Design and characterization of a noncompetitive antagonist of the transient receptor potential vanilloid subunit 1 channel with in vivo analgesic and anti-inflammatory activity.

Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund's adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain. PERSPECTIVE: This study reports the design of a potent TRPV1 noncompetitive antagonist that exhibits anti-inflammatory and analgesic activity in preclinical models of acute and chronic pain. This compound is a lead for analgesic drug development.     

Prevalence and psychosocial correlates of perinatal depression: a cohort study from urban Pakistan

Depression around childbirth is common in low income countries. The aim of this study was to examine the factors associated with persistence of depression from the antenatal to the postnatal period in urban Pakistan. A total of 1,357 pregnant women in their third trimester attending the antenatal clinic were included in the study. From these, 763 mothers who delivered at the study maternity home were reassessed after 3 months of childbirth. Edinburgh Postnatal Depression Scale (EPDS) was administered to measure depression in both the antenatal and the postnatal periods. Psychological distress, disability and life events experienced by mothers were also measured by using the Self-Reporting Questionnaire (SRQ-20), Brief Disability Questionnaire (BDQ), and Life Events Checklist, respectively. We found 25.8% prevalence rate of antenatal depression and 38.3% persistent depression in a private clinic. Persistently depressed mothers had significantly high psychological distress, more disability, and experienced more stressful life events than the resolved group. Our findings confirm the high rates of depression during pregnancy but we found low rates of persistent depression in this urban population as compared to the previous report. There is a need for further investigation of factors associated with persistent depression in order to develop appropriate interventions.     

流动人口生殖健康现状分析及对策研究

随着我国经济发展和城市化进程的不断加快,流动人口数量越来越多,流动人口的生殖健康成为新时期我国计划生育工作必须面对的新问题。本文对我国流动人口生殖健康现状及对策进行研究。结果表明,我国流动人口的生殖健康水平远远低于常住人口,流动人口的生殖健康教育及服务还面临着管理及资金投入上的一系列问题。因此,必须建立流动人口的基本医疗保障体系,通过居住地管理及公共财政投入,全面提高流动人口的生殖健康服务水平。     

Risk factors associated with adverse drug reactions in hospitalised children: international multicentre study

Background  

Understanding the epidemiology and risk factors of adverse drug reactions (ADRs) is important in order to develop appropriate prevention strategies. This study aimed to identify risk factors associated with ADRs in hospitalised children and recommend strategies to minimise ADRs.     

Advances in modulating thermosensory TRP channels

Introduction: Thermosensory channels are a subfamily of the transient receptor potential (TRP) channel family that are activated by changes in the environmental temperature. These channels, known as thermoTRPs, cover the entire spectrum of temperatures, from noxious cold (< 15°C) to injurious heat (> 42°C). In addition, dysfunction of these channels contributes to the thermal hypersensitivity that accompanies painful conditions. Moreover, because of their wide tissue and cellular distribution, thermoTRPs are also involved in the pathophysiology of several diseases, from inflammation to cancer. Areas covered: Although the number of thermoTRPs is increasing with the identification of novel members such as TRPM3, we will cover the recent advances in the pharmacology of the classical thermosensory channels, namely TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. This review will focus on the therapeutic progress carried out for all these channels and will highlight the tenet that TRPV1, TRPM8 and TRPA1 are the most exploited channels, and that the interest on TRPV3 and TRPV4 is growing with the first TRPV3 antagonist that moves into Phase-II clinical trials. In contrast, the pharmacology of TRPV2 is yet in its infancy. Expert opinion: Despite the tremendous academic and industrial investment to develop therapeutic modulators of thermoTRPs, it apparently seems that we are still far from the first successful product, although hope is maintained high for all compounds currently in clinical trials. A major concern has been the appearance of side effects. A better knowledge of the thermosensory protein networks (signal-plexes), along with the application of system biology approaches may provide novel strategies to modulate thermoTRPs activity with improved therapeutic index. A case in point is TRPV1, where acting on interacting proteins is providing new therapeutic opportunities.     

A Qualitative Study of Stress and Coping to Inform the LEADS Health Promotion Trial for African American Adolescents with Overweight and Obesity

The purpose of this study was to conduct in-depth individual interviews with 30 African American adolescents with overweight and obesity and their families (caregiver/adolescent dyads) to gain a better understanding of how to integrate stress and coping essential elements into an existing family-based health promotion program for weight loss. Interview data from 30 African American adolescents with overweight and obesity (Mage = 15.30 ± 2.18; MBMI%-ile = 96.7 ± 3.90) were transcribed and coded for themes using inductive and deductive approaches by two independent coders. Inter-rater reliability was acceptable (r = 0.70–0.80) and discrepancies were resolved to 100% agreement. The themes were guided by the Relapse Prevention Model, which focuses on assessing barriers of overall coping capacity in high stress situations that may undermine health behavior change (physical activity, diet, weight loss). Prominent themes included feeling stressed primarily in response to relationship conflicts within the family and among peers, school responsibilities, and negative emotions (anxiety, depression, anger). A mix of themes emerged related to coping strategies ranging from cognitive reframing and distraction to avoidant coping. Recommendations for future programs include addressing sources of stress and providing supportive resources, as well as embracing broader systems such as neighborhoods and communities. Implications for future intervention studies are discussed.     

Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice

The intestinal microbiota contributes to the development of the immune system, and conversely, the immune system influences the composition of the microbiota. Toll-like receptors (TLRs) in the gut recognize bacterial ligands. Although TLR signaling represents a major arm of the innate immune system, the extent to which TLRs influence the composition of the intestinal microbiota remains unclear. We performed deep 16S ribosomal RNA sequencing to characterize the complex bacterial populations inhabiting the ileum and cecum of TLR- and MyD88-deficient mice. The microbiota of MyD88- and TLR-deficient mouse colonies differed markedly, with each colony harboring distinct and distinguishable bacterial populations in the small and large intestine. Comparison of MyD88-, TLR2-, TLR4-, TLR5-, and TLR9-deficient mice and their respective wild-type (WT) littermates demonstrated that the impact of TLR deficiency on the composition of the intestinal microbiota is minimal under homeostatic conditions and after recovery from antibiotic treatment. Thus, differences between TLR-deficient mouse colonies reflected long-term divergence of the microbiota after extended husbandry in isolation from each other. Long-term breeding of isolated mouse colonies results in changes of the intestinal microbiota that are communicated to offspring by maternal transmission, which account for marked compositional differences between WT and mutant mouse strains.     

Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary

Objective

Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.

Methods

A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.

Results

Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p = 0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p < 0.001).

Conclusion

Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.     

Asia–Pacific consensus statements on Crohn's disease. Part 2: Management

The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia‐Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia‐Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all‐comprehensive and future revisions are likely to be required in this ever‐changing field.