Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia

Defective transepithelial electrolyte transport is thought to initiate cystic fibrosis (CF) lung disease. Yet, how loss of CFTR affects electrolyte transport remains uncertain. CFTR -/- pigs spontaneously develop lung disease resembling human CF. At birth, their airways exhibit a bacterial host defense defect, but are not inflamed. Therefore, we studied ion transport in newborn nasal and tracheal/bronchial epithelia in tissues, cultures, and in vivo. CFTR -/- epithelia showed markedly reduced Cl - and HCO 3 - transport. However, in contrast to a widely held view, lack of CFTR did not increase transepithelial Na + or liquid absorption or reduce periciliary liquid depth. Like human CF, CFTR -/- pigs showed increased amiloride-sensitive voltage and current, but lack of apical Cl - conductance caused the change, not increased Na + transport. These results indicate that CFTR provides the predominant transcellular pathway for Cl - and HCO 3 - in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease. © 2010 Elsevier Inc.published_or_final_versio

A prognostic tool to identify adolescents at high risk of becoming daily smokers

<p>Abstract</p> <p>Background</p> <p>The American Academy of Pediatrics advocates that pediatricians should be involved in tobacco counseling and has developed guidelines for counseling. We present a prognostic tool for use by health care practitioners in both clinical and non-clinical settings, to identify adolescents at risk of becoming daily smokers.</p> <p>Methods</p> <p>Data were drawn from the Nicotine Dependence in Teens (NDIT) Study, a prospective investigation of 1293 adolescents, initially aged 12-13 years, recruited in 10 secondary schools in Montreal, Canada in 1999. Questionnaires were administered every three months for five years. The prognostic tool was developed using estimated coefficients from multivariable logistic models. Model overfitting was corrected using bootstrap cross-validation. Goodness-of-fit and predictive ability of the models were assessed by R², the c-statistic, and the Hosmer-Lemeshow test.</p> <p>Results</p> <p>The 1-year and 2-year probability of initiating daily smoking was a joint function of seven individual characteristics: age; ever smoked; ever felt like you needed a cigarette; parent(s) smoke; sibling(s) smoke; friend(s) smoke; and ever drank alcohol. The models were characterized by reasonably good fit and predictive ability. They were transformed into user-friendly tables such that the risk of daily smoking can be easily computed by summing points for responses to each item. The prognostic tool is also available on-line at <url>http://episerve.chumontreal.qc.ca/calculation_risk/daily-risk/daily_smokingadd.php</url>.</p> <p>Conclusions</p> <p>The prognostic tool to identify youth at high risk of daily smoking may eventually be an important component of a comprehensive tobacco control system.</p

Emerging Concepts for Pelvic Organ Prolapse Surgery: What is Cure?

The objective of this review is to discuss emerging concepts in pelvic organ prolapse, in particular, “What is cure?” In a post-trial data analysis of the CARE (Colpopexy and Urinary Reduction Efforts) trial, treatment success varied tremendously depending on the definition used (19.2%–97.2%). Definitions that included the absence of vaginal bulge symptoms had the strongest relationships with the patients’ assessment of overall improvement and treatment success. As demonstrated by this study, there are several challenges in defining cure in prolapse surgery. Additionally, the symptoms of prolapse are variable. The degree of prolapse does not correlate directly with symptoms. There are many surgical approaches to pelvic organ prolapse. Multiple ways to quantify prolapse are used. There is a lack of standardized definition of cure. The data on prolapse surgery outcomes are heterogeneous. The goal of surgical repair is to return the pelvic organs to their original anatomic positions. Ideally, we have four main goals: no anatomic prolapse, no functional symptoms, patient satisfaction, and the avoidance of complications. The impact of transvaginal mesh requires thoughtful investigation. The driving force should be patient symptoms in defining cure of prolapse

Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

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Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness

Retrieving sequences of enzymes experimentally characterized but erroneously annotated : the case of the putrescine carbamoyltransferase

BACKGROUND: Annotating genomes remains an hazardous task. Mistakes or gaps in such a complex process may occur when relevant knowledge is ignored, whether lost, forgotten or overlooked. This paper exemplifies an approach which could help to ressucitate such meaningful data. RESULTS: We show that a set of closely related sequences which have been annotated as ornithine carbamoyltransferases are actually putrescine carbamoyltransferases. This demonstration is based on the following points : (i) use of enzymatic data which had been overlooked, (ii) rediscovery of a short NH(2)-terminal sequence allowing to reannotate a wrongly annotated ornithine carbamoyltransferase as a putrescine carbamoyltransferase, (iii) identification of conserved motifs allowing to distinguish unambiguously between the two kinds of carbamoyltransferases, and (iv) comparative study of the gene context of these different sequences. CONCLUSIONS: We explain why this specific case of misannotation had not yet been described and draw attention to the fact that analogous instances must be rather frequent. We urge to be especially cautious when high sequence similarity is coupled with an apparent lack of biochemical information. Moreover, from the point of view of genome annotation, proteins which have been studied experimentally but are not correlated with sequence data in current databases qualify as "orphans", just as unassigned genomic open reading frames do. The strategy we used in this paper to bridge such gaps in knowledge could work whenever it is possible to collect a body of facts about experimental data, homology, unnoticed sequence data, and accurate informations about gene context

Exploring men's and women's experiences of depression and engagement with health professionals: more similarities than differences? A qualitative interview study

<p>Abstract</p> <p>Background</p> <p>It is argued that the ways in which women express emotional distress mean that they are more likely to be diagnosed with depression, while men's relative lack of articulacy means their depression is hidden. This may have consequences for communicating with health professionals. The purpose of this analysis was to explore how men and women with depression articulate their emotional distress, and examine whether there are gender differences or similarities in the strategies that respondents found useful when engaging with health professionals.</p> <p>Methods</p> <p>In-depth qualitative interviews with 22 women and 16 men in the UK who identified themselves as having had depression, recruited through general practitioners, psychiatrists and support groups.</p> <p>Results</p> <p>We found gender similarities and gender differences in our sample. Both men and women found it difficult to recognise and articulate mental health problems and this had consequences for their ability to communicate with health professionals. Key gender differences noted were that men tended to value skills which helped them to talk while women valued listening skills in health professionals, and that men emphasised the importance of getting practical results from talking therapies in their narratives, as opposed to other forms of therapy which they conceptualised as 'just talking'. We also found diversity among women and among men; some respondents valued a close personal relationship with health professionals, while others felt that this personal relationship was a barrier to communication and preferred 'talking to a stranger'.</p> <p>Conclusion</p> <p>Our findings suggest that there is not a straightforward relationship between gender and engagement with health professionals for people with depression. Health professionals need to be sensitive to patients who have difficulties in expressing emotional distress and critical of gender stereotypes which suggest that women invariably find it easy to express emotional distress and men invariably find it difficult. In addition it is important to recognise that, for a minority of patients, a personal relationship with health professionals can act as a barrier to the disclosure of emotional distress.</p

The gene encoding interleukin-13: a susceptibility locus for asthma and related traits

Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31

A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 Receptor in allergic inflammation

<p>Abstract</p> <p>Background</p> <p>The identification of novel genes by high-throughput studies of complex diseases is complicated by the large number of potential genes. However, since disease-associated genes tend to interact, one solution is to arrange them in modules based on co-expression data and known gene interactions. The hypothesis of this study was that such a module could be a) found and validated in allergic disease and b) used to find and validate one ore more novel disease-associated genes.</p> <p>Results</p> <p>To test these hypotheses integrated analysis of a large number of gene expression microarray experiments from different forms of allergy was performed. This led to the identification of an experimentally validated reference gene that was used to construct a module of co-expressed and interacting genes. This module was validated in an independent material, by replicating the expression changes in allergen-challenged CD4⁺cells. Moreover, the changes were reversed following treatment with corticosteroids. The module contained several novel disease-associated genes, of which the one with the highest number of interactions with known disease genes, <it>IL7R</it>, was selected for further validation. The expression levels of <it>IL7R </it>in allergen challenged CD4⁺cells decreased following challenge but increased after treatment. This suggested an inhibitory role, which was confirmed by functional studies.</p> <p>Conclusion</p> <p>We propose that a module-based analytical strategy is generally applicable to find novel genes in complex diseases.</p