Cystic Fibrosis

how the loss of this chloride channel pathway contributes This is the second single-topic supplement to Physioto the multiple manifestations of CF in diverse organ syslogical Reviews. In introducing the first supplement, Dantems. In this collection of works, we attempt to remain iel Gardner indicated that the articles reported on the focused on essential physiological issues concerning the progress of a revolution, first recognized by the series function of CFTR. Therefore, little information is provided of papers on membrane currents in nerve published by on CF genetics, and there is only a brief treatment of Hodgkin, Huxley, and colleagues. This supplement reports human genotype-phenotype correlations (5). For these on another revolution in cell physiology and on what is subjects, the interested reader is referred to several excelprobably one of the most intensely studied proteins in lent reviews (1, 3, 9). Rather, we focus on the ''nuts and biomedical science: the cystic fibrosis transmembrane bolts'' of CFTR and its contribution to epithelial cell funcconductance regulator (CFTR). It is now 10 years since tion. identification of the gene responsible for cystic fibrosis Paul Quinton begins this series with a personal ac-(CF) was announced (2, 7, 8); these papers reported not count of the physiological basis of CF that includes not only the chromosomal mapping and sequence of the gene only historical perspectives but also valuable reflections and its protein product but also an amazingly accurate on the complex events that attend deletion of the cAMPprediction of CFTR's secondary structure (7). Lap Chee regulated chloride conductance in epithelial cells. Paul Tsui, John Riordan, and Francis Collins included in their takes us through the critical transition from ''witches to appellation, CFTR, the terms conductance and regulator, science,'' which he has personally witnessed and to which descriptors that the subsequent years' investigations, and his important work has contributed. David Sheppard and the articles in this supplement, show aptly to apply. Michael Welsh review the structure-function relations of In the period B.C., that is, before cloning of the CFTR the CFTR chloride channel. They provide a functional gene, our understanding of the cellular implications of CF survey of the significant domain structures of CFTR and gene mutations was fairly well developed. We understood the manner in which they relate to chloride channel gatthat CF was a disease of epithelial cells and that its celluing. David Dawson, Steven Smith, and Monique Mansoura lar phenotype omitted a cAMP-regulated chloride conducprovide us with a detailed look at CFTR's conduction tance pathway that was crucial for the salt and water pathway for chloride ions. They describe the structural secretory response of many epithelial tissues. We underbasis of anion selectivity and the way in which both disstood that the impairment of epithelial chloride conducease and experimental mutations have contributed to our tance extended to channels localized in membrane fragcurrent understanding of the conduction pathway. David ments at the ends of patch pipettes. The pioneering work Gadsby and Angus Nairn focus their review on the control of Quinton (6), Knowles et al. (4), and other colleagues of CFTR channel gating by phosphorylation and nucleocreated a sea change, not only in our understanding of the tide hydrolysis. Their review details the unique position CF phenotype but also in the numbers of skilled scientists occupied by the CFTR chloride channel in the ABC (ATPwilling to devote significant effort to this protein and the binding cassette) superfamily of transporters; they prodisease that it defines. In the period A.C., after cloning, vide a model that utilizes coordinated nucleotide hydrolythis momentum has exploded, as a tangible and manipusis to effect channel opening and closing rather than orlatable entity was provided to explore the array of cellular ganic solute transport. They also review the control of processes on which CFTR touches. Indeed, this prolifera-CFTR by kinase and phosphatase-mediated R-domain tion is so extensive that detailed chapters can now be phosphorylation in relation to its channel-gating funcwritten on subjects as focused as the conduction and gating properties of CFTR. Evidence supporting the idea that tions. Bruce Schultz, Ashvani Singh, Daniel Devor, and Robert Bridges describe the pharmacology of CFTR. Their CFTR functions as a regulated chloride channel quickly emerged in the period A.C., largely as a result of our ex-detailed overview of compounds that modulate the chloride channel activity of CFTR should be a valuable field isting understanding of the physiology of CF epithelial cells. To be sure, we are still trying to fully appreciate guide for those who are brave enough to approach studies

The impact of sinus surgery on the pulmonary status of cystic fibrosis patients is unknown. This retrospective study reviewed the charts of the cystic fibrosis patients presenting to our institution's cystic fibrosis center with nasal obstruction, recurrent sinusitis, and nasal polyposis. This group subsequently underwent endoscopic ethmoidectomy and antrostomy. Fourteen of the 15 patients, ages 5-24 years, received preoperative and postoperative pulmonary function testing obtained by spirometry. The data were compiled and analyzed statistically. Our results suggested no significant improvement in the pulmonary function of cystic fibrosis patients after sinus surgery.

The purpose of this study was to validate the Portuguese translations of four cystic fibrosis quality of life questionnaires (CFQ). The first three were developed for patients with cystic fibrosis aged from 6 to 11 years, from 12 to 13 years and 14 years or more, while the fourth was developed for the parents of patients aged 6 to 13 years. The four CFQ translations contained from 35 to 50 questions covering nine domains and were validated as follows: translation from English to Portuguese, pilot application, back translation and then approval by the author of the English versions. The four translations were applied to 90 stable patients (30 from each age group) and the parents of patients aged 6-13 years (n = 60), on two occasions with a 13 to 17 day interval. Intraclass Correlation Coefficients (ICC) were used to measure reproducibility. This study was approved by the Commission for Ethics in Research at the institution. Reproducibility was good (ICC = 0.62 to 0.99) for the four t...

Fucosylated glycoconjugates play a role in a wide variety of biological processes, including immune responses, signal transduction, ontogenic events and pathogenesis of several human diseases. Alpha-L-fucosidases, which are responsible for their processing, have been demonstrated to be involved in lysosomal storage disease, inflammation, cystic fibrosis, cancer development and in the interactions between gametes in vertebrates as well as invertebrates. The sequence and comparative genomic analysis of these glycosyl hydrolases and the study of their evolutionary relationships appear therefore to be of considerable interest. In this work we carried out extensive similarity searches and comparative analyses to identify sequences encoding α-L-fucosidases. We have identified novel α-L-fucosidase coding sequences in worms, insects, sea urchin, ascidians, fish, chicken, amphibians, mammals and various bacteria resulting in a total of 39 α-L-fucosidase sequences. Two α-L-fucosidases that are present in all vertebrates likely reflect a distinct biological role for paralogous genes. Comparative sequence analysis of all metazoan α-L-fucosidases reveals a broad conservation of features, including the aspartate residue that constitutes the catalytic nuceophile. However, a cysteine which is thought to be part of the active site is also conserved in metazoa but not in arthropods, where it is replaced by an alanine. Phylogenetic analysis suggests a gene duplication event very early in metazoan evolution with the subsequent differential loss of isoforms in various metazoan lineages.

In numerous airway diseases such as cystic fibrosis, the epithelium is severely damaged and must regenerate to restore its defense functions. Although the human airway epithelial progenitor/stem cells have not been clearly identified yet, it has been recently suggested that epithelial progenitors exist among both fetal basal and suprabasal cell subsets in the human airways. We analyzed the capacity of human adult basal cells, isolated from nasal polyps, to restore a well-differentiated airway epithelium. Cells were seeded in epitheliumdenuded rat tracheae that were grafted subcutaneously in nude mice or on collagencoated porous membranes and grown at the air-liquid interface. We used tissue factor (TF) and tetraspanin CD151, expressed specifically on the surface of basal cells of human airway epithelium, to isolate positive cells with a FACSAria cell sorter. Sorted positive and negative populations were also analyzed for telomerase activity by the telomeric repeat amplification protocol. After cell sorting, pure (>99%) viable TF/CD151-positive basal cell population adhered and proliferated on epithelium-denuded rat tracheae and on collagen-coated porous membranes and was able to restore a fully-differentiated mucociliary airway epithelium, whereas viable negative population (purity >97%) did not. The stem cell telomerase activity was detected in the TF/CD 151-positive population, but not in TF/CD151-negative cells. Our results demonstrate that human adult basal cells are airway epithelial progenitors. Telomerase activity suggests the presence of a stem cell population among the sorted basal cells.

Pancreatic cancer is the fourth leading cause of cancer deaths in the USA in both sexes. Early diagnosis is difficult and the overall mortality rate is high. Individuals at high risk for pancreatic cancer include smokers, and persons with all forms of chronic alcoholic, metabolic, tropical or hereditary pancreatitis. The duration of exposure to inflammation seems to be the major factor involved in the transition from benign to malignant condition. Smoking, which appears to further accelerate the carcinogenic transformation, remains the strongest risk factor amenable to preventive intervention.

Achromobacter xylosoxidans is a non-glicose-fermenting environmental Gramnegative rod with increasing recovering frequency from the respiratory tract of Cystic Fibrosis (CF) patients. The pathogenic role of this microorganism is still unclear including the knowledge of its virulence factors. We are searching for potencial virulence factors in A. xylosoxidans strains isolated from CF pediatric patients seen at the outpatient reference center at our State University Hospital. The strains were identified by conventional tests, by automated Vitek II ® and controlled with LMG ® reference strains and by PCR. The culture supernatants in BHI of 10 different clinical isolates of A. xylosoxidans and the LMG 1863 strain were assayed for cytotoxic activity. Cytotoxic activity was observed only in H-460 (human lung carcinoma), inducing blebbings and cellular death after 18 hours assays for all strains. Microscopic analysis revealed rounding and membrane alterations followed by detachment and cellular death. However no cytotoxic activity was verified on HeLa (human cervix carcinoma), 3T3 (mouse fibroblast) and Vero (green monkey kidney) cells. These results suggest that the cytotoxic activity of A. xylosoxidans to human lung cells (H-460) could be a potencial mechanism of pathogenicity that may participate in the process of lung parenchyma destruction in cystic fibrosis patients and should be better investigated.

Cystic fibrosis (CF) is a complex, chronic, multisystem disease for which there is currently no cure. Nonetheless, advances in management have led to dramatic improvements in patient survival. With this development, new issues have arisen for CF patients and their care providers, including an increased symptom burden and increased frequency of comorbidities as patients reach older ages, leading to the need for a highly complicated and timeconsuming regimen of treatments. Such high symptom and treatment burden often leads to non-adherence and low levels of competence with administration of therapy, both of which may have detrimental impacts on CF outcomes. Optimal management is also hindered by other patient-related factors, including inadequacies in disease education which may lead to issues with self-management. This is particularly important during the transition from parent-directed therapy to independent self-management that occurs during adolescence and early adulthood. Clinicians are also faced with a considerable challenge when selecting interventions for individual patients; although the paradigm of aggressive care necessitates a wide range of therapies, there is a limited evidence base with which to compare available therapeutic regimens. Novel pharmacological agents are being developed to target the underlying cause of CF, while non-pharmacological interventions aim to improve competence and maximize adherence and health outcomes. Comparative effectiveness research is needed to simplify management and facilitate the implementation of appropriate treatment strategies. Pediatr Pulmonol.

Background Mucus hyper-secretion is a feature of several airways diseases such as chronic rhinosinusitis, asthma, and cystic fibrosis (CF). Since mucins are major components of mucus, the knowledge of their distribution and regulation in nasal tissues is likely to improve mucus hyper-secretion therapy. Objective The aim of this study was to evaluate and compare mucin gene expression at epithelial and glandular levels, and to identify potential mucin expression patterns for specific upper airways pathologies. Methods Immunohistochemistry for MUC1, MUC2, and MUC4-MUC8 mucins was performed on healthy nasal mucosa (NM; n = 12), bilateral nasal polyps (NP; n = 38), NP from CF patients (n = 10), and antrochoanal (AC) polyps (n = 11). MUC2, MUC4, MUC5AC, and MUC6 mRNA expression were also analysed by in situ hybridization. Results MUC1, MUC4, and MUC5AC mucins were highly expressed in the epithelium and their expression pattern was similar in all NP types, MUC1 and MUC4 being increased and MUC5AC decreased compared with NM. MUC8 was highly detected at both epithelial and glandular levels with marked variability between groups. MUC5B was mainly detected in glands and the expression in all polyp types was higher than in NM. Moreover, MUC5B expression was higher in NP epithelia from CF patients than in bilateral NP and healthy NM. Although MUC2 expression was low, especially in AC polyps, it was detected in most samples. In NM, MUC6 and MUC7 were scarcely detected and MUC7 expression was restricted to glands. Conclusions These results suggest that NP have a different pattern of mucin expression than healthy NM and that CF polyps (increased MUC5B) and AC polyps (decreased MUC2) have a different mucin expression pattern than bilateral NP.

To determine frequency, perceived effectiveness, and cost of religious, physical, and other nonmedical practices, we interviewed all (n = 402; 100% participation) of our cystic fibrosis patients/families [age, O-45 (median, 18) years]. At least one type of nonmedical therapy was used by/on 264 (66%), two-this of which was religious. Most respondents perceived benefit (e.g., group prayer, 95%; religious articles, 81%; chiropractic, 69%). Only 17 (4.2%) invested over $200 lifetime (minimal compared with medical costs). These treatments, apparently used by most patients/families, rarely interfered with medical care. Physician openness and empathy toward patients' beliefs might enhance rapport and facilitate discussion of possible helpful or adverse effects of nonmedical treatment.

We report two cases of children followed for many years with an original diagnosis of non-A/non-B hepatitis. One child developed serious cirrhosis with portal hypertension. Long-term observation of the course of their hepatic disease provided the diagnosis of cystic fibrosis. These cases demonstrate that cystic fibrosis though rarely presenting with initial hepatic signs, can manifest itself with only long-term hepatic symptoms. We therefore strongly recommend analysis of sweat chloride concentration in cases of hepatic disease of unknown origin.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Knowledge of the cellular and molecular events associated with the formation of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-ᵝ1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has encougaged researchers to continue their research for potent and safer antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown.

Pyocyanin (1-hydroxy-N-methylphenazine) is a cytotoxic pigment secreted by the bacterial species Pseudomonas aeruginosa, which frequently infects the lungs of immunosuppressed patients as well as those with cystic fibrosis. Pyocyanin toxicity results presumably from the ability of the compound to undergo reduction by NAD(P)H and subsequent generation of superoxide and H 2 O 2 directly in the lungs. We report that in the presence of peroxidase mimics, microperoxidase 11, or hemin, pyocyanin undergoes oxidation by H 2 O 2 , as evidenced by loss of the pigment's characteristic absorption spectrum and by EPR detection of a free radical metabolite. The oxidation of pyocyanin is irreversible, suggesting an extensive modification of the pigment's phenazine chromophore. Oxidation of pyocyanin was observed also when exogenous H 2 O 2 was replaced by a H 2 O 2 -generating system consisting of NADH and the pigment itself. That the oxidation involves the phenolate group of pyocyanin was verified by the observation that a related pigment, phenazine methosulfate, which is devoid of this group, does not undergo oxidation by microperoxidase 11/H 2 O 2 . In contrast to intact pyocyanin, oxidized pyocyanin was less efficient in NADH oxidation and stimulation of interleukin-8 release by human alveolar epithelial A549 cells in vitro, suggesting that oxidation of pyocyanin leads to its inactivation. This study demonstrates that pyocyanin may play a dual role in biological systems, first as an oxidant and ROS generator, and second as a substrate for peroxidases, contributing to H 2 O 2 removal. This latter property may cause pyocyanin degradation and inactivation, which may be of considerable biomedical interest. D 2004 Elsevier Inc. All rights reserved.

Although chest physiotherapy is central to the management of cystic fibrosis many report problems with adherence. Research in other long-term conditions suggests that non-adherence may be exacerbated as the child grows older and selfcare responsibilities are transferred to the young person. We explored the nature and variation in roles of family members, how responsibility was transferred from the parent/family to the child, and what factors aided or hindered this process.

of airway obstruction, infection, and ongoing lung damage that is characteristic of this dis-Background -Patients with cystic fibrosis are known to have decreased mucociliary ease. A major goal of therapy in cystic fibrosis is the effective removal of thick tenacious se-clearance. It has previously been shown that inhalation of a 7.0% solution of hyper-cretions.

Osteoporosis is a common complication in cystic fibrosis (CF) patients. In this study, we performed a histomorphometric analysis of the bones of a mouse genetic model of human CF in which both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are inactivated. We find that, even in the absence of obvious nutritional and therapeutic differences, the CFTR mutation is associated with severe osteopenia. Bone mineral density (BMD) of total body and of individual bones is significantly diminished. CFTR mutants display a striking significant (50%) reduction of cortical bone width and thinner trabeculae. Analysis of dynamic parameters indicates a significant reduction of bone formation and a concomitant strong increase in bone resorption. Active osteoclasts where found mostly associated with cortical bone. Our data support the concept that CF-associated osteoporosis is part of the syndromic symptoms associated with the CFTR mutation.

Two adult sisters affected by cystic fibrosis were both shown to carry two different alterations within exon 11 of the CFTR gene, the nonsense mutation G542X and the missense mutation G551D. Both patients exhibit a relatively benign clinical course. In the described patients, G542X functions as a "mild" allele and is, in this respect, dominant to the "severe" G551D.

CF, caused due to abnormal transport of chloride, sodium and bicarbonate ions across epithelial cell membranes, is a multi-organ disorder. More than 1000 mutations causing CF, have been identified in the CFTR gene, of which AF508 is the most severe, predominant mutation. However, data on CF in India is limited. Also, facilities for CF diagnosis are not available at all diagnostic centres across India. AF508 mutation has been reported in 19-56% Indian patients. Also, the spectrum of mutations has been anticipated to be different, due to the identification of a wide range of novel and rare mutations. In addition to mutations, polymorphisms with clinical relevance and practical diagnostic value have also been identified. Clinical profile in Indian patients was also observed to be different. Though, Cystic Fibrosis has always been considered to be a rare disease in India, we hope that the identification of the wide range of mutations, leads us to the recognition of a probable increased ...

Cystic fibrosis is a common lethal genetic disease caused by functional absence of the cystic fibrosis transmembrane conductance regulator (CFTR). Although a candidate disease for in utero gene therapy, demonstration of potentially therapeutic levels of transgene expression in the fetal airways after minimally invasive gene delivery is a mandatory prerequisite before application of this approach in humans can be considered. We report here on the delivery of a b-galactosidase expressing adenovirus directly to the airways of fetal sheep in utero using ultrasound-guided percutaneous injection of the trachea in the fetal chest. Injection of adenoviral particles to the fetal airways was not associated with mortality and resulted in low-level expression in the peripheral airways. However, complexation of the virus with DEAE dextran, which confers a positive charge to the virus, and pretreatment of the airways with Na-caprate, which opens tight junctions, increased transgene expression, and a combination of these two enhancers resulted in widespread and efficient gene transfer of the fetal trachea and bronchial tree. Using a percutaneous ultrasound-guided injection technique, we have clearly demonstrated proof of principle for substantial transgene delivery to the fetal airways providing levels of gene expression that could be relevant for a therapeutic application of CFTR expressing vectors.

Background: We studied whether the sinuses might be foci for Pseudomonas aeruginosa lung infection. Methods: Endoscopic Sinus Surgery was performed in 78 CF patients; PFGE was used for bacterial genotyping. Material from sinuses and lungs were Gram-stained to detect biofilms. Immunoglobulins were measured in serum and saliva. Results: When P. aeruginosa was cultured simultaneously from the sinuses and the lungs they were genetically identical in 38 of the 40 patients (95%). In the sinuses, P. aeruginosa formed biofilms with minimal cellular inflammation, probably because of a significantly higher local production of secretory IgA compared with IgG (p b 0.001). Conclusions: We have shown that P. aeruginosa form biofilm in the sinuses, which constitute an important bacterial reservoir for subsequent lung infection. The high amount of IgA in the upper airways probably protects P. aeruginosa from the inflammatory immune system, and they can proceed unnoticed into a permanent infectious focus that cannot be eradicated with antibiotics.

The collection of exhaled breath condensate (EBC) is simple and noninvasive, however, there are few data on the methodological aspects affecting concentrations of compounds in EBC. The aim of this study was to investigate methodological issues for measuring nitric oxide metabolites (NO x ) in EBC.

In the budding yeast Saccharomyces cerevisiae, 80% of the ~6000 genes are nonessential, indicating that many biological processes are buffered from the phenotypic consequences of genetic perturbation. To examine these functional relationships we developed a method called Synthetic Genetic Array (SGA) analysis, which automates yeast genetics and enables a systematic and highthroughput construction of double mutants from an ordered array of ~4700 viable gene deletion mutants. In particular, double mutants showing reduced fitness (a synthetic sick phenotype) or lethality (a synthetic lethal phenotype) define functional relationships between genes and their corresponding pathways. We have undertaken a project to generate a synthetic genetic interaction network for the yeast cell with the expectation that it will represent a global map of functional relationships amongst most genes. We found that synthetic genetic interactions are more common than anticipated previously, with an average query gene displaying ~30 different interactions. Cluster analysis of a compendium of ~132 SGA screens revealed that genes displaying similar patterns of genetic interactions often encode proteins within the same pathway or complex; therefore, the yeast genetic interaction network predicts precise molec-ular roles of previously uncharacterized genes. Moreover, because a gene deletion mutation provides a model for the effect of a compound that inhibits its corresponding gene product, our compendium of synthetic genetic profiles provides a key for determining the cellular targets of small molecules and drugs. Finally, the surprisingly large number of synthetic genetic interactions observed for defined mutations of inbred laboratory yeast strains suggests that digenic interactions of this type may also occur frequently amongst different alleles of genes found within the individuals of an outbred population and thus similar genetic interactions may underlie many of the inherited phenotypes in other organisms.

Cystic ®brosis (CF) is the most common autosomal-recessive disease in Caucasians. Colonization with Pseudomonas aeruginosa (P. aeruginosa) of the CF airways causes deterioration of pulmonary status. TOBI R (Tobramycin solution for inhalation) is an inhaled antibiotic that can improve the pulmonary disease.

Objective: To assess the quality of life (QoL) of patients with cystic fibrosis (CF) followed at a university referral center for CF. Methods: A cross-sectional study involving application of the Cystic Fibrosis Questionnaire (CFQ) and Shwachman score in CF patients between April of 2008 and June of 2009. Results: The sample consisted of 75 patients. The mean age was 12.5 ± 5.1 years (range, 6.1-26.4 years). The patients were divided into three groups by age in years: group I (< 12), II (12-14), and III (> 14). The highest and lowest CFQ scores were for the nutrition domain in group III (89.3 ± 16.2) and the social domain in group II (59.5 ± 22.3), respectively. Groups I and III differed significantly regarding the treatment domain (p = 0.001). Regarding Shwachman scores, there were significant differences between patients scoring < 70 and those scoring > 70 in the social (group I; p = 0.045), respiratory (group II; p = 0.053), and digestive (p = 0.042) domains. In group III, severity did not correlate with QoL. In groups I and II, patients with an FEV1 < 80% of predicted did not differ from other patients for any CFQ domain. However, in group III, values for the following domains were significantly lower in patients with an FEV1 < 80%: physical (p = 0.012); body image (p = 0.031); respiratory (p = 0.023), emotional (p = 0.041); and social role (p = 0.024). Conclusions: It is important to assess QoL in CF patients, because it can improve treatment compliance.

This study explored the experiences of mothers of children with cystic fibrosis (CF) in postdivorce family structures. In-depth interviews of mothers were conducted by registered nurses with expertise in CF. Interviews focused on responsibility for care of the CF child within the context of postdivorce families (e.g., extent of nonresidential fathers' involvement in children's care, communication between households). Interviews were audiotaped and transcribed verbatim. The constant comparison method was used for analyzing interview data. Marital transitions contributed to the closeness between mothers and children with CF, but they also added to the mothers' sense of being overwhelmed with responsibilities. It is likely that children and mothers are more at risk for stress-related problems when mothers are overburdened by the demands of caregiving, earning a living, and other responsibilities.

The partial amino acid sequence of LI protein light and heavy chains reveals an overall structure identical to the two macrophage proteins. MRP-8 and MRP-14. deduced from the sequence of the eDNA encoding the polypeptides. The light ehain of LI protein (LI-L) was shown to contain two modified amino aeid residues.

Aims: To demonstrate the effectiveness of the care given by a District General Hospital CF team within a regional shared care system. Methods: As a part of annual CF audit, case notes of 23 CF patients under the care of Royal Albert Edward Infirmary, Wigan, sharing care with Alder Hey Children's hospital, Liverpool were analysed for various parameters including growth, chronic infection rates, lung functions (FEV1), Schwachman annual scores and Northern X-ray scores. The cumulative data over the period of 10 years 1995 2004 were obtained. These were compared with available national and international data. Results: Our results identified that the children's growth is near normal. The average lung function has improved steadily over the last 10 years mean FEV1 being 98% at 16 years of age. Although our rate of infection acquisition is the same, our chronic infection rate is currently lower than available figures. Average Schwachman annual scores were in the range 86 100 in 87% of the patients. Consistent improvement trend was noticed over last 10 years average score being 74% in 1995, 84% in 2000 and 89% in 2004. Northern X-ray scores were in the range 0 4 in 86% of the patients and were in the range 5 9 in 14% of the patients. Conclusions: It is widely accepted that high standards of care can go a long way to improve prognosis in Cystic Fibrosis. It is evident that the care given by a local team within a District General Hospital on shared care basis appears to be as effective as care given solely by a specialist centre.

Six loci containing genes involved in the dioxin metabolism (ARNT, AHR, CYP1A1, CYP1A2, CYP1B1 and AHRR) were assigned, for the first time, to cattle (Bos taurus, 2n=60, BTA), river buffalo (Bubalus bubalis, 2n=50, BBU), sheep (Ovis aries, 2n=54, OAR) and goat (Capra hircus, 2n=60, CHI) chromosomes by comparative FISH-mapping and R-banding using bovine BAC-clones. The following chromosome locations were found: ARNT to BTA3q21, BBU6q21, OAR1p21 and CHI3q21, AHR to BTA4q15, BBU8q15, OAR4q15 and CHI4q15; CYP1A1 and CYP1A2 to BTA21q17, BBU20q17, OAR18q17 and CHI21q17; CYP1B1 to BTA11q16, BBU12q22, OAR3p16 and CHI11q16, AHRR to BTA20q24, BBU19q24, OAR16q24 and CHI20q24. All loci were mapped at the same homoeologous chromosomes and chromosome bands of the four bovid species. Comparisons with corresponding human locations were also reported.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in patients with cystic fibrosis (CF). We report a molecular characterization, antimicrobial resistance, and Panton-Valentine leukocidin (PVL) toxin gene detection of MRSA strains from 28 Brazilian pediatric CF patients (1 strain per patient). A significant proportion (50%) of MRSA SCCmec IV isolates was observed. Nearly half of MRSA strains harboring the PVL genes distributed in all SCCmec types detected. Multilocus sequence typing (MLST) analyses showed majority (57.1%) of the isolates belonged to known epidemic lineages, such as UK/EMRSA-3, Pediatric/USA 800, Southwest Pacific clone, and Brazilian/Hungarian clone. To our knowledge, this is the first Brazilian study of molecular epidemiology based on MLST and SCCmec typing and the first description of PVL genes in MRSA from CF patients.

SSK Göztepe Training Hospital, Istanbul , Turkey 23.4% of the patients required surgery. The annual lower respiratory infection rate has decreased from a mean of 6.6 8 4.0 to 2.9 8 2.9 during follow-up (p ! 0.0001). Lung function tests were also found to be improved (mean FEV 1 % 63.3 8 21.0 vs. 73.9 8 27.9; p = 0.01; mean FVC% 68.1 8 22.2 vs. 74.0 8 24.8; p = 0.04). There was clinical improvement in both the surgical (73%) and medical (70.1%) groups (p 1 0.05). Conclusion: In conclusion, bronchiectasis remains a disease of concern to pediatricians, particularly in developing countries. Infections are still important causes of bronchiectasis, and clinical improvement can be achieved by appropriate treatment. Although medical treatment is the mainstay of management, surgery should be considered in selected patients.

In the present paper, we report the detection of mutations implicated in human cystic fibrosis (CF). Nine different oligonucleotides are studied, including three possible mutations related to this specific genetic disease: a deletion of three bases, F508, and two single-nucleotide polymorphisms 1540A/G and 1716G/A. We monitor, in real time and in parallel, hybridizations of a solution of unlabeled oligonucleotide targets to a matrix of 100 spots of oligonucleotide probes using surface plasmon resonance (SPR) imaging of a bio-functionalized gold slide. In order to functionalize our gold slide with the DNA probes, we have developed a self-assembled multilayer (SAM) based on electrostatic interactions and formed with 11-mercaptoundecanoic acid (MUA), poly(ethylenimine) (PEI) and ExtrAvidin layers. Probes are then linked to this SAM by the usual strong binding affinity of the avidin-biotin duplex. The 100 spots array deposited by a robot can be addressed either several times, sequentially, with the various oligonucleotide targets, or once, in parallel, with a mixture of some oligonucleotides. The specific response of our system is established along with the possibility of discriminating between a totally complementary sequence and its mutant form, even for a single base mismatch thus demonstrating the capacity of parallel diagnostic using patient like material.

It has been reported that cystic fibrosis is very rare in Asians, and its clinical expression and genetic mutations are different from those found in Caucasians. We report the case of a boy who had chronic diarrhea with failure to thrive and frequent respiratory tract infections beginning at the age of 2 months. He developed bronchiectasis with chronic severe hypoxemia and pancreatic insufficiency by the age of 3 years and 5 months, which raised the consideration of cystic fibrosis. DNA analysis revealed a homozygous R553X mutation, and both his parents were subsequently proven to be R553X carriers. This case is the first report in a Taiwanese with cystic fibrosis attributable to a mutation commonly seen in Caucasians. However, the age of onset was much younger and the clinical course was more severe than those associated with Western patients. We reviewed the eight reported Taiwanese patients with cystic fibrosis, including the present case. We believe that the incidence of cystic fibrosis in Taiwan may be underestimated. Both genetic and environmental factors may play a role in the phenotypic disparity between Asians and Caucasians.

Background: Because many patients with cystic fibrosis (CF) continue to survive into adulthood, discussion of end-of-life care decisions between clinicians and patients becomes a crucial part of CF adult care. Advance care planning (ACP) promotes alignment of patient care at the end of life with an individual's goals, however minimal research exists on ACP in CF.

Symptoms of anxiety and depression have important consequences for patients with chronic disease, including lower rates of adherence and increased morbidity. This review discusses the prevalence of anxiety and depression in patients with cystic fibrosis (CF) across the life span and highlights current understanding of how these symptoms affect adherence, health outcomes, and health-related quality of life (HRQOL). Anxiety and depression appear to be more common in patients with CF than in the general population. Recent studies also indicate that symptoms of anxiety occur more frequently than depression in this population. Both anxiety and depression have been shown to be associated with poorer disease outcomes, including HRQOL. Depression, specifically, leads to lower adherence to recommended therapies. Given the prevalence and impact of anxiety and depression in CF, it seems appropriate to recommend annual screening using a validated approach, with referral for either pharmacotherapy or cognitive behavioral therapy of those with apparent symptoms. A large-scale epidemiological study of anxiety and depression in CF is under way and should provide better prevalence estimates and more information on the effects of these psychological symptoms.

Why do racial and ethnic controversies become attached, as they often do, to discussions of modern genetics? How do theories about genetic difference become entangled with political debates about cultural and group differences in America? Such issues are a conspicuous part of the histories of three hereditary diseases: Tay-Sachs, commonly identified with Jewish Americans; cystic fibrosis, often labeled a "Caucasian" disease; and sickle cell disease, widely associated with African Americans.

In this captivating account, historians Keith Wailoo and Stephen Pemberton reveal how these diseases—fraught with ethnic and racial meanings for many Americans—became objects of biological fascination and crucibles of social debate. Peering behind the headlines of breakthrough treatments and coming cures, they tell a complex story: about different kinds of suffering and faith, about unequal access to the promises and perils of modern medicine, and about how Americans consume innovation and how they come to believe in, or resist, the notion of imminent medical breakthroughs.

With Tay-Sachs, cystic fibrosis, and sickle cell disease as a powerful backdrop, the authors provide a glimpse into a diverse America where racial ideologies, cultural politics, and conflicting beliefs about the power of genetics shape disparate health care expectations and experiences.