Trans fatty acids induce vascular inflammation and reduce vascular nitric oxide production in endothelial cells

Intake of trans fatty acids (TFA), which are consumed by eating foods made from partially hydrogenated vegetable oils, is associated with a higher risk of cardiovascular disease. This relation can be explained by many factors including TFA's negative effect on endothelial function and reduced nitric oxide (NO) bioavailability. In this study we investigated the effects of three different TFA (2 common isomers of C18 found in partially hydrogenated vegetable oil and a C18 isomer found from ruminant-derived-dairy products and meat) on endothelial NF-κB activation and nitric oxide (NO) production. Human endothelial cells were treated with increasing concentrations of Elaidic (trans-C18:1 (9 trans)), Linoelaidic (trans-C18:2 (9 trans, 12 trans)), and Transvaccenic (trans-C18:1 (11 trans)) for 3 h. Both Elaidic and Linoelaidic acids were associated with increasing NF-κB activation as measured by IL-6 levels and phosphorylation of IκBα, and impairment of endothelial insulin signaling and NO production, whereas Transvaccenic acid was not associated with these responses. We also measured superoxide production, which has been hypothesized to be necessary in fatty acid-dependent activation of NF-κB. Both Elaidic acid and Linoelaidic acid are associated with increased superoxide production, whereas Transvaccenic acid (which did not induce inflammatory responses) did not increase superoxide production. We observed differential activation of endothelial superoxide production, NF-κB activation, and reduction in NO production by different C18 isomers suggesting that the location and number of trans double bonds effect endothelial NF-κB activation.     

Prospective study on the association between harm avoidance and postpartum depressive state in a maternal cohort of Japanese women

Background

Recent studies have displayed increased interest in examining the relationship between personality traits and the onset, treatment response patterns, and relapse of depression. This study aimed to examine whether or not harm avoidance (HA) was a risk factor for postpartum depression measured by the Edinburgh Postnatal Depression Scale (EPDS) and the state dependency of HA.

Methods

Pregnant women (n=460; mean age 31.9±4.2 years) who participated in a prenatal program completed the EPDS as a measure of depressive state and the Temperament and Character Inventory (TCI) as a measure of HA during three periods: early pregnancy (T1), late pregnancy (around 36 weeks), and 1 month postpartum (T2). Changes in EPDS and HA scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group.

Results

There was no significant difference in the level of HA between the ND and PD groups at T1. In the ND group, EPDS and HA scores did not change significantly from T1 to T2. In the PD group, both scores increased significantly from T1 to T2 (EPDS, p<0.0001; HA, p<0.048). In the ND and PD groups, a significant positive correlation was observed in changes in EPDS and HA scores from T1 to T2 (r=0.31, p=0.002).

Conclusions

These results suggest that HA cannot be considered a risk factor for the development of postpartum depression measured by EPDS. Furthermore, HA may be state dependent.     

Rising Diabetes Prevalence among Urban-Dwelling Black South Africans

Objective

To examine the prevalence of and the association of psychosocial risk factors with diabetes in 25–74-year-old black Africans in Cape Town in 2008/09 and to compare the prevalence with a 1990 study.

Research Design and Methods

A randomly selected cross-sectional sample had oral glucose tolerance tests. The prevalence of diabetes (1998 WHO criteria), other cardiovascular risk factors and psychosocial measures, including sense of coherence (SOC), locus of control and adverse life events, were determined. The comparison of diabetes prevalence between this and a 1990 study used the 1985 WHO diabetes criteria.

Results

There were 1099 participants, 392 men and 707 women (response rate 86%). The age-standardised (SEGI) prevalence of diabetes was 13.1% (95% confidence interval (CI) 11.0–15.1), impaired glucose tolerance (IGT) 11.2% (9.2–13.1) and impaired fasting glycaemia 1.2% (0.6–1.9). Diabetes prevalence peaked in 65–74-year-olds (38.6%). Among diabetic participants, 57.9% were known and 38.6% treated. Using 1985 WHO criteria, age-standardised diabetes prevalence was higher by 53% in 2008/09 (12.2% (10.2–14.2)) compared to 1990 (8.0% (5.8–10.3)) and IGT by 67% (2008/09: 11.7% (9.8–13.7); 1990: 7.0% (4.9–9.1)). In women, older age (OR: 1.05, 95%CI: 1.03–1.08, p<0.001), diabetes family history (OR: 3.13, 95%CI: 1.92–5.12, p<0.001), higher BMI (OR: 1.44, 95%CI: 1.20–1.82, p = 0.001), better quality housing (OR: 2.08, 95%CI: 1.01–3.04, p = 0.047) and a lower SOC score (≤40) was positively associated with diabetes (OR: 2.57, 95%CI: 1.37–4.80, p = 0.003). Diabetes was not associated with the other psychosocial measures in women or with any psychosocial measure in men. Only older age (OR: 1.05, 95%CI: 1.02–1.08, p = 0.002) and higher BMI (OR: 1.10, 95%CI: 1.04–1.18, p = 0.003) were significantly associated with diabetes in men.

Conclusions

The current high prevalence of diabetes in urban-dwelling South Africans, and the likelihood of further rises given the high rates of IGT and obesity, is concerning. Multi-facetted diabetes prevention strategies are essential to address this burden.     

IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening

CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens.     

Predictive Clinical Factors in the Diagnosis of Gastrointestinal Kaposi's Sarcoma and Its Endoscopic Severity

Background

The diagnosis of gastrointestinal (GI) involvement in Kaposi''s sarcoma (KS) is important to make because the need for treatment depends on the extent of the disease. Moreover, severe GI lesions can cause serious complications. Endoscopy with biopsy is an extremely useful method to diagnose GI-KS. However, determining the indications for endoscopy is difficult because KS can occur without GI symptoms or cutaneous KS. This study sought to clarify predictive clinical factors for GI-KS and its severity on endoscopy.

Methodology/Principal Findings

A total of 1,027 HIV-infected patients who underwent endoscopy were analyzed. Sexual behavior, CD4 count, HIV RNA, history of highly active antiretroviral therapy (HAART), GI symptoms, and cutaneous KS were assessed. Endoscopic severity including bulky tumor, ulceration, and number of lesions were evaluated. Thirty-three patients had GI-KS and 46 patients cutaneous KS. Among the GI-KS patients, 78.8% (26/33) had no GI symptoms and 24.2% (8/33) had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4 <100 cells/µL, HIV RNA ≥10,000 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among these factors, cutaneous KS was closely related to GI-KS on multivariable analysis. Among patients without cutaneous KS, MSM and CD4 count <100 cells/µL were the only independent clinical factors related to GI-KS. Bulky tumor was significantly associated with CD4 <100 cells/µL and large number of lesions was significantly associated with HIV-RNA ≥10,000 copies/mL.

Conclusions

To diagnose GI-KS, clinical factors need to be considered before endoscopy. The presence of GI symptoms is not useful in predicting GI-KS. MSM and CD4 count <100 cells/µL are predictive factors among patients without cutaneous KS. Caution should be exercised especially in patients with low CD4 counts or high HIV viral loads as they are more likely to develop severe GI-KS lesions.     

Discovery of aminopiperidine-based Smac mimetics as IAP antagonists

A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.     

The influence of meteorology on the spread of influenza: survival analysis of an equine influenza (A/H3N8) outbreak

The influences of relative humidity and ambient temperature on the transmission of influenza A viruses have recently been established under controlled laboratory conditions. The interplay of meteorological factors during an actual influenza epidemic is less clear, and research into the contribution of wind to epidemic spread is scarce. By applying geostatistics and survival analysis to data from a large outbreak of equine influenza (A/H3N8), we quantified the association between hazard of infection and air temperature, relative humidity, rainfall, and wind velocity, whilst controlling for premises-level covariates. The pattern of disease spread in space and time was described using extraction mapping and instantaneous hazard curves. Meteorological conditions at each premises location were estimated by kriging daily meteorological data and analysed as time-lagged time-varying predictors using generalised Cox regression. Meteorological covariates time-lagged by three days were strongly associated with hazard of influenza infection, corresponding closely with the incubation period of equine influenza. Hazard of equine influenza infection was higher when relative humidity was <60% and lowest on days when daily maximum air temperature was 20-25°C. Wind speeds >30 km hour(-1) from the direction of nearby infected premises were associated with increased hazard of infection. Through combining detailed influenza outbreak and meteorological data, we provide empirical evidence for the underlying environmental mechanisms that influenced the local spread of an outbreak of influenza A. Our analysis supports, and extends, the findings of studies into influenza A transmission conducted under laboratory conditions. The relationships described are of direct importance for managing disease risk during influenza outbreaks in horses, and more generally, advance our understanding of the transmission of influenza A viruses under field conditions.     

Metabolic parameters and emotionality are little affected in g-protein coupled receptor 12 (gpr12) mutant mice

Background

G-protein coupled receptors (GPR) bear the potential to serve as yet unidentified drug targets for psychiatric and metabolic disorders. GPR12 is of major interest given its putative role in metabolic function and its unique brain distribution, which suggests a role in emotionality and affect. We tested Gpr12 deficient mice in a series of metabolic and behavioural tests and subjected them to a well-established high-fat diet feeding protocol.

Methodology/Principal Findings

Comparing the mutant mice with wild type littermates, no significant differences were seen in body weight, fatness or weight gain induced by a high-fat diet. The Gpr12 mutant mice displayed a modest but significant lowering of energy expenditure and a trend to lower food intake on a chow diet, but no other metabolic parameters, including respiratory rate, were altered. No emotionality-related behaviours (assessed by light-dark box, tail suspension, and open field tests) were affected by the Gpr12 gene mutation.

Conclusions/Significance

Studying metabolic and emotionality parameters in Gpr12 mutant mice did not reveal a major phenotypic impact of the gene mutation. Compared to previous results showing a metabolic phenotype in Gpr12 mice with a mixed 129 and C57Bl6 background, we suggest that a more pure C57Bl/6 background due to further backcrossing might have reduced the phenotypic penetrance.