MMI-0100对DDC诱导的胆汁淤积性肝损伤的治疗作用研究

目的 探讨MMI-0100对3，5-二乙氧基羰基-1，4-二氢-2，4，6-三甲基吡啶（DDC）诱导的小鼠胆汁淤积性肝损伤的治疗作用。方法 15只Balb/c小鼠随机分为对照组、模型组（DDC），治疗组（DDC+MMI-0100），每组5只。对照组小鼠给予正常饮食2 周，其余2组小鼠给予0.1% DDC饮食喂养1周后，再给予正常饮食1周，同时治疗组小鼠在DDC饲养1周后，每天经腹腔注射MMI-0100进行治疗，注射量剂量为500 μg·kg^-1，连续注射1 周；对照组和模型组小鼠给予等量无菌生理盐水。观察并记录各组小鼠肝脏大体情况，HE和Masson染色观察肝脏的病理改变，免疫组化检测胆管增生指标CK19和Ki67，实时定量PCR检测肝脏纤维化相关基因α-SMA的表达。结果 与模型组相比，治疗组小鼠肝脏纤维化病变减轻（P<0.01），炎症细胞浸润减少（P<0.01），肝脏组织Knodell Score评分降低（P<0.01），同时胆管增生相关指标CK19和Ki67表达降低（P<0.05），肝脏α-SMA的mRNA表达水平降低（P<0.01）。结论 MMI-0100对DDC诱导的小鼠原发性硬化性胆管炎有良好的治疗作用。     

丙酮酸乙酯对利福平致小鼠肝损伤的保护作用

目的 探讨丙酮酸乙酯（EP）对利福平致小鼠肝损伤的保护作用及其可能机制。方法 24只C57BL/6小鼠随机分成3组：正常对照组、模型组（利福平,200 mg·kg^-1·d^-1） 和EP组（利福平200 mg·kg^-1·d^-1+丙酮酸乙酯40 mg·kg^-1·d^-1）,每组8只。造模后第7天处死小鼠,检测小鼠血清谷丙转氨酶（ALT）、总胆红素（TBIL）、直接胆红素（DBIL）、碱性磷酸酶（ALP）,观察小鼠肝脏病理学变化,检测小鼠肝组织总胆汁酸（TBA）、丙二醛（MDA）的含量、超氧化物歧化酶（SOD）活性、高迁移率族蛋白B1 （HMGB1） 及乙酰化的HMGB1（AC-HMGB1）蛋白的表达情况。结果 与正常对照组相比,模型组小鼠血清TBIL、DBIL、ALP、ALT水平升高（P<0.05）;肝细胞空泡变性、脂肪变性明显,部分肝细胞可见嗜酸性变、核溶解或固缩;肝组织TBA、MDA的含量提高（P<0.05）,SOD减少（P<0.05）,HMGB1及AC-HMGB1表达增多（P<0.05）,HMGB1胞浆表达为主。与模型组相比,EP组小鼠血清TBIL、DBIL、ALP、ALT水平降低（P<0.05）;肝组织病理学变化改善;肝组织TBA、MDA的含量降低（P<0.05）, SOD增多（P<0.05）,HMGB1及AC-HMGB1的表达水平降低（P<0.05）,HMGB1以胞核表达为主。结论 丙酮酸乙酯能够减轻利福平所致的小鼠肝损伤,其机制可能与丙酮酸乙酯抗氧化,下调肝组织HMGB1及AC-HMGB1的表达和调节HMGB1的分布有关。     

基于“肠道菌群–胆汁酸代谢”探讨茵栀黄颗粒对胆汁淤积症小鼠的改善作用及其机制

目的 探讨茵栀黄颗粒治疗小鼠胆汁淤积症的作用及其机制。方法 将8周龄C57BL/6小鼠给予含1%胆酸的饲料2周，构建小鼠胆汁淤积症模型，将小鼠分为对照组、模型组、熊去氧胆酸（0.1 g/kg）组以及茵栀黄颗粒（5、10、20 g/kg）组，各组分别ig相应药物，对照组和模型组大鼠ig同体积生理盐水，连续给药4周。分别给予收集小鼠血清，全自动生化仪测定肝功能相关指标，超高效液相色谱串联质谱（UPLC-MS/MS）测定胆汁酸成分；收集小鼠肝组织，苏木精–伊红（HE）染色观察肝脏组织病理变化；RT-qPCR检测肝组织炎症因子和胆汁酸代谢关键基因的mRNA表达水平；Western blotting检测肝组织胆汁酸代谢关键蛋白的表达情况；收集小鼠盲肠内容物，Illumina Miseq测序平台对V₃～V₄可变区进行扩增和测序，对小鼠肠道菌群结构进行分析。结果 与模型组相比，茵栀黄颗粒各组小鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）水平均显著降低（P＜0.05、0.01、0.001）；且能够显著改善小鼠肝组织损伤。与模型组相比，茵栀黄颗粒各剂量组小鼠肝脏白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、单核细胞趋化蛋白-1（MCP-1）mRNA表达水平均显著降低，白细胞介素-1β（IL-1β）、胆固醇7-羟化酶（CYP7A1）、胆盐输出泵（Bsep）、牛磺胆酸钠共转运蛋白（Ntcp）、胆汁酸转运蛋白多药耐药相关蛋白2（Mrp2）、UDP葡糖醛酸基转移酶1家族多肽A1（Ugt1a1）mRNA表达水平均显著升高（P＜0.05、0.01、0.001），并影响胆汁酸代谢关键蛋白的mRNA和蛋白表达。16S rDNA测序显示，茵栀黄颗粒组小鼠肠道菌群中乳杆菌属相对丰度显著升高，罗斯氏菌属和Allobaculum属相对丰度显著降低。胆汁酸代谢组学发现，茵栀黄颗粒能够降低多种次级胆汁酸的含量。结论 茵栀黄颗粒改善胆汁淤积的作用机制可能与调控肠道菌群组成影响胆汁酸代谢有关。     

四逆散改善Mdr2-/-小鼠胆汁淤积性肝纤维化作用

目的 研究四逆散对Mdr2(Abcb4)基因缺陷(Mdr2^-/-)小鼠胆汁淤积性肝纤维化的缓解作用,并探究其作用机制。方法 C57BL/6J小鼠作为对照组;C57BL/6J背景的Mdr2^-/-小鼠作为模型小鼠,设模型组和四逆散低、高剂量(按生药量计为3.12、6.24 g·kg^-1)组。四逆散组连续3周ig给予四逆散水提物,每天1次,对照组给予纯水。试剂盒法检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆汁酸水平;取肝脏、脾脏称质量,计算肝脏、脾脏系数;结合小鼠肝组织HE染色,Masson染色,纤连蛋白(Fibronectin)、细胞角蛋白19(CK19)的免疫组化染色,明确四逆散对Mdr2^-/-小鼠肝纤维化及胆汁淤积的影响。基于小鼠肝脏转录组学测序技术,挖掘四逆散改善Mdr2^-/-小鼠肝损伤的作用靶点,并通过实时荧光定量PCR(qRT-PCR)法检测肝纤维化[fibronectin(Fn1)、胶原蛋白1(Col1a1)、角蛋白19(krt19)]、炎症[白细胞介素-1β(Il1β)、Il6、肿瘤坏死因子-α(Tnfα)、一氧化氮合成酶(Inos)]、细胞焦亡[凋亡相关斑点样蛋白(Pycard)、Il18]、胆汁酸合成[细胞色素P450家族成员7A1(Cyp7a1)]及转运[胆盐输出泵(Abcb11)、ATP结合盒转运蛋白(Abcc3)、钠离子-牛磺胆酸共转运蛋白(Slc10a1)]相关基因的转录水平。结果 与模型组比较,四逆散高剂量显著降低血清总胆汁酸的水平(P＜0.05);明显缓解了Mdr2^-/-小鼠肝脏中央静脉及胆管周围炎性细胞的浸润和胶原纤维的沉积,并显著抑制胆管反应的发生。转录组学及qRT-PCR结果共同表明,四逆散下调Mdr2^-/-小鼠肝脏纤维化、炎症、细胞焦亡相关基因的转录(P＜0.05);同时,四逆散下调胆汁酸合成关键限速酶调控基因Cyp7a1和调控胆汁酸向肝内转运的基因Slc10a1的转录,并上调调控胆汁酸外排的基因Abcb11、Abcc3的转录。结论 四逆散能缓解Mdr2^-/-小鼠胆汁淤积性肝纤维化,机制可能与其调控炎症反应、细胞焦亡以及胆汁酸的合成和转运有关。     

复方斑蝥胶囊联合TAC方案治疗三阴性乳腺癌的临床研究

目的 探讨复方斑蝥胶囊联合TAC方案治疗三阴性乳腺癌的疗效。方法 选取2020年4月—2023年3月在东台市中医院就诊的100例三阴性乳腺癌患者，根据随机数字表法将100例患者分为对照组（50例）和治疗组（50例）。对照组给予TAC方案治疗，第1天静脉注射多西他赛注射液75 mg/m²、静脉滴注注射用环磷酰胺600 mg/m²、静脉注射注射用盐酸表柔比星80 mg/m²。治疗组在对照组基础上口服复方斑蝥胶囊，3粒/次，2次/d。以21 d为1个化疗周期，两组在持续治疗6个周期后分析疗效。比较两组的临床疗效、生活质量、淋巴细胞相关指标、肿瘤标志物、血清指标和不良反应的情况。结果 治疗后，治疗组的总有效率（94.00%）高于对照组（80.00%），组间比较差异显著（P＜0.05）。治疗后，两组的乳腺癌生活质量量表（QLSBC）评分低于治疗前（P＜0.05），且治疗组QLSBC评分低于对照组（P＜0.05）。治疗后，治疗组的CD8⁺比治疗前小，LMR、CD4⁺、CD4⁺/CD8⁺比治疗前大（P＜0.05）；治疗组的CD8⁺比对照组小，LMR、CD4⁺、CD4⁺/CD8⁺比对照组大（P＜0.05）。治疗后，两组的血清糖蛋白抗原（CA153）、癌胚抗原（CEA）水平均比治疗前低（P＜0.05）；治疗组血清CA153、CEA水平比对照组低（P＜0.05）。治疗后，两组的血清脂联素（ADP）水平高于治疗前，血清白细胞介素-8（IL-8）水平低于治疗前（P＜0.05）；治疗组的血清ADP水平高于对照组，血清IL-8水平低于对照组（P＜0.05）。治疗期间，治疗组的不良反应发生率比对照组低，组间比较差异显著（P＜0.05）。结论 复方斑蝥胶囊联合TAC方案有助于提高三阴性乳腺癌的疗效，有助于改善患者的免疫功能和生活质量，降低肿瘤标志物的水平和药物不良反应的发生。     

改良多柔比星脂质体TAC方案治疗HER2阴性乳腺癌的临床研究

目的 探究改良多柔比星脂质体TAC方案治疗HER2阴性乳腺癌的临床效果。方法 选取2019年1月—2020年1月新乡市中心医院收治的98例HER2阴性乳腺癌患者进行前瞻性研究。随机分为对照组和治疗组,每组各49例。对照组患者采用TAC方案治疗,第1天静脉滴注注射用盐酸多柔比星,50 mg/m²;多西他赛注射液,75 mg/m²;注射用环磷酰胺,500 mg/m²。治疗组患者采用改良多柔比星脂质体TAC方案,第1天静脉滴注盐酸多柔比星脂质体注射液,30 mg/m²;多西他赛注射液,75 mg/m²;注射用环磷酰胺,500 mg/m²。21 d为1个周期,两组均治疗6个周期。观察两组患者临床疗效,比较治疗前后两组患者肿瘤标志物糖类抗原19-9（CA19-9）、癌胚抗原（CEA）和糖类抗原15-3（CA15-3）水平,左室射血分数（LVEF）水平,心肌酶谱心肌肌钙蛋白I（cTnI）、肌酸激酶（CK）和肌酸激酶同工酶（CK-MB）水平,血清胸苷激酶1（TK1）、组织多肽特异性抗原（TPS）和微小核糖核酸-132（miR-132）水平,生活质量核心量表（QLQ-C30）评分及不良反应情况。结果 治疗后,治疗组疾病控制率（85.71%）较对照组（67.35%）明显升高（P＜0.05）。治疗后,两组患者血清CA19-9、CEA、CA15-3水平均较治疗前显著降低（P＜0.05）,且治疗组较对照组降低更明显（P＜0.05）。治疗后,两组LVEF水平较治疗前降低,而cTnI、CK、CK-MB较治疗前显著升高（P＜0.05）,但治疗组LVEF较对照组更高,cTnI、CK、CK-MB较对照组更低（P＜0.05）。治疗后,两组血清TK1、TPS水平均较治疗前明显下降,而miR-132明显升高（P＜0.05）;且治疗组血清TK1、TPS和miR-132水平明显好于对照组高（P＜0.05）。治疗后,两组患者QLQ-C30评分均较治疗前降低（P＜0.05）,且治疗组较对照组更低（P＜0.05）。治疗后,治疗组脱发发生率较对照组明显降低（P＜0.05）。结论 相较于TAC方案,采用改良多柔比星脂质体TAC方案治疗HER2阴性乳腺癌效果更为显著,可有效调节血清TK1、TPS、miR-132水平,降低肿瘤标志物水平,减轻心肌损伤,提高生活质量,安全性更高。     

火把花根片联合来氟米特治疗类风湿性关节炎的临床研究

目的 观察火把花根片联合来氟米特治疗类风湿性关节炎的临床效果。方法 选取2019年8月—2021年8月天津市第五中心医院收治的104例类风湿性关节炎患者,按随机数字表法将104例患者分成对照组和治疗组,每组各52例。对照组口服来氟米特片,2片/次,1次/d。治疗组在对照组基础上口服火把花根片,4片/次,3次/d。所有患者均连续治疗12周。观察两组疗效,比较治疗前后两组症状、体征[晨僵时间、关节疼痛视觉模拟量表（VAS）评分、关节肿胀数和压痛数],28个关节疾病活动度（DAS28）评分、健康评估问卷残疾指数（HAQ-DI）评分和血沉（ESR）,血清C反应蛋白（CRP）、白细胞介素（IL）-18、可溶性细胞间黏附分子-1（sICAM-1）、基质金属蛋白酶-13（MMP-13）水平,外周血CD4⁺、CD8⁺水平及其比值（CD4⁺/CD8⁺）。结果 治疗后,治疗组总有效率为88.5%,显著高于对照组的73.1%（P＜0.05）。治疗后,两组晨僵时间均显著缩短,关节疼痛VAS评分均显著降低,关节肿胀数和压痛数均显著减少（P＜0.05）;且均以治疗组改善更显著（P＜0.05）。治疗后,两组DAS28评分和HAQ-DI评分均显著降低（P＜0.05）;且均以治疗组下降更显著（P＜0.05）。治疗后,两组ESR和血清CRP、IL-18、sICAM-1、MMP-13水平均较治疗前显著下降（P＜0.05）;且均以治疗组的降低更显著（P＜0.05）。治疗后,两组外周血CD4⁺水平、CD4⁺/CD8⁺均较治疗前显著降低,外周血CD8⁺水平均较治疗前显著增高（P＜0.05）;且均以治疗组改善更显著（P＜0.05）。结论 火把花根片联合来氟米特治疗类风湿性关节炎的整体疗效确切,能有效改善患者临床表现,降低疾病活动度,减轻关节损害,抑制体内炎症反应,改善免疫功能。     

银杏叶提取物联合泼尼松对慢性阻塞性肺疾病小鼠Ghrelin-Obestatin信号通路的影响

目的 研究银杏叶提取物联合泼尼松对慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）小鼠Ghrelin-Obestatin信号通路的影响。方法 40只健康SPF小鼠随机分为5组。空白组不做处理，其余4组均诱导造COPD小鼠模型，在造模第8天开始，3组治疗组分别灌胃银杏叶提取物（0.4 mL·kg^-1·d^-1）、泼尼松（10 mg·kg^-1·d^-1）、联合药物治疗（0.4 mL·kg^-1银杏叶提取物+10 mg·kg^-1泼尼松），空白组、模型组予以生理盐水，连续给药28 d，采用Buxco系统检测小鼠肺功能PIF、PEF、MV后处死小鼠，采血样及肺组织样本。HE染色考察肺组织病理学变化；RT-PCR检测肺组织Ghrelin、GHSR、GPR39 mRNA表达；Western blotting检测肺组织Ghrelin、GHSR、Obestatin、GPR39蛋白含量；ELISA检测血清TNF-α、IL-6、IL-8水平。结果 与模型组相比，不同给药组均减轻COPD小鼠肺组织病理损伤，联合用药组效果最佳；联合用药组肺功能PIF、PEF、MV较模型组明显升高（P<0.05）；联合用药组Ghrelin、GHSR、GPR39 mRNA及蛋白表达较模型组明显升高（P<0.05），Obestatin蛋白表达较模型组明显升高（P<0.05）；仅联合用药组血清TNF-α、IL-6、IL-8含量较模型组明显降低（P<0.05），效果优于单一药物组。结论 银杏叶提取物联合泼尼松可影响Ghrelin-Obestatin信号通路，减轻炎症反应，改善肺功能，且较单一用药效果更佳。     

藏药青叶胆对实验性慢性肝损伤小鼠T淋巴细胞亚群的影响

目的 观察青叶胆对小鼠慢性肝损伤的保护作用及其对小鼠脾脏T淋巴细胞亚群的调节作用。方法 采用腹腔注射四氯化碳（CCl₄）造成小鼠化学性肝损伤模型,检测小鼠血清天冬氨酸转氨酶（aspartate aminotransferase,AST）、丙氨酸转氨酶（alanine aminotransferase,ALT）、总蛋白（total protein,TP）及总胆红素（total bilirubin,TBI）;HE染色,观察肝组织形态;流式细胞术检测CD3⁺、CD4⁺及CD8⁺阳性细胞数的变化情况,计算CD4⁺/CD8⁺比例,并与模型组和对照组比较。结果 青叶胆对CCl₄造成的小鼠慢性肝脏损伤具有保护作用,与模型组相比,能明显降低小鼠血清ALT、AST含量（P<0.01）,升高TP含量（P<0.01）;与模型组相比,青叶胆低剂量组对CD3⁺细胞具有下调作用（P<0.05）,对CD8⁺细胞的上调作用和对CD4⁺/CD8⁺比值的下调作用具有显著性差异（P<0.01）;高剂量组对CD8⁺细胞的上调作用和对CD4⁺/CD8⁺比值的下调作用具有统计学意义（P<0.05）。结论 青叶胆对CCl₄诱导的小鼠慢性肝损伤具有保护作用,其机制可能是通过调节T淋巴细胞亚群,提高免疫功能。     

金振口服液抑制小鼠流感病毒性肺炎的药效及机制研究

目的 研究金振口服液抑制小鼠流感病毒性肺炎的药效及作用机制。方法 将ICR小鼠随机分为对照组、模型组,金振口服液高、中、低剂量（4.4、2.2、1.1 g/kg）组和磷酸奥司他韦胶囊（0.05 g/kg）组。除对照组外,其余各组小鼠滴鼻感染甲型H1N1流感病毒构建小鼠病毒性肺炎模型,测定各组小鼠存活时间和肺指数;苏木素–伊红（HE）染色法观察肺组织病理变化;流式细胞术检测外周血CD3⁺、CD4⁺、CD8⁺ T淋巴细胞水平;ELISA法检测血清及肺泡灌洗液中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）及白细胞介素-10（IL-10）水平;Western blotting法检测肺组织Toll样受体3（TLR3）、β干扰素TIR结构域衔接蛋白（TRIF）和核转录因子-κB（NF-κB）蛋白表达。结果 与模型组相比,金振口服液给药组和磷酸奥司他韦胶囊组能显著延长小鼠存活时间,降低肺指数（P＜0.05、0.01）;减轻肺组织病理损伤;显著上调外周血CD3⁺、CD4⁺ T淋巴细胞水平及CD4⁺/CD8⁺值,下调CD8⁺ T淋巴细胞水平（P＜0.05、0.01）;明显降低血清及肺泡灌洗液中TNF-α、IL-1β和IL-6水平,升高IL-10水平（P＜0.05、0.01）;显著抑制肺组织TLR3、TRIF及NF-κB蛋白表达（P＜0.05、0.01）。结论 金振口服液能够延长病毒性肺炎小鼠存活时间、降低肺指数,减轻肺部炎性损伤,其抑制小鼠流感病毒性肺炎的机制可能与抑制TLR3/TRIF信号传导、调节抗炎–促炎失衡和改善T细胞免疫有关。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.