IL-17A induces Pendrin expression and chloride-bicarbonate exchange in human bronchial epithelial cells

The epithelium plays an active role in the response to inhaled pathogens in part by responding to signals from the immune system. Epithelial responses may include changes in chemokine expression, increased mucin production and antimicrobial peptide secretion, and changes in ion transport. We previously demonstrated that interleukin-17A (IL-17A), which is critical for lung host defense against extracellular bacteria, significantly raised airway surface pH in vitro, a finding that is common to a number of inflammatory diseases. Using microarray analysis of normal human bronchial epithelial (HBE) cells treated with IL-17A, we identified the electroneutral chloride-bicarbonate exchanger Pendrin (SLC26A4) as a potential mediator of this effect. These data were verified by real-time, quantitative PCR that demonstrated a time-dependent increase in Pendrin mRNA expression in HBE cells treated with IL-17A up to 48 h. Using immunoblotting and immunofluorescence, we confirmed that Pendrin protein expression is increased in IL-17 treated HBE cells and that it is primarily localized to the mucosal surface of the cells. Functional studies using live-cell fluorescence to measure intracellular pH demonstrated that IL-17A induced chloride-bicarbonate exchange in HBE cells that was not present in the absence of IL-17A. Furthermore, HBE cells treated with short interfering RNA against Pendrin showed substantially reduced chloride-bicarbonate exchange. These data suggest that Pendrin is part of IL-17A-dependent epithelial changes and that Pendrin may therefore be a therapeutic target in IL-17A-dependent lung disease. © 2014 Adams et al

Real-time analysis of cAMP-mediated regulation of ciliary motility in single primary human airway epithelial cells

Airway ciliary beat frequency regulation is complex but in part influenced by cyclic adenosine monophosphate (cAMP)-mediated changes in cAMP-dependent kinase activity, yet the cAMP concentration required for increases in ciliary beat frequency and the temporal relationship between ciliary beat frequency and cAMP changes are unknown. A lentiviral gene transfer system was developed to express a fluorescence resonance energy transfer (FRET)-based cAMP sensor in ciliated cells. Expression of fluorescently tagged cAMP-dependent kinase subunits from the ciliated-cell-specifi

Understanding why adult participants at the World Senior Games choose a healthy diet

BACKGROUND: Identifying those seniors most likely to adopt a healthy diet, the relative importance they place on certain perceived benefits associated with a healthy diet, and whether these perceived benefits are associated with selected demographic, lifestyle, and health history variables is important for directing effective dietary health promotion programs. METHODS: Analyses are based on a cross-sectional convenience sample of 670 seniors aged 50 years and older at the 2002 World Senior Games in St. George, Utah. Data are assessed using frequencies, bivariate analysis, analysis of variance, and multiple logistic regression analysis. RESULTS: Fruit and vegetable consumption was significantly higher in individuals aged 70–79, in women, in those not overweight or obese, and in those with excellent overall health. Dietary fiber consumption was significantly higher in former or never smokers, current and previous alcohol drinkers, in those not overweight or obese, and in those with excellent health. The strongest motivating factors identified for adopting a healthy diet were to improve the quality of life, to increase longevity, and to prevent disease. Of intermediate importance were the need to feel a sense of control and to satisfy likes or dislikes. Least important were the desire to experience a higher level of spirituality, social reasons, and peer acceptance. CONCLUSION: Seniors who have adopted a healthy diet are more likely to have chosen that behavior because of perceived health benefits than for personal and social benefits. Overweight or obese individuals and those in poor health were less likely to be engaged in healthy eating behavior and require special attention by dieticians and public health professionals

Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Impact of hyperglycemia on morbidity and mortality, length of hospitalization and rates of re-hospitalization in a general hospital setting in Brazil

<p>Abstract</p> <p>Background</p> <p>Hyperglycemia in hospitalized patients is known to be related to a higher incidence of clinical and surgical complications and poorer outcomes. Adequate glycemic control and earlier diagnosis of type 2 diabetes during hospitalization are cost-effective measures.</p> <p>Methods</p> <p>This prospective cohort study was designed to determine the impact of hyperglycemia on morbidity and mortality in a general hospital setting during a 3-month period by reviewing patients' records. The primary purposes of this trial were to verify that hyperglycemia was diagnosed properly and sufficiently early and that it was managed during the hospital stay; we also aimed to evaluate the relationship between in-hospital hyperglycemia control and outcomes such as complications during the hospital stay, extent of hospitalization, frequency of re-hospitalization, death rates and number of days in the ICU (Intensive Care Unit) after admission. Statistical analyses utilized the Kruskall-Wallis complemented by the "a posteriori" d.m.s. test, Spearman correlation and Chi-squared test, with a level of significance of 5% (p < 0.05).</p> <p>Results</p> <p>We reviewed 779 patient records that fulfilled inclusion criteria. The patients were divided into 5 groups: group (1) diabetic with normal glycemic levels according to American Diabetes Association criteria for in-hospital patients (n = 123); group (2) diabetics with hyperglycemia (n = 76); group (3) non-diabetics with hyperglycemia (n = 225); group (4)diabetics and non-diabetics with persistent hyperglycemia during 3 consecutive days (n = 57) and group (5) those with normal glucose control (n = 298). Compared to patients in groups 1 and 5, patients in groups 2, 3 and 4 had significantly higher mortality rates (17.7% vs. 2.8%) and Intensive Care Unit admissions with complications (23.3% vs. 4.5%). Patients in group 4 had the longest hospitalizations (mean 15.5 days), and group 5 had the lowest re-hospitalization rate (mean of 1.28 hospitalizations). Only 184 (51.4%) hyperglycemic patients had received treatment. An insulin "sliding-scale" alone was the most frequent treatment used, and there was a wide variation in glucose target medical prescriptions. Intra Venous insulin infusion was used in 3.8% of patients in the ICU. Glycohemoglobin(A1C) was measured in 11 patients(2.2%).</p> <p>Conclusions</p> <p>Hospital hyperglycemia was correlated with, among other parameters, morbidity/mortality, length of hospitalization and number of re-hospitalizations. Most patients did not have their glycemic levels measured at the hospital; despite the high number of hyperglycemic patients not diagnosed as diabetics, A1C was not frequently measured. Even when patients are assessed for hyperglycemia, they were not treated properly.</p

DNA Sequence Analysis of SLC26A5, Encoding Prestin, in a Patient-Control Cohort: Identification of Fourteen Novel DNA Sequence Variations

Prestin, encoded by the gene SLC26A5, is a transmembrane protein of the cochlear outer hair cell (OHC). Prestin is required for the somatic electromotile activity of OHCs, which is absent in OHCs and causes severe hearing impairment in mice lacking prestin. In humans, the role of sequence variations in SLC26A5 in hearing loss is less clear. Although prestin is expected to be required for functional human OHCs, the clinical significance of reported putative mutant alleles in humans is uncertain.To explore the hypothesis that SLC26A5 may act as a modifier gene, affecting the severity of hearing loss caused by an independent etiology, a patient-control cohort was screened for DNA sequence variations in SLC26A5 using sequencing and allele specific methods. Patients in this study carried known pathogenic or controversial sequence variations in GJB2, encoding Connexin 26, or confirmed or suspected sequence variations in SLC26A5; controls included four ethnic populations. Twenty-three different DNA sequence variations in SLC26A5, 14 of which are novel, were observed: 4 novel sequence variations were found exclusively among patients; 7 novel sequence variations were found exclusively among controls; and, 12 sequence variations, 3 of which are novel, were found in both patients and controls. Twenty-one of the 23 DNA sequence variations were located in non-coding regions of SLC26A5. Two coding sequence variations, both novel, were observed only in patients and predict a silent change, p.S434S, and an amino acid substitution, p.I663V. In silico analysis of the p.I663V amino acid variation suggested this variant might be benign. Using Fisher's exact test, no statistically significant difference was observed between patients and controls in the frequency of the identified DNA sequence variations. Haplotype analysis using HaploView 4.0 software revealed the same predominant haplotype in patients and controls and derived haplotype blocks in the patient-control cohort similar to those generated from the International HapMap Project.Although these data fail to support a hypothesis that SLC26A5 acts as a modifier gene of GJB2-related hearing loss, the sample size is small and investigation of a larger population might be more informative. The 14 novel DNA sequence variations in SLC26A5 reported here will serve as useful research tools for future studies of prestin

Matched-pair analysis of patients with female and male breast cancer: a comparative analysis

<p>Abstract</p> <p>Background</p> <p>Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management.</p> <p>Methods</p> <p>MBC diagnosed between 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status).</p> <p>Results</p> <p>108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC.</p> <p>Conclusion</p> <p>Our comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer.</p

Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs

Use Of Medical Tourism For Hip And Knee Surgery In Osteoarthritis: A Qualitative Examination Of Distinctive Attitudinal Characteristics Among Canadian Patients

Background Medical tourism is the term that describes patients’ international travel with the intention of seeking medical treatment. Some medical tourists go abroad for orthopaedic surgeries, including hip and knee resurfacing and replacement. In this article we examine the findings of interviews with Canadian medical tourists who went abroad for such surgeries to determine what is distinctive about their attitudes when compared to existing qualitative research findings about patients’ decision-making in and experiences of these same procedures in their home countries. Methods Fourteen Canadian medical tourists participated in semi-structured phone interviews, all of whom had gone abroad for hip or knee surgery to treat osteoarthritis. Transcripts were coded and thematically analysed, which involved comparing emerging findings to those in the existing qualitative literature on hip and knee surgery. Results Three distinctive attitudinal characteristics among participants were identified when interview themes were compared to findings in the existing qualitative research on hip and knee surgery in osteoarthritis. These attitudinal characteristics were that the medical tourists we spoke with were: (1) comfortable health-related decision-makers; (2) unwavering in their views about procedure necessity and urgency; and (3) firm in their desires to maintain active lives. Conclusions Compared to other patients reported on in the existing qualitative hip and knee surgery literature, medical tourists are less likely to question their need for surgery and are particularly active in their pursuit of surgical intervention. They are also comfortable with taking control of health-related decisions. Future research is needed to identify motivators behind patients’ pursuit of care abroad, determine if the attitudinal characteristics identified here hold true for other patient groups, and ascertain the impact of these attitudinal characteristics on surgical outcomes. Arthritis care providers can use the attitudinal characteristics identified here to better advise osteoarthritis patients who are considering seeking care abroad

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.This study was funded by the WT fellowship grant for VV (093705/Z/ 10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. YW is supported by the Fyssen Fondation and MRC Studentships. PD is supported by the Gatsby Charitable Foundation. JEG has received grants from the National Institute of Drug Abuse and the National Center for Responsible Gaming. TWR and BJS are supported on a WT Programme Grant (089589/Z/09/Z). The BCNI is supported by a WT and MRC grant.This is the final published version. It's also available from Molecular Psychiatry at http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201444a.html