
▪ Produced from testosterone by 5 alpha-
reductase in target tissues
▪ Determines
▫ Fetal maturation of external male
genitalia (penis, scrotum, prostate)
▫ Hair distribution (baldness)
▫ Sebaceous gland activity
▪ 5 alpha-reductase inhibitors
block testosterone conversion in
dihydrotestosterone → treats male pattern
baldness, benign prostatic hypertrophy
▫ Propecia (finasteride)
580 OSMOSIS.ORG
NOTES
NOTES
SEXUAL DEVELOPMENT
DEVELOPMENT OF THE
REPRODUCTIVE SYSTEM
osms.it/reproductive-system-dev
SEXUAL DIFFERENTIATION MALE DEVELOPMENT
▪ Series of events begins at conception,
Male gonadal development
ends with sexual characteristics acquisition
(designated biologically male/female) ▪ Embryo genetically male → gene
expression in Sex-determining Region in Y
▪ During first five gestational weeks
chromosome (SRY) promoted
▫ Gonadal ridge develops, later becomes
▫ SRY-region genes promote testis-
differentiated gonads
determining factor production →
▪ Week 6 testis-determining factor acts on
▫ Primordial germ cells start migrating undifferentiated gonads → gonadal
from yolk sac towards gonadal ridge transformation into testes
▪ Week 7 ▫ Gonadal ridge becomes seminiferous
▫ Primordial germ cells promote tubules, rete testis, straight tubules
gene expression contained in sex ▪ Testes contain three functional cell types
chromosomes ▫ Germ cells: produce spermatogonia →
▪ Wolffian, Müllerian ducts: structures that produce male gametes in puberty
will develop into rest of reproductive tract; ▫ Sertoli cells: synthesize anti-Müllerian
remain undifferentiated until week 8 hormone
▫ Leydig cells: synthesize testosterone
Figure 66.1 Illustration of the migration of primordial germ cells to the gonadal ridge in week 6.
At this point, the gonad is undifferentiated, meaning that it can develop into ovaries or testes.
OSMOSIS.ORG 581
Male internal reproductive organ ▫ Promotes Wolffian/mesonephric-duct
development growth, differentiation
▪ Wolffian ducts give rise to male internal ▪ Urogenital sinus: develops into external
genitalia reproductive organs; undifferentiated until
▫ AKA mesonephric duct/mesonephros gestational week 9
▫ Meso = middle, in between; nephros = ▫ Urethral folds → urethra (both)
kidney ▫ Labioscrotal swellings → scrotum
▫ Two functions: connects primitive ▫ Primordial phallus → penis
kidney to cloaca; develops into male
genitalia Male external reproductive organ
▫ Growth, differentiation stimulated by development
testosterone ▪ Male external genitalia differentiation from
▪ Male internal reproductive organ urogenital sinus depends on testosterone
development depends on Sertoli cells, presence
Leydig cells, urogenital sinus ▫ 5 alpha reductase in target tissues
▪ Sertoli cells: synthesize, secrete anti- converts testosterone → more potent
Müllerian hormone; AKA Müllerian dihydrotestosterone
inhibiting substance ▫ Dihydrotestosterone: responsible for
▫ Promotes Müllerian/paramesonephric- masculinizing external genitalia
duct atrophy
▪ Leydig cells: synthesize, secrete
testosterone → become internal male
genitalia
Figure 66.2 Biologically male sexual differentiation, week 7: genes in Sex-determining Region
of Y chromosome (SRY) code for testis-determining factor (which initiates development of
testes). Primitive sex cords → medullary cords that carry primitive germ cells deeper into
mesoderm. The surface epithelial layer of each gonad thins out → tunica albuginea. Later,
medullary cords → seminiferous tubules, straight tubules, rete testis. The primordial germ
cells settle in seminiferous tubules mature into dormant spermatogonia. During puberty,
spermatogonia start dividing → sperm (male gametes). During week 8, some cells in the
seminiferous tubule walls differentiate into Sertoli cells, and cells between the seminiferous
tubules differentiate into Leydig cells.
582 OSMOSIS.ORG
Chapter 66 Reproductive Physiology: Sexual Development
FEMALE DEVELOPMENT ▫ Lack of testosterone induces Wolffian

duct degeneration
Female gonadal development
▫ Lack of anti-Müllerian hormone
▪ Without functional SRY gene promotes Müllerian ducts persistence
▫ Week 9: ovaries begin developing → develop into fallopian tubes, uterus,
▫ Week 10: ovarian cortex, inner medulla upper ⅓ of vaginal canal
distinguishable ▫ Rest of female reproductive organs arise
▪ Ovaries contain three functional cell types from urogenital sinus
▫ Germ cells: produce oogonia; located in
Female external reproductive organ
ovarian cortex (oogonia—haploid cells
development
that remain arrested in prophase 1 of
meiosis until ovulation) ▪ Urogenital sinus develops into external
reproductive organs; undifferentiated until
▫ Granulosa cells: synthesize estradiol
▫ Urethral folds → urethra (both ⚥), labia

gestational week 9
▫ Theca cells: synthesize progesterone
▪ Ovarian follicle: oogonium surrounded by minora
granulosa cells, connective tissue
▫ Labioscrotal swellings → labia majora,
Female internal reproductive organ mons pubis
development ▫ Primordial phallus → clitoris
▪ Müllerian duct → female genitalia ▪ Female external genitalia differentiation
▫ AKA paramesonephric duct/ ▫ Androgen absence-dependent
paramesonephros (testosterone, dihydrotestosterone)
▫ Para = on the side of; meso = middle, in ▪ Phenotypic differentiation complete at
between; nephros = kidney week 12 → earliest ultrasound-based sex-
▪ Female internal reproductive organ determination date
development primarily depends on testes
absence
Figure 66.3 Biologically-female sexual differentiation. Since there is no Y chromosome to

secrete Testis-determining factor, the undifferentiated gonads develop into ovaries. The rest of
the reproductive tract acquires female characteristics in the absence of testosterone.
OSMOSIS.ORG 583
Figure 66.4 The genital ducts are initially undifferentiated, tubular structures that run down the
embryo’s back inside the two nephrogenic cords on either side of the embryo. The Wolffian and
Müllerian ducts start in the thoracic and upper lumbar region and continue down the embryo’s
back until they open into the part of the cloaca called the urogenital sinus.
Figure 66.5 Male internal reproductive organ differentiation and descent of gonads.
Figure 66.6 Female internal reproductive organ differentiation and descent of gonads.
584 OSMOSIS.ORG
SEX VS. GENDER Internal, external reproductive organ

▪ Gender structure
▫ Socially-constructed characteristics/ ▪ Male genitalia
behaviors associated with biologically ▫ Internal: prostate, seminal vesicles, vas
male/female people deferens, epididymis
▫ E.g. norms, roles, relationships between ▫ External: penis, scrotum
individuals ▪ Female genitalia
▪ Genetic sex ▫ Internal: fallopian tubes, uterus, upper ⅓
▫ Individual’s chromosomal composition vaginal canal
▫ XY: males ▫ External: clitoris, labia majora, labia
▫ XX: females minora, lower ⅔ vaginal canal
▫ Established by oocyte, sperm cell fusion
▪ Gonadal sex
▫ Individual’s reproductive organs
▫ Male: testes
▫ Female: ovaries
▪ Phenotypic sex
Figure 66.7 Male and female external sex organs. Phenotypical differentiation is complete at
week 12.
OSMOSIS.ORG 585
PUBERTY & TANNER STAGING
osms.it/puberty-tanner-staging
PUBERTY Adrenarche
▪ Sexual maturation process involving ▪ ↑ adrenal androgen production by adrenal
endocrine, physical changes; controlled by cortex
hypothalamic-pituitary-gonadal axis
▪ Begins between ages 10–14 in females; Thelarche
between age 12–16 in males ▪ Breast tissue appears
▫ Ovarian estradiol-guided
GnRH secretion
▪ Pulses from hypothalamus regulate Menarche
luteinizing hormone (LH), follicle- ▪ First menstruation occurs
stimulating hormone (FSH) secretion from ▫ Ovarian estradiol-guided
anterior pituitary → development of sexual ▫ First menstrual cycles tend to be
characteristics anovulatory
▫ Primary sex characteristics: genitals
(organs directly involved in sexual Spermarche
reproduction) ▪ First sperm production occurs
▫ Secondary sex characteristics: ▫ FSH, LH, testosterone-guided
sex-specific physical characteristic ▫ Nocturnal sperm emissions, sperm
not necessary involved in sexual appears in urine
reproduction (e.g. pubic hair—both
sexes, voice changes—males, breast Pubarche
development—females) ▪ Pubic hair appears
▫ Adrenal androgens-guided
Gamete production
▫ Association: body hair; acne; apocrine
▪ Oocytes (females); sperm (males)
sweat glands activation
▪ Males: LH acts on Leydig cells → produces
testosterone; FSH acts on Sertoli cells →
produces sperm
▪ Females: LH acts on ovarian follicles →
produces progesterone, androstenedione
(converted into estrogen)
▫ Estrogen, progesterone levels vary
according to menstrual cycle phases
Gonadal steroid production

▪ Testosterone (males), estradiol (females)
secretion → ↑ circulating sex hormones
▪ Secondary sexual characteristics develop
▪ Stimulate bone growth, ossification
▪ Involved in growth hormone production → Figure 66.8 Puberty begins when pulse
growth spurt generator in hyothalamus begins secreting
GnRH in pulses → pulsatile secretion of
FSH and LH. In puberty, GnRH receptors in
EVENTS OF PUBERTY anterior pituitary become more sensitive to
GnRH stimulation: small ↑ GnRH = large ↑
Gonadarche
FSH, LH levels.
▪ Gonadal activation by FSH, LH
586 OSMOSIS.ORG
TANNER STAGING
▪ ⚥ Pubic hair becomes coarser
Stage 3
▪ ♂ Penis begins to enlarge in size, length

▪ System for describing predictable steps
during sexual maturation
▪ Centers on two, independent criteria ▪ ♀ Breast mounds form
▫ Appearance: pubic hair in males,
▪ ⚥ Pubic hair begins to cover pubic area

females Stage 4
▪ ♂ Penis begins to widen

▫ Genital development: ↑ testicular
▪ ♀ Breast enlargement forms “mound-on-

volume, penile growth (males); breast
development (females)
mound” breast contour
FIVE CATEGORIES OF TANNER
▪ ⚥ Pubic hair extends to inner thigh
Stage 5: adult
STAGING
▪ ♂ Penis, testes enlarged to adult size
▪ ⚥ No pubic hair present in either sex ▪ ♀ Breast takes on adult contour
Stage 1: pre-pubertal
▪ ♂ Small penis, testes

▪ ♀ Have flat-chest
▪ ⚥ Soft pubic hair appears

Stage 2
▪ ♂ Measurable testes enlargement

▪ ♀ Breast buds appear
Figure 66.9 Illustration of the five stages of the Tanner scale in males and females.
OSMOSIS.ORG 587
NOTES
NOTES
RESPIRATORY SYSTEM
osms.it/respiratory-anatomy-physiology
RESPIRATORY SYSTEM
▪ Upper respiratory tract
▫ Nose, pharynx, associated structures
▪ Lower respiratory tract
▫ Larynx, trachea, bronchi, lungs
Respiratory system function

▪ Gas exchange between blood, atmosphere
▪ Protection against harmful particles,
substances
▪ pH homeostasis
▪ Vocalization
Conducting vs. respiratory zone

▪ Conducting zone
▫ Does not participate in gas exchange
▫ Nose to terminal bronchioles
▫ Function: inspire, warm, humidify, filter
air before gas exchange
▫ Smooth muscle layer contains
autonomic nervous system
(sympathetic, parasympathetic nerves)
▫ Smooth muscle along trachea, first
few bronchial branches have beta-2- Figure 67.1 Respiratory system overview,
adrenergic receptors categorized into upper, lower respiratory
▫ Sympathetic nerves stimulate beta- tracts.
2-adrenergic receptors → ↑ airway
diameter
▫ Parasympathetic nerves stimulate
muscarinic receptors → ↓ airway
diameter
▪ Respiratory zone
▫ Participates in gas exchange
▫ Lined with alveoli
▫ Terminal bronchioles–alveoli
588 OSMOSIS.ORG
Chapter 67 Respiratory Physiology: Anatomy & Physiology
RESPIRATORY SYSTEM ANATOMY Pharynx

▪ AKA throat
Nose
▪ Passageway connecting nasal cavity,
▪ Function: humidifies, warms, filters inspired
larynx, oral cavity, esophagus
air; voice resonance chamber; houses
olfactory receptors ▪ Nasopharynx: region connecting nasal
cavity to pharynx
▪ Nasal vibrissae (hairs) coated with mucus
→ traps large particles (e.g. dust, pollen) ▫ Posterior to nasal cavity, inferior to
sphenoid bone, superior to soft palate
Nasal cavity ▫ Air-only passageway
▪ Nasal cavity division ▫ Pharyngeal tonsils (adenoids); located
▫ Midline nasal septum: composed of on posterior wall; traps, kills pathogens
septal cartilage, anteriorly ▫ Pseudostratified ciliated epithelium (part
▫ Vomer bone: posteriorly of mucociliary escalator)
▪ Four paranasal sinuses (air-filled spaces ▪ Oropharynx: region connecting pharynx to
inside bones) connected to nasal cavity oral cavity
▫ Ethmoid, frontal, sphenoid, maxillary ▫ Posterior to oral cavity, continuous with
sinuses isthmus of fauces
▫ Function: warms, moistens inspired air; ▫ Soft palate superior, epiglottis inferior
amplifies voice; lightens skull ▫ Food, air passageway
▪ Roof formed by ethmoid, sphenoid bones ▫ Pseudostratified columnar epithelium
▪ Floor formed by palate of nasopharynx → stratified squamous
▪ Two mucous membrane types epithelium
▫ Olfactory mucosa: olfactory epithelium ▫ Palatine tonsils located on lateral walls
containing smell receptors ▫ Lingual tonsils cover posterior tongue
▫ Respiratory mucosa: pseudostratified ▪ Laryngopharynx: part of pharynx
ciliated columnar epithelium containing continuous with larynx (voice box)
goblet cells; secretes mucus containing ▫ Food, air passageway
lysozyme, defensins ▫ Stratified squamous epithelium
▪ Nasal conchae ▫ Epiglottis anterior, esophagus posterior
▫ Three mucosa-covered projections
(superior, middle, inferior nasal conchae) Larynx
of nasal cavity’s lateral wall ▪ Cartilage, connective tissue framework
▫ Meatus: groove inferior to each conchae ▫ Connects pharynx to trachea; houses
(superior, middle, inferior meatus) vocal cords, epiglottis (cartilage flap
▫ Function: ↑ turbulence inside cavity to atop larynx that seals airway off when
filter, humidify inspired air; reabsorb swallowing—prevents food entering
heat, moisture during nasal expiration larynx)
▪ Location
Palate ▫ Third to sixth cervical vertebra
▪ Separates nasal cavity from oral cavity ▫ Superior: hyoid bone
▫ Hard palate: anterior portion supported ▫ Inferior: trachea
by palatine bones
▪ Function
▫ Soft palate: posterior portion not
▫ Routes food, air into appropriate
supported by bones
passageway; voice production
▫ Soft palate, uvula move together; forms
▪ Histology
valve that closes nasopharynx when
swallowing (prevents food from entering ▫ Superior portion: contacts food;
nasopharynx) stratified squamous epithelium
▫ Inferior portion: below vocal folds;
pseudostratified ciliated columnar
epithelium (part of mucociliary escalator)
OSMOSIS.ORG 589
Figure 67.2 Anatomy of upper respiratory tract, surrounding structures.
▪ Contains nine cartilages maintains open passage for air)

▫ Thyroid cartilage: large shield-shaped ▫ Connected by trachealis muscle
midline cartilage, produces laryngeal ▫ Runs from larynx, divides into two main
prominence (”Adam’s apple”) bronchi inferiorly at carina
▫ Cricoid cartilage: ring-shaped cartilage ▪ Layers (superficial to deep)
inferior to thyroid cartilage, superior to ▫ Mucosa: pseudostratified epithelium
trachea with goblet cells; mucociliary escalator
▫ Arytenoid, cuneiform, corniculate ▫ Submucosa: connective tissue layer
cartilages: form posterior, lateral larynx (supported by 16–20 C-shaped
walls (arytenoid cartilages anchor vocal cartilage rings)
cords)
▫ Adventitia: connective tissue layer
▫ Epiglottis: spoon-shaped cartilage is encasing cartilage rings
pulled superiorly to cover laryngeal inlet
during swallowing (prevents food from Right & left mainstem bronchus
passing through larynx) ▪ Right mainstem bronchus
▪ Vocal folds/ligaments ▫ Wider, more vertical
▫ Attach arytenoid cartilages to thyroid ▫ Something accidentally inhaled → goes
cartilage into right lung (more likely)
▫ True vocal cords: sound production ▪ Inside lungs
(function); composed of elastic fibers; ▫ Main bronchus subdivides into lobar
core of mucosal folds; appears white bronchi → segmental bronchi →
(avascularity) terminal bronchioles
▫ False vocal cords: superior to true ▪ Trachea, first three bronchial generations
vocal cords; does not participate in
▫ Wide, supported by cartilage rings
sound production; close glottis during
swallowing (function) ▪ Large airways lined by ciliated columnar
cells, goblet cells (secrete mucus)
Trachea ▫ Mucociliary escalator: mucus traps
▪ AKA windpipe particles → ciliated columnar cells beat
▪ Mainstem bronchi, airways rhythmically → moves mucus, trapped
▪ Trachea particles towards pharynx → spit out/
swallowed
▫ Tube smooth muscle, connective tissue,
C-shaped cartilage (provides support,
590 OSMOSIS.ORG
Figure 67.3 Section of tracheal wall showing its histology. Stimulation by sympathetic nerves
dilates airways, stimulation by parasympathetic nerves constricts airways.
Histological changes as conducting tubes exchange occurs between alveolar gas,

decrease pulmonary capillary blood; thin walls,
▪ Cartilage large alveoli surface-area maximizes
▫ Cartilage amount ↓ while elastic fibers ↑ gas exchange diffusion capabilities
(bronchioles contain no cartilage) ▫ Type II pneumocytes: secrete surfactant
▪ Epithelium (↓ surface tension within alveoli →
eases expansion, prevents collapsing
▫ Mucosal epithelium changes from
pseudostratified columnar → columnar ▪ Alveolar macrophages phagocytize
→ cuboidal particles inside lungs → conducting
bronchioles → mucociliary escalator
▫ Goblet cells, cilia ↓ (completely absent in
bronchioles) ▪ Respiratory membrane
▪ Smooth muscle ↑ ▫ Capillary, alveolar walls; basement
membranes
Bronchioles ▪ Alveolar pores connect adjacent alveoli
▪ Narrow airways after first three bronchial ▪ Blood supply
generations ▫ Pulmonary capillary networks
▪ Terminal bronchioles: last part of terminal
bronchioles, end of conducting zone Lungs
▪ Respiratory bronchioles: distal to terminal ▪ Main respiration organs
bronchioles, first part of respiratory zone ▪ Right lung
▪ Terminal bronchiole → respiratory ▫ Three lobes: upper, middle, lower lobe
bronchiole → alveolar ducts → alveolar sac ▪ Left lung
→ alveoli ▫ Two lobes: upper, lower lobe
Alveoli ▪ Base of lungs rest on diaphragm
▪ Alveolar wall ▪ Pleura: double-layered serosa covering
lungs, pleural fluid lining pleural cavity
▫ Composed of a single simple squamous
between two layers
epithelium layer
▫ Parietal pleura: outer layer adherent
▪ Elastic fibers surround alveoli → allow lung
to thoracic wall, superior surface of
expansion during inspiration, recoil during
diaphragm
expiration
▫ Visceral pleura: inner layer adherent to
▫ Type I pneumocytes: primary gas
external lung surface
exchange site; oxygen–carbon dioxide
OSMOSIS.ORG 591
▪ Pulmonary circulation venous blood from lungs (with
▫ Pulmonary veins (anterior to main pulmonary veins)
bronchi) bring oxygen-rich blood to ▫ High-pressure, low-volume circulation
lungs from heart ▪ Innervation
▫ Pulmonary arteries bring oxygen-poor ▫ Pulmonary plexus
systemic venous blood for oxygenation ▫ Parasympathetic motor causes
▫ Low-pressure, high-volume circulation bronchoconstriction
▪ Bronchial circulation ▫ Sympathetic motor causes
▫ Bronchial arteries: provide oxygenated bronchodilation
systemic blood to lung tissue ▫ Visceral sensory
▫ Bronchial veins: drain deoxygenated ▫ Diaphragm innervated by phrenic nerve
Figure 67.4 Trachea and lung anatomy. Numbered labels show sequence of airflow going into
the airways from (trachea to alveoli).
Figure 67.5 Alveolus structure. Gas exchange occurs at the blood-gas barrier. De-oxygenated
blood from pulmonary arteries are oxygenated then sent to pulmonary veins.
592 OSMOSIS.ORG
VENTILATION
▪ Ventilation (breathing): moving air in, out of
lungs
▪ Oxygen pathway
▫ Air inhaled through nostrils → nasal
cavity → pharynx → larynx → trachea
→ mainstem bronchus → conducting
bronchioles → terminal bronchioles →
respiratory bronchioles → alveolar duct
→ alveoli → capillary → body
▫ Carbon dioxide moves in reverse
▪ Airflow from atmosphere to lungs
▫ Higher pressure → lower pressure
▪ Muscle movement creates pressure
gradient
▫ Primary respiration muscles: diaphragm,
external intercostals, scalenes
▫ Forceful breathing: other muscles
recruited
▪ Airflow resistance: function of respiratory
passage diameter
▪ Passive inhalation: negative pressure inside
body generated → moves air into lungs
▫ Diaphragm contracts downwards,
chest muscles pull ribs outward → ↑
intrathoracic volume → ↓ intrathoracic
pressure → air moved into lungs (air
flows down pressure gradient)
▪ Passive exhalation: ↑ intrathoracic pressure
generated → moves air out of lungs
▫ Diaphragm relaxes (returns to resting
position), external intercostal muscles
relax, thoracic cage recoils → elastic
lung recoil → ↓ intrathoracic volume → ↑
intrathoracic pressure → air pushed out
of lungs
OSMOSIS.ORG 593
NOTES
NOTES
BREATHING MECHANICS
LUNG VOLUMES & CAPACITIES

osms.it/lung-volumes-capacities
▪ Spirometry: spirometer used to measure air ▪ VT + inspiratory reserve volume = 3.5L
volume moving in, out of lungs ▪ Vital capacity (VC)
▪ Static lung volumes: volumes not involved ▫ VT + inspiratory reserve volume (IRV) +
in airflow rate ERV = 4.7L
▪ Capacities: combination of > one lung ▪ Total lung capacity (TLC)
volume ▫ Combination of all lung capacities = 5.9L
Volume variations
▪ Related to age, sex, body size, posture MEASURING FRC
▪ Tidal volume (VT)
Helium dilution method
▫ 500mL
▪ Helium placed in spirometer → inhaled
▫ Air volume inspired, expired during quiet
▪ Helium concentration in lungs equalizes
breathing
with amount of helium placed in spirometer
▪ Inspiratory reserve volume (helium insoluble in blood) after few breaths
▫ Maximum volume inhaled air above VT ▪ Total helium mass measured in spirometer
= 3L = FRC
▪ Expiratory reserve volume
▫ Maximum expired air volume below VT Body plethysmograph method
= 1.2L ▪ Application of Boyle’s law (P X V = k)
▪ Residual volume (RV) ▪ Person sits inside plethysmograph (airtight
▫ Air remaining in lungs after forced box) → breathes in/out through mouthpiece
expiration = 1.2L (not measured by → measures air pressure in mouth
spirometry) ▪ Mouthpiece closed after expiring VT; as
▪ Functional residual capacity (FRC) person attempts to breathe FRC calculated
▫ Expiratory reserve volume (ERV) + RV using measurements of alveolar pressure,
= 2.4L lung volume, pressure changes within
plethysmograph
594 OSMOSIS.ORG
Chapter 68 Respiratory Physiology: Breathing Mechanics
ANATOMIC & PHYSIOLOGIC

DEAD SPACE
osms.it/anatomic-physiologic-dead-space
▪ Dead space: air volume enters airways, ▫ Anatomic dead space = physiologic
lungs; no gas exchange occurs dead space
VT = VD + VA
ANATOMIC DEAD SPACE ▫ VT = tidal volume
▪ Air inaccessible to body for gas exchange ▫ VD = physiological dead space volume
(due to anatomical structure) ▫ VA = air volume present in functioning
▪ Air contained in conducting zone (nose → alveoli
terminal bronchioles)
▪ Conduit for air movement in/out of lungs;
warms, humidifies air; removes debris,
pathogens
▪ Volume = 150mL (⅓ of tidal volume)
Figure 68.2 The green block represents

residual air from the previous inhalation that
participated in gas exchange. The purple
blocks represent new oxygenated tidal
volume inhaled during the current breath.
Some of this new air also ends up being dead
Figure 68.1 The volume of air contained in space air (“alveolar dead space”) due to an
the conducting zone is called anatomic dead inadequate blood supply to the alveolus.
space because no gas exchange occurs here;
therefore, no oxygen can be extracted from
this air. Physiological dead space volume (Bohr
equation)
▪ Assumptions
PHYSIOLOGIC DEAD SPACE
amount ≅ 0.04%)
▫ Environmental air CO2 = 0 (actual
▪ Air physiologically inaccessible to body for
gas exchange ▫ Dead space CO2 contribution = 0
▪ Composition: anatomic dead space + dead ▫ All CO2 in exhaled air comes from
space in respiratory zone (respiratory functioning alveoli
bronchioles, alveolar duct, alveolar sac, ▪ VD = VT x arterial CO2 partial pressure
alveoli) that does not partake in gas (PaCO2) - expired CO2 partial pressure
exchange (PeCO2) ÷ PaCO2
▫ Ventilation/perfusion defect: alveoli
ventilated, not well perfused (alveolar PaCO − PeCO
dead space) VD = VT × 2 2
PaCO
▪ Volume = approx. 0 (in healthy adult) 2
OSMOSIS.ORG 595
VENTILATION
osms.it/ventilation
▪ Air movement between environment, lungs ▪ Partial pressure: proportional to fractional
▪ Ventilation rates: measure air volume concentration of that gas in mixture; based
moving in/out of lungs over period of time on constant K
▫ Assumes gases are saturated with
water vapor (normal body temperature,
MINUTE VENTILATION (VE) sea-level atmospheric pressure)
▪ VE = amount of air moved in/out of lungs in
▫ CO2 partial pressure in alveolar air:
one minute; does not factor in physiological
PCO2 = FCO2 x K
dead space
▫ Alveolar ventilation equation:
VE = (VT) x (Respiratory Rate/RR) VA = [(VCO2) / (PCO2)] x K
VE = 500mL x 15/minute = 7.5L/minute ▫ Replacing PCO2 with CO2 pressure in
arterial blood (PaCO2) in alveolar equation
▫ Inverse relationship between alveolar
ventilation, CO2 partial pressure in
ALVEOLAR VENTILATION (VA) alveolar air, pulmonary arteries (e.g. ↑ air
▪ VA = VE corrected for physiological dead ventilating the alveoli → ↓ CO2 in blood,
space vice versa)
VA = (VT - VD) x RR VCO × K

VA = (500 mL - 150mL) x 15 = 5.2L/minute VA = 2
PACO
2
▪ VA without measuring dead space

▫ VA = volume of CO2 (VCO2) ÷ fraction CO2
(FCO2)
VA = (VCO2) / (FCO2)
596 OSMOSIS.ORG
ALVEOLAR GAS EQUATION

osms.it/alveolar-gas-equation
▪ Pressure in alveoli = atmospheric pressure ▪ Pressure exerted by O2 > pressure
(Patm); air in alveoli contains water vapor exerted by CO2 (proportional to fractional
▪ Alveolar pressure (Patm) = water vapor concentrations)
pressure (Pvapor) + gas mixture pressure ▫ If Pgases = 20mmHg; partial pressure
→ total alveolar pressure exerted from all of O2 = 14mmHg (0.7 x 20); partial
gases minus water vapor = Patm- Pvapor pressure of CO2 = 6mmHg (0.3 x 20)
▪ O2 partial pressure dissolved in blood (PaO2) ▫ Partial pressure of inspired air (PiO2),
= CO2 partial pressure in alveoli (PACO2) ÷ by fractional oxygen concentration in
R (respiratory quotient) inspired air (FiO2), accounting for water
PaO2 = (PACO2) / R vapor
▪ Partial pressure of O2 inside alveolus (PAO2) PiO2 = FiO2 x (Patm- Pvapor)
= partial pressure of inspired oxygen (PiO2)
Alveolar gas equation
minus partial pressure of oxygen going into
blood (PaO2) ▪ Relationship between O2 partial pressure
inside alveolus to CO2 partial pressure in
Partial pressure: gas particle mixture alveolus
▪ Gas’ partial pressure proportional to
fractional gas concentration in mixture PAO2 = [FiO2 x (Patm- Pvapor)] - [(PACO2) / R]
▪ Fractional CO2 concentration (FCO2) = 0.3 PAO2 = 150 - (1.25 x PACO2)
▫ Accounts for 30% of gas molecules
(FCO2 x total pressure of gas mixture ▫ FiO2 = 0.21 (normal air = 21% O2)
Pgases) ▫ Atmospheric pressure = 760mmHg
▪ Fractional concentration of O2 (FO2) = 0.7 ▫ Water vapor pressure i = 47mmHg
▫ Accounts for remaining 70% (FO2 x total ▫ R = 0.8
pressure of gas mixture Pgases)
COMPLIANCE OF LUNGS &

CHEST WALL
osms.it/compliance-lungs-chest-wall
▪ Compliance measures how changes in ▪ ↑ compliance → lungs easier to fill with air
pressure → lung volume change ▫ Forces promoting open alveoli:
▪ Lung, chest wall compliance: inversely compliance, transmural pressure
correlated with elastic, “snap back” gradient, surfactant
properties (elastance) ▪ ↓ compliance → lungs harder to fill with air
▫ Compliance = ΔV/ΔP ▫ Forces promoting collapse of alveoli:
▫ Elastance = ΔP/ΔV elastic recoil/elastance, alveolar surface
tension
OSMOSIS.ORG 597
COMBINED PRESSURE-VOLUME
CURVES FOR THE LUNG &
CHEST WALL
osms.it/pressure-vol_curves_lung_chest_wall
▪ Pressure-volume relationship is curvilinear ▫ ↓ lung recoiling force
▪ Volume at FRC (zero airway pressure) ▫ ↑ chest wall outward force
▫ Lung inward recoil: balanced with chest ▪ Pressure-volume curves plotted on graph
wall’s tendency to expand outward ▫ X-axis: pressure
(e.g. at equilibrium with no tendency to ▫ Y axis: volume
collapse/expand)
▫ Slope of curve = compliance
▪ Volume > FRC
▪ Curve flattens out when lung, chest wall
▫ Positive transmural pressure compliance combined
▫ ↑ lung recoiling force ▪ Hysteresis: compliance for inspiration,
▫ ↓ chest wall outward force expiration are different → slopes will be
▪ Volume < FRC (forced expiration) different
▫ Negative transmural pressure
ALVEOLAR SURFACE TENSION &

SURFACTANT
osms.it/alveolar-surface-tension-surfactant
▪ Alveoli lined with fluid film; water tends to ▪ Smaller alveolus (r = 1) → ↑ pressure
form spheres (e.g. drops) ▫ P = 2 x 50/1 = 100
▫ Due to intrinsic surface tension (caused ▪ Larger alveolus (r = 2) → ↓ pressure
by attraction of water molecules to each ▫ P = 2 x 50/2 = 50
other)
▪ Alveoli are small (allows ↑ surface area
▪ Surface tension creates pressure → pulls relative to volume), so have ↑ collapsing
alveoli closed → collapses into sphere → ↓ pressure
gas exchange
▪ Law of Laplace: pressure that promotes
lungs’ collapse is (1) directly proportional to SURFACTANT
surface tension, (2) inversely proportional ▪ ↓ collapsing pressure in alveoli → ↑ gas
to alveoli radius exchange, ↑ lung compliance, ↓ work of
P = 2T/r breathing
▫ P = pressure on alveolus ▫ Lipoprotein mixture primarily containing
▫ T = surface tension dipalmitoyl phosphatidylcholine (DPPC)
▫ r = alveolar radius ▫ Synthesized by type II pneumocytes,
coats inside of alveoli
598 OSMOSIS.ORG
▫ Contains both hydrophilic, hydrophobic repelling hydrophobic groups, attracting

group (amphipathic nature)— hydrophilic groups → ↓ surface tension,
intermolecular forces produced by collapsing pressure
AIRFLOW, PRESSURE, &

RESISTANCE
osms.it/airflow-pressure-resistance
AIR FLOW & PRESSURE
8nl
▪ Airflow in lungs determined by Ohm’s law R=
πr4
▫ Air flow directly proportional to pressure
difference between alveoli, mouth/ ▫ R = resistance
nose; inversely proportional to airway ▫ n = gas viscosity
resistance
▫ 𝞹r4 = flow is related exponentially to
▫ l = length of airway
Q = ΔP/R
▫ Q = air flow airway’s radius
▫ ΔP = change in pressure ▪ Highlights critical importance of airway
▫ R = resistance diameter on airflow
▪ Pressure gradient ▫ E.g. if airway radius ↓ by a factor of 2 →
▫ Driving force for air flow ↑ resistance by 24 (16-fold)
▫ Diaphragm contracts during inspiration
Resistance changes
→ creates pressure gradient (↑ lung
volume, ↓ alveolar pressure) → air flows ▪ Parasympathetic muscarinic receptor
into lungs stimulation → bronchial smooth muscle
constriction → ↓ airway diameter → ↓
airflow; sympathetic stimulation of β2
RESISTANCE receptors → bronchial smooth muscle
relaxation → ↑ airway diameter → ↑ airflow
Poiseuille’s law
▪ ↓ lung volume → ↑ resistance; ↑ lung
▪ Resistance in lungs determined by volume → ↓ resistance
Poiseuille’s law
▪ ↑ viscosity (e.g. deep sea diving) → ↑
▫ Air flow directly proportional to resistance; ↓ viscosity (e.g. inhaling helium)
resistance along airway → ↓ resistance
OSMOSIS.ORG 599
BREATHING CYCLE
osms.it/breathing-cycle
▪ Normal, quiet breathing phases muscles contract (innervated by intercostal
▫ Rest (period between breaths), nerves) contract, elevate ribs outward,
inspiration, expiration upward → enlarge thoracic cavity → ↑
▪ Involves changes in air volume, intrapleural lung volume → ↓ pressure in lungs (Palv =
pressure, alveolar pressure -1cm/0.39in H20)
▪ Affected by respiratory system’s resistance, ▫ Boyle’s law (P = k/V): gas pressure (P)
compliance in container (thorax, alveoli) at constant
temperature (k) inversely proportional to
Rest volume (V)
▪ Alveolar pressure (Palv) = atmospheric ▪ Pressure gradient causes air to flow into
pressure (Patm) = 0 lungs until Palv = Patm at inspiration’s end
▪ No air movement in/out of lungs ▪ Volume in lungs = FRC + VT
▫ Due to pressure gradient’s absence ▪ Intrapleural pressure = -8cm/3.1in H20 at
▪ Air volume in lungs = FRV expiration’s end
▪ Intrapleural pressure = -0.5cm0.2in H20 Expiration
▫ Transmural pressure gradient ▪ Passive process
(intrapleural pressure always less than
▪ Elastic forces of lungs compress alveolar air
alveolar pressure) keeps lungs inflated
volume → ↑ pressure in lungs → Palv > Patm
▪ Diaphragm relaxed → pressure gradient causes air to flow out
of lungs until Palv = Patm at inspiration’s end
Inspiration
▪ Diaphragm, external intercostal muscles
▪ Active process (requires muscle activity)
relax → ↓ thoracic cavity size → ↓ lung
▪ Diaphragm (major inspiratory muscle; volume → ↑ pressure in lungs
innervated by phrenic nerve) contracts,
▪ VT expired → lung volume = FRC
moves downward; external intercostal
600 OSMOSIS.ORG
NOTES
NOTES
BREATHING REGULATION
BREATHING CONTROL
osms.it/breathing-control
WHAT IS BREATHING CONTROL? ▪ Receives input from cerebral cortex
▪ Breathing (ventilation): movement of
gasses in, out of lungs Apneustic center
▪ Regulation maintains arterial partial ▪ Located in lower pons
pressures of O2, CO2 (PaO2, PaCO2) ▪ Prolongs DRG inspiratory signal,
▪ Components: brainstem respiratory diaphragm contraction → inspiratory gasps
centers; peripheral, central chemoreceptors; (apneusis)
mechanoreceptors in lungs, muscles of ▪ Associated with damage to pons/upper
respiration, joints medulla
BRAINSTEM RESPIRATORY VOLUNTARY CONTROL

CENTERS
Cerebral cortex
Dorsal respiratory group (DRG) ▪ Sends commands to voluntarily override
▪ Inspiratory center, located in dorsal medulla autonomic control of ventilation
▪ Sets basic rhythm of breathing ▪ Hyperventilation
▪ Receives sensory input via cranial nerves ▫ Voluntarily breathing at rate > that
(CN) IX, X from peripheral chemoreceptors, needed by metabolism
mechanoreceptors in lungs → sends motor ▫ Self-limiting: hyperventilation → ↓
output via phrenic nerve to stimulate PaCO2 (strongly inhibits autonomic
contraction of diaphragm respiratory centers, ventilation)
▫ DRG neurons generate repeating ▪ Hypoventilation
bursts of action potentials → period of ▫ Voluntarily breathing at rate insufficient
quiescence for metabolism
▫ Bursts occur → action potential ▫ Self-limiting: hypoventilation → ↓ PaO2,
frequency “ramps up” → ↑ lung volume ↑ PaCO2
Ventral respiratory group (VRG)
▪ Expiratory center, located in ventral medulla HYPOTHALAMIC CONTROL
▪ Inactive during basic, quiet breathing ▪ Strong emotions, pain: act via
hypothalamus, limbic system → signal
▪ Provides high respiratory drive when
respiratory centers → modify respiratory
ventilation needs to increase (e.g. exercise)
rate, depth
Pneumotaxic center ▪ Rise in body temperature → ↑ respiratory
▪ Located in upper pons rate
▪ Limits inspiration by inhibiting DRG ▪ Drop in body temperature → ↓ respiratory
▪ Limits tidal volume, increases respiratory rate
rate
OSMOSIS.ORG 601
PULMONARY CHEMORECEPTORS &
MECHANORECEPTORS
osms.it/pulmonary-central-peripheral-chemoreceptors
CENTRAL CHEMORECEPTORS Irritant receptors
▪ Located in ventral surface of medulla ▪ Respond to noxious gasses; particulates via
▪ Sensitive to changes in H+ indirectly by CN X → coughing, bronchoconstriction
sensing acute changes in PaCO2 (unable to
Juxtacapillary (J) receptors
cross blood-brain barrier)
▪ Located in alveoli, near capillaries
▫ ↑ PaCO2 → conversion to carbonic acid
(H2CO3) by enzyme carbonic anhydrase ▪ Respond to capillary engorgement → ↑
→ dissociation into H+, HCO3- → ↓ CSF respiratory rate
pH (↑ CSF [H+]) → stimulates central
chemoreceptors → stimulates DRG → ↑
ventilation → ↓ PaCO2 (40mmHg)
▪ Crucial minute-to-minute control
▫ Match ventilation with metabolism by
monitoring PaCO2
PERIPHERAL CHEMORECEPTORS
▪ Located in carotid bodies at bifurcation
(near aortic arch)
▪ Responds directly to changes in PaO2,
PaCO2
▫ Strongly stimulated in linear fashion
when PaO2 < 60mmHg
▫ Weakly stimulated by ↑ PaCO2
▫ Carotid bodies only: stimulated by ↑
arterial [H+]
▪ Afferents send information to DRG via
CN IX, X → directs ventilatory response to
hypoxemia, acidemia, alkalemia
MECHANORECEPTORS
Lung stretch receptors
▪ Located in airway smooth muscle
▪ Respond to lung inflation → termination
of inspiration (Hering–Breuer inspiratory-
inhibitory reflex)
Figure 69.1 The brainstem is the respiratory
Joint and muscle receptors center of the body. Many receptors throughout
▪ Respond to bodily movement → ↑ the body send signals to the brainstem so that
respiratory rate it can regulate the breathing rate accordingly.
602 OSMOSIS.ORG
NOTES
NOTES
GAS EXCHANGE
GAS EXCHANGE & LAWS the solubility of a gas, the higher the
▪ Diffusion of oxygen (O2), carbon dioxide concentration in solution
(CO2) in lungs, peripheral tissues ▪ In solution only dissolved gas molecules
▪ Alveolar O2 from inhaled gas → pulmonary contribute to partial pressure
capillary blood → circulation → tissue ▪ Of the gases inspired as air, only nitrogen is
capillaries → cells exclusively carried in dissolved form
▪ CO2 from cells → tissue capillaries →
circulation → pulmonary capillary blood → Bound gas
CO2 for exhalation from alveoli ▪ O2, CO2, CO are bound to proteins in blood
▪ Gas exchange, gas behavior in solution ▪ O2, CO2, CO can all bind to hemoglobin
is governed by fundamental physical gas ▪ CO2 also binds to plasma proteins
properties → represented by gas laws
Chemically modified gas
▪ The ready back and forth conversion of
FORMS OF GAS IN SOLUTION CO2 to bicarbonate (HCO3-) in presence
Dissolved gas of enzyme carbonic anhydrase allows
CO2 to contribute to gas equilibria despite
▪ All gas in solution are to some extent
chemical conversion
carried in a freely dissolved form
▪ Majority of CO2 in blood carried as HCO3-
▪ For given partial pressure, the higher
IDEAL (GENERAL) GAS LAW

osms.it/ideal-gas-law
▪ Relates multiple variables to describe state ▪ In gas phase: body temperature, pressure
of a hypothetical “ideal gas” under various (BTPS) used
conditions ▫ T = 37°C/98.6°F/310K
▫ Ideal gas: theoretical gas composed of ▫ P = Ambient pressure
many randomly moving point particles ▫ Gas is saturated with water vapor
whose only interactions are perfectly (47mmHg)
elastic collisions
▪ In liquid phase/solution: standard
▫ All gas laws can be derived from general temperature, pressure (STPD) used
gas law
▫ T = 0°C/32°F/273K
▪ PV = nRT
▫ P = 760mmHg
▫ P = Pressure (millimeters of mercury
▫ Dry gas (no humidity)
(mmHg)
▪ Ideal gas law can be used to interconvert
▫ V = Volume (liters (L)
between properties of same gas under
▫ n = Moles (mol) BTPS, STPD conditions
▫ R = Gas constant (8.314 J/mol) ▫ E.g. gas volume (V1) at BTPS → gas
▫ T = Temperature (Kelvin [K]) volume at STPD (V2)
OSMOSIS.ORG 603
T1 P1 − Pw1
V2 = V1 × ×
T2 P2 − Pw2
273 760 − 47
V2 = V1 × ×
310 760 − 0
V2 = V1 × 0.826
BOYLE'S LAW
osms.it/Boyles-law
▪ Describes how pressure of gas ↑ as ▪ If PV constant + lung volume ↑ → pressure
container volume ↓ ↓
▪ P1V1 = P2V2 ▪ Pressure ↓ → disequilibrium between
▪ For gas at given temperature, the product room, lung air pressures → air fills lungs to
of pressure, volume is constant equalize pressure
▪ Inspiration → diaphragm contraction → ↑
lung volume
DALTON'S LAW
osms.it/Daltons-law
▪ Total pressure exerted by gaseous mixture ▫ Px = (PB - PH2O) x F
= sum of all partial pressures of gases ▫ PH2O = Water vapor pressure at
in mixture → partial pressure of gas in 37°C/98.6°F (47mmHg)
gaseous mixture = pressure exerted by that ▫ If the sum of partial pressures in a
gas if it occupied total volume of container mixture = total pressure of mixture
▪ Px = PB x F → barometric pressure (PB) is sum of
▫ Px = partial pressure of gas (mmHg) the partial pressures of O2, CO2, N2
▫ PB = barometric pressure (mmHg) (nitrogen), and H2O
▫ F = fractional concentration of gas (no ▫ At barometric pressure (760 mmHg)
unit) composition of humidified air is O2, 21%;
▪ Partial pressure = total pressure X fractional N2, 79%; CO2, 0%
concentration of dry gas ▫ Within airways, air is humidified thus
▪ For humidified gases water vapor pressure is obligatory = to
47mmHg at 37°C/98.6°F
604 OSMOSIS.ORG
Chapter 70 Respiratory Physiology: Gas Exchange
HENRY'S LAW
osms.it/Henrys-law
▪ For concentrations of dissolved gases ▪ To calculate gas concentration in liquid
▪ When gas is in contact with liquid → phase
gas dissolves in proportion to its partial ▫ Partial pressure of gas in gas phase
pressure → greater concentration of → partial pressure in liquid phase →
a particular gas, in gas phase → more concentration in liquid
dissolves into solution at faster rate ▫ Partial pressure of gas in liquid phase
▫ Cx = Px x Solubility (at equilibrium) = partial pressure of gas
▫ Cx = concentration of dissolved gas (mL in gaseous phase
gas / 100mL blood) ▫ If alveolar air has PO2 of 100mmHg →
▫ Concentration of gas in solution only PO2 of capillary blood that equilibrates
applies to dissolved gas that is free in with alveolar air = 100mmHg
solution
▫ Concentration of gas in solution HYPERBARIC CHAMBERS
does not include any gas that is ▪ Hyperbaric chambers employ Henry’s law
presently bound to any other dissolved
▫ Contain O2 gas pressurized to above 1
substances (e.g. plasma proteins/
atm → greater than normal amounts of
hemoglobin)
O2 forced into the blood of the enclosed
▫ Px = partial pressure of gas (mmHg) individual
▫ Solubility = solubility of gas in blood (mL ▫ Used to treat carbon monoxide
gas / 100mL blood per mmHg) poisoning, gas gangrene due to
▪ Henry’s law governs gases dissolved within anaerobic organisms (cannot live in
solution (e.g. O2, CO2 dissolved in blood) presence of high concentrations of O2),
improve oxygenation of skin grafts, etc.
FICK'S LAWS OF DIFFUSION

osms.it/Ficks-law-of-diffusion
▪ Describes diffusion of gases in partial pressures of gas (ΔP) across
membrane (not the concentration
DAΔP difference)
Vx =
Δx ▫ If PO2 of alveolar air = 100mmHg
▫ PO2 of mixed venous blood entering
▫ Vx = volume of gas transferred per unit pulmonary capillary = 40mmHg
time ▫ Driving force across membrane is
▫ D = gas diffusion coefficient 60mmHg (100mmHg - 40mmHg)
▫ A = surface area ▪ Diffusion coefficient of gas (D) is a
▫ ΔP = partial pressure difference of gas combination of usual diffusion coefficient
▫ Δx = membrane thickness (dependent on molecular weight) and gas
▪ Driving force of gas diffusion is difference solubility
▪ Diffusion coefficient dramatically affects
OSMOSIS.ORG 605
diffusion rate, e.g. diffusion coefficient for (DLCO) is measured using a single breath
CO2 is approximately 20x greater than ▫ Individual breathes a mixture of gases
that of O2 → for a given partial pressure with a low CO concentration → rate
difference CO2 would diffuse across the of CO disappearance is predictable in
same membrane 20x faster than O2 different disease states
▫ Emphysema → destruction of alveoli
LUNG DIFFUSION CAPACITY (DL) → decreased surface area for gas
▪ A functional measurement which takes into exchange → decreased DLCO
account ▫ Fibrosis/pulmonary edema → increase
▫ Diffusion coefficient of gas used in membrane thickness (via fluid
accumulation in the case of edema) →
▫ Membrane surface area
decreased DLCO
▫ Membrane thickness
▫ Anemia → reduced hemoglobin →
▫ Time required for gas to combine with reduced protein binding in a given time
proteins in pulmonary capillary blood period → decreased DLCO
(e.g. hemoglobin)
▫ Exercise → increased utilization of
▪ Measured using carbon monoxide (CO) → lung capacity, increased recruitment of
CO transfer across alveolar-capillary barrier pulmonary capillaries → increased DLCO
exclusively limited by diffusion process
▪ Lung diffusion capacity of carbon monoxide
GRAHAM'S LAW
osms.it/Grahams-law
▪ Diffusion rate of gas through porous ▫ Kinetic energy = ½mv2
membranes varies inversely with the ▫ ½m1v12 = ½m2v22
square root of its density ▫ v12 / v22 = m2 / m1
▪ To compare rate of effusion (movement ▫ v1 / v2 = √(m2 / m1)
through porous membrane) of two gases →
▫ Which can be rewritten to give
velocity of molecules determine the rate of
Graham’s law
spread
▪ Kinetic temperature in kelvin of a gas is Rate1 M2
directly proportional to average kinetic =
energy of gas molecules → at the same Rate2 M1
temperature, molecule of heavier gas will
have a slower velocity than those of lighter
gas
606 OSMOSIS.ORG
GAS EXCHANGE IN THE LUNGS

osms.it/gas-exchange-in-lungs
PULMONARY GAS EXCHANGE Pulmonary capillaries
▪ AKA external respiration ▪ Blood entering pulmonary capillaries is
▪ Pulmonary capillaries perfused with blood mixed venous blood
from right heart (deoxygenated) ▪ Tissues (metabolic activity alters
▪ Gas exchange occurs between pulmonary composition of blood) → venous
capillary, alveolar gas vasculature → right heart → pulmonary
▫ Room air → inspired air → humidified circulation
tracheal air → alveoli ▪ PO2 = 40mmHg
▫ O2 diffuses from alveolar gas → ▪ PCO2 = 46mmHg
pulmonary capillary blood
Systemic arterial blood (oxygenated)
▫ CO2 diffuses from pulmonary capillary
blood → alveolar gas ▪ Gas partial pressures of systemic arterial
blood designated “Pa”
▫ Blood exits the lungs → left heart →
systemic circulation ▪ In a healthy individual, diffusion of gas
across alveolar, capillary membrane is
Dry inspired air so rapid that we can assume equilibrium
▪ PO2 is approximately 160mmHg is achieved between alveolar gases,
pulmonary capillaries → PO2 and PCO2 of
▫ Barometric pressure x fractional
blood leaving pulmonary capillaries =
concentration of O2 (21%)
alveolar air
▫ PO2 = 760mmHg x 0.21
▪ PAO2 = PaO2 = 100mmHg
▫ Assume no CO2 in dry inspired air
▪ PACO2 = PaCO2 = 40mmHg
Humidified tracheal air ▪ This blood enters systemic circulation to
▪ PO2 of humidified tracheal air is 150mmHg eventually return to lungs
▫ Air is fully saturated with water vapor Physiological shunt
→ “dilution” of partial pressures →
▪ Small fraction of pulmonary blood flow
calculations must correct for water
bypasses alveoli → physiological shunt →
vapor pressure (subtracted from
blood not arterialized → systemic blood has
barometric pressure)
slightly lower PO2 than alveolar air
▫ At 37°C/98.6°F, PH2O is 47mmHg
▪ Shunting occurs due to
▫ PO2 = (760mmHg − 47mmHg) x 0.21
▫ Coronary venous blood, drains directly
▫ Assume no CO2 in humidified inspired into left ventricle
air
▫ Bronchial blood flow
Alveolar air ▪ Shunting may be increased in various
▪ Pressures of alveolar gas designated “PA” pathologies → ventilation-perfusion
▪ Alveolar gas exchange in lungs sees a defects/mismatches
drop in O2 partial pressure, increase in CO2 ▪ As shunt size increases → alveolar gas,
partial pressure pulmonary capillary blood do not equilibrate
▪ PAO2 = 100mmHg → blood is not fully arterialized
▪ PACO2 = 40mmHg ▪ A-a difference: difference in PO2 between
alveolar gas (A), systemic arterial blood (a)
▪ Amount of these gases entering/leaving
alveoli correspond to physiological body ▫ Physiological shunting → negligible/
needs (i.e. O2 consumption, CO2 production) small differences
▫ Pathology → notably increased
difference
OSMOSIS.ORG 607
FACTORS AFFECTING EXTERNAL mechanisms → continuously respond to
RESPIRATION local conditions → some control in blood
flow around lungs
Thickness of respiratory membrane
▪ Arteriolar diameter controlled by PO2
▪ In healthy lungs, respiratory membrane →
▫ If alveolar ventilation is inadequate
0.5–1 micrometer thick
→ blood taking O2 away faster than
▪ Presence of small amounts of fluid (left ventilation can replenish it → low local
heart failure, pneumonia) → significant loss PO2 → terminal arteriole restriction →
of efficiency, equilibration time dramatically blood redirected to respiratory areas
increases → the 0.75 seconds blood with high PO2, oxygen pickup more
cells spend in transit through pulmonary efficient
circulation may not be sufficient
▫ In alveoli where ventilation is maximal
Surface area of respiratory membrane → high PO2 → pulmonary arteriole
dilation → blood flow into pulmonary
▪ Greater surface area of respiratory
arterioles increases
membrane → greater amount of gas
exchange ▫ Pulmonary vascular muscle
autoregulation is opposite of that in
▪ Healthy adult male lungs have surface area
systemic circulation
of 90m2
▪ Bronchiolar diameter controlled by PCO2
▪ Pulmonary diseases (e.g. emphysema)
→ walls of alveoli break down → alveolar ▫ Bronchioles connecting areas where
chambers enlarge → loss of surface area PACO2 high → dilation → allows CO2 to
be eliminated from body
▪ Tumors/pneumonia → prevent gas from
occupying all available lung → loss of ▫ Those with low CO2 → constrict
surface area ▪ Independent autoregulation of arterioles,
bronchioles → matched perfusion,
Partial pressure gradients and gas ventilation
solubilities ▪ Ventilation-perfusion matching is imperfect
▪ Partial pressures of O2, CO2 drive ▫ Gravity → regional variation in blood,
diffusion of these gases across respiratory air flow (apices have greater ventilation
membrane but lesser perfusion, bases have greater
▪ Steep O2 partial pressure gradient exists perfusion, lesser ventilation)
▫ PO2 of deoxygenated blood in ▫ Occasionally alveolar ducts may be
pulmonary arteries = 40mmHg plugged with mucus → unventilated
▫ PO2 of 104mmHg in alveoli areas
▫ O2 diffuses rapidly from alveoli into
pulmonary capillary blood INTERNAL RESPIRATION
▪ O2 equilibrium (PO2 of 104mmHg on both ▪ Capillary gas exchange in body tissue
sides of respiratory membrane) occurs in
▪ Partial pressures, diffusion gradients are
around 0.25 seconds of transit through
reversed from lungs however physical laws
lungs (about ⅓ of the time available)
governing the exchanges remain identical
▪ CO2 has smaller gradient → 5mmHg
▪ Cells in body continuously use O2, produce
(45mmHg vs 40mmHg), although pressure
CO2
gradient for O2 is much steeper than for
CO2, CO2 is 20x more soluble in plasma, ▫ PO2 always lower in tissue than arterial
alveolar fluid than O2 → equal amounts of blood (40mmHg vs 100mmHg) → O2
gas exchanged moves rapidly from blood → tissues
until equilibrated
Ventilation-perfusion coupling ▫ CO2 moves rapidly down its pressure
▪ Ventilation: amount of gas reaching alveoli gradient (PCO2 of 40mmHg in fresh
▪ Perfusion: amount of blood flow in blood arriving at capillary beds beds vs.
pulmonary capillaries PCO2 of 45mmHg in tissues) → venous
blood → right heart
▪ These are regulated by local autoregulatory
608 OSMOSIS.ORG
▪ Gas exchange at tissue level driven

by partial pressures, occurs via simple
diffusion
DIFFUSION-LIMITED & PERFUSION-

LIMITED GAS EXCHANGE
osms.it/diffusion-limited-perfusion-limited-gas-exchange
Diffusion-limited gas exchange gas exchange with alveolar N2O →

▪ Diffusion is limiting factor determining total “perfusion-limited gas exchange”
amount of gas transported across alveolar- ▫ O2 at rest
capillary barrier ▫ CO2
▪ As long as partial pressure gradient is
maintained, diffusion continues Limitations of O2 transport
▫ Gas readily diffuses across permeable ▪ Under physiological conditions O2 transport
membrane into pulmonary capillaries → perfusion-
▫ Blood flow away from alveoli/chemical limited
binding → partial pressure of gas on ▪ Diseased or abnormal conditions →
systemic end does not rise → partial diffusion-limited
pressure maintenance ▪ Perfusion-limited O2 transport
▫ Given a sufficiently long capillary bed ▫ PAO2 is constant = 100mmHg
diffusion will continue along entire ▫ At beginning of capillary PaO2 =
length as equilibrium is not achieved 40mmHg (mixed venous blood) →
▪ Examples include large partial pressure gradient → drives
▫ CO across alveolar-pulmonary capillary diffusion
barrier ▫ As O2 diffuses into pulmonary capillary
▫ Oxygen during strenuous exercise/ blood → increase in PaO2
emphysema/fibrosis ▫ Hemoglobin binds O2 → resists increase
in PaO2 → initially gradient is maintained;
Perfusion-limited gas exchange eventually equilibrium is achieved →
▪ Perfusion (blood flow) is the limiting perfusion-limitation
factor determining total amount of gas ▫ Therefore pulmonary blood flow
transported across alveolar-capillary barrier determines net O2 transfer (changes in
▪ Increasing blood flow → increasing amount pulmonary blood flow will affect net O2
gas transported; examples include transfer)
▫ Nitrous oxide (N2O): not bound in
Diffusion-limited O2 transport
blood → entirely free in solution; PAN2O
is constant, PaN2O = zero at start of ▪ Fibrosis → thickening of alveolar walls
capillary → initial large A-a difference → increased diffusion distance for O2
→ because no N2O binds to any other (decreases DL) → slowed rate of diffusion
components of blood, all of it remains → prevents equilibration → partial pressure
free in solution → partial pressure gradient maintained along length of
builds rapidly → rapid equilibration, capillary
most of capillary length does not ▪ Increasing capillary length allows for more
participate in gas exchange; new blood time for equilibrium to occur → diffusion-
must be supplied to partake in further limitation
OSMOSIS.ORG 609
O2 transport at high altitude
▪ High altitude reduces barometric pressure
→ reduced partial pressures
▪ Reductions in PaO2 → reduce oxygen
amount available to diffuse into blood →
reduced rate of equilibration at capillary →
more time required for gas exchange, lower
peak oxygen concentration reached once
equilibrated
610 OSMOSIS.ORG
NOTES
NOTES
GAS TRANSPORT
OXYGEN BINDING CAPACITY &

OXYGEN CONTENT
osms.it/oxygen-binding-capacity-oxygen-content
MEASURES OF OXYGEN ▪ CaO2 (ml O2/100mL blood) = ([Hb] × 1.34 x
AVAILABILITY SaO2) + (PaO2 × 0.003)
O2 binding capacity
▪ Maximum amount of O2 bound to
O2 DELIVERY TO TISSUES
hemoglobin when 100% saturated (per ▪ Dependent on blood flow (determined by
blood volume) cardiac output), blood’s oxygen content
▫ More hemoglobin → more oxygen (per ▪ O2 delivery = cardiac output × oxygen
blood volume) content
▪ Measurement
▫ Expose blood to air with high PO2 → OXYGEN TRANSPORT
complete hemoglobin saturation ▪ Majority of oxygen in blood bound to
▫ Hemoglobin’s oxygen affinity → 1g of hemoglobin, remainder dissolved in solution
hemoglobin A binds 1.34mL of O2
Dissolved O2
▫ Normal hemoglobin A concentration in
blood → 15g/100mL ▪ Free in solution (1.5% of total blood O2
content)
▫ O2 binding capacity = hemoglobin
concentration × hemoglobin’s affinity for ▪ Only free O2 contributes to partial pressure
oxygen → drives O2 diffusion
▪ Example: O2 binding capacity = 15g/100mL ▪ O2 solubility in blood = 0.003mL O2/100mL
× 1.34mL O2/g hemoglobin = 20.1mL blood per mmHg → at normal PaO2 of
O2/100mL blood 100mmHg → concentration of dissolved O2
is 0.3mL O2/100mL blood
Oxygen content (CaO2) ▪ Normal consumption of O2 = 250mL O2/
▪ Oxygen (mL) per 100mL of blood minute
▪ CaO2 = O2 binding capacity × % saturation ▪ Only dissolved O2 delivered to tissues
+ oxygen dissolved in solution (cardiac output 5L/min) × dissolved
▫ Correction for dissolved O2 → solubility O2 concentration → 15mL O2/min →
of O2 in blood → 0.003mL O2/100mL incompatible with life
blood per mmHg ▪ Hemoglobin increases amount of O2 carried
▪ CaO2 = hemoglobin concentration by blood
(g/100mL blood) × hemoglobin oxygen
Hemoglobin bound
affinity (mL O2/g) × SaO2 (arterial oxygen
saturation) + partial pressure of oxygen ▪ Hemoglobin → greater concentrations of
(mmHg) × solubility of O2 in blood (mL O2/ O2 carried to tissues by blood
blood/mmHg) ▪ 98.5% of O2 in blood bound to hemoglobin
OSMOSIS.ORG 611
▪ Four subunits of hemoglobin molecule ▪ Heme binds oxygen in lungs →
▫ Each subunit contains heme moiety: oxyhemoglobin
iron-binding porphyrin, polypeptide ▫ Oxygen diffuses from alveoli → across
chain (alpha/beta) single cell thick alveolar walls → diffuses
▫ Adult hemoglobin subunits (α2β2): two into blood → through red blood cell
alpha chains, two beta chains → each (RBC) membrane → interacts with heme
contains one iron molecule (Fe2+) → → oxyhemoglobin (bright red blood)
binds one O2 molecule → four molecules ▪ Oxygen binding to hemoglobin →
of O2 per molecule of hemoglobin → conformational shift in heme structure
oxyhemoglobin → ↑ oxygen binding affinity → sigmoidal
▫ Deoxygenated hemoglobin → (S-shaped) oxygen-binding affinity/
deoxyhemoglobin dissociation curve
▪ At tissue level: association process
reversed
▫ O2 released → deoxyhemoglobin (dark
red blood)
▫ 20% of dissolved CO2 → binds
with globin amino acids (not heme
group) of deoxyhemoglobin →
carbaminohemoglobin
Fetal oxygen transport

▪ Fetal blood requires higher affinity for
oxygen to facilitate movement of O2 from
maternal to fetal blood
Figure 71.1 Each of the four hemoglobin
▪ Fetal variant hemoglobin (hemoglobin F)
subunits contains a heme group capable of
binding one oxygen molecule. ▫ Contains two alpha chains, two gamma
chains (α2γ2) → greater affinity for
oxygen
OXYGEN-HEMOGLOBIN
DISSOCIATION CURVE
osms.it/oxygen-hemoglobin_dissociation_curve
▪ Proportion of saturated hemoglobin plotted capillary beds) → hemoglobin binds to

against partial pressure of oxygen oxygen in lungs, releases at tissue level
▪ Illustrates how blood carries, releases ▫ Oxyhemoglobin dissociation curve:
oxygen as partial pressures vary determined by hemoglobin affinity
▫ Hemoglobin: primary oxygen for oxygen; rate hemoglobin acquires,
transporter in blood releases oxygen into surrounding fluid;
▫ Amount of oxygen bound to hemoglobin plots SO2 against PO2
at any given time determined by
environmental partial pressure of
oxygen (high in lungs, lower in tissue
612 OSMOSIS.ORG
Chapter 71 Respiratory Physiology: Gas Transport
Figure 71.2 Each hemoglobin molecule can bind four O2 molecules, but each hemoglobin
isn't always 100% saturated, or bound, by O2. A hemoglobin molecule with no O2 bound (0%
saturation) is called deoxyhemoglobin.
SIGMOIDAL SHAPE P50

▪ Oxyhemoglobin dissociation curve is ▪ P50: partial pressure of oxygen in blood
sigmoidal when hemoglobin 50% saturated (e.g.
▫ Positive cooperativity → each 26.6mmHg)
successive oxygen molecule binding to ▪ Conventional measure of hemoglobin
heme group → ↑ affinity affinity for oxygen
▫ Approaches maximum saturation limit ▪ Physiological/disease processes may shift
→ few binding sites remain → little dissociation curve to left/right, alter P50
additional binding possible → curve ▫ Left shift → lower P50 → ↑ oxygen
levels off → large ↑ in oxygen partial affinity
pressure → no effect on hemoglobin ▫ Right shift → raised P50 → ↓ oxygen
saturation beyond saturation point affinity
▫ Partial pressures ↓ at tissue level →
oxygen release → with each successive
oxygen molecule release, subsequent RIGHT SHIFT
release eases → rapid oxygen unloading ▪ Right shift → lower oxygen affinity → 50%
at low partial pressures saturation occurs at higher PO2 → oxygen
unloading
↑ PCO2, ↓ pH
▪ ↑ metabolic activity of tissues → ↑ CO2 → ↑
H+ concentration → ↓ pH → ↓ hemoglobin
oxygen affinity → oxygen unloading in
metabolically active tissues
▪ Effect of PCO2, pH on oxygen-hemoglobin
dissociation curve → Bohr effect
↑ temperature
▪ Very metabolically active tissue (e.g.
active muscle → ↑ heat production → ↓
hemoglobin oxygen affinity)
↑ 2,3-diphosphoglycerate (2,3-DPG) con-

centration
▪ 2,3-DPG (glycolysis byproduct) → binds
Figure 71.3 The oxygen-hemoglobin deoxyhemoglobin beta chains → ↓ oxygen
dissociation curve. O2 saturation is influenced affinity → binds to hemoglobin beta chains
by the PO2 of the blood. P50 indicates the → oxygen unloading
partial pressure at which hemoglobin ▪ 2,3-DPG production ↑ under hypoxic
proteins are 50% saturated. conditions (e.g. living at high altitude) →
OSMOSIS.ORG 613
hypoxemia → 2,3-DPG production in red Hemoglobin F
blood cells → greater oxygen delivery to ▪ Alternate molecular structure → ↑ oxygen
tissues affinity → left shift
▪ 2,3-DPG doesn’t bind strongly to HbF
LEFT SHIFT gamma chains
▪ Left shift → higher oxygen affinity → 50%
Carbon monoxide (CO)
saturation occurs at lower PO2 → impairs
oxygen unloading ▪ Causes left shift, ↓ maximum saturation
possible (curve levels off at lower PO2)
↓ PCO2, ↑ pH ▪ CO binds to hemoglobin with 250x affinity
▪ ↓ tissue metabolism → ↓ CO2 production → of O2 (at partial pressure; 1/250 O2, =
↓ H+ concentration → ↑ pH → left shift → O2; CO bound to hemoglobin) → forms
O2 tightly bound to hemoglobin carboxyhemoglobin (longer-living molecule
than oxyhemoglobin)
↓ temperature ▪ CO binding to heme → confirmation shift
▪ ↓ tissue metabolism → ↓ heat production → → ↑ remaining heme molecules’ affinity for
↓ O2 unloading oxygen (reducing oxygen release efficiency)
→ CO poisoning reduces blood’s absolute
↓ 2,3-DPG concentration oxygen-carrying capacity, impairs oxygen
▪ ↓ tissue metabolism → ↓ 2,3-DPG release → hypoxic injury
concentration → ↓ O2 unloading
Figure 71.4 Summary of factors that can shift the oxygen-hemoglobin dissociation curve to the
left (↑ hemoglobin's affinity for O2) and to the right (↓ hemoglobin's affinity for O2).
614 OSMOSIS.ORG
ERYTHROPOIETIN (EPO)
osms.it/erythropoietin
▪ Glycoprotein cytokine secreted by kidney RENAL SENSING OF HYPOXIA
(cellular hypoxia response) → stimulates ▪ To effectively regulate EPO secretion,
erythropoiesis → RBCs kidneys must distinguish between
following:
RENAL INDUCTION OF EPO Decreased blood flow
SYNTHESIS
▪ → ↓ O2 availability
▪ ↓ O2 delivery to kidneys (↓ hemoglobin
▫ ↓ renal blood flow → ↓ glomerular
concentration/PaO2) → increased
filtration → ↓ sodium (Na+) filtration/
production of alpha subunit of hypoxia-
reabsorption → ↓ O2 consumption
inducible factor 1 (HIF1)
(Na+ resorption closely linked to O2
▪ Hypoxia-inducible factor 1-alpha (HIF1A) consumption in kidney)
→ acts on fibroblasts in renal cortex,
▫ O2 delivery, consumption remain
medulla → upregulation of EPO messenger
matched → EPO production not
RNA (mRNA) → increased EPO synthesis
triggered
▪ EPO → promotes proerythroblast
differentiation → mature to form Decreased arterial blood O2 content
erythrocytes (maturation not EPO- ▪ → ↓ O2 availability
dependent)
▫ Renal blood flow remains normal →
normal glomerular filtration → normal
Na+ filtration/reabsorption → reduced
oxygen availability for given metabolic
demand → stimulus for EPO secretion
CARBON DIOXIDE TRANSPORT

IN BLOOD
osms.it/carbon-dioxide-transport-in-blood
▪ Carried as dissolved carbon dioxide ▪ Concentration = 2.8mL CO2/100mL blood
(CO2), carbaminohemoglobin (bound to (5% of total CO2 content of blood)
hemoglobin), bicarbonate (HCO3-)
CARBAMINOHEMOGLOBIN
DISSOLVED CO2 ▪ CO2 binds to terminal amino groups on
▪ Small fraction of CO2 dissolved in blood proteins (e.g. albumin, hemoglobin)
(similar to oxygen) ▪ CO2 bound to hemoglobin →
▪ Henry’s law: CO2 concentration in blood = carbaminohemoglobin (3% of total blood
partial pressure x solubility of CO2 CO2)
▪ Solubility: 0.07mL CO2/100mL blood per ▫ CO2 binding to hemoglobin at different
mmHg site than oxygen → conformational shift
▪ Partial pressure: 40mmHg of protein structure → ↓ oxygen affinity
OSMOSIS.ORG 615
→ right shift in dissociation curve ▫ If H+ remains free in solution → acidifies
▫ Haldane effect: less O2 bound to RBCs, venous blood → H+ must be
hemoglobin → ↑ CO2 affinity buffered
▫ H+ buffered by deoxyhemoglobin,
carried in venous blood
BICARBONATE (deoxyhemoglobin more efficient buffer
▪ 90% of CO2 in blood than oxyhemoglobin)
▪ Tissue level: CO2 produced by aerobic ▫ H+ production favors oxyhemoglobin
metabolism → driven by partial pressure conversion → deoxyhemoglobin (Bohr
gradient → CO2 diffuses across cell effect)
membrane, capillary wall → enters RBCs
▪ HCO3- transported into plasma (exchanged
RBC blood pH regulation for chloride)
▪ RBCs regulate blood pH via interaction ▫ Band 3 protein facilitates anion
with CO2 in blood exchange of Cl- for HCO3- (chloride shift)
▪ RBCs contain enzyme, carbonic anhydrase ▫ HCO3- carried in plasma to lungs
→ catalyzes conversion of CO2, water
Respiratory system blood pH regulation
→ carbonic acid (also catalyzes reverse
reaction) ▪ Respiratory system further regulates blood
pH
▪ Carbonic acid dissociates into bicarbonate,
▫ Controls CO2 elimination rate → CO2
▫ CO2 + H2O ⇌ H2CO3 ⇌ HCO3- + H+
hydrogen ion in blood
elimination ↑ pH by shifting equation to
left
▫ Mass action drives reaction to right as
▫ RBCs, carbonic anhydrase allow rapid
tissues continuously supply CO2
reaction in lungs → reverse processes in
▪ H2CO3 dissociates → H+, HCO3- blood at tissue level
▪ H+ remains in RBCs → buffered by
deoxyhemoglobin
Figure 71.5 CO2 transport in the form of bicarbonate. CO2 undergoes a chemical reaction with
H2O to form carbonic acid, which then dissociates into hydrogen ions and bicarbonate ions. This
reaction can occur in the plasma, but is sped up in red blood cells by the presence of carbonic
anhydrase enzymes. Ionic exchange of bicarbonate ions and chloride occurs via facilitated
diffusion to ensure charges stay balanced. Bicarbonate then travels to the lungs in the plasma.
616 OSMOSIS.ORG
REGULATION OF PULMONARY
BLOOD FLOW
osms.it/pulmonary-blood-flow-regulation
▪ Regulated by altering arteriole resistance Leukotrienes
→ controlled by arteriolar smooth muscle ▪ Product of arachidonic acid metabolism via
tone lipoxygenase pathway
▪ Regulatory changes mediated by local ▪ Potent airway constrictor
vasoactive substance concentrations
LUNG VOLUME
PULMONARY VASOACTIVE ▪ Pulmonary blood vessels → alveolar
SUBSTANCES & STATES capillaries that surround alveoli, extra-
Nitric oxide (NO) alveolar vessels which do not (arteries,
veins)
▪ Retains similar function on pulmonary
vascular beds (compared to systemic) → Increased lung volume
vasodilation ▪ Crushes alveolar capillaries → ↑ resistance
▪ Nitric oxide (NO) synthase inhibition → to blood flow
hypoxic vasoconstriction enhancement ▪ Intrapleural pressure becomes more
▪ Inhaled NO → reduction in/prevention of negative (↓ resistance) → pulls open extra
hypoxic vasoconstriction alveolar vessels
Thromboxane A2 ▪ Total pulmonary vascular resistance: sum
of alveolar, extra-alveolar resistance →
▪ Product of arachidonic acid metabolism increased lung volume effect dependent on
via cyclooxygenase pathway (macrocytes, larger effect
leukocytes, endothelial cells)
▫ Low lung volumes (extra-alveolar
▪ Lung injury → potent vasoconstrictor of vessels dominate) → ↑ volume →
pulmonary arterioles, veins extra-alveolar vessels pulled open → ↓
Prostaglandin I2 (prostacyclin) resistance
▪ Product of arachidonic acid metabolism via ▫ High lung volume (alveolar capillaries
cyclooxygenase pathway (endothelium) dominate) → ↑ lung volume → alveolar
vessels crushed, sharp ↑ resistance
▪ Potent local vasodilator
Figure 71.6 Blood vessel resistance associated with increased lung volume.
OSMOSIS.ORG 617
ZONES OF PULMONARY BLOOD
FLOW
osms.it/zones-of-pulmonary-blood-flow
POSITIONAL EFFECT ▪ PA generally = atmospheric pressure; can be
▪ Supine gravitational effect largely uniform overcome by low-pressure lung circulation
▪ Upright distribution of blood flow ▪ Positive pressure ventilation → PA > Pa in
(perfusion), ventilation throughout lungs apices of lung → blood vessels collapse →
not uniform physiological dead space (ventilated, not
▪ Blood flow favors gravity-dependent lung perfused)
regions → ↑ pulmonary arterial hydrostatic
Zone II
pressure moving inferiorly → blood flow in
inferior (basal) regions > superior (apical) ▪ Pa > PA > pulmonary venous pressure (PV)
regions ▪ Capillary compression not problematic
▪ Ventilation favors apices → ventilation ↓ ▪ Perfusion driven by difference between Pa,
with move towards bases of lungs PA (not Pa, PV; as in systemic vascular beds)
Zone III
LUNG ZONES ▪ Majority of healthy lung volume
▪ Lungs divided into three vertical sections ▪ No external resistance to blood flow
(based on pressure differences between ▪ Flow determined by Pa - PV (both exceed
compartments) PA)
Zone I
▪ Unobserved in healthy lung: pulmonary
arterial pressure (Pa) > alveolar pressure
(PA) in all parts of lung
Figure 71.7 Relationships between PA, Pa, and Pv in the three lung zones.
618 OSMOSIS.ORG
PULMONARY SHUNTS
osms.it/pulmonary-shunts
▪ Shunts occur when blood flow redirected LEFT-TO-RIGHT SHUNTS
from expected route, bypassing circulatory ▪ More common
conduit ▪ Blood shunted from left to right heart
▫ Due to septal defects (e.g. trauma,
PHYSIOLOGICAL SHUNTS patent ductus arteriosus)
(ANATOMICALLY NORMAL) ▪ Blood intended for systemic circulation
▪ Bronchial blood flow: fraction of pulmonary directly circulated back to lungs →
blood which bypasses alveoli to supply pulmonary blood flow exceeds systemic
bronchi blood flow → fraction of blood does reach
▪ Coronary blood flow: thebesian venous systemic circulation fully oxygenated → no
network allows for alternative myocardium hypoxia
drainage directly into left ventricle (not
reoxygenated)
Figure 71.8 Physiologic shunts.
OSMOSIS.ORG 619
RIGHT-TO-LEFT SHUNTS Shunt fraction equation
▪ Defect in wall between right, left sides of ▪ Oxygenation bypass of venous blood in
heart → blood shunted from right to left lung capillaries
side of heart ▪ QS/QT = (CCO2 - CAO2)/(CCO2 - CVO2)
▪ Allows for large cardiac output fraction to ▪ QS: blood flow through right-to-left shunt
be shunted (approx. 50%) → bypasses (L/min)
lungs → oxygenated blood diluted with ▪ QT: cardiac output (L/min)
shunted deoxygenated blood → hypoxemia
▪ CCO2: oxygen content of nonshunted
▪ Not responsive to high PO2 gas treatment pulmonary capillary blood
→ complete pulmonary blood saturation
▪ CaO2: oxygen content of systemic arterial
doesn’t improve shunted blood oxygenation
blood
▪ Causes minimal PaCO2 change → central
▪ CVO2: oxygen content of venous blood
chemoreceptors responsive to small PaCO2
increases (shunted blood not available for
gas exchange) → ↑ ventilation rate → extra
CO2 expired
▪ Central O2 receptors significantly less
sensitive than CO2 receptors → only ↑
ventilation once PaO2 < 60mmHg
Figure 71.9 Pathologic shunts occurring in the left-to-right (more common) and right-to-left
directions.
620 OSMOSIS.ORG
VENTILATION PERFUSION RATIOS

& V Q MISMATCH
osms.it/ventilation-perfusion-ratios-V-Q-mismatch
▪ Ratio of amount of air to amount of blood High V̇/Q̇
reaching alveoli per minute (V̇ /Q̇ ratio) ▪ High ventilation relative to perfusion
(ventilation wasted)
IDEAL SCENARIO ▪ Usually due to ↓ blood flow (limited blood
▪ Oxygen provided saturates blood fully → flow → limited gas exchange)
ratio of 1 ▪ Relatively high ventilation → pulmonary
capillary blood with high PO2, low PCO2
▪ Emphysema
NORMAL SCENARIO
▪ Average across entire lung → ratio of 0.8 Low V̇/Q̇
(apex higher, bases lower) ▪ Low ventilation relative to perfusion
▪ Normal breathing rate, tidal volume, cardiac (perfusion wasted)
output ▪ Usually due to ↓ ventilation → pulmonary
capillary blood with low PO2, high PCO2
DEFECTS ▪ Asthma, chronic bronchitis, pulmonary
▪ Mismatching between ventilation, perfusion edema, etc.
→ abnormal gas exchange
Right-to-left shunt
Dead space ▪ Perfusion of lung regions not ventilated
▪ Ventilation of lung regions not perfused ▪ No gas exchange occurs (no gas available
▪ No gas exchange (no blood to facilitate gas to exchange)
exchange) ▪ Same blood composition as mixed venous
▪ Alveolar gas same composition as blood (PaO2 = 40mmHg, PaCO2 = 46mmHg)
humidified inspired air (PAO2 = 150mmHg, ▪ Airway obstruction, right-to-left cardiac
PACO2 = 0) shunts, etc.
▪ Pulmonary embolism
Figure 71.10 Normal V̇ /Q̇, Pa, and PA compared to pulmonary embolism and airway obstruction.
OSMOSIS.ORG 621
HYPOXEMIA & HYPOXIA
osms.it/hypoxemia-and-hypoxia
HYPOXEMIA Diffusion defects (fibrosis, pulmonary
▪ Decrease in arterial PaO2 edema)
▪ Increased diffusion distance/decreased
High altitude surface area → impaired equilibration
▪ Barometric pressure is decreased → ▪ Normal PAO2, decreased PaO2 → ↑ A–a
decrease in PO2 of inspired air → decreased gradient
PAO2
▪ Breathing supplemental O2 → raised PAO2
▪ Equilibration of alveolar air, pulmonary → increased driving force for diffusion →
capillary blood (normal) raised PaO2
▪ Systemic arterial blood achieves same
(lower) PO2 of alveolar air Ventilation/perfusion mismatches
▪ Normal alveolar–arterial (A–a) gradient ▪ Regions of well-ventilated (high PAO2),
▪ High altitude breathing supplemental O2 → poorly-ventilated (low PAO2), well-perfused,
raised inspired PO2 → raised PAO2 → raised poorly-perfused lung
PaO2 ▪ Poor perfusion to well-ventilated areas,
adequate perfusion to areas poorly
Hypoventilation ventilated → low PaO2
▪ Less inspired fresh air → decrease in PAO2 ▪ Supplemental oxygen → raised PAO2 in
▪ Normal equilibration → pulmonary capillary poorly-ventilated areas with adequate
blood achieves same (lower) PAO2 as A–a perfusion → increase in PaO2
gradient ▪ ↑ A–a gradient
▪ Hyperventilation: breathing supplemental
O2 → raised PAO2 → raised PaO2
622 OSMOSIS.ORG
Right-to-left shunts (right-to-left cardiac ▪ Carbon monoxide poisoning →

shunts, intrapulmonary shunts) irreversible binding with hemoglobin → ↓
▪ Shunted blood completely bypasses alveoli, oxyhemoglobin concentration in blood → ↓
cannot equilibrate oxygen delivery to tissues → hypoxia
▪ Shunted blood mixes with, “dilutes” blood ▪ Cyanide poisoning → interferes with O2
that did pass through alveoli → ↓ PaO2 utilization on cellular level
(even if PAO2 normal)
▪ ↑ A–a gradient HYPOXIC VASOCONSTRICTION
▪ Limited supplemental O2 effect → raises ▪ Alveolar partial pressure of oxygen (PAO2)
PAO2, PaO2 of nonshunted blood, does major factor controlling pulmonary blood
not address underlying shunted blood/ flow
oxygenated blood mixing → larger shunt, ▪ ↓ PAO2 → vasoconstriction (opposite to
less effective supplemental O2 systemic vasculature where ↓ in PaO2 →
vasodilation)
HYPOXIA ▫ Vasoconstriction in response to poor
▪ ↓ O2 delivery to/utilization by tissues oxygenation ensures blood flow coupled
▪ O2 delivery → determined by cardiac to areas of good ventilation → optimal
output, O2 content of blood gas exchange
▪ ↓ cardiac output/localized blood flow → ▫ In localized lung disease, areas of
hypoxia poorly-ventilated, diseased lung
circumvented → blood directed towards
▪ Hypoxemia (any cause) → ↓ PaO2 → ↓
healthy lung
hemoglobin saturation → ↓ oxyhemoglobin
concentration in blood → ↓ oxygen delivery
to tissues → hypoxia
▪ Anemia (↓ hemoglobin concentration) → ↓
oxyhemoglobin concentration in blood →
decreased oxygen delivery to tissues →
hypoxia
OSMOSIS.ORG 623
Alveolar PO2 direct action on vascular FETAL HYPOXIC
smooth muscle → hypoxic vasoconstriction VASOCONSTRICTION
▪ Pulmonary microcirculation surrounds ▪ Fetal circulation must acquire oxygen
alveoli from maternal circulation via placenta
▪ O2 highly lipid soluble → permeable across → significantly lower PaO2 → fetal lung
cell membranes vasoconstriction → reduction of blood flow
▪ Normal PAO2 (100mmHg), O2 diffuses to lungs (15% of cardiac output)
from alveoli → arteriolar smooth muscle → ▪ At birth low pressure placenta circuit
maintains relaxation, dilation of arterioles removed → ↑ systemic blood pressure
▪ PAO2 decreases (70–100mmHg) → vascular → first breath after birth → ↑ PAO2 →
smooth muscle sense change (hypoxia) → 100mmHg → ↓ hypoxic vasoconstriction
vasoconstriction → ↓ pulmonary blood flow → ↓ pulmonary vascular resistance →
to region pulmonary blood flow begins to normalize
▫ Vasoconstriction mechanism likely due
to hypoxia → vascular smooth muscle
depolarization → voltage-gated calcium
channels open → calcium enters smooth
muscle → contraction
HIGH ALTITUDE & HYPOXIC

VASOCONSTRICTION
▪ Entire lung exposed to ↓ PAO2 (e.g. high
altitudes) → global ↑ in pulmonary arteriolar
resistance → ↑ pulmonary vascular
resistance
▪ Chronic ↑ pulmonary vascular resistance
→ ↑ right heart afterload → right heart
hypertrophy
624 OSMOSIS.ORG
NOTES
NOTES
NORMAL VARIATIONS
PULMONARY CHANGES
DURING EXERCISE
osms.it/pulmonary_changes_during_exercise
RESPIRATORY RESPONSE TO ▪ Exercise cessation → initial small abrupt
EXERCISE decline in ventilation (higher neurological
▪ Exercise → muscle workload increase → stimulation ends) → followed by gradual
consumption of significant O2 amounts, decrease to pre-exercise respiratory rate
above baseline production of CO2, lactic (gradual decrease in CO2 flow to lungs)
acid
▪ Increased O2 demand → hyperpnea PULMONARY CIRCULATORY
(ventilation increases 10–20x to RESPONSE
compensate) ▪ Cardiac output increases to meet tissue O2
▪ Hyperpnea vs. hyperventilation demand → increased right heart output →
▫ Hyperpnea: aims to maintain increased blood flow through pulmonary
homeostasis → blood O2 ,CO2 levels circulation → increased blood return to
remain relatively constant left heart → increased output to systemic
▫ Hyperventilation: excessive ventilation, circulation → increased O2 tissue delivery
blowing off too much CO2 → low PCO2, ▪ Exercise → pulmonary resistance
respiratory alkalosis decrease → perfusion of more pulmonary
▪ Exercise-induced ventilation not initially capillary beds → more even distribution
prompted by alterations in blood gases of pulmonary perfusion, ventilation
(rising PCO2 , declining PO2, pH) → improved V/Q ratio (decreased
▪ Ventilation increases abruptly as exercise physiological dead space) → increased gas
begins due to neural factors exchange efficiency
▫ Psychological stimuli (conscious exercise
anticipation) HEMATOLOGICAL RESPONSE
▫ Simultaneous cortical motor activation
of skeletal muscle, respiratory centers Bohr effect
▫ Proprioceptors moving muscles, ▪ Hemoglobin’s oxygen binding affinity is
tendons, joints → stimulate respiratory inversely related to acidity, carbon dioxide
centers concentration
▫ Initial neural regulation → early ▫ Exercise → increased tissue PCO2,
compensation to exercise as opposed to decreased tissue pH, increased
waiting for change in blood values temperature → right shift of O2-
hemoglobin dissociation curve →
▪ Initial abrupt increase in ventilation is
decreased affinity of hemoglobin for
followed by gradual increase (reflective
O2 → greater unloading of oxygen to
of lung CO2 delivery rate) → eventually,
exercising muscle
steady state of ventilation appropriate for
intensity achieved
OSMOSIS.ORG 625
Regulation of blood gases during exercise
▪ Arterial PCO2, PO2 remain nearly constant
during exercise
▪ Venous PCO2, PO2 may change significantly
during exercise
▫ Ventilation increases sufficiently to blow
off all excess CO2, maintain arterial
homeostasis
Anaerobic respiration
▪ Leads to rise in lactic acid levels
▪ Not due to inadequate respiratory function
▪ Alveolar ventilation, pulmonary perfusion
remain well matched during exercise →
hemoglobin fully saturated
▪ Cardiac output limitation/limits of skeletal
muscle to utilize oxygen → rising lactic acid
626 OSMOSIS.ORG
Chapter 72 Respiratory Physiology: Normal Variations
PULMONARY CHANGES AT HIGH

ALTITUDE & ALTITUDE SICKNESS
osms.it/pulmonary_changes_high_altitude_altitude_sickness
RESPIRATORY RESPONSE TO with carbonic anhydrase inhibitors

ALTITUDE → increased HCO3- excretion → mild
▪ Humans typically live at altitudes between compensatory metabolic acidosis
sea level and 2400m/7800ft ▪ Hematological
▪ Altitudes > 2400m/7800ft → lower overall ▫ Increase in 2,3-bisphosphoglyceric acid
atmospheric pressure → lower PO2 → (2,3-BPG) concentration → hemoglobin
hemoglobin less saturated at baseline affinity for O2 reduced → increased
▫ At rest at sea level hemoglobin typically unloading of O2 at tissue level (also
unloads 20–25% O2 content on a single decreases efficiency of oxygen loading
trip through the circulatory system in lungs)
▫ Significant functional reserve allows ▪ Cardiac
for survival due to further hemoglobin ▫ Increased heart rate
unloading when poorly saturated ▫ Right heart hypertrophy: low PO2
alveolar gas → pulmonary vasculature
ACCLIMATIZATION vasoconstriction → increase in
pulmonary vascular resistance →
▪ Long-term, slow steady move from sea
increased right heart strain → right
level to higher altitude → respiratory,
ventricular hypertrophy
hematopoietic adaptation
▪ Oxygen conservation
▪ Decrease in arterial PO2 → peripheral
chemoreceptors more responsive to ▫ Non-essential body functions
increases in PCO2 → chemoreceptors suppressed → reduction in food
stimulate medullary inspiratory center → digestion efficiency (decreased
increased breathing rate circulation in favor of perfusing more
important organs)
Initial (fast) adaptation
Late (slow) acclimatization
▪ Some changes occur immediately, others
over course of days ▪ Occurs over weeks to months
▪ Pulmonary ▪ Hematological: hypoxia → kidneys produce
more erythropoietin → stimulates bone
▫ Minute ventilation → 2–3L/min higher
marrow production of red blood cells
than sea level
→ total O2 carrying capacity of blood
▫ Increased ventilation → decreased increased
arterial CO2 (<40mmHg) → respiratory
▫ Essential compensation for living at
alkalosis → increased blood pH
altitude
→ inhibition of central, peripheral
chemoreceptors → offset increase in ▫ Increases blood viscosity → greater
ventilation rate (initial effect) blood flow resistance → greater heart
workload
▫ As adaptation occurs → HCO3- excretion
increases → HCO3- concentration in ▫ Full acclimatization: increase in red
cerebrospinal fluid (CSF) decreases → blood cell plateaus
CSF pH decreases toward normal → ▪ Effect on complete blood count parameters
increased ventilation rate resumes ▫ Total red cells: ↑
▫ Respiratory alkalosis as result of rapid ▫ Hemoglobin: ↑
ascent to high altitude managed ▫ Hematocrit: ↑
OSMOSIS.ORG 627
▫ Mean corpuscular volume: unchanged ACUTE MOUNTAIN SICKNESS
▫ Mean corpuscular hemoglobin ▪ AKA altitude sickness
concentration: ↑ ▪ Commonly associated with altitudes above
2400m/7800ft
Exercise at altitude
▫ Minor symptoms may occur at as low as
▪ Adaptations normally serve to achieve 1500m/5000ft
homeostasis at rest → unless fully
▫ Death zone: 5500m/18000ft, altitude
acclimatized intense physical activity →
considered incompatible with human
homeostasis loss → severe hypoxia
life; acclimatization not possible
▪ This transient intentional hypoxia can be
▪ Caused by sudden transition to altitude
exploited by athletes → further adaptive
without sufficient acclimatization → low
changes to altitude → blood with greater
atmospheric pressure → low PO2 → hypoxia
oxygen carrying capacity → improved
performance at lower altitude ▪ Contributing factors
▪ Late phase acclimatization of skeletal ▫ Rate of ascent
muscle includes: increased capillary ▫ Rate of water vapor loss from lungs
concentration, increased myoglobin ▫ Activity level
amount, increased mitochondria number, ▪ Sudden increase in altitude without taking
increased aerobic metabolism enzyme time to acclimatize
concentration
Symptoms
▪ Headache, shortness of breath, nausea,
dizziness, peripheral edema
Complications
▪ Severe complications of high altitude can
be fatal
▪ High altitude pulmonary edema (HAPE)
▫ Low atmospheric pressure → decreased
oxygen partial pressures, poor
oxygenation → increased pulmonary
arterial, capillary pressures, idiopathic
increase in permeability of vascular
endothelium → fluid extravasation →
pulmonary edema
▪ High altitude cerebral edema (HACE)
▫ Hypoxia → increased cerebral
microvascular permeability, failure
of cellular ion pumps → vasogenic,
cytotoxic edema
Treatment
▪ Supplemental oxygen/immediate descent
628 OSMOSIS.ORG

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PHYSIOLOGY

Causation & validity Placebo effect & masking 74

Causality 48 Case-control (retrospective) study 74

Bias 49 Cohort study 75

Confounding 50 Cross-sectional (prevalence) study 76

Modes of infectious disease Testing

Stroke volume, ejection fraction, &

Liver, gall bladder, and pancreas Role of vitamin K in coagulation 367

Bile secretion & enterohepatic Anticoagulation, clot retraction, &

Pancreatic secretion 337

Bone remodeling & repair 410 Somatosensory receptors 484

Fibrous, cartilage, & synoial joints 411 Photoreception 486

Muscles Optic pathways 487

Muscular system anatomy & Auditory transduction & pathways 489

Distal convoluted tubule 537 Puberty & Tanner staging 586

CITRIC ACID CYCLE

ELECTRON TRANSPORT CHAIN &

Chapter 1 Biochemistry: Carbohydrate Metabolism

glycerol-3-phosphate (via glycerol-3- ▪ Fructose-6-phosphate (via isomerase) →

Figure 1.5 The process of gluconeogenesis.

Figure 1.6 The process of glycogen synthesis.

PENTOSE PHOSPHATE PATHWAY

Figure 1.10 Glycolysis.

Figure 2.2 Cholesterol synthesis regulation.

FATTY ACID SYNTHESIS

KETONE BODY METABOLISM

KETONE BODY SYNTHESIS

Figure 2.10 Ketone body breakdown.

Figure 3.4 DNA nucleotide synthesis from diphosphates of RNA nucleotides.

Figure 3.5 Breakdown of purines into uric acid.

AMINO ACIDS & PROTEIN FOLDING

Figure 4.1 The 20 amino acids used by humans.

▪ Amino acids: organic compounds with

Figure 4.3 Amide (peptide) bonds form

Figure 4.4 Enantiomers are two forms

Figure 4.7 Michaelis–Menten graph: used

▪ Km: substrate concentration when reaction

Figure 4.6 Transition state: intermediate step

▪ Enzyme kinetics: catalysis rate

Figure 4.10 Processes that ↑ Vmax ↓ 1/Vmax

Figure 4.9 The Lineweaver–Burk plot shows

AMINO ACID METABOLISM

aminotransferase + vitamin B6 cofactor) ⇄

Figure 4.11 Ammonia → urea in the liver.

Chapter 4 Biochemistry: Protein Metabolism

NITROGEN & THE UREA CYCLE

Figure 4.15 The glucose-alanine cycle of ammonia reaching the liver.

Urea cycle ▪ Argininosuccinate lyase: argininosuccinate

Figure 4.19 Elongation: RNA polymerase

Three RNA types required

POPULATION & SAMPLE TYPES OF HYPOTHESES

Population Null hypothesis (H0)

MEAN, MEDIAN, MODE

▪ Can be inﬂuenced by an extreme value

▪ Odd number of values → one “middle”

Standard deviation (SD)

Figure 5.8 Types of data.

been known to cause lung pathology Not necessary but sufﬁcient

MODES OF INFECTIOUS DISEASE

Chapter 7 Biostatistics & Epidemiology: Community Health