Carvedilol: Therapeutic Application and Practice Guidelines

Current knowledge of the mechanisms contributing to progression of heart failure suggests that therapies that limit or interfere with the consequences of neurohormonal activation and improve myocardial energetics appear to be most beneficial. Carvedilol, a nonselective β-adrenergic blocker with peripheral vasodilating properties, reduces mortality, slows progression of disease, and improves quality of life in patients with heart failure when added to standard therapy. When administered according to recommended guidelines, carvedilol is well tolerated. Clinical guidelines on the use of carvedilol in heart failure are provided.     

Interleukin-4 induces a substance in bone marrow stromal cells that reversibly inhibits factor-dependent and factor-independent cell proliferation

Bone marrow-derived stromal cell monolayers pretreated with recombinant interleukin-4 (IL-4) inhibit the growth of hematopoietic cells. This was demonstrated by inhibition of fresh bone marrow-derived, IL-3- induced soft agar colonies as well as by inhibition of proliferation of IL-3-dependent cell lines and of a Friend virus-transformed erythroleukemic cell line. Pretreatment of stromal cells with IL-4 for five to seven days induced the inhibitory activity. IL-4 could then be removed before "plating" the bone marrow cells in soft agar, indicating that the inhibitory activity did not depend on the action of IL-4 on the precursors of the soft agar colonies. The inhibitory activity appears to be mediated by a soluble factor since inhibition was achieved even if the stromal cell layer was separated from the colony forming cells by an "empty" agar layer. However, supernatants of IL-4- induced stromal cell layers had no detectable inhibitory activity. The inhibitory action of the IL-4-pretreated stromal cell lines was not the result of killing of the precursor cells since it could be reversed if the agar layer containing the colony-forming cells was removed from the stromal cell layer and cultured with IL-3. Hydrocortisone (HC) blocked the inhibitory effect if added either in the IL-4 preincubation phase or during the colony formation stage, implying that HC blocked both induction of the inhibitory activity and its release or its effector function. A homogenous long-term stromal cell line could not be induced to exert the inhibitory activity; partial inhibition could be achieved with pure macrophages stimulated with IL-4 and CSF-1, suggesting that the inhibitory activity induced by IL-4 in mixed stromal cell layers may depend on a complex mechanism involving more than one cell type. Northern analysis of RNA from IL-4-induced and uninduced stromal cells indicated that IL-4 did not upregulate expression of CSF-1 or transforming growth factor-beta (TGF-beta) and only modestly increased expression of tumor necrosis factor, suggesting that these cytokines were not responsible for the inhibitory activity. The capacity of IL-4 to induce inhibitory activity in stromal cell layers suggests that IL-4 may play a role in the regulation of hematopoiesis.     

健康人心室复极的昼夜变化研究

目的 探讨健康人心室复极的昼夜变化规律. 方法 对34例健康体检者的24h动态心电图进行回顾性分析.测定其心率、Q-T间期、QRS波群起点至T波波峰的时间(Q-Tp间期).计算T波波峰至终点的时间(Tp-e时间)、心率校正的Q-T间期(Q-Tc间期)和Tp-e时间(Tp-ec时间)、Tp-e/Q-T值,并比较一天中8个等分时间段的上述参数. 结果 Q-T间期和Tp-e时间呈日间短、凌晨及午夜长的昼夜节律变化,各时间段差异有统计学意义(P<0.01或0.05);Q-T间期与心率呈高度负相关(r=-01796，P<0.01)．而Tp-e时间与心率呈低度负相关(r=-01267，P<0.01)；各时间段Q-Tc间期接近,而Tp-ec时间呈07:00～09:00最高、10:00～12:00次之、01:00～03:00最低的昼夜节律变化,各时间段差异有统计学意义(P<0.05),Tp-e／Q-T值昼夜变化节律与Tp-ec时间相近.结论 反映心室复极跨壁离散度的Tp-e时间除受心率影响外,尚受昼夜节律的影响.     

细胞因子在慢性肝衰竭合并全身炎症反应综合征病例中的意义

目的探讨TNF-α、IFN-γ、LPS、IL-10、IL-12、IL-18在慢性肝衰竭合并全身炎症反应综合征(SIRS)中的意义。方法运用双抗体夹心酶联免疫吸附法检测正常人、一般肝炎患者、慢性肝衰竭组的TNF-α、IFN-γ、LPS、IL-10、IL-12、IL-18。结果自正常对照组到一般肝炎组、慢性肝衰竭非SIRS组、慢性肝衰竭SIRS组,血清中TNF-α、LPS、IL-12及IL-18水平依次升高,IL-10分子水平依次减低,且各组间比较均具有显著性差异。结论TNF-α、LPS、IL-10、IL-12、IL-18水平可以反应出乙型肝炎患者的肝脏损伤程度和疾病严重程度,可能在慢性肝衰竭合并SIRS的发病过程中起到相当重要的作用。     

湖南省临床艾滋病检测筛查实验室基本情况调查

目的了解各级临床实验室开展HIV血清学筛查试验的情况。方法采用问卷调查方式对141家临床艾滋病检测筛查实验室进行调查,利用Excel表建立数据库并进行分析。结果141家实验室2006年度共检测样本303045份,筛查阳性样本2404份,确认阳性样本276份,筛查阳性检出率和确认符合率分别为0.09%和11.48%。送检样本最多的科室是外、内、急诊和妇儿科。多数实验室采用国产酶联免疫吸附试剂。多数实验室缺少生物安全防护设备。结论进一步加强对实验室的管理,提高检测质量。     

EBNA1 and LMP1 variants in multiple sclerosis cases and controls

Simon KC, Yang X, Munger KL, Ascherio A. EBNA1 and LMP1 variants in multiple sclerosis cases and controls.
Acta Neurol Scand: 2011: 124: 53–58.
© 2010 John Wiley & Sons A/S. Background – Prior infection with Epstein–Barr virus (EBV) is an established risk factor for multiple sclerosis (MS). Some findings from observational studies, including possible epidemics and differences in prevalence, may be explained if different strains of EBV conferred different MS risk. Methods – DNA was extracted from peripheral lymphocytes obtained from 66 MS cases and 66 age‐ and cohort‐matched controls. Nested polymerase chain reaction (PCR) was performed to amplify the N‐ and C‐terminus regions of EBNA1 and the hyper‐variable region of the LMP1 gene. For EBNA1, we compared the presence of the prototype B95.8 vs variant sequence and the presence of multiple strains in MS cases and controls. For LMP1, we considered differences in the proportions of mutations between cases and controls. Results – Comparing the proportion of mutant sequence between MS cases and controls in the EBNA1 N‐terminal (0/28 vs 1/27) and C‐terminal regions (3/40 vs 8/36) revealed no significant differences (P > 0.05). No individual variants in LMP1 were associated with risk of MS (all P > 0.05). Neither EBNA1 nor LMP1 variation was associated with anti‐EBNA1 IgG antibody titers. Conclusions – These findings do not support a strong role for variation in EBNA1 N‐terminus, EBNA1 C‐terminus or LMP1 contributing to MS risk.     

Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3

Cervical carcinomas are initiated through a series of well-defined stages that rely on the expression of human papillomavirus (HPV) oncogenes. A panel of 100 small hairpin RNAs that target essential kinases in many tumor types was used to study the stepwise appearance of kinase requirements during cervical tumor development. Twenty-six kinases were commonly required in three cell lines derived from frank carcinomas, and each kinase requirement was traced to the specific stage in which the requirement emerged. Six kinases became required following HPV-induced immortalization, and the requirement for two kinases, SGK2 and PAK3, was mapped to the inactivation of p53 in primary human epithelial cells. Loss of the p53 tumor suppressor in other primary epithelial cells also induced dependence on SGK2 and PAK3. Hence, SGK2 and PAK3 provide important cellular functions following p53 inactivation, fulfilling the classical definition of synthetic lethality; loss of p53, SGK2, or PAK3 alone has little effect on cell viability, whereas loss of p53 together with either SGK2 or PAK3 loss leads to cell death. Whereas tumor suppressor gene mutations are not directly druggable, other proteins or pathways that become obligatory to cell viability following tumor suppressor loss provide theoretical targets for tumor suppressor-specific drug discovery efforts. The kinases SGK2 and PAK3 may thus represent such targets for p53-specific drug development.