Bcl-2蛋白家族和p53基因在细胞凋亡中的调控效应

目的:细胞凋亡是个体发育过程中由一系列基因控制的细胞主动死亡过程。在多数细胞类型中,原癌基因Bcl-2蛋白家族与p53是重要的细胞凋亡调节因子,在细胞凋亡中相互联系,相互作用,从而调控细胞凋亡。文章探讨Bcl-2蛋白家族和p53基因对细胞凋亡的调控机制。资料来源:引用计算机检索1995/2006PubMed、Springer link的相关文章,检索词“apoptosis,Bcl-2protein family,p53”,并限定文章语言种类为English。同时计算机检索1995/2006中国期刊全文数据库或万方数据库的相关文章,检索词为“凋亡,Bcl-2,Bax”,限定文章语言种类为中文。并手工检索《细胞凋亡基础与临床》。资料选择:对资料进行初审,被选文献符合以下标准:①Bcl-2蛋白家族与凋亡的关系。②p53基因与凋亡的关系。③细胞凋亡基因调控的研究。④Bcl-2蛋白家族、p53基因调节细胞凋亡的机制研究。排除重复研究。资料提炼:共收集到70篇相关文献,中文文献均为全文,大部分外文文献为全文,其他为摘要。入选关于Bcl-2蛋白家族、p53基因与凋亡的关系及机制,细胞凋亡基因调控的相关文献32篇。资料综合:①Bcl-2蛋白家族是细胞凋亡相关基因研究得最多的一类蛋白质。包含抑制和促进细胞凋亡两类功能相反的蛋白质。Bcl-2蛋白家族及其家族成员共同构成一个异常复杂的相互作用网络,调控细胞凋亡。其调节细胞凋亡的机制可能于Bcl-2蛋白家族与线粒体、Bcl-2蛋白的相互作用、细胞内Ca2 ;及氧自由基有关。②p53基因对防止细胞增生和保持DNA受损基因组的完整性有重要作用。p53调控细胞凋亡包括对外源性凋亡途径的调节和内源性凋亡途径的调控,p53基因究竟通过什么样的途径调控细胞凋亡?不同的实验因为不同的遗传学背景和微环境而不同。③目前主要有3种实验方法来研究p53基因对细胞凋亡的调控作用:第1种方法是通过识别p53激活的基因组的DNA断片,或者是启动所包含的依赖p53激活的因子。第2种方法是系统地识别受p53基因分别调控的基因组(或DNA组)。第3种方法是识别受p53调控的基本凋亡因子。结论:大量的凋亡因子是依赖p53激活调节细胞凋亡的,细胞凋亡中Bcl-2蛋白家族、p53基因的调控机制的分析,充分发挥细胞凋亡对机体有利的方面,对治疗各种癌症和心血管疾病具有广阔的应用前景。     

MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell–mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4–producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4–deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4⁺ T cells from wild-type mice, but not from IL-4–deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell–derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4–producing CD4⁺ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.     

Prevalence and Associated Factors of Metabolic Syndrome Among South Korean Adults

This study analyzed the prevalence of metabolic syndrome (MetS) and evaluated the factors associated with MetS. Subjects numbered 2,213 adults who participated in the health screening survey. Results show that the prevalence of MetS, Risk-MetS, and Non-MetS was 28.2%, 44.9%, and 26.9% respectively. Factors influencing variables were age, gender, history of hypertension and diabetes mellitus, abdominal obesity, high-density lipoprotein cholesterol, triglyceride, blood pressure, fasting blood glucose, alcohol consumption, and level of physical activity. Community health nurses should plan to develop MetS management programs that target Mets or Risk-MetS groups to promote health.     

Detection of two distinct malignant B cell clones in a single patient using anti-idiotype monoclonal antibodies and immunoglobulin gene rearrangement

Immunoglobulin gene rearrangement analysis and somatic cell hybridization techniques were used to examine the malignant cell population in an unusual patient with hairy cell leukemia and macroglobulinemia (N Engl J Med 296:92, 1977). Although previous investigations suggested that the IgM macroglobulin was secreted by the circulating leukemia cells, anti-idiotype monoclonal antibodies raised to the IgM macroglobulin failed to react with the malignant cells in the circulation and bone marrow. In contrast, approximately 50% of the mononuclear cells from an enlarged inguinal lymph node reacted strongly with the anti-idiotype antibodies. Subsequent reanalysis of all cell populations demonstrated that whereas the circulating and bone marrow cells were IgM kappa-bearing, the macroglobulin was IgM gamma-bearing and the lymph node cells were evenly divided among IgM kappa-bearing and IgM gamma-bearing. Immunofluorescence flow cytometry indicated that those lymph node cells that reacted strictly with the anti-idiotype antibody were IgM gamma-bearing, demonstrating that they were the source of macroglobulin. An analysis of immunoglobulin gene DNA confirmed the coexistence of two distinct malignant B cell populations in the lymph node and indicated that the IgM kappa-bearing lymph node cells were identical to the circulating and bone marrow leukemic cells.     

Research productivity following nursing research initiative grants

Background

In 1995, VA's Office of Research and Development launched the Nursing Research Initiative (NRI), to encourage nurses to apply for research funding and to increase the role of nurse investigators in the VA's research mission. This program provides novice nurse researchers the opportunity to further develop their research skills with the guidance of a mentor.

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial

BACKGROUND: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. METHODS: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). FINDINGS: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). INTERPRETATION: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. FUNDING: Myriad Pharmaceuticals.     

Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.     

Frequency and predictors of tachycardia-induced cardiomyopathy in patients with persistent atrial flutter

BACKGROUND

There are few data on the frequency and predictors of tachycardia-induced cardiomyopathy (TICM) in patients with persistent atrial flutter.

OBJECTIVES

To examine the incidence of TICM in patients undergoing ablation for persistent atrial flutter, and to examine predictors for the development of TICM.

METHODS AND RESULTS

One hundred eleven patients met the inclusion criteria for the present study. Twenty-eight of 111 (25%) patients had cardiomyopathy before ablation. Sixteen of 28 (57%) patients showed significant improvement in their left ventricular (LV) function postablation. LV function improved to normal in 12 of 16 (75%) patients. Nineteen of 28 (68%) cardiomyopathy patients had preablation LV function in the range in which they would be considered for an implantable cardioverter defibrillator for primary prevention of sudden cardiac death. In nine of 19 (47%) patients, the ejection fraction improved such that an implantable cardioverter defibrillator was no longer indicated. In multivariate analysis, average ventricular rate during atrial flutter was the only independent predictor of reversibility of cardiomyopathy (P=0.013).

CONCLUSIONS

Sixteen of 28 (57%) cardiomyopathy patients with persistent atrial flutter had significantly improved LV function postablation. In 75% of these patients, LV function improved to normal.     

Fall prevention through patient partnerships

Falls in community-dwelling older adults are often preventable, yet remain the leading cause of deaths due to injury and a major cost to the healthcare system. Primary care nurse practitioners who care for older adults can minimize the risk for falls by using specific assessment and prevention strategies.