替米沙坦对压力超负荷性大鼠心室重构及心肌营养素-1表达的影响

目的研究血管紧张素Ⅱ受体拮抗剂替米沙坦对压力超负荷性大鼠心室重构及心肌营养素-1(CT-1)表达的影响。方法20只雄性SD大鼠行腹主动脉缩窄术后2周造成后负荷增高型大鼠模型,存活大鼠随机分为肥厚组和替米沙坦组,另设8只作为假手术组。替米沙坦组灌胃给药(3mg·kg-1·d-1),连续4周。测定血流动力学指标和心室质量指数,放免法测定心肌和血浆的血管紧张素Ⅱ(AngⅡ)含量,原位杂交法检测心肌的CT-1mRNA表达水平。结果与假手术组比较,肥厚组SBP、DBP和MABP显著升高(P<0.05),LVMI和RVMI亦明显升高(P<0.05);心肌组织AngⅡ含量和CT-1mRNA表达水平明显增加(P<0.05)。替米沙坦改善血流动力学指标(P<0.05),降低LVMI和RVM(IP<0.05),AngⅡ含量显著降低(P<0.01),CT-1mRNA的表达明显下调(P<0.05)。结论压力超负荷性大鼠表达上调的CT-1参与心室重构;替米沙坦下调CT-1的过度表达可能是其防治心室重构的机制之一。     

卡维地洛对压力负荷性大鼠心室重构及ET-1 mRNA表达的影响

目的研究第三代β受体阻滞剂卡维地洛对压力负荷性大鼠心室重构及心肌ET-1 mRNA表达的影响.方法 20只Wistar大鼠行腹主动脉缩窄术造成后负荷增高型大鼠模型,随机分为肥厚组和卡维地洛组,4周药物干预后测定血流动力学指标和心室重量指数,心肌ET-1mRNA的表达水平.结果肥厚组MBP和LVSP升高(P＜0.05),LVMI和RVMI升高18.1%,27.7%(P＜0.05),ET-1mRNA表达增加209%(P＜0.01);卡维地洛改善血液动力学指标(P＜0.01～0.05),降低LVMI和RVMI(P＜0.05),下调心肌ET-1 mRNA的表达(P＜0.05).结论压力负荷性大鼠表达上调的ET-1参与心室重构.卡维地洛下调ET-1的过度表达可能是其防治心室重构的机制之一.     

替米沙坦对压力负荷过重所致心衰大鼠心肌ACE2和AT1R表达的影响

目的 探讨替米沙坦对压力负荷过重所致心衰大鼠血管紧张素Ⅱ(AngⅡ)、心肌血管紧张素Ⅱ1型受体(AT1R)、血管紧张素转化酶2(ACE2)及MAS蛋白表达的影响。方法 采用SD雄性大鼠通过腹主动脉缩窄术构建压力负荷性心肌肥厚致心力衰竭(HF)模型。将大鼠随机分为假手术对照组(n=12)、HF模型组(n=12)和替米沙坦干预组(n=12)。替米沙坦干预组每天给予替米沙坦连续8周,检测各组大鼠血流动力学参数、心脏指数、血浆AngⅡ含量、心肌中AT1R、ACE2和MAS蛋白的表达情况。结果 HF模型组心脏指数、血流动力学指标、血浆AngⅡ的含量及心肌AT1R、ACE2蛋白的表达明显升高(P<0.01),MAS蛋白表达明显下降(P<0.01);替米沙坦干预组心脏指数、血流动力学指标明显下降(P<0.01),血浆AngⅡ的含量及心肌AT1R蛋白的表达明显下降(P<0.01),而MAS和ACE2蛋白的表达明显升高(P<0.01)。结论 应用替米沙坦可明显改善HF大鼠心室重构,可能与AngⅡ和AT1R的下调,而MAS和ACE2的上调有关。     

替米沙坦对压力超负荷大鼠心肌内皮素-1表达和GATA DNA结合活性的影响

目的 研究压力超负荷心肌肥厚大鼠心肌组织(GATA)DNA结合活性和内皮素(ET)-1蛋白表达的变化及其意义,观察替米沙坦对压力超负荷心肌肥厚大鼠血流动力学参数[收缩压(SBP)、舒张压(DBP)和平均压(MBP)]、左室质量指数(LVMI)、心肌细胞横径(DC)、心肌组织GATA DNA结合活性和ET-1蛋白表达的影响.方法 腹主动脉缩窄法建立压力超负荷大鼠心肌肥厚模型.健康SD大鼠24只,随机分为三组:假手术组(n=8);手术组(n=8);替米沙坦组(手术后第7天给替米沙坦3 mg·kg-1·d-1灌胃4 w,n=8).测定大鼠SBP、DBP、MBP、LVMI及DC;免疫组化半定量检测心肌组织ET-1蛋白的表达,电泳迁移率变动分析检测ET-1与GATA的特异性结合及GATA DNA结合活性的变化.结果 ①与假手术组比较,手术组SBP、DBP、MBP、LVMI和DC均显著升高(P均<0.05);光镜下见心肌实质、间质结构改变;心肌组织ET-1蛋白表达和GATA DNA结合活性均明显增加(P均<0.05);心肌组织ET-1蛋白表达与LVMI和DC均呈显著正相关(r=0.895,r=0.899,P均<0.01);②与手术组比较,替米沙坦组SBP、MBP、LVMI、DC、心肌组织ET-1蛋白表达和GATA DNA结合活性均明显降低(P均<0.05).结论 (1)GATA DNA结合活性增加使ET-1蛋白表达增加与压力超负荷大鼠的心肌肥厚有关;(2)替米沙坦能够抑制压力超负荷大鼠的心肌肥厚,其机制可能与替米沙坦降低GATA DNA结合活性从而下调ET-1蛋白表达有关.     

替米沙坦对高血压大鼠血管重构和AngⅡ1型受体表达的影响

目的 探讨替米沙坦对实验性高血压大鼠血管重构和AngⅡ1型受体(AT1R)的影响.方法 腹主动脉部分缩窄构建高血压大鼠模型,24只雌雄各半SD大鼠随机分成高血压组和替米沙坦组(3 mg·kg-1· d-1),另设假手术组为对照组.测定血流动力学指标和心室质量指数,主动脉进行图像分析,检测大鼠血浆与主动脉组织匀浆中血管紧张素Ⅱ(AngⅡ)含量,测定主动脉血管内皮细胞、血管平滑肌细胞AT1R蛋白的表达.结果 ①与假手术组比较,高血压组收缩压(SBP)、舒张压(DBP)、平均动脉压(MABP)、左室质量指数(LVMI)、中膜厚度/内径、中膜面积/内腔面积显著升高(P均＜0.05);高血压组大鼠血浆与主动脉组织匀浆中AngⅡ含量和AT1R表达较对照组明显增高(P均＜0.05);②高血压组血浆AngⅡ、血管平滑肌细胞AT1R、主动脉中膜厚度/内径比值或中膜面积/内腔面积比值三者之间互为显著正相关(r=0.88 ～0.93,P＜0.01 ～0.001);主动脉匀浆AngⅡ、血管平滑肌细胞AT1R、主动脉中膜厚度/内径比值或中膜面积/内腔面积比值三者之间亦互为显著正相关(r=0.82 ～0.91,P＜0.01～0.001).③替米沙坦能显著改善血流动力学指标,降低LVMI、中膜面积/内腔面积(P均＜0.05);替米沙坦组主动脉匀浆中AngⅡ水平、血管内皮细胞和平滑肌细胞AT1R均较高血压组降低(P均＜0.05).结论 过度表达的AT1R在高血压大鼠血管重构中起到了重要作用,替米沙坦通过抑制AT1R的表达从而逆转血管重构.     

卡维地洛对压力负荷性大鼠心室重构及ET-1 mRNA表达的影响

目的　研究第三代 β受体阻滞剂卡维地洛对压力负荷性大鼠心室重构及心肌ET 1mRNA表达的影响。 方法　 2 0只Wistar大鼠行腹主动脉缩窄术造成后负荷增高型大鼠模型 ,随机分为肥厚组和卡维地洛组 ,4周药物干预后测定血流动力学指标和心室重量指数 ,心肌ET 1mRNA的表达水平。结果　肥厚组MBP和LVSP升高 (P <0 0 5 ) ,LVMI和RVMI升高 18 1% ,2 7 7% (P <0 0 5 ) ,ET 1mRNA表达增加 2 0 9% (P <0 0 1) ;卡维地洛改善血液动力学指标 (P <0 0 1～0 0 5 ) ,降低LVMI和RVMI(P <0 0 5 ) ,下调心肌ET 1mRNA的表达 (P <0 0 5 )。结论　压力负荷性大鼠表达上调的ET 1参与心室重构。卡维地洛下调ET 1的过度表达可能是其防治心室重构的机制之一     

替米沙坦联合氨氯地平对血管紧张素Ⅱ诱导乳鼠心肌成纤维细胞增殖的影响

目的分析替米沙坦联合氨氯地平对血管紧张素Ⅱ(AngⅡ)诱导的乳鼠心肌成纤维细胞增殖的影响以及相关机制。方法新生1~3 d Wistar大鼠30只,雌雄不拘,培养原代心肌细胞,采用差速贴壁获得心肌成纤维细胞,传代培养。取对数期成纤维细胞,分组并给予处理,对照组:加入15%胎牛血清DEME培养液,AngⅡ组:15%胎牛血清DEME培养液+AngⅡ,替米沙坦组:在AngⅡ组基础上加入替米沙坦,氨氯地平组:在AngⅡ组基础上加入氨氯地平,联合组:在AngⅡ组基础上加入替米沙坦+氨氯地平。鉴定成纤维细胞。CCK-8法检测各组细胞增殖情况,应用免疫组化染色测定血凝素样氧化低密度脂蛋白受体-1(LOX-1)及肿瘤坏死因子-α(TNF-α)蛋白水平,应用RT-PCR法测定LOX-1及TNF-αm RNA表达水平。结果心肌成纤维细胞胞体较大,胞浆透明,细胞呈梭形,细胞核呈椭圆形,通常含2~3个核,细胞纯度高达98%。与对照组相比,AngⅡ组增殖活性升高,而加入替米沙坦和氨氯地平后,抑制AngⅡ诱导的增殖,联合应用替米沙坦和氨氯地平较单药抑制作用更明显,差异有统计学意义(P均0.05)。与对照组相比,AngⅡ组心肌成纤维细胞TNF-α及LOX-1 m RNA表达水平显著升高,差异有统计学意义(P均0.05)。各药物干预组与AngⅡ组相比,TNF-α及LOX-1 m RNA表达水平显著降低,其中联合组下降最明显,差异有统计学意义(P均0.05)。与对照组相比,AngⅡ组心肌成纤维细胞TNF-α及LOX-1蛋白表达水平显著升高,差异有统计学意义(P均0.05)。各药物干预组与AngⅡ组相比,TNF-α及LOX-1蛋白表达水平显著降低,联合组较替米沙坦组和氨氯地平组两种蛋白的表达降低,差异有统计学意义(P均0.05)。结论替米沙坦联合氨氯地平能有效抑制AngⅡ诱导的心肌成纤维细胞增殖,其可能机制为抑制LOX-1及TNF-α过度表达。     

替米沙坦通过调节Krüppel样因子4的表达延缓心肌纤维化

目的研究SHR大鼠心肌Krüppel样因子4(KLF4)及其相关因子变化,同时观察替米沙坦治疗后的效果。方法 10周左右的SHR大鼠分别给予生理盐水和替米沙坦10 mg·kg-1·d-1干预(WKY为对照组)。8周后测血压,左室重量及左室重量指数评定左室肥厚情况;同时观察心肌组织中KLF4、内皮一氧化氮合酶(e NOS)及纤溶酶原激活抑制物-1(PAI-1)、基质金属蛋白酶抑制物-1(TIMP-1)和Ⅳ型胶原的mRNA和蛋白表达水平的变化。为进一步明确其机制,用AngⅡ刺激内皮细胞,同时测定KLF4的表达进一步明确病理机制。结果 SHR大鼠血压、左室重量(LVW)及左室重量指数(LVW/BW)较WKY大鼠明显增加(均为P0.05),替米沙坦可以显著降低血压,逆转SHR大鼠的LVW及LVW/BW变化(均为P0.01)。SHR大鼠KLF4、e NOS的mRNA及蛋白表达水平较WKY大鼠显著降低(均为P0.05),而替米沙坦治疗组KLF4的表达较SHR组明显增加(均为P0.05);相反,SHR大鼠PAI-1、TIMP-1和Ⅳ型胶原的mRNA及蛋白水平较WKY大鼠明显增加(均为P0.05),而替米沙坦治疗后较SHR组明显降低(均为P0.05)。AngⅡ作用于内皮细胞,e NOS的磷酸化明显降低(2.37±0.22比1.57±0.31)(P0.05),同时PAI-1、TIMP-1和Ⅳ型胶原的表达明显增加(均为P0.05),过表达KLF4可以使e NOS的磷酸化显著回升(1.57±0.31比2.08±0.28)(P0.05),同时PAI-1、TIMP-1和Ⅳ型胶原的表达较AngⅡ作用下明显减低(均为P0.05)。结论KLF4在高血压大鼠心肌心肌纤维化过程中发挥重要作用,替米沙坦降压治疗可以明显延缓或逆转此病理过程。     

内源性二氧化硫抑制血管紧张素Ⅱ致心肌肥厚小鼠心肌细胞自噬的研究

目的探讨内源性二氧化硫(SO_2)对血管紧张素Ⅱ(AngⅡ)致心肌肥厚小鼠心肌细胞自噬的抑制作用。方法 9周龄健康C57BL小鼠16只,按随机数字表法随机分为野生型对照组(WT Con组)、野生型+AngⅡ组(WT AngⅡ组);心肌特异性天冬氨酸氨基转移酶2(AAT2)转基因小鼠16只,按随机数字表法随机分为AAT2对照组(AAT2 Con组)、AAT2+AngⅡ组(AAT2 AngⅡ组)。每组8只。每只小鼠在背部皮下植入预装生理盐水或AngⅡ的胶囊渗透压泵,连续给药4周。检测4组小鼠全心重/体重(HW/BW)比值;HE染色观察心肌细胞结构变化;免疫组织化学染色检测心肌标志分子α重链肌球蛋白(α-MHC)的表达;高效液相色谱检测心肌组织SO_2含量;Western blot检测内源性SO_2生成酶AAT1和AAT2、心肌表型标志分子α-MHC和β-MHC以及心肌自噬标志分子Beclin-1、LC3、Atg4B以及p62蛋白表达变化。结果与WT Con组相比,WT AngⅡ组心肌组织SO_2含量显著降低(P0.01),AAT1蛋白表达无明显变化(P0.05),AAT2蛋白表达显著减少(P0.05),HW/BW明显增加(P0.01),心肌纤维明显增粗,免疫组织化学法显示心肌细胞浆中α-MHC蛋白表达明显减弱,Western blot结果显示心肌细胞α-MHC蛋白表达显著降低(P0.01),β-MHC蛋白表达显著升高(P0.01),心肌组织LC3Ⅱ/LC3Ⅰ比值显著升高,Beclin-1和Atg4B蛋白表达显著升高,p62蛋白表达显著降低(均P0.01)。与WT Con组相比,AAT2 AngⅡ组小鼠心肌组织SO_2含量和AAT2蛋白表达显著升高(P0.01),AAT1的蛋白表达无显著变化(P0.05),HW/BW显著降低(P0.05),心肌纤维的增粗显著减轻,α-MHC蛋白向β-MHC蛋白的转化显著降低(P0.01),心肌细胞自噬水平显著降低。结论内源性SO_2/AAT2体系可抑制AngⅡ致小鼠心肌肥厚及心肌细胞自噬。     

替米沙坦联合氨氯地平对乳鼠转化生长因子-β1及Ⅰ、Ⅲ型胶原蛋白表达的影响

目的探讨替米沙坦联合氨氯地平对血管紧张素(Ang)Ⅱ诱导的乳鼠心肌成纤维细胞增殖及细胞中转化生长因子(TGF)-β1、Ⅰ、Ⅲ型胶原蛋白表达的影响。方法对Wistar乳鼠心肌成纤维细胞行体外原代及传代培养,将培养好的细胞分为5组:对照组(加入15%小牛血清DEME培养液)、AngⅡ组(15%小牛血清DEME培养液+1×10~(-6)mol/L AngⅡ),替米沙坦组(TE组,在AngⅡ组基础上加入10μmol/L替米沙坦),氨氯地平组(AM组,AngⅡ组基础上加入1μmol/L氨氯地平)及替米沙坦+氨氯地平组(TE+AM组),在AngⅡ组基础上加入10μmol/L替米沙坦+1μmol/L氨氯地平),每组3份。观察各组细胞不同时期增殖情况及TGF-β1、Ⅰ、Ⅲ型胶原蛋白、p27蛋白表达情况。结果与对照组相比,AngⅡ组心肌成纤维细胞在S期时增殖率较高,而在G_0/G_1期、G_2/M期时增殖率下降(P0.05),TGF-β1、Ⅰ、Ⅲ型胶原蛋白、p27蛋白表达水平显著升高(P0.05)。与AngⅡ组相比,TE组、AM组及TE+AM组心肌成纤维细胞在S期时增殖率显著下降,而在G_0/G_1期、G_2/M期时增殖率升高(P0.05),TGF-β1、Ⅰ、Ⅲ型胶原蛋白、p27蛋白表达水平下降(P0.05),其中TE+AM组心肌成纤维细胞在G_0/G_1期、G_2/M期增殖较TE组、AM组显著,而TGF-β1、Ⅰ、Ⅲ型胶原蛋白、p27蛋白表达水平低于TE组、AM组。结论替米沙坦联合氨氯地平能有效抑制AngⅡ诱导的心肌成纤维细胞增殖,其可能机制与抑制TGF-β1、Ⅰ、Ⅲ型胶原蛋白及p27蛋白过度表达有关。     

Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo

Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC50=2.24 nM, 95% CI=1.20-3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED90 of artesunate by approximately 15.6-fold in a pyronaridine-resistant P. berghei line and by approximately 200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.     

Parameters of anorectal and colonic motility in health and in severe constipation

Anorectal function and colonic transit was assessed in 17 severely constipated patients and 15 age-matched controls. The constipated patients were divided into those who had immobile perineum (perineal descent 1.0 cm during attempted defecation) and those who had a normal descent (>1.0 cm) of the perineum. When constipation was accompanied by an immobile perineum, patients had impaired balloon expulsion, impaired and delayed artificial stool expulsion, decreased straightening of the anorectal angle, decreased descent of the pelvic floor with defecation, and prolonged rectosigmoid colon transit compared with the patients with constipation who had a mobile perineum and with normal controls. The mobile-perineum group differed from controls only in colon transit times, having prolonged total colon transit. Anal sphincter resting pressures, immediate artificial stool expulsion, resting anorectal angles, and electromyography of the external anal sphincter and puborectalis did not differentiate the constipated patients from the controls. We concluded that descent of the perineum of <1 cm was associated with impaired expulsion, an adynamic anorectal angle, and slowed distal colon transit. This simple sign of pelvic floor function distinguished constipated patients with disordered expulsion from constipated patients with normal pelvic floor function. These patients may respond poorly to surgery and conventional management and would therefore be candidates instead for pelvic floor retraining. Accurate characterization and appreciation of pelvic floor dysfunction in patients with severe chronic constipation may improve the selection for and results of surgical and nonsurgical intervention.Supported in part by Research Grants DK37990, RR585, and DK34988 from the National Institutes of Health and by the Mayo Foundation, Rochester, Minnesota.     

Effects of dietary phytoestrogens in vivo and in vitro in rainbow trout and Siberian sturgeon: interests and limits of the in vitro studies of interspecies differences

A study of the effects of dietary genistein on trout and sturgeon in vivo showed that sturgeon was sensitive to 20 ppm of genistein, whereas trout was not. To analyze the origin of this interspecies difference in sensitivity, a cell culture technique was developed with hepatocytes from sturgeon and compared to results obtained with hepatocytes from trout in the same system. The hepatocyte culture proved to be useful as bioassay for estrogenicity. Vitellogenin (VTG), assayed by a specific enzyme-linked immunosorbent assay, was used as a biomarker of the estrogenic activity. 17 beta-Estradiol, its glucuronide and sulfate derivatives, and estradiol analogues (ethynylestradiol and diethylstilbestrol) were tested. Nonestrogenic compounds such as androgens, progesterone, and cortisol were tested as negative controls. VTG production was monitored at doses ranging from 1 nM to 10 microM estradiol. Phytoestrogens, from the isoflavone family, were tested individually at increasing doses exhibiting dose response curves for concentrations from 500 nM to 10 microM. With tamoxifen, an antagonist of estrogen receptors, the estrogenic effect was partially reduced. The effect was the same with ICI182,780 in sturgeon, whereas the effect was the opposite in trout. The estrogenic potency of the isoflavones ranged differently between the two species in the following order: biochanin A < daidzein = formononetin < genistein < equol in trout and biochanin A < genistein < daidzein < formononetin < equol in sturgeon. Further, in sturgeon, formononetin was the most potent phytoestrogen in vitro, whereas its activity was weakest in vivo. These data suggest that one must reconsider the relevance of heterologous estrogenic tests and of homologous in vitro tests for estrogenic potency of chemicals.     

The role of alcohol and drugs in homicides in England and Wales

BACKGROUND: The annual number of homicide convictions in England and Wales is increasing. Previous studies have highlighted the aetiological role of alcohol and drugs in homicide. AIMS: To examine rates of alcohol and drug misuse and dependence in people convicted of homicide; the role of alcohol and drugs in the offence; the social and clinical characteristics of alcohol- and drug-related homicides; and the social and clinical characteristics of patients with dual diagnosis who commit homicide. METHODS: A national clinical survey based on a 3-year (1996-9) consecutive sample of people convicted of homicide in England and Wales. Information on rates of alcohol and drug misuse/dependence, the role of alcohol and drugs in the offence and social and clinical characteristics of perpetrators were collected from psychiatric reports prepared for the court in homicide convictions. Detailed clinical information was gathered from questionnaires completed by mental health teams for those in contact with mental health services. RESULTS: Of the 1594 homicide perpetrators, more than one-third (42%) occurred in people with a history of alcohol misuse or dependence and 40% in people with a history of drug misuse or dependence. Alcohol or drug misuse played a contributory role in two-fifths of homicides. Alcohol played a major role in 52 (6%) and a minor role in 364 (39%) homicides. Drugs played a major role in six (1%) and a minor role in 138 (14%) homicides. Forty-two homicides (17%) were committed by patients with severe mental illness and substance misuse. Alcohol- and drug-related homicides were generally associated with male perpetrators who had a history of violence, personality disorders, mental health service contact and with stranger victims. CONCLUSIONS: Substance misuse contributes to the majority of homicides in England and Wales. A public health approach to homicide would highlight alcohol and drugs before severe mental illness.     

Trends in COPD mortality and hospitalizations in countries and regions of Asia-Pacific

Background and objective: The growing burden of COPD in the Asia‐Pacific region supports the need for more intensive research and analysis of the epidemiology of COPD to raise awareness of the disease and its causes, to ensure the development of effective national health policies and to facilitate equitable deployment of finite health‐care resources in the prevention and management of COPD. This study estimated and compared COPD mortality and hospital morbidity rates and trends in these rates over time across countries and regions of Asia‐Pacific. Methods: Data consistent with standard definitions of COPD (ICD‐9/ICD‐10) for the period 1991–2004 were obtained from national health statistics agencies. For countries/regions with complete national mortality and hospitalization data (Australia, Pacific Canada (British Columbia, Hong Kong, South Korea and Taiwan), annual age‐standardized mortality and hospitalization rates were calculated for men and women aged ≥ 40 years. Negative binomial regression modelling was used to estimate rate ratios for country/region, gender and age differences and general trends over time. Results: Mortality rates per 10 000 population ranged 6.4–9.2 in men, 2.1–3.5 in women and 3.7–5.3 overall in 2003. Corresponding ranges for morbidity were 32.6–334.7, 21.2–129 and 28.1–207.3 per 10 000. Trend analysis of data since 1997 produced annual percentage changes in mortality versus hospitalization of ?4.4% versus ?0.7% in Australia, ?3.6% versus 7.5% in Pacific Canada (British Columbia), ?7.15% versus ?5.6% in Hong Kong and ?2.9% versus ?4.2% in Taiwan. Conclusions: In Asia‐Pacific, overall mortality and morbidity rates are high and trends in mortality and morbidity vary between countries/regions. Differences in rates and trends for men and women most likely reflect the different trends in historical and prevalent smoking profiles for COPD in the different countries and regions.     

Morbidity and maternal and infant outcomes of hypertensive disorder in pregnancy in China in 2018

Hypertensive disorder in pregnancy is a disease that occurs during pregnancy. We aimed to analyze the morbidity and maternal and infant outcomes with respect to the hypertensive disorder in pregnancy in China in 2018. Clinical data of 38 590 cases from 161 hospitals were retrospectively collected. The differences in morbidity and maternal and infant mortality among the major regions and provinces were compared. The overall national average morbidity was 4.74%, and the ratios of gestational hypertension, preeclampsia, eclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia were 29.17%, 55.02%, 0.66%, 6.53%, and 8.62%, respectively. The overall maternal mortality was 0.61/100 000, and the case fatality was 0.13%. Morbidity associated with hypertensive disorder in pregnancy was 7.74% in North China, 6.62% in Northwest China, 6.40% in Central China, 5.83% in Northeast China, 4.28% in East China, 3.85% in South China, and 2.88% in Southwest China. The morbidity in each province was 1.62‐11.28%. The overall perinatal mortality was 3.59% (81.09% for stillbirths; 18.91% for neonatal deaths). Perinatal mortality decreased with increasing gestational weeks from 24 to 37 + 6 weeks. Perinatal mortality for delivery at 32 weeks of gestation in all regions of the country was <10%. Morbidity varied across regions in China, with the lowest in Southwest and the highest in North China. The low maternal mortality is related to the large‐scale development of standardized maternal health care in China. For severe hypertensive disorder patients, gestation should be prolonged to 32 weeks as often as possible for better neonatal survival rates.     

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.