Clinical and Molecular Human Genetics

The association between Down syndrome (DS) and maternal polymorphisms in genes encoding folic acid metabolizing enzymes remains a controversial issue. A meta-analysis was performed to evaluate the association of maternal MTHFR 677C [ T polymorphism and the risk of having a child with DS. Case-control studies were screened from major literature databases. Twenty articles from 13 countries worldwide, with a total of 2,101 DS and 2,702 control mothers, attended the inclusion criteria. We found a 50 % increase for the association of maternal homozygous TT genotype and DS in both fixed (OR = 1.51; 95 % CI 1.22-1.87) and random effects models (OR 1.54; 95 % 1.15-2.05). Similarly, a significant pooled OR was found for the heterozygote CT, with an OR 1.26; 95 % CI 1.10-1.43 (fixed effects model) and OR 1.28; 95 % 1.08-1.51 (random effects model). As ultra-violet B solar radiation highly depends on latitude, and can promote, in less pigmented skin, intravascular folate photolysis, we stratified the analysis by latitude region, defining as Tropical (between 23.5°S and 23.5°N), Sub-Tropical (between 23.5°and 40°N and S), and Northern (C40 o N). Significant association was only found for Sub-Tropical area, both using fixed and random effect models. In conclusion, MTHFR 677C [ T polymorphism is a moderate risk factor for DS for some populations, and populations located in Sub-Tropical region seem to be at greater risk. Latitude, ethnicity, skin pigmentation, and red blood cell folate are important variables to be considered in future studies.

Context: Inbreeding increases the level of homozygotes for autosomal recessive disorders and is the major objective in clinical studies. The prevalence of consanguinity and the degree of inbreeding vary from one population to another depending on ethnicity, religion, culture and geography. Global epidemiological studies have revealed that consanguineous unions have been significantly associated with increased susceptibility to various forms of inherited diseases. Objective: The study aimed to determine the role of consanguinity in human health and to highlight the associated risks for various diseases or disorders. Methods: PubMed and Google Scholar search engines were used to explore the published literature on consanguinity and its associated risks using the key words " consanguinity " , " prevalence " , " inbreeding depression " , " coefficient of inbreeding " , " child health " , " mortality " , " human health " , " homozygosity " and " complex diseases " in different combinations. The studies were screened for eligibility on the basis of their epidemiological relevance. Results: This comprehensive assessment highlights the deleterious consequences in populations with a higher prevalence of consanguinity among different countries worldwide. Conclusions: To avoid the inbreeding load there is the need to improve socioeconomic and educational status and to increase public awareness of reproductive health and anticipated deleterious effects. Premarital and pre-conception counselling of consanguineous populations should be an integral part of health policy to train people and make people aware of its harmful consequences. Furthermore, runs of homozygosity (ROH) and whole-exome sequencing (WES) are useful tools in exploring new genomic signatures for the cause of inbreeding depression.

The purpose of this research project was to determine the best bioinformatic fetal DNA fraction estimation method in NIPT (Non-Invasive Prenatal Testing) samples using genome-wide paired-end sequencing by comparing two commercially available library preparation kits for whole genome sequencing (Illumina® TruSeq® Nano DNA and Rubicon Genomics® ThruPLEX® Plasma-seq) and by analysing three different bioinformatic methods (size-based, SeqFF, and Y chromosome read proportion based). The results were compared to the method running in the clinical laboratory where fetal fraction is determined by SNP genotyping (considered the golden standard).

This project provides recommendations to achieve efficient workflow of noninvasive prenatal test in clinical genetics setting.

Asthma is a disease characterized by wide variations in
pathogenesis that cause resistance to flow in intrapulmonary
airways. The dramatic changes in the architecture of the airway
walls are usually connected to allergic reaction or other forms of
hyper sensitivity, causing marked spasms that lead to difficulty in
breathing. It is possible to relieve or remove the symptoms in the
majority of patients by adopting the clinical guidelines for
pharmacotherapy of asthma which include inhaled corticosteroids,
long and short acting beta agonists, muscarinic antagonists,
leukotriene modifiers, xanthine drugs and some allergy medicines.
The proper use of these agents can aid in reducing or reversing
many symptoms of asthma. Certain methods of using medicines,
for example the correct use of the inhaler for relief and
maintenance therapy, are also associated with a significant
reduction in symptoms. This can be achieved by a pharmacist’s
intervention that can provide a detailed understanding of the
current rational drug choices and proper medication use to the
patient. Nowadays massive resources are being ploughed into
research in a concerted effort to halt the progress of this illness
that can strike in all ages.

Phenylhydrazine (PHZ), a potent chemical causes toxicity on various tissues at various levels. Administration of phenylhydrazine mainly causes haematotoxicity which leads to the haemolytic anemia. In mammals PHZ induced anemia increased the iron absorption in spleen, liver and duodenum and finally iron metabolism was altered. Local demand and supply of Fe would increase erythropoeitic activity of the spleen so the size of spleen was increased that create the splenomegaly. PHZ induced anemia activate immune response which triggers phagocytosis in the spleen and liver. Apart from this administration of PHZ interfere the binding of erythropoietin (EPO) with erythropoietin receptors (EPOR) so that JAK-STAT would be affected.PHZ also showed genotoxic effect by creating single strand DNA damage.

Consanguinity is the union of closely related individuals – which can have genetic implications on the health of offspring(s). Consanguineous families with disorders have been extensively analysed by geneticists and this has led to the identification of many autosomal recessive disorder causal variants and genes. Two copies of the ‘inactivating’ or loss of function (LoF) allele are required to cause an autosomal recessive disorder, one inherited from the mother and the other from the father. In outbreeding populations these LoF alleles very rarely meet their counterpart (as it requires both parents to possess the allele), thus are passed down the generations silently – sometimes for millennia. However, consanguineous and/or endogamous offspring have elevated levels of homozygosity, which dramatically increases the probability of any allele to be in a homozygous (or more correctly autozygous) state. This increase in probability applies to LoF mutations also; and this elevation of levels of homozygosity is the main reason why extremely rare autosomal recessive disorders are usually only seen in populations where consanguinity (and/or endogamy) levels are high.

With the ever decreasing prices of DNA sequencing, whole-genome sequencing is becoming a reality for many laboratories. However, for now, whole-exome sequencing (WES) is the most feasible sequencing technique mostly due to cost factors. Combining the concepts of consanguinity and WES, the aim of this thesis was to identify ‘causal’ variants by analysing whole-exome data obtained from consanguineous families/individuals affected from autosomal recessive disorders such as Primary Ciliary Dyskinesia (PCD) and Autosomal Recessive Intellectual Disability (ARID). Using autozygosity mapping, a novel region located on chromosome 19 (p13.3) was identified to be associated with ARID (later sequenced by another research group and ADAT3 was identified as the causal gene). Using WES, rare homozygous nonsense mutations p.E309* in CCDC151 and p.R136* in DNAAF3 were found to be causal of PCD. Other variants such as p.M263T in MNS1, p.R263* in DNALI1, p.G734fs in HEATR2 and p.E328* in LRRC48 have also been identified which may be causal of PCD but studies in this thesis remained inconclusive due to various reasons. Additionally, a rare missense mutation p.G300D in CTSC was found to be Papillon-Lèfevre syndrome (PLS) causal. This latter finding illustrated the additional information that can be gained from WES data – which is discussed in the thesis.

Finding novel causal variants and gene functions can improve genetic counselling and lead to the identification of targets for preventive and/or curative medicine. In this respect, analysing consanguineous populations as a whole rather than ‘cherry picking’ families with disorders will have additional benefits and facilitate our understanding of the human genome – and this subject is also discussed in this thesis.

It gives me great pleasure to warmly welcome you here to Dubai and the UAE to conduct your important scientific deliberations in the field of human genomics. Your focus on 'Genomics of Human Diversity and Heritable Disorders' along with the 4 th Pan Arab Human Genetics Conference is extremely relevant and of great consequence globally. It is of particular interest to us here in the Arab region, for as many of you are acutely aware, the prevalence of genetic disorders is disproportionately high in our communities. Many factors contribute to this situation and we are looking forward to working with you in the future to address those factors.

It gives me great pleasure to warmly welcome you here to Dubai and the UAE to conduct your important scientific deliberations in the field of human genomics. Your focus on 'Genomics of Human Diversity and Heritable Disorders' along with the 4 th Pan Arab Human Genetics Conference is extremely relevant and of great consequence globally. It is of particular interest to us here in the Arab region, for as many of you are acutely aware, the prevalence of genetic disorders is disproportionately high in our communities. Many factors contribute to this situation and we are looking forward to working with you in the future to address those factors.

Beare-Stevenson syndrome is characterized by cutis gyrata, acanthosis nigricans, skin furrows, skin tags, craniosynostosis, Crouzonoid-like features in some cases and cloverleaf skull in others, anogenital anomalies, and prominent umbilical stump. Reported causes are an FGFR2 Tyr375Cys mutation in nine cases and an FGFR2 Ser372Cys mutation in one case. Here, we report on a second patient with the FGFR2 Ser372Cys mutation. ß

Nuclear factor kappa B (NFkB) a pro-infl ammatory transcription factor, plays a signifi cant role in carcinogenesis. An A to G variation detected in the 3’UTR of the NFkB1A gene has been linked to crohn’s disease, which in turn is associated with increased susceptibility to Colorectal cancer. No data are available regarding the frequencies of NFkB1A genotype in Malaysian population and its association with CRC susceptibility. So a case control study involving 118 CRC patients and 117 normal controls was carried out to determine the frequencies of A to G variant NFkB1A genotype in Malaysian population and to investigate its infl uence on CRC susceptibility risk, employing PCR-RFLP technique. On analyzing the CRC susceptibility associated risk, the AG genotype showed signifi cant risk with OR 1.920 (p = 0.020) and GG genotype showed non signifi cant risk with OR 1.24 (p = 0.469). When the heterozygous and homozygous variant genotypes were combined, the associated risk was signifi cantly more pronounced with OR 2.124 (p = 0.005). The results suggest that, the A to G variant genotype of NFkB1A has signifi cant infl uence on CRC predisposition in Malaysian population.

As a strong heritability component has recently been identified in a whole exome sequencing study in SARS-CoV-2 infected COVID-19 patients, the ongoing identification of host susceptibility factors appears to be a worthwhile endeavour. In this article, α1-antitrypsin deficiency (A1AT deficiency) is proposed to represent a host susceptibility background in some COVID-19 patients. A1AT possesses general anti-inflammatory and immune-modulating properties in addition to maintaining the protease/antiprotease balance in the lung. A1AT deficiency is a common, underdiagnosed, inherited disorder. Associated immunological and clinical responses show overlap with post infectious residual problems experienced by some COVID patients. Research hypotheses to investigate the possibility of a A1AT deficiency-COVID 19 link include 1) investigating whether there is a causal connection between pathogenic A1AT deficiency alleles and COVID morbidity and mortality based on shared immunopathological features 2) whether altered glycosylation in AIAT deficiency has an effect on viral envelope glycosylation properties/gender glycosylation differences/hyposmia? 3) Is the COVID associated Kawasaki-like multisystem inflammatory syndrome in children (MIS-C) similar to AIAT - associated Kawasaki syndrome? 4) Do post- COVID infection disease states underlie the triggering of ongoing AIAT associated pathogenicity in various ways in specific A1AT pathogenic allele variant carriers? 5) Do international infection hotspots overlap with the geographical distribution of specific A1AT pathogenic allele variants? A1AT deficiency has previously been shown to alter host responses to atypical mycobacteria and HIV infectivity. It appears urgent to clarify whether superimposed COVID-19 infection in A1AT deficiency carriers results in an altered, more severe or prolonged illness. Demonstration of a pathophysiological relationsip between the two conditions will allow consideration of an additional therapeutic option in COVID 19 infection, the FDA-approved medication (Prolastin) (purified A1AT obtained from pooled human serum) is available for the neutrophil - driven immunopathology associated with genetic AIAT deficient disorders.

Background
DNA repair genes have critical role in protecting the genome against endogenous and environmental agents. We hypothesize that, polymorphisms DNA repair genes might be predisposing factors for CRC susceptibility. In order to check this hypothesis, a case control study was designed to examine the frequencies of polymorphism Lys751Gln of XPD/ERCC2, Arg399Gln of XRCC1 and Thr241Met of XRCC3 gene in Malaysian CRC patients and healthy controls and investigate the associated CRC susceptibility.
Methods
Genotyping for the above DNA repair polymorphisms were performed in 118 colorectal cancer patients and 118 healthy normal controls by using PCR-RFLP.
Results/Conclusion
No association was found between the XPD/ ERCC2 Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and risk of colorectal cancer susceptibility when studied singly or in combinations. Our preliminary results, showing the lack association of XPD/ERCC2 Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms with CRC susceptibility risk, could be attributed to the small sample size, interaction of other polymorphic DNA repair genes and also low frequency of variant alleles for the polymorphisms studied in this population.

We Present the first mutation proven case of Fanconi–Bickel syndrome, a rare type of glycogen storage disease, from India. A four-year-old girl presented with severe growth retardation, genu varum and hepatomegaly. Investigations confirmed severe hypophosphatemic rickets and Fanconi syndrome. Molecular analysis confirmed a homozygous deletion insertion mutation in Glut 2 gene.

Background:
Colorectal cancer (CRC) results from the interaction between environmental exposures and genetic predisposition factors. Aims: A case control study was designed and to investigate the genotype frequencies of P53Arg72Pro polymorphism in Malaysian CRC patients and healthy controls and to determine the associated risk of this polymorphism with CRC predisposition.
Methods:
In this case-control study, peripheral blood samples of 202 sporadic CRC patients and 201 normal controls were collected, DNA extracted and genotyped using the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) technique.
Results: Genotype analysis showed the frequency of homozygous variant (Pro/Pro) genotype (21%) to be significantly higher in cases compared to controls (13%), (p=0.013). On examining the association between variant genotypes and CRC risk, the Pro/Pro homozygous variant genotype showed significantly higher risk association with CRC susceptibility (OR: 2.047, CI: 1.063-4.044, p=0.033). When stratified according to age, we observed that, individuals aged above 50 years and carriers of pro/pro genotype had significantly higher risk with OR: 3.642, CI: 1.166-11.378, p=0.026. Conclusions:
Our results suggest that the codon 72 SNP which results in amino acid substitution of Arginine to Proline in cell cycle regulatory gene P53, is associated with sporadic CRC risk and carriers of Pro/Pro genotype and more than 50 years old may have high susceptibility.

"The clinical bacteria of multi-drug resistant to some antibiotics are
considered a common problem in the world wide. Alternative
antibacterial strategies are urgently needed, and thus this situation
has led to a re-evaluation of the therapeutic use of ancient
remedies, such as plants and plant-based products, including
Nigella sativa (N. sativa). This study aimed to evaluate the
antibacterial activity of Yemeni N. sativa oil against some Clinical
Bacterial Isolates (CBI) and Control Strains of Bacteria (CSB) in
comparison with Augmentin® (Amoxicillin and Clavulanic Acid).
This study was carried out in Sana’a city during the period of one
year from May 2012 to April 2013. The antibacterial activity of oil
with different concentrations was determined by using disc agar
diffusion technique against CBI (Staphylococcus aureus and
Pseudomonas aeruginosa) and CSB (Staphylococcus aureus
ATCC25619, Pseudomonas aeruginosa ATCC29737), also the
Minimum Inhibition Concentration (MIC) of oil extract was
determined. The results indicated that, the highest significant
antibacterial activity was at the maximum concentration of the oil
against Staphylococcus aureus and Pseudomonas aeruginosa in
comparison with Augmentin ® discs (p < 0.05) respectively. This
study observed that, there was strong positive correlation between
the diameter zone (DZ-mm) and oil concentrations (%). In
addition, the DZ (mm) of the oil for CSB was higher than CBI.
Also the oil activity was found to be more effective against
Staphylococcus aureus than Pseudomonas aeruginosa. On the
other hand, the MIC of the oil against CBI were ranged between ≥
0.5% and 4%. Whereas, the CSB particularly Staphylococcus
aureus were sensitive to low concentrations of oil. It could be
concluded that, the oil had high antibacterial effect against CSB
and CBI with high concentration and more effective than
Augmentin® discs."

Objective: To evaluate public awareness level of G6PD deficiency in Bahrain.
Design: Cross sectional survey.
Setting: Bahrain Schools, Public Gathering Centers (commercial malls and others).
Method: A questionnaire was distributed among 2000 individuals from the public (nonprobability
convenience sample). It was conducted from December 2006 to February 2007. The
participants were personally interviewed by a health professional or a trained interviewer.
Result: One thousand eight hundred fifty-nine (93.9%) has heard of G6PD deficiency and
1,586 (79.8%) recognized it as a blood disease, only 690 (34.7%) recognized it as a gender
related disease. One thousand seven hundred three (85.7%) knew that fava bean ingestion can
be a triggering factor for hemolysis in affected individuals. Females showed better knowledge
than males and married persons seem to know more about G6PD deficiency than unmarried.
Conclusion: The study revealed a good level of knowledge of G6PD deficiency. Some of the
respondents were confused about the pattern of inheritance. Females are more knowledgeable
of the disease, which affects mainly males, and married individuals seem to know more than
singles. There is a general acceptance of hemoglobinopathies prevention campaigns, which is
conducted in Bahrain, such as the premarital service and the student-screening program.

The completion of the Human Genome Project in 2003 heralded in a new era marked by remarkable advances in biomedical research leading to the establishment of genomics‐based translational medicine mainly in the developed world. However, the development of such advances has been hampered in most parts of the developing world due to scarcity of resources and trained personnel. Genetics and genomic med- icine are currently in the process of being integrated into the Sri Lankan health care system. These developments have taken place mainly due to the heightened aware- ness and increasing demands made by the public for provision of genetic diagnostic and therapeutic services in clinical care. Due to the exorbitant costs incurred in the maintenance of these services and the dearth of adequately trained manpower, only a few centers in the country, mainly in Universities or private sector, are currently engaged in providing these services to the public. This article aims to provide an overview of the genetics and genomic medicine services in Sri Lanka from its early developments to the current state.

The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising biomarkers that have proven difficult to uncover. They come in two flavors: those that affect transcription (regulatory single-nucleotide polymorphisms (rSNPs)) and those that affect RNA functions such as splicing, turnover, and translation (termed structural RNA SNPs (srSNPs)). This review focuses on the role of srSNPs in drug metabolism, transport, and response. An understanding of the nature and diversity of srSNPs and rSNPs enables clinical scientists to evaluate genetic biomarkers.

Our laboratory has been involved in the study of glutathionesulfhydryl-transferase-pi (GST-pi) for several years. We have recently observed that during haematopoiesis in BMSC liquid cultures from CML patients who were candidates for transplant GST-pi was expressed in presumably malignant cells during different stages of cellular maturation. To confirm this finding, in the present work we are detecting GSTpi expression by immunofluorescence in BCR-ABL+ and BCR-ABL-cells done by FISH of PB from 30 CML patients during different clinical status: treatment (T), hematological relapse (R), blastic crisis (BC) or post-allotrasplant (PT). As well as in PB from 30 Blood-Bank donors. The results were %BCR0, BC = 0 and PT = 0. GST-pi was not expressed in donor cells. The results obtained confirm our previous observations and suggest that GST-pi expression might be used for the evaluation of the minimal residual disease in CML patients.

X-linked adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder (1/15 000 males) is characterized biochemically by the accumulation of very-longchain fatty acids (VLCFA) in white matter, adrenal glands, fibroblasts, and plasma due to an impaired P-oxidation of these fatty acids in peroxisomes. A clinical phenotype heterogeneity can be found even within the same family.'-3 The ALD gene, recently identified by positional cloning: encodes an integral peroxisomal membrane protein, ALD protein (ALDP), with a molecular weight of 75 kDa. ALDP, whose function remains unknown, belongs to the ATP binding cassette superfamily of transp o r t e r~.~ Several alterations in the ALD gene have now been reported in ALD kindred with different origins. Those include 5-7% of partial deletions, 15-25% of one of three base pair deletions, 40-50% of missense mutations, 20-25% of nonsense mutations and 5% of splice mutation^.^-* A study conducted on ALD fibroblasts

Introduction:
Genes encoding xenobiotic metabolizing enzymes especially CYP1A2 play an important role in determining the out come of carcinogen exposure and Colorectal Cancer susceptibility risk. Functional polymorphisms of G3860A, T739G and C729T of CYP1A2 gene have been identifi ed.
Aims
A case control study was designed to genotype the Malaysian normal controls and CRC patients to determine the variant allele frequencies of three polymorphisms of CYP1A2 and to evaluate whether variant genotype has any association either singly or in combination with CRC susceptibility risk.
Material & method
Genotyping of the 3 polymorphisms (G3860A, T739A & C729T) CYP1A2 genes was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 111 sporadic histopathologically confirmed CRC patients and 123 normal healthy controls.
Result
When the 3 polymorphisms G3860A, T739G and C729T were analyzed singly, there was no signifi cant association. When the risk association was evaluated using combination genotypes, the combination of G3860A / T739T genotype showed statistically signifi cant risk with OR 1.75.

A completely new mutational event associated with human diseases -the dynamic mutation -was discovered in the last decade. The molecular mechanism underlying dynamic mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon

In Human Gene Mutation article unfortunately at page 320, under the heading "Gene symbol: SH3TC2", one of the author name was repeated twice in the author group of online published article. Author group should read as 'Dolores Martínez-Rubio, José M. Millán, Francesc Palau, Carmen Espinós'.

Female age influence on male reproductive performance and also female fitness
traits. The male recorded such as courtship activities, mating latency, copulation
duration, and female fitness traits, such as, fecundity, has been used  from isofemale
lines of  Drosophila melanogaster. The female age including, 2-3 days aged old
(young aged), 17-18 days aged old (middle aged) and 31-32 days aged old (old aged)
mated with virgin male (5-6  days aged old) that all of the flies were exposure of
middle temperature (22°c). The results of SPSS software analyzed that in almost all of
experimental young aged old had significantly level than middle and old age.
Courtship activities elements, in young age female were greater than middle and old
age, when mated with young age male. This  variability suggests  that parental age
effected on the male reproductive performance and female fitness traits. Therefore,
the female age specific possibility occurrence on reproductive access as follows by:
young aged> middle aged>old aged.

BackgroundArterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene.Case presentationWe describe the clinical findings and molecular characterization of three new ATS families, which prov...

Background: Oral carcinogenesis is a multi-step process. Broadly, oral squamous cell carcinoma (OSCC) can be well-, moderately- or poorly-differentiated, and either keratinizing or non-keratinizing. Most cases are moderately to poorly-differentiated. Precursor lesions (dysplasia) can be categorized into mild, moderate, or severe (carcinoma in situ).In the present study, the pattern of keratin expression in oral squamous cells during carcinogenesis is vividly analysed. Materials and Methods: Samples in the form of scraped and exfoliated cytosmear were collected from the affected sites of the clinically diagnosed 136 oral cancer patients and were immediately fixed in acetoalcohol (1:3). The wet fixed smears were stained by routine Papanicolaou’s staining protocol and Giemsa’s solution. Stained tissues were studied under the microscope. Results: Cytological pleomorphism is a unique feature observed during carcinogenesis. There appears to be a spectrum of degrees of keratinization rather than distinct types, and the degree of keratinization is reflected in the degree of packing and orientation of keratin filaments. It is presumed that alteration in the architectural regularity of the cell membrane is an important aspect of keratinization which leads to cytological pleomorphism during oral carcinogenesis. Conclusion: Pattern of keratinization alongwith cytological pleomorphism in exfoliated epithelial squamous cells has a practical utility in the diagnosis and early detection of oral cancer during carcinogenesis.
Keywords: Carcinogenesis, Keratinization, Keratins, Oral squamous cell carcinoma.

Members of the ICE/CED-3 protease family appear to play an essential role in programmed cell death process. In this paper the chromosomal localization of the human genes CPP32, Mch2, Mch3 and Ich-1 is reported, obtained by Radiation Hybrid Mapping. CPP32 was assigned to chromosome 4q33-q35.1, Mch2 to chromosome 4q25-q26, Mch3 to chromosome 10q25.1-q25.2 and Ich-1 to chromosome 7q35. Ich-1 was found to map very close to the marker WI-9353. The possible overlapping of the two independent locus assignments is considered. The genomic distribution of these genes is discussed, with particular reference to the co-location with some human genetic diseases all characterized by autosomal dominant inheritance and by similar malformative features.

Purpose: New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor a, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR).

Objective: The aim of this study was to evaluate the hepatoprotective and antioxidant effects of Withania somnifera against Paracetamol-induced liver injury in rats. Methods: In the present study, the protective effect of Withania somnifera was investigated against Paracetamol-induced hepatotoxicity and compared with Silymarin, a standard hepatoprotective reference drug. The rats received a single dose of paracetamol (900 mg/kg body weight, i.p.); Withania somnifera (500 mg/kg body weight and 1000mg/kg body weight, p.o.) and Silymarin (25 mg/kg body weight, p.o.) were administered 30 min after the injection of paracetamol. Liver marker enzymes (Aspartate Transaminase, Alanine Transaminase and Alkaline Phosphatase), Total Protein content, Bilirubin, Antioxidant status (Reduced Glutathione, Superoxide Dismutase, Catalase and Glutathione-S-Transferase) were evaluated and histopathological analysis was done for the control and experimental rats. Results: Paracetamol treatment leads to elevated levels of liver marker enzymes and bilirubin and there was deterioration in total protein content, histological observations, and antioxidant status. However, treatment with Withania somnifera significantly reversed (p < 0.05) the above changes compared to the control group as observed in the paracetamol-challenged rats. Conclusion: The results clearly demonstrate that Withania somnifera possesses promising hepatoprotective effects through its antioxidant activity and hence suggests its use as a potential therapeutic agent for protection from paracetamol overdose.

Osteoporosis is a skeletal disorder characterized by an increased risk of fractures. Studies have shown that BMD and bone turnover are under strong genetic control. The polymorphisms in the Vitamin D receptor (VDR) have been implicated in many studies as a cause of osteoporosis. We aimed at developing a molecular diagnostic kit to detect osteoporosis. We started with designing multiplex primers and finally designed T-ARMS PCR Kit for the VDR locus. We used the currently available softwares for primer designing like PerlPrimer, Primer3, Primer1, BatchPrimer3, WASP, Primer-BLAST and AutoDimer. Our T-ARMS PCR Kit for the VDR locus included the penultimate primer position mismatch to increase the specificity and a universal sequence and tag to assist successful amplification of all primers within the desired annealing temperature range. Our osteoporosis detection kit is an in-silico approach and has to be validated through in vitro PCR amplicifactions.

Background: RareDDB repository for rare disease or orphan disease (http://rareddb.xcelrislabs.com/) is a freely accessible web-based user friendly database which provides detailed information for different types of rare diseases with their associated genes, SNPs along with functional annotations and drug's information.

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein.