15-deoxy-Delta(12,14)-Prostaglandin J(2) inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism

Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors

Describing the longitudinal course of major depression using Markov models: Data integration across three national surveys

BACKGROUND: Most epidemiological studies of major depression report period prevalence estimates. These are of limited utility in characterizing the longitudinal epidemiology of this condition. Markov models provide a methodological framework for increasing the utility of epidemiological data. Markov models relating incidence and recovery to major depression prevalence have been described in a series of prior papers. In this paper, the models are extended to describe the longitudinal course of the disorder. METHODS: Data from three national surveys conducted by the Canadian national statistical agency (Statistics Canada) were used in this analysis. These data were integrated using a Markov model. Incidence, recurrence and recovery were represented as weekly transition probabilities. Model parameters were calibrated to the survey estimates. RESULTS: The population was divided into three categories: low, moderate and high recurrence groups. The size of each category was approximated using lifetime data from a study using the WHO Mental Health Composite International Diagnostic Interview (WMH-CIDI). Consistent with previous work, transition probabilities reflecting recovery were high in the initial weeks of the episodes, and declined by a fixed proportion with each passing week. CONCLUSION: Markov models provide a framework for integrating psychiatric epidemiological data. Previous studies have illustrated the utility of Markov models for decomposing prevalence into its various determinants: incidence, recovery and mortality. This study extends the Markov approach by distinguishing several recurrence categories

Subthreshold depression as a risk indicator for major depressive disorder: a systematic review of prospective studies.

Objective: In order to examine whether the incidence of major depressive disorder (MDD) is increased in subjects with subthreshold depression, or sD (clinically relevant depressive symptoms, without meeting criteria for a full-blown MDD), we conducted a review of prospective studies examining the incidence of MDD in subjects with sD. Method: A systematic literature search was conducted. For all studies, the relative risk of developing MDD was calculated, based on person-years. Results: Twenty studies (23 comparisons) were found, based on community samples, general medical patients and high-risk subjects. Most comparisons showed that subjects with sD had a consistently larger chance of developing MDD. The studies differed considerably in the definition of sD, the recency (occurrence of the last sD) and the in-/ exclusion of lifetime MDD. Conclusion: The incidence of MDD in subjects with sD is larger than in subjects without sD. Otherwise, the concept of sD is too broad to be used. In future studies, some consensus should be reached regarding the definition of sD

Population Based Study of 12 Autoimmune Diseases in Sardinia, Italy: Prevalence and Comorbidity

BACKGROUND: The limited availability of prevalence data based on a representative sample of the general population, and the limited number of diseases considered in studies about co-morbidity are the critical factors in study of autoimmune diseases. This paper describes the prevalence of 12 autoimmune diseases in a representative sample of the general population in the South of Sardinia, Italy, and tests the hypothesis of an overall association among these diseases. METHODS: Data were obtained from 21 GPs. The sample included 25,885 people. Prevalence data were expressed with 95% Poisson C.I. The hypothesis of an overall association between autoimmune diseases was tested by evaluating the co-occurrence within individuals. RESULTS: Prevalence per 100,000 are: 552 rheumatoid arthritis, 124 ulcerative colitis, 15 Crohn's disease, 464 type 1 diabetes, 81 systemic lupus erythematosus, 124 celiac disease, 35 myasthenia gravis, 939 psoriasis/psoriatic arthritis, 35 systemic sclerosis, 224 multiple sclerosis, 31 Sjogren's syndrome, and 2,619 autoimmune thyroiditis. An overall association between autoimmune disorders was highlighted. CONCLUSIONS: The comparisons with prevalence reported in current literature do not show outlier values, except possibly for a few diseases like celiac disease and myasthenia gravis. People already affected by a first autoimmune disease have a higher probability of being affected by a second autoimmune disorder. In the present study, the sample size, together with the low overall prevalence of autoimmune diseases in the population, did not allow us to examine which diseases are most frequently associated with other autoimmune diseases. However, this paper makes available an adequate control population for future clinical studies aimed at exploring the co-morbidity of specific pairs of autoimmune disease

Predicting the onset of major depression in subjects with subthreshold depression in primary care: A prospective study.

Objective: That subjects with subthreshold depression have an increased probability of developing major depression has been confirmed by many studies. However, the factors which may predict the onset of major depression have yet to be fully examined. Method: We examined the control group of a randomized trial in primary care patients with subthreshold depression (N ¼ 109), of whom 20 had developed major depression 1 year later. Using the vulnerability-stress theory, we examined which factors predicted the onset of major depression. Results: In both univariate and multivariate analyses, family history and chronic illnesses predicted the onset of major depression. Conclusion: It is possible to predict to a certain degree whether a subject with subthreshold depression will develop major depression within a year

The impact of attrition on the representativeness of cohort studies of older people

Background: There are well-established risk factors, such as lower education, for attrition of study participants. Consequently, the representativeness of the cohort in a longitudinal study may deteriorate over time. Death is a common form of attrition in cohort studies of older people. The aim of this paper is to examine the effects of death and other forms of attrition on risk factor prevalence in the study cohort and the target population over time

How Equity-Oriented Health Care Affects Health: Key Mechanisms and Implications for Primary Health Care Practice and Policy

Policy Points A consensus regarding the need to orient health systems to address inequities is emerging, with much of this discussion targeting population health interventions and indicators. We know less about applying these approaches to primary health care. This study empirically demonstrates that providing more equity-oriented health care (EOHC) in primary health care, including trauma- and violence-informed, culturally safe, and contextually tailored care, predicts improved health outcomes across time for people living in marginalizing conditions. This is achieved by enhancing patients’ comfort and confidence in their care and their own confidence in preventing and managing health problems. This promising new evidence suggests that equity-oriented interventions at the point of care can begin to shift inequities in health outcomes for those with the greatest need. Context: Significant attention has been directed toward addressing health inequities at the population health and systems levels, yet little progress has been made in identifying approaches to reduce health inequities through clinical care, particularly in a primary health care context. Although the provision of equity-oriented health care (EOHC) is widely assumed to lead to improvements in patients’ health outcomes, little empirical evidence supports this claim. To remedy this, we tested whether more EOHC predicts more positive patient health outcomes and identified selected mediators of this relationship. Methods: Our analysis uses longitudinal data from 395 patients recruited from 4 primary health care clinics serving people living in marginalizing conditions. The participants completed 4 structured interviews composed of self-report measures and survey questions over a 2-year period. Using path analysis techniques, we tested a hypothesized model of the process through which patients’ perceptions of EOHC led to improvements in self-reported health outcomes (quality of life, chronic pain disability, and posttraumatic stress [PTSD] and depressive symptoms), including particular covariates of health outcomes (age, gender, financial strain, experiences of discrimination). Findings: Over a 24-month period, higher levels of EOHC predicted greater patient comfort and confidence in the health care patients received, leading to increased confidence to prevent and manage their health problems, which, in turn, improved health outcomes (depressive symptoms, PTSD symptoms, chronic pain, and quality of life). In addition, financial strain and experiences of discrimination had significant negative effects on all health outcomes. Conclusions: This study is among the first to demonstrate empirically that providing more EOHC predicts better patient health outcomes over time. At a policy level, this research supports investments in equity-focused organizational and provider-level processes in primary health care as a means of improving patients’ health, particularly for those living in marginalizing conditions. Whether these results are robust in different patient groups and across a broader range of health care contexts requires further study

Impact of mental health problems on case fatality in male cancer patients

Background: Although mortality rates are elevated in psychiatric patients relative to their healthy counterparts, little is known about the impact of mental health on survival in people with cancer. / Methods and results: Among 16 498 Swedish men with cancer, survival was worse in those with a history of psychiatric hospital admissions: multiply-adjusted hazard ratio (95% confidence interval) comparing cancer mortality in men with and without psychiatric admissions: 1.59 (1.39, 1.83). / Conclusion: Survival in cancer patients is worse among those with a history of psychiatric disease. The mechanisms underlying this association should be further explored

15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism

Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14- Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors