CD40／CD40配体结合产生共刺激信号对干细胞及B细胞增殖分化的影响

目的：探讨CD40／CD40配体结合产生的共刺激信号对干细胞、B细胞增殖分化的影响及CD40配体抗白血病的作用。 资料来源：检索Pubmed和Springer数据库1995—01／2005-12与CD40／CD40配体、白血病干细胞及白血病相关文献，检索词为“CD40，CD40L，Leukemia，Leukemic stem cell”，限定文献语种为英语。 资料选择：对资料进行初审，选取实验包括实验组和对照组的文献，排除明显不随机实验和临床研究及重复性研究。 资料提炼：共收集到30篇关于CD40／CD40配体结合产生的共刺激信号对干细胞、B细胞增殖分化的影响及CD40配体抗白血病作用的实验文章，23篇符合纳入标准，排除的7篇均为同一研究。 资料综合：综合23个实验包括CD40／CD40配体对白细胞干细胞、B细胞增殖分化的影响，对白血病患者预后的影响及CD40配体对白血病患者的治疗作用，并对CD40／CD40配体对白细胞干细胞、B细胞及白血病患者的影响、作用进行分析。 结论：CD40／CD40L结合所产生的共刺激信号可促进白血病干细胞和B细胞的增殖分化，与白血病的发生、发展和预后有密切关系。CD40／CD40L在免疫应答中起关键作用，广泛应用于白血病的免疫治疗。     

The safety and effectiveness profile of daily teriparatide in a prospective observational study in Japanese patients with osteoporosis at high risk for fracture: interim report

This postmarketing surveillance study assessed the safety and effectiveness of daily teriparatide treatment in patients with osteoporosis in a Japanese clinical setting. In this prospective, multicenter, observational study, patients with osteoporosis at high risk for fracture received subcutaneous injections of teriparatide (20 μg/day) for a maximum of 24 months. For this interim report, data from 1,671 patients were eligible for analysis at the cutoff date. The mean age was 75.3 years; 93 % of patients (1,552/1,671 patients) were women. There were 117 adverse drug reactions (ADRs) reported in 101 of 1,671 patients (6.04 %); the most common reported ADRs were nausea, dizziness, headache, and palpitations. No clinically significant safety issues were identified, although 5 serious ADRs were reported in 4/1,671 (0.24 %) patients. At 12 months, 71.9 % of patients remained on teriparatide treatment. From 1 month, there were rapid increases in the biomarkers of bone formation P1NP and, to a lesser extent, BAP. In contrast, increases in the biomarkers of bone resorption, serum NTX, urinary NTX, and TRACP5b, were smaller. After 12 months of treatment, there was an increase in bone mineral density at the lumbar spine, femoral neck, and total hip, and a decrease in the Visual Analog Scale score for back pain. The incidence of new vertebral and nonvertebral fractures was 1.21 % and 3.18 %, respectively. In conclusion, the favorable safety profile and effectiveness of teriparatide observed in this population of Japanese patients with osteoporosis were accompanied by relatively high persistence with treatment, which is a key factor in the success of osteoporosis treatment.     

日间手术中心复合局部麻醉下腰骶部筋膜脂肪疝的治疗

目的：探讨分析日间手术中心（ambulatory surgery center,ASC）复合局部麻醉下腰骶部筋膜脂肪疝的手术治疗体会。方法回顾性分析2012年10月至2013年7月,佛山市第一人民医院ASC接收手术治疗腰骶部筋膜脂肪疝患者33例的临床资料。手术方式：疝囊口扩大＋内容物切除术。麻醉方式：复方利多卡因乳膏表面麻醉＋哌卡因局部浸润麻醉。结果本组患者均在复合局部麻醉下顺利完成手术治疗,术中、术后无手术相关并发症发生。术后随访6个月,手术疗效价：优良率为93．94％。结论 ACS复合局部麻醉下手术治疗腰骶部筋膜脂肪疝疗效确切、安全可靠,减少了患者在院时间,节省了医疗成本。     

小剂量倍他乐克治疗中年白大衣高血压疗效观察

中年白大衣高血压在现实社会中因紧张的竞争环境而颇多见,如把白大衣高血压作为“良性状态”不给予治疗,反复发作白大衣高血压也会累及靶器官。本文对50例中年白大衣高血压患者应用小剂量倍他乐克治疗,效果良好。1资料与方法1.1病例来源选自2001～2006年门诊和住院患者,白大衣高血压者96例,男性40例,女性56例,年龄41～59岁。病史11～35年不等。     

Preclinical Characterization of the Antiviral Activity of SCH 900518 (Narlaprevir), a Novel Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease

Small-molecule hepatitis C virus (HCV) NS3 protease inhibitors such as boceprevir (SCH 503034) have been shown to have antiviral activity when they are used as monotherapy and in combination with pegylated alpha interferon and ribavirin in clinical trials. Improvements in inhibitor potency and pharmacokinetic properties offer opportunities to increase drug exposure and to further increase the sustained virological response. Exploration of the structure-activity relationships of ketoamide inhibitors related to boceprevir has led to the discovery of SCH 900518, a novel ketoamide protease inhibitor which forms a reversible covalent bond with the active-site serine. It has an overall inhibition constant (K*_i) of 7 nM and a dissociation half-life of 1 to 2 h. SCH 900518 inhibited replicon RNA at a 90% effective concentration (EC₉₀) of 40 nM. In biochemical assays, SCH 900518 was active against proteases of genotypes 1 to 3. A 2-week treatment with 5× EC₉₀ of the inhibitor reduced the replicon RNA level by 3 log units. Selection of replicon cells with SCH 900518 resulted in the outgrowth of several resistant mutants (with the T54A/S and A156S/T/V mutations). Cross-resistance studies demonstrated that the majority of mutations for resistance to boceprevir and telaprevir caused similar fold losses of activity against all three inhibitors; however, SCH 900518 retained more activity against these mutants due to its higher intrinsic potency. Combination treatment with alpha interferon enhanced the inhibition of replicon RNA and suppressed the emergence of resistant replicon colonies, supporting the use of SCH 900518-pegylated alpha interferon combination therapy in the clinic. In summary, the results of the preclinical characterization of the antiviral activity of SCH 900518 support its evaluation in clinical studies.Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Despite recent advances, the eradication of chronic HCV infection remains challenging. Approximately 50% of patients infected with the most prevalent form of the virus (genotype 1) fail to respond to treatment with the current standard of care of pegylated alpha interferon in combination with ribavirin (4, 13). Thus, there is a great unmet medical need for the development of new agents with activity against HCV to improve the sustained virological response (SVR). The HCV genome is translated as a single polyprotein precursor which is processed by cellular and viral proteases into structural proteins (the C, E1, and E2 proteins), followed by nonstructural (NS) proteins (the p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B proteins). The NS3 protein is multifunctional, with the N-terminal region (amino acids 1 to 181) encoding a serine protease and the remaining polypeptide encoding a helicase. The NS3 protease noncovalently binds to the cofactor NS4A, which contributes to the formation and stability of the active site and helps to anchor the NS3/NS4A complex to the membrane. The NS3 protease is responsible for the processing of the HCV polyprotein at the NS3-NS4A, NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B junctions (for a review, see reference 19).The NS3 protease is essential for viral replication (6) and represents an important target for antiviral therapy. The clinical efficacies of NS3 protease inhibitors were first demonstrated with compounds targeting the enzyme active site in monotherapy and in combination with pegylated interferon: BILN 2061, a macrocyclic tripeptide in a short monotherapy trial (8), and boceprevir (SCH 503034) and telaprevir (VX-950), both of which are ketoamide derivatives (21, 22, 27, 28). Mutations conferring resistance to these small-molecule inhibitors have been identified in the NS3 protease domain by selection of replicon cells in the presence of compounds; many of the mutations selected in vitro have also been detected in patients during clinical trials of boceprevir and telaprevir (9, 11, 21, 25, 27, 28). Although encouraging clinical results have been achieved with these first-generation protease inhibitors, additional improvements in inhibitor potency and pharmacokinetic properties offers opportunities to increase drug coverage and to further increase the SVR.The combination of medicinal chemistry and structure-based design has led to the synthesis of a new compound, SCH 900518 (narlaprevir; Fig. ​Fig.1)1) (1), with improved antiviral activity in the replicon system compared with the activities of boceprevir (12) and telaprevir (16, 17). The characterization of its inhibition mechanism and in vitro resistance profile is presented in this report.Open in a separate windowFIG. 1.Structure of SCH 900518. P1 to P4 refer to different side chains.     

Adenovirus-expressed human hyperplasia suppressor gene induces apoptosis in cancer cells

Hyperplasia suppressor gene (HSG), also called human mitofusin 2, is a novel gene that markedly suppresses the cell proliferation of hyperproliferative vascular smooth muscle cells from spontaneously hypertensive rat arteries. This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. In this report, we showed that an adenovirus vector encoding human HSG (Ad5-hHSG) had an antitumor activity in a wide range of cancer cell lines. We further focused on the lung cancer cell line A549 and the colon cancer cell line HT-29 and then observed that Ad5-hHSG induced apoptosis both in vitro and in vivo. Confocal laser scanning microscopy and electron microscopy revealed that cells infected with Ad5-hHSG formed dose-dependent perinuclear clusters of fused mitochondria. Adenovirus-mediated hHSG overexpression induced apoptosis, cell cycle arrest, mitochondrial membrane potential (DeltaPsim) reduction and release of cytochrome c, caspase-3 activation, and cleavage of PARP in vitro. Overexpression of hHSG also significantly suppressed the growth of subcutaneous tumors in nude mice both ex vivo and in vivo. In addition, Ad5-hHSG increased the sensitivity of these cell lines to two chemotherapeutic agents, VP16 and CHX, and radiation. These results suggest that Ad5-hHSG may serve as an effective therapeutic drug against tumors.     

单耳堵塞对沙土鼠中脑下丘神经元谷氨酸受体密度的影响

目的考察单耳堵塞对沙土鼠中脑下丘(IC)背侧核(ICd)、外侧核(ICx)和中央核(ICc)部位谷氨酸(Glu)受体密度的影响。方法实验在30只沙土鼠上进行,雌雄不拘。分别在沙土鼠出生后3周龄(21dpn)、6周龄(42dpn)和成年(70dpn)实施单耳堵塞,4周后以体外受体标记放射自显影方法,考察比较IC左右侧各部位的银粒密度变化,并以此为相对指标,分析动物IC的神经元Glu受体密度的变化。结果成年组两侧IC神经元Glu受体密度没有显著性差异;3周龄和6周龄组呈现堵耳对侧的Glu受体密度明显少于堵耳同侧的不均衡分布(ICd部位:t=2.53,P=0.0186,t=1.77,P=0.0443;ICx部位:t=1.90,P=0.0359,t=2.03,P=0.0367;ICc部位:t=1.07,P=0.0332;t=2.35,P=0.0208)。并且3周龄组ICc部位的两侧Glu受体密度比值最小(0.61±0.03)。结论出生后6周前单耳堵塞对沙土鼠IC的神经元Glu受体发育具有明显影响,与Glu受体相关的下丘听觉功能发育将延续到出生后6周。