Regulation of Inflammatory Responses in Shock-Related Syndromes by Synthetic Oligopeptides and Steroids

Inflammation is the body’s way of responding to disturbances in homeostasis. Depending on the triggering event and the site of inflammation, the inflammatory response has different physiological purposes and pathological consequences (Figure 1). Inducers of inflammation are either foreign molecules or molecules derived from the body itself (self-molecules). These molecules, of which a selection is listed in Table 1, often contain highly conserved molecular patterns that are recognized by specific receptors that are expressed by cells of the immune system, but also by other cell types. Receptor binding of these molecularly conserved patterns leads to the production and secretion of inflammatory mediators that alter tissue functionality such that the tissue adapts to the harmful insult and homeostasis can be restored

Identification of quiescent, stem-like cells in the distal female reproductive tract

In fertile women, the endometrium undergoes regular cycles of tissue build-up and regression. It is likely that uterine stem cells are involved in this remarkable turn over. The main goal of our current investigations was to identify slow-cycling (quiescent) endometrial stem cells by means of a pulse-chase approach to selectively earmark, prospectively isolate, and characterize label-retaining cells (LRCs). To this aim, transgenic mice expressing histone2B-GFP (H2B-GFP) in a Tet-inducible fashion were administered doxycycline (pulse) which was thereafter withdrawn from the drinking water (chase). Over time, dividing cells progressively loose GFP signal whereas infrequently dividing cells retain H2B-GFP expression. We evaluated H2B-GFP retaining cells at different chase time points and identified long-term (LT; >12 weeks) LRCs. The LT-LRCs are negative for estrogen receptor-α and express low levels of progesterone receptors. LRCs sorted by FACS are able to form spheroids capable of self-renewal and differentiation. Upon serum stimulation spheroid cells are in

A multicomponent prehabilitation pathway to reduce the incidence of delirium in elderly patients in need of major abdominal surgery

__Background:__ Due to the increase in elderly patients who undergo major abdominal surgery there is a subsequent increase in postoperative complications, prolonged hospital stays, health-care costs and mortality rates. Delirium is

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Background: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health

The β-human chorionic gonadotropin-related peptide LQGV exerts anti-inflammatory effects through activation of the adrenal gland and glucocorticoid receptor in C57BL/6 mice

The systemic inflammatory response syndrome is a complex host response to a variety of clinical insults, generally leading to severe pathology. The human chorionic gonadotropin β-chain-related tetrapeptide leucine-glutamine- glycine-valine (LQGV) reduces hemorrhagic and LPS-induced systemic inflammatory response syndrome, but its mechanisms of action are not yet fully understood. Through the combination of in vivo, in vitro, and ex vivo approaches, we demonstrate that LQGV actively stimulates corticosterone production in mice and thereby suppresses in vivo TLR4-directed inflammation upon LPS administration. Blocking in vivo glucocorticosteroid receptor signaling reduced the prosurvival effect of LQGV. Also, upon multiple TLR activation by heat-killed Listeria monocytogenes, splenocytes from LQGV-treated mice produced significantly less TNF-α and IL-6, which was absent after in vitro blockage of the glucocorticosteroid receptor. Using adrenal gland and adrenal cell line cultures, we show that LQGV stimulates corticosterone production. Moreover, by using specific pharmacological inhibitors of the adrenocorticotropic hormone (ACTH) and luteinizing hormone receptors as well as of cAMP signaling, we demonstrate that LQGV stimulates the ACTH receptor. These data show that the b-human chorionic gonadotropin-related tetrapeptide LQGV stimulates adren

The impact of early- and late-onset preeclampsia on umbilical cord blood cell populations

Pregnancies complicated by preeclampsia (PE) are characterised by an enhanced maternal and fetal inflammatory response with increased numbers of leukocytes in maternal peripheral blood. The impact of PE on newborn umbilical cord blood cell (UCBC) populations however, has been scarcely studied. We hypothesise that PE deranges fetal haematopoiesis and subsequently UCBC populations. Therefore, the objective of this study was to investigate newborn umbilical cord blood cell populations in early- (EOPE) and late-onset PE (LOPE). A secondary cohort analysis in The Rotterdam Periconceptional Cohort was conducted comprising 23 PE cases, including 11 EOPE and 12 LOPE, and 195 controls, including 153 uncomplicated and 23 fetal growth restriction- and 19 preterm birth complicated controls. UCBC counts and differentials were quantified by flow cytometry and analysed as main outcome measures. Multivariable regression analysis revealed associations of EOPE with decreased leucocyte- (monocytes, neutrophils, eosinophils, immature granulocytes) and thrombocyte counts and increased NRBC counts (all p < 0.05). EOPE remained associated with neutrophil- (β-0.92, 95%CI -1.27,-0.57, p < 0.001) and NRBC counts (β1.11, 95%CI 0.27,1.95, p = 0.010) after adjustment for gestational age and birth weight. LOPE did not reveal any significant association. We conclude that derangements of fetal haematopoiesis, in particular of neutrophil- and NRBC counts, are associated with EOPE only, with a potential impact for future health of the offspring. This heterogeneity in UCBC should be considered as confounder in epigenetic association studies examining EOPE