Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.Molecular Psychiatry advance online publication, 18 October 2016; doi:10.1038/mp.2016.167

Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: An electronic health record-based study.

Low-grade inflammation is a risk factor for depression, psychosis and other major psychiatric disorders. It is associated with poor response to antidepressant and antipsychotics, and could potentially be a treatment target. However, there is limited data on the prevalence of low-grade inflammation in major psychiatric disorders, and on the characteristics of patients who show evidence of inflammation. We examined the prevalence of low-grade inflammation and associated socio-demographic and clinical factors in acute psychiatric inpatients. An anonymised search of the electronic patient records of Cambridgeshire and Peterborough NHS Foundation Trust was used to identify patients aged 18-65 years who were hospitalised between 2013 and 2016 (inclusive). We excluded patients on antibiotics or oral steroids, or with missing data. Inflammation was defined using serum C-reactive protein (>3 mg/L) or total white cell count (>9.4 × 109/L) as measured within 14 days of admission. Out of all 599 admissions, the prevalence of inflammation (serum CRP >3 mg/L) in the ICD-10 diagnostic groups of psychotic disorders (F20-29), mood disorders (F30-39), neurotic disorders (F40-48) and personality disorders (F60-69) was 32%, 21%, 22% and 42%, respectively. In multivariable analyses, low-grade inflammation was associated with older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, benzodiazepines, and with current treatment for medical comorbidities. A notable proportion of acutely unwell psychiatric patients from all ICD-10 major diagnostic groups show evidence of low-grade inflammation, suggesting inflammation may be relevant for all psychiatric disorders

Adolescent Bisphenol-A Exposure Decreases Dendritic Spine Density: Role of Sex and Age

Bisphenol-A (BPA), a common environmental endocrine disruptor, modulates estrogenic, androgenic, and anti-androgenic effects throughout the lifespan. We recently showed that low dose BPA exposure during adolescence increases anxiety and impairs spatial memory independent of sex. In the current study, six week old Sprague Dawley rats (n=24 males, n=24 females) received daily subcutaneous injections (40 µg/kg bodyweight) of BPA or vehicle for one week. Serum corticosterone levels in response to a 1 h restraint stress and spine density were examined at age 7 (cohort 1) and 11 (cohort 2) weeks. Adolescent BPA exposure did not alter stress dependent corticosterone responses but decreased spine density on apical and basal dendrites of pyramidal cells in the medial prefrontal cortex (mPFC) and hippocampal CA1 region (CA1). Sex differences in spine density were observed on basal dendrites of the mPFC and CA1 with females having greater spine density than males. This sex difference was further augmented by both age and treatment, with results indicating that BPA-dependent decreases in spine density were more pronounced in males than females on mPFC basal dendrites. Importantly, the robust neuronal alterations were observed in animals exposed to BPA levels below the current U.S.E.P.A. recommended safe daily limit. These results are the first demonstrating that BPA given during adolescence leads to enduring effects on neural morphology at adulthood. Given that humans are routinely exposed to low levels of BPA through a variety of sources, the decreased spine density reported in both male and female rats after BPA exposure warrants further investigation

Electronic Health Records (EHR) Implementation and Post Implementation Challenges

The US Healthcare Industry lags behind other industries in its use of technologies for process improvement and improvement in quality of services for its patients. Globally, United States is significantly behind some European and Australian countries in implementation of EHR. While the federal government is now mandating this change and also offering incentive programs, healthcare providers remain slow to comply because of challenges they face regarding EHR implementation. This paper discusses EHR architecture, presents implementation challenges, provides a case study and offers future research ideas. The information provided in this research could be beneficial for successful EHR implementation

Bisphenol-A Exposure During Adolescence Leads to Enduring Alterations in Cognition and Dendritic Spine Density in Adult Male and Female Rats

We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescence in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40 μg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood

Excitation functions of deuteron-induced nuclear reactions on erbium in the energy range of 4–24 MeV

Excitation functions for the natEr(d,x)163,165,166,167,168,170Tm and natEr(d,x)171Er nuclear reactions were measured from the respective thresholds up to 24 MeV by using a stacked-foil activation technique combined with HPGe γ-ray spectrometry. Measured data show a partial agreement when compared with the available literature data, theoretical data extracted from the TENDL-2019 library, and predicted data by the model code EMPIRE-3.2.2. Estimated physical thick target yields of the reaction products show close values to the directly measured ones available in the literature. The deduced yield curves indicate that a typical irradiation (Ed = 15 MeV, Id = 100 µA, tirr = 72 h) of enriched 167Er target by a low energy deuteron cyclotron is suitable to obtain more than a hundred GBq activity of 167Tm with negligible impurity from 168Tm. Measured data of 170Er(d,p)171Er reaction have great significance to improve the predicting capability of the model code

Schizophrenia and cardiometabolic abnormalities: A Mendelian randomization study

Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. / Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. / Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10−8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. / Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001–0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002–0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. / Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis

Association between childhood infection, serum inflammatory markers and intelligence: findings from a population-based prospective birth cohort study.

A link between infection, inflammation, neurodevelopment and adult illnesses has been proposed. The objective of this study was to examine the association between infection burden during childhood - a critical period of development for the immune and nervous systems - and subsequent systemic inflammatory markers and general intelligence. In the Avon Longitudinal Study of Parents and Children, a prospective birth cohort in England, we examined the association of exposure to infections during childhood, assessed at seven follow-ups between age 1·5 and 7·5 years, with subsequent: (1) serum interleukin 6 and C-reactive protein (CRP) levels at age 9; (2) intelligence quotient (IQ) at age 8. We also examined the relationship between inflammatory markers and IQ. Very high infection burden (90+ percentile) was associated with higher CRP levels, but this relationship was explained by body mass index (adjusted odds ratio (OR) 1·19; 95% confidence interval (CI) 0·95-1·50), maternal occupation (adjusted OR 1·23; 95% CI 0·98-1·55) and atopic disorders (adjusted OR 1·24; 95% CI 0·98-1·55). Higher CRP levels were associated with lower IQ; adjusted β = -0·79 (95% CI -1·31 to -0·27); P = 0·003. There was no strong evidence for an association between infection and IQ. The findings indicate that childhood infections do not have an independent, lasting effect on circulating inflammatory marker levels subsequently in childhood; however, elevated inflammatory markers may be harmful for intellectual development/function

Exposure to diesel exhaust particles increases susceptibility to invasive pneumococcal disease.

BACKGROUND: The World Health Organization estimates that air pollution is responsible for 7 million deaths per annum, with 7% of these attributable to pneumonia. Many of these fatalities have been linked to exposure to high levels of airborne particulates, such as diesel exhaust particles (DEPs). OBJECTIVES: We sought to determine whether exposure to DEPs could promote the progression of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae to invasive pneumococcal disease. METHODS: We used mouse models and in vitro assays to provide a mechanistic understanding of the link between DEP exposure and pneumococcal disease risk, and we confirmed our findings by using induced sputum macrophages isolated from healthy human volunteers. RESULTS: We demonstrate that inhaled exposure to DEPs disrupts asymptomatic nasopharyngeal carriage of S pneumoniae in mice, leading to dissemination to lungs and blood. Pneumococci are transported from the nasopharynx to the lungs following exposure to DEPs, leading to increased proinflammatory cytokine production, reduced phagocytic function of alveolar macrophages, and consequently, increased pneumococcal loads within the lungs and translocation into blood. These findings were confirmed by using DEP-exposed induced sputum macrophages isolated from healthy volunteers, demonstrating that impaired innate immune mechanisms following DEP exposure are also at play in humans. CONCLUSION: Lung inhaled DEPs increase susceptibility to pneumococcal disease by leading to loss of immunological control of pneumococcal colonisation, increased inflammation, tissue damage, and systemic bacterial dissemination