Effect of Inhalational Anesthetics on Cytotoxicity and Intracellular Calcium Differently in Rat Pheochromocytoma Cells （PC12）

Isoflurane, a commonly used inhaled anesthetic, induces apoptosis in rat pheochromocytoma cells （PC12） in a concentration- and time-dependent manner with unknown mechanism. We hypothesized that isoflurane induced apoptosis by causing abnormal calcium release from the endoplasmic reticulum （ER） via activation of inositol 1,4,5-trisphosphate （IP3） receptors. Alzheimer＇s presenilin-1 （PS 1） mutation increased activity of IP3 receptors and therefore rendered cells vulnerable to isoflurane-induced cytotoxicity. Sevoflurane and desflurane had less ability to disrupt intracellular calcium homeostasis and thus being less potent pared the cytotoxic effects of various inhaled to cause cytotoxicity. This study examined and com-anesthetics on PC12 cells transfected with the Alzheimer＇s mutated PS 1 （L286V） and the disruption of intracellular calcium homeostasis. PC 12 cells transfected with wild type （WT） and mutated PS 1 （L286V） were treated with equivalent of 1 MAC of isoflurane, sevoflurane and desflurane for 12 h. MTT reduction and LDH release assays were performed to evaluate cell viability. Changes of calcium concentration in cytosolic space （[Ca^2＋]c） were determined after exposing different types of cells to various inhalational anesthetics. The effects of IP3 receptor antagonist xestospongin C on isoflurane-induced cytotoxicity and calcium release from the ER in L286V PC12 cells were also determined. The results showed that isoflurane at 1 MAC for 12 h induced cytoxicity in L286V but not WT PC12 cells, which was also associated with greater and faster elevation of peak [Ca^2＋]c in L286V than in the WT cells. Xestospongin C significantly ameliorated isoflurane cytotoxicity in L286V cells, as well as inhibited the calcium release from the ER in L286V cells. Sevoflurane and desflurane at equivalent exposure to isoflurane did not induce similar cytotoxicity or elevation of peak [Ca^2＋]c in L286V PC 12 cells. These results suggested that isoflurane induced cytoxicity by partially     

前列安颗粒治疗慢性前列腺炎的药效学研究

目的验证前列安颗粒疗效，为临床用药提供依据。方法将大鼠随机分为6组，观察前列安颗粒（1．5g／kg、3．0g／kg、5．0g／kg）和前列舒乐颗粒（2．4g／kg）对大鼠前列腺内白细胞数及卵磷脂小体密度的影响；将小鼠随机分为5组，观察前列安颗粒（2、0g／kg、4．0g／kg、8．0g／kg）和醋酸泼尼松（8．0mg／kg）对小鼠耳肿胀的影响；将小鼠随机分为5组，观察前列安颗粒（2．0g／kg、4．0g／kg、8．0g／kg）和醋酸泼尼松（8．0mg／kg）对小鼠腹腔毛细血管通透性的影响；将大鼠随机分为5组，观察前列安颗粒（1．5g／kg、3．0g／kg、5、0g／kg）和醋酸泼尼松（6，0mg／kg）对大鼠足跖肿胀的影响。结果前列安颗粒可抑制角叉莱胶所致大鼠前列腺非细菌性炎症，增加前列腺组织内卵磷脂小体密度，并可明显抑制棉球肉芽肿形成；对二甲苯所致小鼠炎症均有明显抑制作用；可明显抑制0．6％醋酸所致小鼠腹腔毛细血管通透性的增加。结论前列安颗粒具有明显抑制前列腺炎的作用。     

五倍子对表皮葡萄球菌的抗菌作用及其形态学变化

目的观察五倍子乙醇提取物对表皮葡萄球菌的体外抗菌活性及其形态学变化。方法采用新的中药抑菌实验方法对五倍子乙醇提取物进行124株表皮葡萄球菌的最低抑菌浓度测定,同时用显微镜观察用药后菌细胞形态和结构改变。结果五倍子乙醇提取物对43株耐甲氧西林的表皮葡萄球菌(MRSE)和81株甲氧西林敏感的表皮葡萄球菌(MSSE)的MIC90分别为0.288、0.144mg/mL;在显微镜下,经五倍子处理的表皮葡萄球菌菌细胞逐渐膨胀、增大,可能是五倍子进入菌细胞后,其抗菌物质与菌细胞发挥杀菌作用所致。膨胀到一定大小时细胞内含物逐渐消失。结论五倍子乙醇提取物对表皮葡萄球菌具有较强的抗菌作用,可使菌细胞形态发生显著改变。     

Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder

The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [¹¹C]GR205171 was used healthy volunteers receiving 1–100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of > 30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients¹ suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 (N = 77), placebo (N = 74), or 20 mg/d paroxetine (N = 38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.     

Genetic variants in IL33 and IL1RL1 genes confer susceptibility to HBV-related liver cirrhosis in Chinese Han population

IntroductionPrevious studies indicate that the IL-33/ST2 pathway is involved in hepatitis B virus (HBV) -related liver diseases. This study aimed to determine the relationship between genetic variants in IL-33/ST2 pathway with susceptibility to liver cirrhosis.Materials and methodsA total of 2632 Han Chinese samples met the inclusion and exclusion criteria, including 840 negative controls (NeC), 691 chronic hepatitis B (CHB), 680 HBV-related liver cirrhosis (LC) and 421 HBV-related hepatocellular carcinoma (HCC) (without LC) patients. Four polymorphisms (IL33-rs4742170, rs1048274, rs10975519 and IL1RL1-rs1041973) were selected and genotyping was performed. All statistical analyses were performed by SPSS21.0, mainly using the Hardy-Weinberg equilibrium test, Pearson chi-square, unconditional Logistic regression and haplotype analysis.ResultsAfter adjusting for age, sex, smoking and drinking, significant associations were observed between IL33-rs4742170, rs1048274 and rs10975519 polymorphisms with LC risk. NeC with IL33-rs4742170 CC genotype was 1.80 times more likely to develop LC compared with TT genotype, while NeC with rs10975519(TC + CC) genotype was 1.32 times more likely to develop LC when compared with the TT genotype. CHB cases with rs4742170(CC + TC) genotype had 1.30 times higher susceptibility to develop LC compared with the TT genotype. The IL33-rs1048274G allele occurred more frequently in the LC group compared with the HCC group in codominant model (AG/AA: P = 0.001, OR = 1.66, 95%CI = 1.22–2.25; GG/AA: P = 0.018, OR = 1.54, 95%CI = 1.08–2.20). The IL33 haplotype CG conformed by rs10975519C and rs1048274G was more frequent in the LC group than in the NeC group and CHB group. Moreover, the IL33 haplotype CCG conformed by rs4742170C, rs10975519C and rs1048274G was found to be more frequent in the LC group than the HCC group. However, there was no association between IL1RL1-rs1041973 and LC risk.ConclusionOur findings demonstrate the association between genetic variants in IL33 with susceptibility to liver cirrhosis. IL33-rs4742170C, rs1048274G and rs10975519C could serve as biomarkers of LC.     

椎-基底动脉病变引起脑干形态及位置变化的3.0TMRI研究

目的 探讨椎-基底动脉病变与脑干形态及位置之间的系.资料与方法 2006年10月至2007年7月经临床及MRA或CTA检查发现有椎-基底动脉血管异常218例及正常对照组218名,常规行MRI及MRA检查.观察并记录脑实质MRI表现分型、颅内椎-基底动脉形态位置分级、血管与脑干的系、脑干有无旋转,对资料进行统计学分析.结果 病例组椎动脉越过中线及基底动脉移位数量均高于对照组,两者间差异有统计学意义(右椎动脉:χ2＝60.398,P＜0.05;左椎动脉:χ2＝54.461,P＜0.05;基底动脉:χ2＝205.007,P＜0.05).病例组脑干与血管接触高于对照组,两者间差异有统计学意义(χ2＝26.037,P＜0.05).对照组脑干未见旋转,病例组103例患者脑干发生旋转,椎动脉是否越过中线与脑干旋转之间有系(χ2＝19.467,P＜0.05)且系密切(C=0.89),椎动脉粗细与脑干旋转之间有系(χ2＝19.357,P＜0.05)且系密切(C=0.76).结论 应用先进的MRI技术对椎-基底动脉病变进行分析、研究,能够准确真实地显示血管移位、脑干变形旋转等形态学上的改变,为诊断和进行针对性治疗提供重要的依据.     

Systemic treatment of patients with gastrointestinal stromal tumor: Current status and future opportunities

Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings.     

Observation on effect of Shenmai injection in treating patients of congestive heart failurein treating patients of congestive heart failure

Objective: To observe the clinical therapeutic effect of Shenmai Injection (SMI) in treating patients of congestive heart failure.Methods: Effect of 16 cases treated with either SMI or potassium magnesium aspartate was observed by randomized crossover method and compared.Results: By using SMI for 2 weeks, the patients’ left ventricular ejective fraction (LVEF) was increased from 29.5 ± 9.0 to 36.6 ± 10.2 (P < 0.05), the heart function of 68.75% patients was improved, no side effect or toxicity was observed. Potassium magnesium aspartate improved the heart function in 37. 50% patients only but showed no effect on LVEF.Conclusion: SMI is an effective and safe drug in treating patients with congestive heart failure.     

Pathological findings in rats with experimental allergic encephalomyelitis

The aim of this study was to establish an animal model of experimental allergic encephalomyelitis (EAE) and examine the basic pathological changes, as well as expression and distribution of MMP‐2 and MMP‐9, in Wistar rats. Tissue sections were processed for HE staining, Weil myelin staining, and modified Bielschowsky staining. Expression and distribution of glial fibrillary acidic protein (GFAP), matrix metalloproteinase‐2 (MMP‐2) and matrix metalloproteinase‐9 (MMP‐9) were detected with immunohistochemistry. We divided the EAE into five types, depending on pathological characteristics and clinical manifestations: acute EAE, relapsing‐remitting EAE, progressive EAE, benign EAE, and asymptomatic EAE. Rats with acute EAE suffered from quick, severe attacks with widespread inflammatory cells and axonal loss. No demyelination or astrocytic hyperplasia was found around the lesions. Rats with relapsing‐remitting EAE broke down twice, with many perivascular cuffs and demyelinating plaques in lesions; hyperplastic and hypertrophic astrocytes characterized old lesions and axonal loss was evident. Rats suffering from progressive EAE exhibited continuous aggravation without improvement, accompanied by perivascular cuffs, demyelination, increased gliocytes and axonal damage. Rats with benign EAE recovered to a normal state with obviously decreased inflammatory cells and almost entirely unaffected myelin and axons. Rats with asymptomatic EAE also had various pathological changes that were not coincident with their clinical manifestations. Elevated expression of MMP‐2 and MMP‐9 was concordant in different types of EAE, but the extent differed in each type of EAE. MMP‐2 and MMP‐9 can be expressed in the form of vascular endothelial cells, meninges, or accumulated inflammatory cells. Multiple clinical courses of disease were demonstrated in Wistar rat EAE, with attributes similar to multiple sclerosis (MS) in clinical and pathological characteristics. Elevated expression of MMP‐2 and MMP‐9 may play a role in some aspects of pathological changes in EAE, for example, destroying the blood‐brain barrier, degrading the myelin sheath, and damaging axons.