化瘀祛痰方通过调节ApoE-/-小鼠胆固醇代谢相关基因表达抗动脉粥样硬化

目的 观察化瘀祛痰方对载脂蛋白E基因敲除（ApoE^－/－）小鼠粥样斑块以及胆固醇代谢相关基因的影响,探讨化瘀祛痰方抗动脉粥样硬化（As）作用及可能的机制。方法 10只C57BL/6/J小鼠作为空白对照组,30只ApoE^－/－小鼠随机分为模型组、化瘀祛痰组［20 g/（kg·d）］和辛伐他汀组［0.005 g/（kg·d）］。全自动生化分析仪检测血清甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDLC）、低密度脂蛋白胆固醇（LDLC）,HE染色观察主动脉结构及动脉粥样硬化程度,油红O染色观察主动脉脂质沉积,RT-PCR和Western blot检测肝脏低密度脂蛋白受体（LDLR）、卵磷脂胆固醇酰基转移酶（LCAT）及主动脉CD36 mRNA和蛋白表达水平,流式细胞术检测腹腔巨噬细胞CD36蛋白表达。结果 与空白对照组相比,模型组小鼠血清TC、TG、LDLC水平显著升高;HDLC水平显著降低,主动脉管腔中形成较大粥样斑块,管壁形成大量脂质沉积,肝脏LDLR、LCAT 基因表达显著下调,主动脉、巨噬细胞CD36基因表达显著上调。通过药物干预,与模型组相比,化瘀祛痰组和辛伐他汀组小鼠TC、TG、LDLC水平显著下降,HDLC显著升高,主动脉管腔中粥样斑块面积和管壁脂质沉积量明显减少,肝脏LDLR、LCAT 基因表达显著上调,主动脉、巨噬细胞CD36基因表达显著下调。结论 化瘀祛痰方可抑制ApoE^－/－小鼠主动脉斑块形成,其机制可能与调控血脂及胆固醇代谢相关基因LDLR、LCAT及CD36的表达有关。     

绞股蓝总甙调控mTOR/ULK1通路对ApoE－/－小鼠动脉粥样硬化的影响

目的基于mTOR/ULK1自噬信号通路探讨绞股蓝总甙改善动脉粥样硬化模型小鼠主动脉脂质沉积的作用机制。方法 30只健康ApoE~(-/-)小鼠随机分为模型对照组、绞股蓝总甙组和辛伐他汀组,每组10只。10只C57BL/6J小鼠作为正常组。模型对照组、绞股蓝总甙组和辛伐他汀组采用高脂饲料喂养4周,绞股蓝总甙组和辛伐他汀组分别采用绞股蓝总甙2.973 g/(kg·d)、辛伐他汀2.275 mg/(kg·d)灌胃8周,模型对照组、正常组予等量生理盐水灌胃。HE染色观察小鼠动脉粥样硬化斑块形成情况,全自动生化分析仪检测血脂水平,Western blot检测主动脉ULK1、Beclin1、LC3、p-mTOR的蛋白表达。结果与正常组相比,模型对照组TG、TC和LDLC水平升高(P0.05),HDLC水平降低(P0.05),主动脉管腔见较大粥样斑块,ULK1、Beclin1、LC3蛋白表达水平下调(P0.01),pmTOR蛋白表达水平上调(P0.01);与模型对照组相比,绞股蓝总甙组和辛伐他汀组TG、TC和LDLC水平降低(P0.05),HDLC水平升高(P0.05),主动脉管腔粥样斑块明显减少,ULK1、Beclin1、LC3蛋白表达水平上调(P0.01),p-mTOR蛋白表达水平呈下调趋势(P0.01或P0.05)。结论绞股蓝总甙可能通过调控自噬缓解动脉粥样硬化斑块形成,进而防治动脉粥样硬化。     

生长素对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块与炎症因子的影响

目的观察生长素对载脂蛋白E基因敲除(ApoE~(-/-))小鼠血浆白细胞介素8(IL-8)、单核细胞趋化因子1(MCP-1)、肿瘤坏死因子α(TNF-α)水平和血管壁核转录因子κBp65(NFκBp65)表达及动脉粥样斑块的影响。方法8周龄雄性ApoE~(-/-)小鼠12只饲以西方类型膳食12周建立动脉粥样硬化模型,遗传背景相同的6只8周龄雄性C57BL/6J小鼠饲以同类型膳食作对照。第8周时模型组分为腹腔内注射生长素(100μg/kg)组(n=6)和注射生理盐水(0.1mL)组(n=6),C57BL/6J小鼠亦给予生理盐水(0.1mL)腹腔内注射。第12周时眼眶取血,分离血浆,酶联免疫吸附试验(ELISA)法检测IL-8、MCP-1、TNF-α水平。取小鼠主动脉进行苏丹Ⅳ染色,观察主动脉粥样硬化病变面积占主动脉内膜面积的比例,行主动脉窦HE及油红O染色,观察主动脉窦动脉粥样斑块面积占管腔总面积的比例,行主动脉免疫组化染色,观察NFκBp65的表达。结果与C57BL/6J小鼠比较,ApoE~(-/-)小鼠和ApoE~(-/-)+生长素小鼠总胆固醇和低密度脂蛋白胆固醇高[(6.7±0.5),(7.6±2.0)比(5.5±0.2)mmol/L,(5.6±0.3),(6.0±0.5)比(2.2±0.1)mmol/L,均P0.05],ApoE~(-/-)+生长素小鼠高密度脂蛋白胆固醇比ApoE~(-/-)组高[(0.5±0.1)比(0.3±0.1)mmol/L,P0.05]。与C57BL/6J小鼠比较,ApoE~(-/-)小鼠主动脉粥样硬化病变面积占主动脉内膜面积比例增加[(15.1±1.7)%比0],ApoE~(-/-)+生长素小鼠主动脉粥样病变面积占主动脉内膜面积比例较ApoE~(-/-)小鼠降低[(10.1±0.5)%比(15.1±1.7)%,P0.05];C56BL/6J小鼠主动脉窦无动脉斑块形成(0%),ApoE~(-/-)组和ApoE~(-/-)+生长素组均有动脉斑块形成,但ApoE~(-/-)+生长素组小鼠主动脉窦斑块面积占管腔总面积的比例较ApoE~(-/-)组低[(22.6±2.2)%比(32.4±3.2)%,P0.01]。ApoE~(-/-)小鼠TNF-α、IL-8和MCP-1水平较C57BL/6J小鼠增高[分别为(24.5±1.7)比(10.1±0.5)ng/L,(33.5±16.7)比(16.8±8.8)ng/L,(78.0±5.6)比(13.5±1.8)ng/L;均P0.05],ApoE~(-/-)+生长素组TNF-α、IL-8和MCP-1水平较ApoE~(-/-)组降低[分别为(15.5±1.0)比(24.5±1.7)ng/L,(22.0±1.2)比(33.5±16.7)ng/L,(45.5±4.5)比(78.0±5.6)ng/L;均P0.05]。ApoE~(-/-)小鼠血管壁NF-κBp65表达较C57BL/6J增高,ApoE~(-/-)小鼠+生长素组血管壁NF-κBp65表达较ApoE~(-/-)小鼠组降低(P0.05)。结论生长素通过抑制炎症反应减少ApoE~(-/-)小鼠动脉粥样斑块形成。     

基于血脂代谢紊乱理论研究血管软化丸抗动脉粥样硬化的作用机制

目的观察血管软化丸对载脂蛋白E基因敲除(ApoE-/-)小鼠血脂、血液流变学指标、血小板活化标志物CD63表达、主动脉粥样斑块病理形态及病灶处核转录因子-κB(NF-κB)的影响。方法采用高脂饲料喂饲ApoE-/-小鼠,60只ApoE-/-小鼠随机分为4组,正常对照组喂普通饲料,其他各组喂养饲高脂饲料建立动脉粥样硬化模型,各组按规定连续灌胃8周后测定血清血脂水平[总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)],血液流变学指标(全血黏度、血浆黏度、红细胞聚集指数)、血小板活化标志物CD63表达、主动脉粥样斑块病理形态及病灶处NF-κB的含量。结果高脂饮食引起小鼠血脂及血液流变学指标显著升高,导致ApoE-/-小鼠主动脉粥样斑块形成。与模型组比较,血管软化丸组TC、TG、LDL-C水平降低(P 0.05),HDL-C升高(P 0.05);全血低、中、高切黏度、血浆黏度、红细胞聚集指数降低(P 0.05)。各组小鼠主动脉斑块出现不同程度的染色强阳性,中药组平均光密度值较辛伐他汀组明显减小(P 0.05)。结论血管软化丸通过调控高脂饮食引起的血脂代谢紊乱及异常血液流变学指标,降低血小板活化标志物CD63表达和周围血管壁NF-κB含量,起到抗动脉粥样硬化的作用。     

多不饱和脂肪酸不同构成及配比对ApoE－/－小鼠动脉粥样硬化的影响

目的观察多不饱和脂肪酸不同构成及其配比对ApoE~(-/-)小鼠动脉粥样硬化(As)的预防作用,为合理使用脂肪酸预防As提供科学依据。方法设置对照组、模型组、3组实验油组,按饱和脂肪酸(SFA)∶单不饱和脂肪酸(MUFA)∶多不饱和脂肪酸(PUFA)=0.25∶1∶1比例配制3种实验油定制饲料。设计实验油1和油2中ω-6/ω-3 PUFA比例为2.5∶1,实验油3中ω-6/ω-3 PUFA比例为10∶1。其中实验油1中ω-3 PUFA来源为α-亚麻酸(ALA),实验油2及实验油3中ω-3 PUFA来源为二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和α-亚麻酸(ALA)。记录小鼠体质量变化,主动脉大体油红O染色及主动脉窦HE染色观察主动脉内膜斑块形成情况;肝脏油红O染色观察肝脏脂质蓄积情况;酶法检测肝脏甘油三酯(TG)和总胆固醇(TC)水平;酶法检测血清TG、TC、低密度脂蛋白胆固醇(LDLC)和高密度脂蛋白胆固醇(HDLC)水平。结果与模型组比较,3组实验油均能减少主动脉As斑块形成(P0.05),降低肝脏TG、TC(P0.05),降低血清TG、TC、 LDLC(P0.05),改善肝脏脂质蓄积。与实验油1组及实验油3组比较,实验油2组更能有效抑制主动脉As斑块形成(P0.05),显著降低肝脏TG、TC(P0.05),降低血清TG、TC、LDLC,升高血清HDLC(P0.05),改善肝脏脂质蓄积。结论减少SFA摄入,增加MUFA和PUFA摄入具有抗动脉粥样硬化的作用,EPA、DHA和ALA共同作为ω-3 PUFA的供体比ALA单独提供ω-3 PUFA抗动脉粥样硬化效果更好,低比例ω-6/ω-3PUFA比高比例ω-6/ω-3PUFA抗动脉粥样硬化效果更好。     

宁心解毒汤、血塞通、瑞舒伐他汀对ApoE－/－小鼠炎症因子和As斑块的影响

目的通过建立ApoE~(-/-)小鼠动脉粥样硬化(As)模型,探讨宁心解毒汤、血塞通、瑞舒伐他汀对小鼠血脂、炎性因子和斑块结构的影响。方法高脂喂养80只8周龄ApoE~(-/-)小鼠4周后,随机分为宁心解毒汤组、血塞通组、瑞舒伐他汀组和对照组。药物灌胃8周后处死。处死前测量体重、尾动脉血压,小鼠尾静脉取血,检测小鼠总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、白细胞介素6(IL-6)、白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)的浓度。分离主动脉,观察主动脉粥样硬化斑块特征。结果对照组ApoE~(-/-)小鼠血总胆固醇、甘油三酯、低密度脂蛋白胆固醇较其他3组差异有显著性,且瑞舒伐他汀组与宁心解毒汤组、血塞通组差异也有显著性(P0.05)。对照组ApoE~(-/-)小鼠体重、血压较其他3组差异无显著性(P0.05)。对照组ApoE~(-/-)小鼠IL-6、IL-1β、TNF-α的血清浓度,明显高于较其他3组(P0.05);而宁心解毒汤组、血塞通组、瑞舒伐他汀组3组间差异无显著性(P0.05)。对照组动脉斑块分布弥漫,而其他3组的整个动脉也有斑块,明显轻于对照组(P0.05)。结论ApoE~(-/-)小鼠+高脂饮食能够理想构建动脉粥样硬化动物模型。宁心解毒汤、血塞通、瑞舒伐他汀可以通过调脂、减低炎性因子的表达来发挥抗As作用。瑞舒伐他汀控制斑块发展的效果更好,考虑与其调脂相关。     

STAT4基因敲除通过miR-9促进泡沫细胞形成及动脉粥样硬化

目的探究动脉粥样硬化斑块发生发展过程中信号转导与转录激活因子4(STAT4)信号通路在巨噬细胞分化及泡沫细胞形成中的作用及调控机制。方法将STAT4基因敲除(STAT4~(-/-))小鼠与载脂蛋白E基因敲除(ApoE~(-/-))小鼠进行杂交,筛选出ApoE/STAT4纯合子双基因敲除(DKO)小鼠,研究新型动脉粥样硬化相关小鼠模型的易感性和机制。将3月龄小鼠分为野生型(WT)、STAT4~(-/-)、ApoE~(-/-)、DKO共4组,经过12周高脂胆固醇饮食喂养,分别采用油红O染色及石蜡切片HE/Masson染色检测主动脉斑块形成情况。采用流式细胞术分析小鼠外周血、骨髓及脾脏髓系细胞各亚群比例。从小鼠骨髓分离CD11b~+髓系细胞进行体外培养,采用巨噬细胞集落刺激因子(M-CSF)进行诱导,流式分析巨噬细胞不同亚型分化情况。采用实时定量聚合酶链反应(PCR)及Western blot分别检测基因表达水平及蛋白水平。结果 ApoE~(-/-)小鼠动脉粥样硬化斑块局部的CD11b~+细胞中可检测到STAT4表达。ApoE~(-/-)及DKO小鼠经12周高脂喂养,油红O染色阳性的主动脉斑块主要分布在主动脉根部至髂动脉分叉处,DKO小鼠的斑块较ApoE~(-/-)小鼠明显增多;HE及Masson染色显示DKO小鼠的主动脉斑块较ApoE~(-/-)小鼠具有更薄的纤维帽及更大的脂质核心,且斑块中的纤维更稀疏,排列也相对更紊乱。体外细胞实验显示STAT4基因敲除可促进CD11b~+Gr-1~+未成熟髓系细胞的异常动员、巨噬细胞的M1极化以及泡沫化。STAT4基因缺失通过磷酸肌醇3激酶(PI3K)/丝氨酸苏氨酸激酶(Akt)/核因子κB(NF-κB)通路下调miR-9的表达,上调酰基辅酶A胆固醇酰基转移酶(ACAT-1)表达,进而促进巨噬细胞的脂质蓄积及泡沫细胞形成,最终加速动脉粥样硬化斑块的发生发展。结论 STAT4通过调控免疫炎症反应及脂质代谢,在巨噬细胞分化及泡沫细胞形成过程中发挥关键作用。STAT4相关信号通路可作为未来动脉粥样硬化性疾病的潜在治疗靶点。     

大蒜素对高脂饮食ApoE－/－小鼠动脉粥样硬化形成的影响

目的观察大蒜素对高脂饮食诱导的ApoE~(-/-)小鼠巨噬细胞泡沫化及动脉粥样硬化形成的影响,并从清道夫受体调控的角度探讨其相关的作用机制。方法 6周雄性ApoE~(-/-)小鼠随机分为4组:正常饮食组、高脂饮食组、高脂饮食+低剂量大蒜素组、高脂饮食+高剂量大蒜素组。采用血脂检测试剂盒测定小鼠血脂水平;使用油红O染色法观察小鼠主动脉根部斑块形成面积和腹腔巨噬细胞泡沫化情况;Western blot法检测腹腔巨噬细胞中清道夫受体SR-A和CD36表达以及JNK和p38激酶磷酸化水平。结果大蒜素可呈剂量依赖性降低高脂饮食小鼠总胆固醇、甘油三酯及低密度脂蛋白胆固醇的水平(P0.05),并显著减少主动脉根部斑块面积以及腹腔巨噬细胞泡沫化的形成(P0.05)。Western blot结果显示大蒜素不仅抑制高脂饮食所诱导的腹腔巨噬细胞中SR-A和CD36表达的增加(P0.05),还能够显著减少JNK和p38激酶磷酸化水平。结论大蒜素减少SR-A和CD36表达,并抑制JNK和p38激酶激活,从而发挥抗泡沫化和动脉粥样硬化的作用。     

养心氏片对动脉粥样硬化模型小鼠的作用机制研究

目的探讨养心氏片治疗动脉粥样硬化(AS)的可能作用机制。方法以高脂饲料喂养雄性载脂蛋白E基因敲除(ApoE~(-/-))小鼠12周,复制AS模型。将AS小鼠随机分成模型组,养心氏片高剂量组、中剂量组、低剂量组及阳性对照组,每组8只。另设雄性C57BL/6J小鼠8只作为正常对照组。养心氏片高剂量组、中剂量组、低剂量组及阳性对照组给药量分别相当于70 kg成人临床剂量的2倍、1倍、0.5倍及1倍。养心氏片高剂量组、中剂量组、低剂量组给予养心氏片,剂量分别为1.40 g/(kg·d)、0.70 g/(kg·d)、0.35 g/(kg·d)灌胃,阳性对照组给予阿托伐他汀剂量为2.57 mg/(kg·d)灌胃,共给药12周。采用苏木素-伊红(HE)染色法观察小鼠升主动脉病理学变化,Image J软件测定小鼠升主动脉斑块校正后斑块面积。采用实时定量PCR(qPCR)法检测各组小鼠主动脉组织核转录因子-κB(NF-κB)、单核细胞趋化蛋白-1(MCP-1)、血管内皮细胞黏附分子-1(VCAM-1)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)mRNA的表达。结果与模型组比较,养心氏片高剂量组、中剂量组、低剂量组及阳性对照组升主动脉斑块校正后斑块面积呈现不同程度的降低(P0.05),以养心氏片高剂量组小鼠升主动脉斑块校正后斑块面积最低,而养心氏片高剂量组小鼠升主动脉斑块校正后斑块面积与阳性对照组相比差异无统计学意义(P0.05)。与正常对照组比较,模型组小鼠主动脉组织NF-κB、MCP-1、VCAM-1、IL-6、TNF-αmRNA的表达水平明显升高(P0.05),各药物干预组小鼠主动脉组织NF-κB、MCP-1、VCAM-1、IL-6、TNF-αmRNA表达水平较模型组均显著降低(P0.05),与养心氏片高剂量组相比,养心氏片中剂量组及低剂量组小鼠主动脉NF-κB、MCP-1、VCAM-1、IL-6、TNF-αmRNA表达升高(P0.05),而养心氏片高剂量组小鼠主动脉NF-κB、MCP-1、VCAM-1、IL-6、TNF-αmRNA表达与阳性对照组相比差异无统计学意义(P0.05)。结论养心氏片可抗动脉粥样硬化,并具有剂量依赖性,养心氏片给药组以养心氏片高剂量组抗AS效果最佳,其机制可能与降低AS小鼠升主动脉斑块校正后斑块面积及下调主动脉NF-κB信号通路相关因子mRNA表达有关。     

冠心舒通胶囊干预NF-κB信号通路抗动脉粥样硬化的机制研究

目的观察冠心舒通胶囊是否通过调控核转录因子-κB(NF-κB)信号通路,控制或延缓动脉粥样硬化的进展。方法选取16只6~8周龄雄性C57BL/6小鼠为正常对照组,予普通饮食;选取48只6~8周龄雄性同系ApoE基因敲除(ApoE-/-)小鼠,采用高脂饲料喂养,至12周建立动脉粥样硬化模型(杀死3只,油红O染色,脂质斑块形成,造模成功),造模成功小鼠随机分为3组:模型组、冠心舒通组、阿托伐他汀组,每组15只。冠心舒通组给予冠心舒通胶囊0.41 g/(kg·d)灌胃,阿托伐他汀组给予阿托伐他汀钙片5 mg/(kg·d)灌胃,对照组和模型组给予等体积生理盐水灌胃。灌胃8周后,采用酶联免疫吸附实验(ELISA)检测血清中白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平;取主动脉,免疫组织化学染色法检测主动脉组织中NF-κB p65蛋白表达水平;蛋白免疫印迹法(Western Blot)检测主动脉组织中TNF-α蛋白表达水平。结果与正常对照组相比,模型组血清IL-6、TNF-α水平均升高(P<0.01),主动脉组织中NF-κB p65和TNF-α蛋白表达水平明显升高(P<0.01);与模型组相比,冠心舒通组和阿托伐他汀组血清IL-6、TNF-α水平均降低(P<0.01),主动脉组织中NF-κB p65蛋白和TNF-α蛋白表达水平明显降低(P<0.01)。结论冠心舒通胶囊对ApoE-/-小鼠具有抗动脉粥样硬化的作用,其作用机制可能与其抑制NF-κB信号通路及相关炎性因子(IL-6、TNF-α)的表达,发挥抗炎、抗动脉硬化作用有关。     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Language of CTO interventions – Focus on hardware

The knowledge of variety of chronic total occlusion (CTO) hardware and the ability to use them represents the key to success of any CTO interventions. However, the multiplicity of CTO hardware and their physical character and the terminology used by experts create confusion in the mind of an average interventional cardiologist, particularly a beginner in this field. This knowledge is available but is scattered. We aim to classify and compare the currently used devices based on their properties focusing on how physical character of each device can be utilized in a specific situation, thus clarifying and simplifying the technical discourse.     

High prevalence of distal sensory polyneuropathy in antiretroviral-treated and untreated people with HIV in Tanzania

Objectives To describe the prevalence of distal sensory polyneuropathy (DSP), a complication of both advanced HIV disease and of antiretroviral therapy (ART), amongst Tanzanians with HIV, on and off ART (including stavudine) with CD4 counts above and below 200 cells/μl. Methods We recruited participants attending ART clinic into four groups: >6 months ART exposure and (i) CD4 < 200 cells/μl or (ii) CD4 > 200 cells/μl (ART/CD4 < 200 and ART/CD4 > 200, respectively); ART‐naïve and (iii) CD4 < 200 cells/μl or iv)CD4 > 200 cells/μl (noART/CD4 < 200 and noART/CD4 > 200, respectively). Primary outcome was DSP, as defined by presence of at least one symptom and one sign. Results Of 326 evaluable participants, 81 (32 men, median age 38 years, median CD4 142 cells/μl) were enrolled in the ART/CD4 < 200 group, 78 (17 men, median age 37 years, median CD4 345 cells/μl) in ART/CD4 > 200, 81 (30 men, median age 37 years, median CD4 128 cells/μl) in noART/CD4 < 200 and 86 (22 men, median age 33 years, median CD4 446 cells/μl) in noART/CD4 > 200. Numbness was the most commonly reported symptom. DSP prevalence ranged from 43.2% in ART/CD4 < 200 to 20.9% in noART/CD4 > 200. DSP was more common among men (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.2–3.3) and older participants (aOR 2.7, 95% CI 1.1–6.2 for age 40 + vs. <30 years). Conclusion Distal sensory polyneuropathy is common amongst those attending this clinic, even those with no ART exposure and a CD4 count above 200 cells/μl. Stavudine and didanosine expose HIV‐infected patients to an additional avoidable risk of DSP. Access to non‐neurotoxic ART regimes as well as earlier HIV diagnosis and initiation of ART is needed.