Expression and function of the purinergic receptor P2X7 in patients with pulmonary tuberculosis

P2X(7) is a channel receptor gated by adenosine triphosphate (ATP) that is involved in the killing of intracellular mycobacteria. To explore further the role of P2X(7) in immunity against Mycobacterium tuberculosis, we studied its expression and function in 19 patients with pulmonary tuberculosis (TB) and 19 healthy contacts. Flow cytometry analysis showed a similar and variable expression of P2X(7) in TB patients and healthy subjects. In contrast, P2X(7) mARN levels were significantly higher in TB patients. When the function of the P2X(7) receptor in peripheral blood mononuclear cells (PBMC) was assessed by the effect of exogenous ATP on apoptosis, the uptake of the fluorescent marker Lucifer yellow or extracellular signal regulated kinase (ERK) phosphorylation, no significant differences were detected in patients and controls. However, mRNA macroarray analysis showed that upon stimulation with ATP, the PBMC from TB patients showed a significant induction of a higher number of cytokine genes (27 of 96), and a lower number of apoptosis genes (20 of 96) compared to healthy controls (17 and 76 genes, respectively). These results suggest that although the PBMC from TB patients do not show apparent abnormalities in the expression of P2X(7), and the intracellular signals generated through it, the pattern of gene expression induced by ATP in these cells is different from that found in healthy contacts. This phenomenon suggests a defective function of P2X(7) in the immune cells from TB patients, a condition that may contribute to the inability of these patients to eliminate the mycobacteria.     

Unraveling the biological mechanisms in Alzheimer's disease--lessons from genomics

Alzheimer's disease (AD) is the most common form of dementia and the most common neurodegenerative disease, with a complex genetic background. Genome-wide association studies (GWAS) have yielded important new insights into genetic mechanisms of AD pathology. Current results unequivocally confirm apolipoprotein E (APOE) as a major genetic risk factor for development of late onset AD. Additional associations of more than twenty genes have also been identified and replicated in subsequent genetic studies. Despite the exciting new GWAS data which have emerged in the last few years, it has become clear that common variants within the genome cannot fully explain the underlying genetic risk for AD. Novel approaches such as genome-wide analysis of copy number variations (CNV) or low-frequency rare functional gene variants may provide additional insight into genetic basis of AD. In this review we summarize the findings of eighteen GWAS studies in AD performed to date, with an emphasis on potential future developments in the quest for genetic risk factors of AD.     

Blocking glutamate‐mediated signalling inhibits human melanoma growth and migration

Glutamate is an excitatory neurotransmitter that has been shown to regulate the proliferation, migration and survival of neuronal progenitors in the central nervous system through its action on metabotropic and ionotropic glutamate receptors (GluRs). Antagonists of ionotropic GluRs have been shown to cause a rapid and reversible change in melanocyte dendritic morphology, which is associated with the disorganization of actin and tubulin microfilaments in the cytoskeleton. Intracellular expression of microtubule‐associated protein (MAP) 2a affects the assembly, stabilization and bundling of microtubules in melanoma cells; stimulates the development of dendrites; and suppresses melanoma cell migration and invasion. In this study, we investigated the relationship between glutamate‐mediated signalling and microtubules, cell dendritic morphology and melanoma cell motility. We found that metabotropic GluR1 and N‐methyl‐d ‐aspartate receptor antagonists increased dendritic branching and inhibited the motility, migration and proliferation of melanoma cells. We also demonstrated that the invasion and motility of melanoma cells are significantly inhibited by the combination of increased expression of MAP2a and either metabotropic GluR1 or N‐methyl‐d ‐aspartate receptor antagonists. Moreover, the blockade of glutamate receptors inhibited melanoma growth in vivo. Collectively, these results demonstrate the importance of glutamate signalling in human melanoma and suggest that the blockade of glutamate receptors is a promising novel therapy for treating melanoma.     

Mast cell activation and arterial hypotension during proximal aortic repair requiring hypothermic circulatory arrest

Objective

Aortic surgeries requiring hypothermic circulatory arrest evoke systemic inflammatory responses that often manifest as vasoplegia and hypotension. Because mast cells can rapidly release vasoactive and proinflammatory effectors, we investigated their role in intraoperative hypotension.

孕酮预处理对大鼠局灶性脑缺血再灌注损伤的保护作用及机制

目的 探讨孕酮预处理对局灶性脑缺血再灌注损伤(focal cerebral ischemic and reperfusion injury,fCIRI)的作用及机制.方法 在建立大鼠fCIRI模型前96、48、1h分别给予孕酮(8mg/kg)1次性腹腔注射.建立大鼠fCIRI模型,在fCIRI后第3～8天,检查大鼠的空间记忆功能和缺血侧海马CA1区存活神经元数量.检测孕酮预处理后1～96 h的海马细胞外信号调节激酶1/2(ERK1/2)磷酸化水平和活化ERK1/2核转移.结果 造模前48、1h经孕酮预处理的大鼠海马CA1区神经元存活数量(mm-1)较造模后明显增多(164.3±11.0、218.5±9.1与142.7±12.1,F=29.45,P＜0.01);造模前48、1h经孕酮预处理的大鼠能明显缩短脑缺血导致的水迷宫逃避潜伏期(s)延长(32.4±14.3、10.3±11.1与19.2±9.6;F=35.84,P＜0.01).海马CA1区ERK1/2磷酸化水平在孕酮给药后的12 ～48 h明显增强,96 h恢复基线.核内ERK1/2磷酸化水平在孕酮给药后2h增加,并持续到48 h.孕酮增加胞质ERK1/2及胞核内ERK1/2磷酸化的水平能被RU486阻断.结论 孕酮预处理对缺血引起的海马CA1区神经元死亡有保护作用,并能改善空间记忆功能;孕酮预处理的神经保护作用有48 h以上的有效时间窗;在孕酮的神经保护作用依赖于孕酮受体介导的ERK1/2信号通路.     

Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase

Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.     

肾周脂肪梅奥粘连概率评分系统在肾癌后腹腔镜肾部分切除术中的应用

目的探讨肾周脂肪梅奥粘连概率评分系统（MAP）在肾癌后腹腔镜肾部分切除术中的临床应用价值。 方法回顾性分析2015年1月至2020年6月徐州医科大学附属淮安医院泌尿外科收治的行后腹腔镜肾部分切除术的153例肾癌患者的临床病例资料。依据MAP评分系统将其分为低度复杂组、中度复杂组和高度复杂组三组。比较各组间的手术时间、术中出血量、术中及术后并发症、术中热缺血时间、术后住院时间及术后血肌酐变化情况。 结果在153例患者中，低度复杂组68例，中度复杂组58例和高度复杂组27例。三组患者在年龄、性别、术前血肌酐水平、肿瘤最大径、肿瘤位置、BMI、RENAL评分等方面差异无统计学意义（P>0.05）。随着复杂程度的提高，手术时间、术中出血量也在不断增加（P<0.05）；而术中热缺血时间、术后住院时间及术后血肌酐水平无明显变化（P>0.05）。在术中并发症方面，随着复杂程度的提高，术中并发症的发生率也在增加（P<0.05），且高度复杂组的术后并发症发生风险是低度复杂组的13.895倍（P=0.002)，MAP评分系统预测术中并发症发生的精度较高（AUC=0.757，P=0.002）。但是术后并发症各组比较差异无统计学意义（P>0.05）。 结论MAP评分系统在肾癌后腹腔镜肾部分切除术中，对预估手术难度及术中并发症发生风险有较好的临床应用价值。     

Validation of the Mayo Adhesive Probability score as a predictor of adherent perinephric fat and outcomes in open partial nephrectomy

BackgroundAdherent perinephric fat (APF) contributes to surgical complexity and can be associated with adverse perioperative outcomes for partial nephrectomy (PN). The Mayo Adhesive Probability (MAP) score accurately predicts the presence of APF during robotic-assisted partial nephrectomy (RAPN). Our primary aim is to validate MAP score as a predictor of APF in open partial nephrectomy (OPNx).MethodsWe reviewed 105 consecutive OPNx (100 patients) performed by a single surgeon with intraoperative determination of APF. We evaluated the ability of the MAP score to discriminate between those with APF and those without APF by estimating the area under the receiver operating characteristic curve (AUROCC). The association of perioperative outcomes with APF was evaluated as well.ResultsForty-three patients [49%; 95% confidence interval (CI), 39–59%] had intraoperative identification of APF. The MAP score had excellent ability to predict APF in OPNx (AUROCC, 0.82; 95% CI, 0.74–0.92). APF was observed in 6% of patients with a MAP score of 0-1, 27% with score 2, 52% with score 3, 75% with score 4, and 90% with score 5. The presence of APF was associated with longer operative times (P=0.004) and higher estimated blood loss (EBL) (P=0.003). Although not statistically significant, our study did suggest that APF may be associated with postoperative complications and prolonged length of stay (LOS) (>3 days).ConclusionsMAP score accurately predicts the presence of APF in patients undergoing OPNx. APF is associated with longer operative time and higher blood loss in OPNx.