Induction of apoptosis by crambene protects mice against acute pancreatitis via anti-inflammatory pathways

Apoptosis is a teleologically beneficial form of cell death in acute pancreatitis. Our previous work has demonstrated that induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis. However, little is known about how the induction of apoptosis reduces the severity of acute pancreatitis. Because the clearance of apoptotic cells might suppress inflammation and critically regulate immune responses, we postulate that clearance of apoptotic cells stimulates an anti-inflammatory response, which has a protective action against acute pancreatitis. To test this hypothesis, induction of apoptosis in acute pancreatitis in vivo and co-cultures of peritoneal resident macrophages with apoptotic acinar cells in vitro were used as experimental systems, testing expression of phagocytic receptors and levels of inflammatory mediators. Moreover, neutralizing anti-interleukin (IL)-10 monoclonal antibody (2.5 mg/kg) was used before the induction of apoptosis in acute pancreatitis, testing whether the protection from apoptosis induction would be removed. Our study showed that clearance of apoptotic acinar cells, which may occur essentially through the CD36-positive macrophage, stimulates the release of anti-inflammatory mediators like IL-10. IL-10 plays an important role in crambene-induced protection in acute pancreatitis. Thus, induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis via induction of anti-inflammatory pathways.     

A female-specific pentraxin, CrOctin, bridges pattern recognition receptors to bacterial phosphoethanolamine

Pathogen recognition and binding are crucial functions of innate immunity. It has been observed that the short pentraxin superfamily including C-reactive protein (CRP) and serum amyloid P component are pathogen pattern recognition receptors (PRR) in the plasma. We isolated and characterized a novel and distinctive pentraxin from the plasma of horseshoe crab, Carcinoscorpius rotundicauda, henceforth named CrOctin, which binds to bacteria via phosphoethanolamine (PE), a chemical component present on lipid A and core polysaccharide moieties of bacterial lipopolysaccharide (LPS). Infection enhances the formation of the PRR interactome constituting CrOctin, CRP and galactose-binding protein. In particular, infection increases the affinity of CRP to CrOctin by 1000-fold. Furthermore, we observed that by binding to PE, CrOctin acts as a linker that bridges the PRR interactome to the inner core of LPS. On the other hand, under normal physiological conditions, binding of CrOctin to PE appears to obscure other PRR from interacting directly with PE. Interestingly, the cluster of "CrOctin-interactive PRR" is sex specific. We report, for the first time, the change in PRR protein profiles with a distinctive gender difference during Pseudomonas infection.     

Differential effects of ceramide species on exocytosis in rat PC12 cells

Increases in several ceramide species have been shown by non-targeted lipid profiling (lipidomics) of the rat hippocampus after kainate lesions (Guan et al. FASEB J 20:1152–1161, 2006). This study was carried out to examine possible effects of ceramide species on exocytosis. Significant increase in membrane capacitance in voltage-clamped rat pheochromocytoma (PC12) cells, an indication of exocytosis, was detected immediately after external application of C2, C6, and C18 ceramide. In contrast, no increase in capacitance was found after addition of C16 and C20 ceramide, or DMSO vehicle. The effect of ceramide on exocytosis was dependent on the integrity of lipid rafts. Treatment of cells with the cholesterol binding agent/disruptor of lipid rafts, methyl β cyclodextrin, prior to addition of C18 ceramide suppressed the increase in capacitance induced by this lipid species. The ability of C2, C6 and C18 ceramide to trigger exocytosis was confirmed using total internal reflection fluorescence microscopy (TIRFM) experiments. External application of these species caused an exponential decrease in the number of subplasmalemmal neuropeptide Y (NPY)-enhanced green fluorescence protein (EGFP) labeled vesicles, indicating exocytosis. Interestingly, C18 is also the ceramide species that showed the greatest increase in the rat hippocampus after kainate excitotoxicity. It is postulated that C18 ceramide might facilitate exocytosis of glutamate from damaged neurons, thus propagating neuronal injury.     

Vitamin D Binding Protein and Vitamin D Levels in Multi-Ethnic Population

Introduction

Low levels of 25-hydroxyvitamin D (25(OH)D) has been associated with many negative health outcomes including falls and fractures. 25(OH)D is largely bound to vitamin D binding protein (VDBP). There is increasing evidence that free or bioavailable 25(OH)D may be a better measure of vitamin D deficiency.

Objective

To determine the prevalence of 25(OH)D deficiency and VDBP levels in multi-ethnic population, and its impact on muscle strength.

Design and methods

Cross-sectional study of older adults in Western region of Singapore. 295 participants from three ethnic groups were selected from the Healthy Older People Everyday (HOPE) cohort for measurements of total 25(OH)D and VDBP levels. Total 25(OH)D, VDBP, frailty status, Timed-Up-and-Go (TUG) and grip strength (GS) were assessed. Albumin, free and bioavailable 25(OH)D were only available for 256 participants.

Results

53% of Malay and 55% of Indians were deficient in 25(OH)D compared with 18.2% of ethnic Chinese participants. Chinese also had higher total 25(OH)D concentrations with a mean of 29.1 ug/l, (p = <0.001). Chinese had the lowest level of VDBP (169.6ug/ml) followed by Malay (188.8 ug/ml) and Indian having the highest (220.1 ug/ml). Calculated bioavailable and free 25(OH)D levels were significantly higher in Chinese, followed by Malays and Indians, which also correlated with better grip strength measures amongst the Chinese.

Conclusion

The Malays and Indians had overall lower free, bioavailable and total 25(OH)D compared with ethnic Chinese. Chinese ethnic group also had the lowest VDBP and better overall grip strength.

     

Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies

Introduction: Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection. Given the role of microglia in neuroinflammation, recent studies have attempted to unravel the mechanisms that aid to establish microglial cell-based therapy.

Areas covered: While total suppression of microglial activation may compromise its beneficial role in tissue repair in the aftermath of an insult, the benefits of modulating microglial activation and promoting microglia polarization to a neuroprotective phenotype have been highlighted recently.

Expert opinion: So far, the therapeutic strategy focussed on neutralizing microglia-mediated neuroinflammation using drugs that block the release of pro-inflammatory mediators has limitations, such as unwarranted side effects. Recent advances reveal several alternative molecular targets and potential epi-drugs that are capable of modulating microglial function and promoting neuroprotection. This review discusses the recent progress made in understanding the mechanisms of microglia-mediated neuroinflammation in various neuropathologies, and the emerging anti-inflammatory therapeutic strategies in this field.     

Evaluation of adenovirus 19a as a novel vector for mucosal vaccination against influenza A viruses

Since preexisting immunity and enhanced infection rates in a clinical trial of an HIV vaccine have raised some concerns on adenovirus (Ad) serotype 5-based vaccines, we evaluated the subgroup D adenovirus serotype Ad19a for its suitability as novel viral vector vaccine against mucosal infections. In BALB/c mice, we compared the immunogenicity and efficacy of E1/E3-deleted Ad19a vectors encoding the influenza A virus (IAV)-derived antigens hemagglutinin (HA) and nucleoprotein (NP) to the most commonly used Ad5 vectors. The adenoviral vectors were applied intranasally and induced detectable antigen-specific T cell responses in the lung and in the spleen as well as robust antibody responses. A prior DNA immunization significantly improved the immunogenicity of both vectors and resulted in full protection against a lethal infection with a heterologous H3N2 virus. Nevertheless, the Ad5-based vectors were slightly superior in reducing viral replication in the lung which corresponded to higher NP-specific T cell responses measured in the lungs.     

BCG vaccine: WHO position paper,February 2018 – Recommendations

This article presented the World Health Organization’s (WHO) recommendations on the use of on Bacille Calmette-Guérin (BCG) vaccine excerpted from the BCG vaccines: WHO position paper – February 2018 published in the Weekly Epidemiological Record [1]. This position paper replaces the 2004 WHO position paper on Bacille Calmette-Guérin (BCG) vaccine [2] and the 2007 WHO revised BCG vaccination guidelines for infants at risk for human immunodeficiency virus (HIV) infection [3]. It incorporates recent developments in the tuberculosis (TB) field, provides revised guidance on the immunization of children infected with HIV, and re-emphasizes the importance of the birth dose. This position paper also includes recommendations for the prevention of leprosy.Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO’s current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_background_docs/en/     

A simple signaling rule for variable life‐adjusted display derived from an equivalent risk‐adjusted CUSUM chart

The variable life‐adjusted display (VLAD) is the first risk‐adjusted graphical procedure proposed in the literature for monitoring the performance of a surgeon. It displays the cumulative sum of expected minus observed deaths. It has since become highly popular because the statistic plotted is easy to understand. But it is also easy to misinterpret a surgeon's performance by utilizing the VLAD, potentially leading to grave consequences. The problem of misinterpretation is essentially caused by the variance of the VLAD's statistic that increases with sample size. In order for the VLAD to be truly useful, a simple signaling rule is desperately needed. Various forms of signaling rules have been developed, but they are usually quite complicated. Without signaling rules, making inferences using the VLAD alone is difficult if not misleading. In this paper, we establish an equivalence between a VLAD with V‐mask and a risk‐adjusted cumulative sum (RA‐CUSUM) chart based on the difference between the estimated probability of death and surgical outcome. Average run length analysis based on simulation shows that this particular RA‐CUSUM chart has similar performance as compared to the established RA‐CUSUM chart based on the log‐likelihood ratio statistic obtained by testing the odds ratio of death. We provide a simple design procedure for determining the V‐mask parameters based on a resampling approach. Resampling from a real data set ensures that these parameters can be estimated appropriately. Finally, we illustrate the monitoring of a real surgeon's performance using VLAD with V‐mask.     

A univariate perspective of multivariate genome‐wide association analysis

Multiple correlated phenotypes are frequently collected in genome‐wide association studies (GWASs), and a systematic, simultaneous analysis of multiple phenotypes can integrate the signals from single phenotypes, therefore increasing the power of detecting genetic signals. However, fundamental questions remain open, including the conditions and reasons under which the multivariate analysis is beneficial, how a highly significant signal arises in the multivariate analysis. To understand these issues, we propose to decompose the multivariate model into a series of simple univariate models. This transformation offers a clearer quantitative analysis of the circumstances under which a multivariate approach can be beneficial for the bivariate phenotypes case. A real data analysis is employed to illustrate how to interpret how the signals arising from multivariate GWASs.