Evidence for long-term sensitization of the bowel in patients with post-infectious-IBS.

Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling

Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells

BACKGROUND: In liver injury, the pool of hepatic stellate cell (HSC) increases and produces extracellular matrix proteins, decreasing during the resolution of fibrosis. The profibrogenic role of endothelin-1 (ET-1) in liver fibrosis remains disputed. We therefore studied the effect of ET-1 on proliferation, apoptosis and profibrogenic gene expression of HSCs. RESULTS: First passage HSC predominantly expressed endothelin A receptor (ETAR) mRNA and 4th passage HSC predominantly expressed the endothelin B receptor (ETBR) mRNA. ET-1 had no effect on DNA synthesis in 1st passage HSC, but reduced DNA synthesis in 4th passage HSC by more than 50%. Inhibition of proliferation by endothelin-1 was abrogated by ETBR specific antagonist BQ788, indicating a prominent role of ETBR in growth inhibition. ET-1 did not prevent apoptosis induced by serum deprivation or Fas ligand in 1st or 4th passage HSC. However, ET-1 increased procollagen α1(I), transforming growth factor β-1 and matrix metalloproteinase (MMP)-2 mRNA transcripts in a concentration-dependent manner in 1st, but not in 4th passage HSC. Profibrogenic gene expression was abrogated by ETAR antagonist BQ123. Both BQ123 and BQ788 attenuated the increase of MMP-2 expression by ET-1. CONCLUSION: We show that ET-1 stimulates fibrogenic gene expression for 1st passage HSC and it inhibits HSC proliferation for 4th passage HSC. These data indicate the profibrogenic and antifibrogenic action of ET-1 for HSC are involved in the process of liver fibrosis

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Diabetes with Hypertension as Risk Factors for Adult Dengue Hemorrhagic Fever in a Predominantly Dengue Serotype 2 Epidemic: A Case Control Study

Dengue is a major vector borne disease in the tropical and subtropical regions. An estimated 50 million infections occur per annum in over 100 countries. A severe form of dengue, characterized by bleeding and plasma leakage, known as dengue hemorrhagic fever (DHF) is estimated to occur in 1–5% of hospitalized cases. It can be fatal if unrecognized and not treated in a timely manner. Previous studies had found a number of risk factors for DHF. However, screening and clinical management strategies based on these risk factors may not be applicable to all populations and epidemics of different serotypes. In this study, we found significant association between DHF and diabetes mellitus and diabetes mellitus with hypertension during the epidemic of predominantly serotype 2 (year 2007 and 2008), but not during the epidemic of predominantly serotype 1 (year 2006). Diabetes mellitus and hypertension are prevalent in Singapore and most parts of South-East Asia, where dengue is endemic. Therefore, it is important to address the risk effect of these co-morbidities on the development of DHF so as to reduce morbidity and mortality. Our findings may have impact on screening and clinical management of dengue patients, when confirmed in more studies

Tolerability of breast ductal lavage in women from families at high genetic risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>Ductal lavage (DL) has been proposed as a minimally-invasive, well-tolerated tool for obtaining breast epithelial cells for cytological evaluation of breast cancer risk. We report DL tolerability in <it>BRCA1/2 </it>mutation-positive and -negative women from an IRB-approved research study.</p> <p>Methods</p> <p>165 <it>BRCA1/2 </it>mutation-positive, 26 mutation-negative and 3 mutation unknown women underwent mammography, breast MRI and DL. Psychological well-being and perceptions of pain were obtained before and after DL, and compared with pain experienced during other screening procedures.</p> <p>Results</p> <p>The average <b><it>anticipated </it></b>and <b><it>experienced </it></b>discomfort rating for DL, 47 and 48 (0–100), were significantly higher (<it>p </it>< 0.01) than the <b><it>anticipated </it></b>and <b><it>experienced </it></b>discomfort of mammogram (38 and 34), MRI (36 and 25) or nipple aspiration (42 and 27). Women with greater pre-existing emotional distress experienced more DL-related discomfort than they anticipated. Women reporting DL-related pain as worse than expected were nearly three times more likely to refuse subsequent DL than those reporting it as the same or better than expected. Twenty-five percent of participants refused repeat DL at first annual follow-up.</p> <p>Conclusion</p> <p>DL was anticipated to be and experienced as <b>more </b>uncomfortable than other procedures used in breast cancer screening. Higher underlying psychological distress was associated with decreased DL tolerability.</p

Does transition from an unstable labour market position to permanent employment protect mental health? Results from a 14-year follow-up of school-leavers

<p>Abstract</p> <p>Background</p> <p>Having secure employment, in contrast to being unemployed, is regarded as an important determinant of health. Research and theories about the negative health consequences of unemployment indicated that transition from unemployment to a paid job could lead to improved health. The objective of this study was to test the hypothesis that obtaining permanent employment after being in an unstable labour market position protects mental health.</p> <p>Methods</p> <p>A 14-year follow-up of all graduates from compulsory school in an industrial town in northern Sweden was performed at ages 16, 18, 21 and 30 years. Complete data on the cohort were collected for 1044 individuals with the aid of a comprehensive questionnaire. The response rate was 96.4%. The health measurement used in this study was the psychological symptoms analysed by multivariate logistic regression. Those who obtained permanent employment were the focus of the analysis. This group consisted of people who were in an unstable labour market position for a year or more between the ages of 25 and 29, and who had acquired a permanent job one year before and at the time of the investigation.</p> <p>Results</p> <p>After controlling for gender as well as for an indicator of health-related selection, possible confounders and mediators, an association was found between the lower probability of psychological symptoms and obtaining permanent employment (OR = 0.35, 95% CI 0.19–0.63) as well as having permanent employment (OR = 0.22, 95% CI 0.10–0.51).</p> <p>Conclusion</p> <p>Our findings suggest that transition from an unstable labour market position to permanent employment could be health-promoting, even after controlling for possible confounders and mediators, as well as for an indicator of health-related selection. However, as there are few studies in the field, there is a need for more longitudinal studies in order to further analyse the relationship and to examine possible explanations. The policy implication of our study is that the transformation of unstable labour market positions into permanent employment could contribute to better public health.</p

Cost-effectiveness of ward-based pharmacy care in surgical patients: protocol of the SUREPILL (Surgery & Pharmacy In Liaison) study

<p>Abstract</p> <p>Background</p> <p>Preventable adverse drug events (pADEs) are widely known to be a health care issue for hospitalized patients. Surgical patients are especially at risk, but prevention of pADEs in this population is not demonstrated before. Ward-based pharmacy interventions seem effective in reducing pADEs in medical patients. The cost-effectiveness of these preventive efforts still needs to be assessed in a comparative study of high methodological standard and also in the surgical population. For these aims the SUREPILL (Surgery & Pharmacy in Liaison) study is initiated.</p> <p>Methods/Design</p> <p>A multi-centre controlled trial, with randomisation at ward-level and preceding baseline assessments is designed. Patients admitted to the surgical study wards for elective surgery with an expected length of stay of more than 48 hours will be included. Patients admitted to the intervention ward, will receive ward-based pharmacy care from the clinical pharmacy team, i.e. pharmacy practitioners and hospital pharmacists. This ward-based pharmacy intervention includes medication reconciliation in consultation with the patient at admission, daily medication review with face-to-face contact with the ward doctor, and patient counselling at discharge. Patients admitted in the control ward, will receive standard pharmaceutical care.</p> <p>The primary clinical outcome measure is the number of pADEs per 100 elective admissions. These pADEs will be measured by systematic patient record evaluation using a trigger tool. Patient records positive for a trigger will be evaluated on causality, severity and preventability by an independent expert panel. In addition, an economic evaluation will be performed from a societal perspective with the costs per preventable ADE as the primary economic outcome. Other outcomes of this study are: severity of pADEs, number of patients with pADEs per total number of admissions, direct (non-)medical costs and indirect non-medical costs, extra costs per prevented ADE, number and type of pharmacy interventions, length of hospital stay, complications registered in a national complication registration system for surgery, number of readmissions within three months after initial admission (follow-up), quality of life and number of non-institutionalized days during follow-up.</p> <p>Discussion</p> <p>This study will assess the cost-effectiveness of ward-based pharmacy care on preventable adverse drug events in surgical patients from a societal perspective, using a comparative study design.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2258">NTR2258</a></p

Packages of Care for Epilepsy in Low- and Middle-Income Countries

In the second in a series of six articles on packages of care for mental health disorders in low- and middle-income countries, Caroline Mbuba and Charles Newton discuss treatment for epilepsy

Development of an In Vitro Model for the Multi-Parametric Quantification of the Cellular Interactions between Candida Yeasts and Phagocytes

We developed a new in vitro model for a multi-parameter characterization of the time course interaction of Candida fungal cells with J774 murine macrophages and human neutrophils, based on the use of combined microscopy, fluorometry, flow cytometry and viability assays. Using fluorochromes specific to phagocytes and yeasts, we could accurately quantify various parameters simultaneously in a single infection experiment: at the individual cell level, we measured the association of phagocytes to fungal cells and phagocyte survival, and monitored in parallel the overall phagocytosis process by measuring the part of ingested fungal cells among the total fungal biomass that changed over time. Candida albicans, C. glabrata, and C. lusitaniae were used as a proof of concept: they exhibited species-specific differences in their association rate with phagocytes. The fungal biomass uptaken by the phagocytes differed significantly according to the Candida species. The measure of the survival of fungal and immune cells during the interaction showed that C. albicans was the more aggressive yeast in vitro, destroying the vast majority of the phagocytes within five hours. All three species of Candida were able to survive and to escape macrophage phagocytosis either by the intraphagocytic yeast-to-hyphae transition (C. albicans) and the fungal cell multiplication until phagocytes burst (C. glabrata, C. lusitaniae), or by the avoidance of phagocytosis (C. lusitaniae). We demonstrated that our model was sensitive enough to quantify small variations of the parameters of the interaction. The method has been conceived to be amenable to the high-throughput screening of mutants in order to unravel the molecular mechanisms involved in the interaction between yeasts and host phagocytes