Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala

Recent advances suggest that acetaldehyde mediates some of the neurobiological properties of ethanol. In a recent study, we have shown that ethanol elicits the phosphorylation of extracellular signal‐regulated kinase (pERK) in the nucleus accumbens and extended amygdala, via a dopamine D₁ receptor‐mediated mechanism. The aim of this study was to determine whether acetaldehyde and ethanol‐derived acetaldehyde elicit the activation of ERK in the nucleus accumbens and extended amygdala. The effects of acetaldehyde (10 and 20 mg/kg) and ethanol (1 g/kg), administered to rats intragastrically, were assessed by pERK peroxidase immunohistochemistry. To establish the role of ethanol‐derived acetaldehyde, the alcohol dehydrogenase inhibitor, 4‐methylpyrazole (90 mg/kg), and the acetaldehyde‐sequestering agent, D ‐penicillamine (50 mg/kg), were administered before ethanol. Acetaldehyde increased pERK immunoreactivity in the nucleus accumbens and extended amygdala. Inhibition of ethanol metabolism and sequestration of newly synthesized acetaldehyde completely prevented ERK activation by ethanol. In addition, to establish the role of D₁ receptors stimulation in acetaldehyde‐elicited ERK phosphorylation, we studied the effect of the D₁ receptor antagonist, SCH 39166. Pretreatment with the D₁ receptor antagonist (50 μg/kg) fully prevented acetaldehyde‐elicited ERK activation. Overall, these results indicate that ethanol activates ERK by means of its metabolic conversion into acetaldehyde and strengthen the view that acetaldehyde is a centrally acting compound with a pharmacological profile similar to ethanol. Synapse 64:916–927, 2010. © 2010 Wiley‐Liss, Inc.     

Clinical predictors of stress-induced transient left ventricular dilatation in patients with nonsignificant coronary disease

Left ventricular transient dilatation (TD) during stress myocardial perfusion imaging has been associated with extensive and severe coronary artery disease (CAD). The authors investigated the clinical predictors of TD in patients with nonsignificant CAD. The authors retrospectively studied 134 consecutive patients with exercise (n=59) or dipyridamole (n=75) stress-induced TD who had undergone coronary angiography within 6 months of the test. Significant CAD was defined as diameter stenosis ≥70% in at least one major coronary artery, and significant left main disease as >50% diameter stenosis. Angiographically-significant CAD was found in 126 patients (94%), and nonsignificant CAD in the remaining 8 patients (6%). No differences in gender, history of smoking, hyperlipidemia, family history of CAD, body mass index, and left ventricular ejection fraction were found between patients with significant and nonsignificant CAD. All 8 nonsignificant CAD patients had a history of either hypertension (7/8) or electrocardiographic criteria for left ventricular hypertrophy (1/8), compared with 58% of the hypertensive patients in the significant CAD group (P=.02). Nonsignificant CAD patients were also characterized by lack of diabetes mellitus (P=.05) or prior myocardial infarction (P=.05). Hypertension seems to be an important clinical predictor of TD in patients with nonsignificant CAD.     

Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study

Aliment Pharmacol Ther 2011; 34: 649–655

Summary

Background Aspirin has detrimental effects on the gastrointestinal tract mucosa and may play a role in the aetiology of inflammatory bowel disease. Aim To investigate if the regular use of aspirin is associated with the development of Crohn’s disease (CD) and ulcerative colitis (UC) using, for the first time, a prospective cohort study design. Methods A total of 135 780 men and women in Europe, aged 30–74 years, were recruited into the European Prospective Investigation into Cancer and Nutrition study. Participants completed questionnaires at baseline detailing their regular aspirin use and were then followed up to identify those who developed either incident CD or UC. Each case was matched with four controls and odds ratios (OR) were calculated, adjusting for cigarette smoking. Potential interactions between aspirin and smoking were assessed. Results A total of 35 participants developed CD and a further 84 were diagnosed with UC. Regular aspirin intake was positively associated with the risk of developing CD (OR = 6.14, 95% CI = 1.76–21.35). In those who took aspirin and smoked there was no detectable increased risk of CD (OR = 0.30, 95% CI = 0.03–3.08). No association was found between regular aspirin use and UC (OR = 1.29, 95% CI = 0.67–2.46). Conclusions A strong positive association between regular aspirin use and CD, but not UC, was observed. The data suggest that regular aspirin use should be measured in epidemiological work on CD. If such findings are consistent in other work then aspirin may affect the development of CD in a middle‐aged to elderly population.     

Influence of maternal redox status on birth weight

The aim of this study was to determine the influence that maternal redox status, between 30 and 36 weeks of healthy human pregnancy, has on birth weight. Ferric reducing potential (FRP), extracellular superoxide dismutase (ecSOD) activity and erythrocyte reduced glutathione (eGSH) concentration were measured as antioxidant indicators, and serum malondialdehyde (MDA) concentration as a lipoperoxidation indicator. Consumption of dietary micronutrients with antioxidant capacity was recorded. We observed a direct correlation between birth weight and ecSOD activity and eGSH concentration. An interaction between eGSH with FRP and serum ecSOD activity also correlated directly with birth weight. Other correlating factors included maternal thiamine consumption and interactions between vitamins C and E and carotenoids and vitamin E intake. These findings support the notion that antioxidant status has a positive influence on birth weight.     

Expression and genetic analysis of miRNAs involved in CD4+ cell activation in patients with multiple sclerosis

MicroRNA (miRNA)-mediate RNA interference has been identified as a novel mechanism that regulates protein expression. It is recognised that miRNAs play essential roles in the immune system and for correct function in the brain. Moreover, it is now clear that abnormal miRNA expression is a common feature of several diseases involving the immune system including multiple sclerosis (MS). Expression analysis for miR-21, miR-146a and -b, miR-150, miR-155 was carried out in peripheral mononuclear cells (PBMC) from a cohort of 29 MS patients and 19 controls. Subsequently, a case control study for miR-146 rs2910164 variant was performed in an overall population of 346 MS cases and 339 controls. A statistically significant increased expression of miR-21, miR-146a and -b was observed in relapsing remitting (RR)MS patients as compared with controls (1.44 ± 0.13 vs 0.79 ± 0.06, P = 0.036; 1.50 ± 0.12 vs 0.84 ± 0.08, P = 0.039; 1.54 ± 0.15 vs 0.72 ± 0.08, P = 0.001 respectively). On the contrary, no differences were found in the expression levels of both miR-150 and miR-155 in patients as compared with controls (P > 0.05). The genetic association study failed to find any differences in the frequencies of rs2910164 between patients and controls. miRNA dysregulation may contribute to the pathogenesis of MS and highlights the possibility to define different disease entities with specific miRNAs profile.     

Trypanosoma cruzi infection in pregnant mice induces a cellular immune response with citokines production in their fetuses

The objective of this study was to detect the cytokines IFN-gamma, IL-4 and IL-10 expressed by CD4+ T cells in tissues of fetal mice with acute chagasic infection. For this, we examined the fetuses of NMRI mice whose mothers were infected with 22x10(3) metacyclic trypomastigotes of the M/HOM/BRA/53/Y strain of T. cruzi and made pregnant during the acute phase of infection. For the detection and localization of inflammatory infiltrates, nest parasites, antigens of T. cruzi a nd cytokines w eused hematoxylin-eosin techniques, peroxidase-anti-peroxidase and immunofluorescence. The immunohistochemical study revealed the presence of inflammatory infiltrates and antigens with amastigote nests in fetal skeletal muscle. CD4 + T cells producing IFN-gamma, as well as deposits of IFN-gamma and IL-10, were detected in sections of placenta, heart and skeletal muscle of fetuses of mice infected, while CD4+/IL-10+ was found only in skeletal muscle; in addition, deposits of IL-4 were detected only in placentas of healthy mice. These results indicate that fetuses are capable of generating their own immune response to antigens transmitted by their mother, which induces the secretion of cytokines and that, acting in synergy with the maternal antibodies, confer them a state of protection against infection; and that the transmission of the parasite depends on factors specific to each mother, which may modify its ability to control such transmission at the placental or systemic levels.     

Intra-aortic balloon pump induced pulsatile perfusion reduces endothelial activation and inflammatory response following cardiopulmonary bypass

Objective: Intra-aortic balloon pump (IABP)-induced pulsatile perfusion has demonstrated that it can preserve organ function during cardiopulmonary bypass (CPB). We evaluated the role of IABP pulsatile perfusion on endothelial response. Methods: Forty consecutive isolated CABG undergoing preoperative IABP were randomized to receive IABP pulsatile CPB during aortic cross-clamping (group A, 20 patients) or standard linear CPB (group B, 20 patients) during cross-clamp time. Hemodynamic results were analyzed by Swan-Ganz catheter [mean arterial pressure (MAP), cardiac index (CI), indexed systemic vascular resistances (ISVR), indexed pulmonary vascular resistances (IPVR), wedge pressure (PCWP)]. Inflammatory/endothelial response was analyzed by pro-inflammatory (IL-2, IL-6, IL-8), anti-inflammatory cytokines (IL-10), and endothelial markers [vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1)]. All measurements were recorded preoperatively (T0), before aortic declamping (T1), at the end of surgery (T2), 12 h (T3) and 24 h (T4) postoperatively. ANOVA for repeated measures was used to evaluate the differences of means. Results: Hemodynamic response was comparable except for higher MAP (p = 0.01 at T1) and lower ISVR (p = 0.001 at T1, p = 0.003 at T2) in group A. No differences were found in perioperative leakage of IL-2, IL-6, and IL-8 between the two groups (within-group p = 0.0001 either in group A and group B; between-groups p = NS at 2-ANOVA). Group A showed significantly lower VEGF (between-groups p = 0.001 at 2-ANOVA, p = 0.001 at T1, T2) and MCP-1 (between-groups p = 0.001 at 2-ANOVA, p = 0.001 at T1, T2) with higher IL-10 secretion (between-groups p = 0.001 at 2-ANOVA, p = 0.01 at T1, T2, T3). Conclusions: IABP-induced pulsatile perfusion allows lower endothelial activation during CPB and higher anti-inflammatory cytokines secretion.