17-β estradiol attenuates ovariectomy-induced changes in cardiomyocyte contractile function via activation of AMP-activated protein kinase

Menopause increases the risk of cardiometabolic diseases in women. This circumstance is usually attributed to a deficiency in circulating estrogen levels although the underlying mechanism remains elusive. Given the pivotal role of AMP-activated protein kinase (AMPK) in the regulation of energy metabolism and cardiac function, this study was designed to examine the role of AMPK in estrogen deficiency and replacement-exerted cardiomyocyte responses. Adult female WT and AMPK kinase dead (KD) mice were subjected to bilateral ovariectomy (OVX) or sham operation. A cohort of ovariectomized mice received 17β-estradiol (E2) (40 μg/kg/day, i.p.) for 6 weeks. Mechanical and intracellular Ca²⁺ properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90%-relengthening (TR₉₀), and maximal velocity of shortening/relengthening (±dL/dt). Levels of AMPK, Akt JNK, ACC, SERCA, membrane Glut4, AS160 and PGC-1α were assessed using Western blot. OVX significantly decreased PS, ±dL/dt and intracellular Ca²⁺ rise in responsible to electric stimulus, prolonged TR₉₀ and intracellular Ca²⁺ decay without affecting TPS and resting intracellular Ca²⁺, the effects of which were reconciled by E2 replacement. Western blot analysis depicted that OVX suppressed phosphorylation of Akt AMPK and ACC although it promoted JNK phosphorylation, the effects of which were mitigated or significantly attenuated by E2 treatment in WT but not KD mice. Moreover, OVX procedure downregulated SERCA2a and membrane Glut4 while inhibiting AS160 phosphorylation without affecting PGC-1α levels. In vitro study revealed that E2 corrected cardiomyocyte contractile dysfunction elicited by OVX in cardiomyocytes from WT but not the AMPK kinase dead mice. Taken together, these data suggest that E2 treatment ameliorates estrogen deficiency-induced changes in cardiac contractile function possibly through an AMPK-dependent mechanism.     

Seroepidemiology of hepatitis A virus infection among school children in Delhi and north Indian patients with chronic liver disease: implications for HAV vaccination

BACKGROUND: Universal vaccination against hepatitis A virus (HAV) has been recommended for children because of the changing epidemiological pattern of HAV. Vaccination has also been advised for patients with chronic liver disease as HAV superinfection in these patients can result in severe or even fatal disease. In India, the indications for HAV vaccination are not clear due to contradictory seroepidemiological data in children and lack of data on HAV seroprevalence in patients with chronic liver disease. METHODS: Sera were collected from children studying in two government-run schools and from patients with chronic liver disease attending the Liver Clinic at the All India Institute of Medical Sciences (AIIMS). The sera were tested for anti-HAV antibodies. The incidence of HAV-induced acute hepatitis and acute liver failure at AIIMS over the last 10 years was also assessed. RESULTS: A total of 93.2% (1328/1424) of the school children between 4-18 years of age who were included in the study had anti-HAV antibody in their sera. Eighty percent of the children had antibodies against HAV in their sera by the age of 5 years, whereas all the children above 16 years were positive for anti-HAV antibody. A total of 256 patients with chronic liver disease (94 with cirrhosis of the liver, 160 with chronic hepatitis) were tested for the presence of anti-HAV antibody. Of them, 97.6% (248/254) had anti-HAV antibody in their sera. The annual frequency of HAV-induced acute viral hepatitis and acute liver failure at AIIMS during the last 10 years did not show any change. CONCLUSION: Mass vaccination against HAV is not required in north India because of the presence of protective antibodies against HAV in the majority of the population.     

Biphasic effects of haloperidol on sodium currents in guinea pig ventricular myocytes

Aim： To study the effects of haloperidol on sodium currents （INa） in guinea pig ventricular myocytes. Method： Whole-cell patch clamp technique was employed to evaluate the effects of haloperidol on INa in individual ventricular myocytes. Results： Haloperidol （0.1-3 wnol/L） inhibited INa in a concentration-dependent manner with an IC50 of 0.253±0.015 larnol/L. The inhibition rate of haloperidol （0.3 μmol/L） on INa was 22.14%±0.02%, and the maximum conductance was reduced. Haloperidol significantly reduced the midpoints for the activation and inactivation of INa by 2.09 and 4.09 mV, respectively. The time constant of recovery was increased. The increase in time intervals could only recover by 90.14%±1.4% （n=6）; however, haloperidol at 0.03 μmol/L enhanced INa conductance. The midpoints for the activation and inactivation Of INa were shifted by 1.38 and 5.69 mV, respectively, at this concentration of haloperidol. Conclusion： Haloperidol displayed a biphasic effect on INa in guinea pig cardiac myocytes. High concentrations of haloperidol inhibited INa, while lower concentrations of haloperidol shifted the activation and inactivation curve to the left. Full recovery of recovery curve was not achieved after 0.3 μmol/L haloperidol administration, indicating that the drug affects the inactivated state of sodium channels.     

老年甲状腺功能亢进症146例临床分析

目的 探讨老年甲状腺功能亢进(甲亢)患者临床表现及甲状腺激素、血糖、血脂代谢特点,从而引出临床诊断及治疗的注意事项.方法 随机抽取甲亢Graves'病患者146例.根据年龄分为老年组(年龄≥60,n=56)和非老年组(年龄＜60,n=90),对病例行回顾性分析.结果 (1)老年组临床症状不典型发生率较非老年组高,差异有统计学意义(χ2=36.12,P<0.05).老年组甲状腺结节、心律失常、房颤、心衰的发生率较非老年组明显升高,而弥漫性甲状腺肿大、突眼的发生率明显低于非老年组,差异有统计学意义(χ2=41.67,P<0.05);(2)老年组血清总三碘甲状腺原氨酸(TT3)、血清总甲状腺素(TT4)、游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)较非老年组低,而促甲状腺素(TSH)、空腹血糖、总胆固醇、甘油三酯、低密度脂蛋白、载脂蛋白-B、载脂蛋白-α比非老年组高,差异有统计学意义(P＜0.05).结论 (1)老年甲亢患者临床症状不典型,甲状腺结节、心律失常、房颤、心衰的发生率高,而甲状腺弥漫性肿大、突眼的发生率较低;(2)老年甲亢患者TT3、TT4的测定没有FT3、FT4敏感,TSH明显高于非老年患者;(3)老年甲亢患者易出现糖、脂代谢紊乱,且临床易误诊、漏诊.     

新疆焉耆县奶牛巴氏杆菌病诊断报告

2007年5月13日至2007年6月16日,在新疆焉耆县永宁镇下岔河村养殖小区奶牛发生一起以败血症和炎症性出血过程为特征的传染病,经过流行病学调查、临床症状、病理变化、病原分离鉴定以及动物试验等方法最终确诊为巴氏杆菌病.采取了综合防治措施后控制了本病的流行.     

Evaluation of procollagen-III peptide as a marker for veno-occlusive disease after bone marrow transplantation

 Procollagen-III peptide (PIIIP) has been suggested as a marker for hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). Using the RIA-gnost PIIIP assay, we examined frozen plasma samples from three groups of patients. The groups included (A) four patients with clinically proven VOD, (B) nine patients with remarkably uneventful post-BMT courses, and (C) patients with either early complications other than VOD or pulmonary fibrosis in their later course. In group A, PIIIP levels increased parallel to the clinical course, with maximum values of 2.7–5.5 units/ml. In group B, values did not exceed 1.4 units/ml. In group C, higher values were occasionally observed. In one patient with early relapse of a lymphoma PIIIP peaks correlated with episodes of fever and graft versus host disease (GVHD). In another patient mild VOD seems possible retrospectively. The highest levels (>15 units/ml) occurred in one patient with ileus. Several patients with interstitial pneumonia (IP), adult respiratory distress syndrome (ARDS), or lung fibrosis showed increases in PIIIP levels corresponding to the clinical course; most of these events occurred later than day 30 after BMT. One patient with severe GVHD of the liver showed a maximum of only 1.4 units/ml. PIIIP elevation correlated with clinical VOD and may help to differentiate it from hepatic GVHD. In the presence of other complications (pulmonary, gastrointestinal), some caution in interpreting the results may be advisable. Received: 21 September 1995 / Accepted: 20 March 1996     

低氧条件下食管癌细胞中PRRX1通过p53介导线粒体通路诱导细胞凋亡的研究

目的:探究低氧条件下配对相关同源框1（PRRX1）通过p53介导的线粒体通路诱导食管癌细胞凋亡。方法:GEPIA2数据库分析PRRX1基因在食管癌组织和正常食管组织中的表达变化。RT-qPCR和Western blotting分别检测HEEC、Eca-109、TE-1细胞中PRRX1的mRNA和蛋白表达。二氧化钴处理模拟低氧微环境,在常氧和低氧条件下检测Eca-109、TE-1细胞中PRRX1的mRNA和蛋白表达情况。采用小干扰RNA（Si-PRRX1）转染TE-1细胞,设置分组为Hypoxia-Si-NC、Hypoxia-Si-PRRX1。流式细胞术检测TE-1细胞凋亡,RT-qPCR检测p53 mRNA表达,Western blotting检测p53、BCL-2、BAX、Cleaved-Caspase3等蛋白表达,在TE-1-PRRX1 KO细胞系中过表达p53,检测 BCL-2、BAX、Cleaved-Caspase3等蛋白表达。结果:PRRX1在食管癌组织及细胞系中均高表达。在TE-1细胞中敲低PRRX1,抑制细胞凋亡,下调p53的mRNA及蛋白表达,抑制BAX、Cleaved-Caspase3蛋白表达,促进BCL-2蛋白表达;过表达PRRX1则上调p53蛋白表达。在TE-1-PRRX1 KO细胞系中过表达p53显著抑制BCL-2蛋白表达,促进BAX、Cleaved-Caspase3蛋白表达。结论:低氧条件下,PRRX1通过p53介导的线粒体通路诱导食管癌细胞凋亡。     

Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction

AMPK, a metabolic sensor, protects against ischemic injury and cardiac hypertrophy although its role in obesity is unclear. This study was designed to examine the impact of AMPK deficiency on cardiac dysfunction following high fat feeding. Adult WT and transgenic mice overexpressing a kinase dead (KD) α2 isoform (K45R mutation) of AMPK were fed a low or high fat diet for 20 weeks. DEXA was used to confirm adiposity. Wheat germ agglutinin immunostaining was used to evaluate myocardial histology. Myocardial function was evaluated using echocardiography and edge-detection. AMPK activity was analyzed using fluorescence polarization assays. [1-¹⁴C] oleate was used to determine fatty acid oxidation. Expression of AMPK, α1, α2, ACC, Akt, the Glut-4 translocation mediator Akt substrate of 160KD (AS160), mTOR, total and membrane Glut-4 was evaluated using Western blot. AMPK activity was decreased in KD mice regardless of diet regimen. High fat diet led to obesity, glucose intolerance and cardiac hypertrophy with accentuated glucose intolerance, dampened fatty acid oxidation and cardiac hypertrophy in KD mice. High fat feeding triggered lower fractional shortening, increased LV mass, left ventricular end diastolic/systolic diameter, decreased PS, ± dL/dt, prolonged TR₉₀ and intracellular Ca²⁺ mishandling with a more pronounced effect in KD mice. High fat diet and AMPK KD lessened AMPKα2 isoform activity and ACC phosphorylation. AMPK deficiency unveiled or accentuated high fat diet-induced decrease in phosphorylation of Akt and AS160, membrane fraction of Glut-4 and mTOR expression (a greater mTOR phosphorylation). Taken together, these data suggest that AMPK deficiency exacerbates obesity-induced cardiac hypertrophy and contractile dysfunction, possibly associated with AS160 and mTOR signaling.     

Neuroendocrine-immune disorder in type 2 diabetic patients with retinopathy

1. Diabetes mellitus is usually accompanied by hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis. Diabetic retinopathy is one of the most devastating complications in diabetes although little is known with regards to the HPA activity in type 2 diabetic patients (T2DM) with diabetic retinopathy. The present study was designed to evaluate the HPA axis activity in type 2 diabetic patients with diabetic retinopathy. 2. Diabetic retinopathy was examined by fluorescein fundus angiography (FFA) in 174 consecutive type 2 diabetic patients. Levels of / were measured using flow cytometry. Serum concentrations of interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α), adrenocorticotrophic hormone (ACTH) and cortisone were measured by radioimmunoassay. Plasma levels of monoamines norepinephrine (NE) and dopamine (DA) were assessed using high performance liquid chromatograph equipped with a fluorescence detection. Patients were grouped into the non-diabetic retinopathy (NDR), non-proliferating diabetic retinopathy (NPR) and proliferating diabetic retinopathy (PDR) categories. 3. Patients with PDR showed significantly less than those with NDR and NPR (P<0.05). No significant correlation was found in / and NK or severity of retinopathy among the three patient groups. There was no significant difference in serum IL-1β, IL-6 and TNF-α levels among the different patient groups (P>0.05). The serum concentrations of ACTH and cortisone were lower in PDR patients than other groups. There was no significant difference in plasma concentrations of DA and NE among all three groups (P>0.05). 4. Our data suggest that HPA and immune dysfunction might play a role in the development and/or progression of PDR.