Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.     

Hemodialysis in the United Kingdom

Hemodialysis was a neglected aspect of nephrology in the UK. At the request of the Renal Association, the first UK Haemodialysis Masterclass was organized in 2007. The articles in this supplement arose from that meeting. Here, an overview of UK hemodialysis services and nephrology training is presented as background. Government‐funded dialysis should be provided to all UK citizens who require it. In 2005, there were 17,645 patients receiving hemodialysis, 5057 on peritoneal dialysis and 19,074 with kidney transplants, looked after by 359 nephrologists working in 73 National Health Service renal units. Renal replacement therapy incidence and prevalence remain comparatively low, at 108 and 694 per million population, respectively. Whether this represents inadequate provision or genuinely lower need remains unclear. The Renal Association sets clinical practice guidelines for dialysis, and audits performance via the UK Renal Registry. Postgraduate medical education is undergoing radical change in the UK. This is driven by the reduction in trainee doctors' working hours to 48 hr/week (mandated by the European Working Time Directive), and the governments' wish to reduce the duration of training, but also by a desire to formalize training, Our challenge is to continue to produce talented clinical nephrologists educated in breadth and depth, despite the reduced emphasis on clinical experience and omission of period of scientific research. The future for hemodialysis services in the UK is, however, promising with an expansion in the number of specialists and dialysis centers, and a growing interest in dialysis practice and research.     

Alternatives to standard hemodialysis

Survival of patients on hemodialysis remains poor, but the benefits of increasing urea clearance have probably been maximized within our current treatment schedules. Long dialysis sessions (8 hr) produce impressive outcomes, with mortality 53% to 55% lower than conventional schedules. Even increasing from 4 to 5 hr may improve survival. Increased frequency of dialysis (6 times weekly) produces impressive reductions in left ventricular mass and could conceivably be implemented in‐center. Preliminary data suggest a 61% reduction in mortality with increased frequency. Nightly dialysis combines longer sessions with increased frequency and has produced remarkable clinical gains in blood pressure, left ventricular mass, serum phosphate, and sleep apnea. However, the data are mainly from case series and impact on mortality remains unknown. Expansion of home hemodialysis would be necessary for this modality to grow. Convective therapies remove middle molecules more effectively, and observational data suggest hemodiafiltration has the potential to improve mortality by 35% to 36%. Hemodiafiltration has the advantage of being relatively easy to implement. The uremic milieu is complex and further investigation of the underlying pathophysiology is needed to inform future dialysis interventions. The survival data above are from observational studies, and hence benefits are likely to be exaggerated. Randomized trials of dialysis interventions are desperately needed. They remain difficult to perform, because of the complexity of both the patient population and the interventions, and because of limited available funding.     

Behavioral depression during cocaine withdrawal is associated with decreased spontaneous activity of ventral tegmental area dopamine neurons.

Withdrawal from an escalating-dose, bingelike regimen of cocaine administration in rats produced significantly depressed levels of locomotor activity during the nocturnal portion of the day-night cycle. This effect was observed during the first 48 hrs of testing. Extracellular single-unit recordings of ventral tegmental area (VTA) dopamine (DA) neurons revealed no differences between saline- and cocaine-treated rats with respect to basal firing rates. However, significantly fewer spontaneously active VTA DA neurons were encountered in rats withdrawn from binge cocaine. As with the nocturnal hypoactivity, this effect was observed only during the first 48 hrs of withdrawal. These findings suggest that short-term DA neuron dysfunction during cocaine withdrawal temporally corresponds to behavioral disruptions that are similar to those described in human addicts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

针对肌肉功能障碍患者的数据库研究与开发

建立标准数据库是临床研究病情变化的重要手段,建立适用于肌肉功能障碍患者的标准数据库模板更具有重要临床意义。本研究针对临床上所采集的具有肌肉功能障碍患者的肌力、肌电数据,通过ODBC连接方式,引入了统一建模语言(UML),使用VC++开发工具,设计和完成了Access数据库,以对获取到的大量的肌力、肌电数据进行管理和使用。数据库有效存储并管理肌力、肌电数据,同时能减少数据占有空间和数据冗余,它更好地满足了医院康复科的需求。     

Choline Acetyltransferase Induces the Functional Regeneration of the Salivary Gland in Aging SAMP1/Kl -/- Mice

Salivary gland dysfunction induces salivary flow reduction and a dry mouth, and commonly involves oral dysfunction, tooth structure deterioration, and infection through reduced salivation. This study aimed to investigate the impact of aging on the salivary gland by a metabolomics approach in an extensive aging mouse model, SAMP1/Klotho -/- mice. We found that the salivary secretion of SAMP1/Klotho -/- mice was dramatically decreased compared with that of SAMP1/Klotho WT (+/+) mice. Metabolomics profiling analysis showed that the level of acetylcholine was significantly decreased in SAMP1/Klotho -/- mice, although the corresponding levels of acetylcholine precursors, acetyl-CoA and choline, increased. Interestingly, the mRNA and protein expression of choline acetyltransferase (ChAT), which is responsible for catalyzing acetylcholine synthesis, was significantly decreased in SAMP1/Klotho -/- mice. The overexpression of ChAT induced the expression of salivary gland functional markers (α–amylase, ZO-1, and Aqua5) in primary cultured salivary gland cells from SAMP1/Klotho +/+ and -/- mice. In an in vivo study, adeno-associated virus (AAV)-ChAT transduction significantly increased saliva secretion compared with the control in SAMP1/Klotho -/- mice. These results suggest that the dysfunction in acetylcholine biosynthesis induced by ChAT reduction may cause impaired salivary gland function     

P2Y11 Agonism Prevents Hypoxia/Reoxygenation- and Angiotensin II-Induced Vascular Dysfunction and Intimal Hyperplasia Development

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H₂O₂ release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions.     

Cell-Free DNA Fragments as Biomarkers of Islet β-Cell Death in Obesity and Type 2 Diabetes

Type 2 diabetes (T2D) typically occurs in the setting of obesity and insulin resistance, where hyperglycemia is associated with decreased pancreatic β-cell mass and function. Loss of β-cell mass has variably been attributed to β-cell dedifferentiation and/or death. In recent years, it has been proposed that circulating epigenetically modified DNA fragments arising from β cells might be able to report on the potential occurrence of β-cell death in diabetes. Here, we review published literature of DNA-based β-cell death biomarkers that have been evaluated in human cohorts of islet transplantation, type 1 diabetes, and obesity and type 2 diabetes. In addition, we provide new data on the applicability of one of these biomarkers (cell free unmethylated INS DNA) in adult cohorts across a spectrum from obesity to T2D, in which no significant differences were observed, and compare these findings to those previously published in youth cohorts where differences were observed. Our analysis of the literature and our own data suggest that β-cell death may occur in subsets of individuals with obesity and T2D, however a more sensitive method or refined study designs are needed to provide better alignment of sampling with disease progression events.     

Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.     

肾缺血再灌注细胞内钙水平与氧化应激损伤研究

目的 观察肾细胞中游离钙([Ca~(2+)]i)及氧自由基在缺血再灌注损伤过程中的改变情况,探讨二者在再灌注肾损伤中发生作用机制。方法 摘除Wistar大鼠左肾,钳夹右侧肾蒂,建立急性缺血再灌注肾损伤模型,应用Fura-2/AM荧光指示剂测定缺血再灌注大鼠肾细胞内[Ca~(2+)]i浓度的变化,同时测定谷胱甘肽过氧化物酶(GSH-Px)活性、超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量。结果 缺血再灌注不同时期肾细胞内[Ca~(2+)]i浓度均有不同程度增高,与对照组相比差异有显著意义,各实验组SOD活力水平降低,与对照组相比差异有显著意义,MDA生成高于对照组,GSH-Px在再灌注早期活力减弱,明显低于对照组,晚期活力基本恢复。结论 1.缺血再灌注不同时期大鼠肾细胞内[Ca~(2+)]i超载和不同程度的氧化侵袭,在缺血再灌注肾损伤病理过程中起重要作用;2.再灌注时间与肾细胞内[Ca~(2+)]i超载呈正相关,提示再灌注损伤通过不同机制加重细胞钙超载。