FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty-seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.     

Oxalate-induced ceramide accumulation in Madin-Darby canine kidney and LLC-PK1 cells

BACKGROUND: Oxalate exposure produces oxidant stress in renal epithelial cells leading to death of some cells and adaptation of others. The pathways involved in these diverse actions remain unclear, but appear to involve activation of phospholipase A2 (PLA2) and redistribution of membrane phospholipids. The present studies examined the possibility that oxalate actions may also involve increased accumulation of ceramide, a lipid-signaling molecule implicated in a variety of pathways, including those leading to apoptotic cell death. METHODS: Ceramide accumulation was examined in renal epithelial cells from pig kidney (LLC-PK1 cells) and from dog kidney [Madin-Darby canine kidney (MDCK cells)] using the diacylglycerol kinase assay. Sphingomyelin degradation was assessed by monitoring the disappearance of 3H-sphingomyelin from cells that had been prelabeled with [3H]-choline. The effects of oxalate were compared with those of other oxidants (peroxide, xanthine/xanthine oxidase), other organic acids (formate and citrate), and a known activator of sphingomyelinase in these cells [tumor necrosis factor-alpha (TNF-alpha)]. Separate studies determined whether oxalate-induced accumulation of ceramide could be blocked by pretreatment with antioxidants [Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin (Mn TMPyP, a superoxide dismutase mimetic) or N-acetylcysteine (NAC; an antioxidant)], with an inhibitor of ceramide synthase [fumonisin B1 (FB1)] or with an inhibitor of PLA2 [arachidonyl trifluoromethylketone (AACOCF3)]. RESULTS: Oxalate exposure produced a significant time- and concentration-dependent increase in cellular ceramide. A reciprocal decrease in 3H-sphingomyelin was observed under these conditions. Increases in cellular ceramide levels were also observed after treatment with other oxidants (hydrogen peroxide, and xanthine/xanthine oxidase), activators of sphingomyelinase (TNF-alpha), exogenous sphingomyelinase, or arachidonic acid. Formate produced similar (albeit smaller) effects, and citrate did not. The oxidant-induced increases in ceramide were attenuated by pretreatment with NAC (a glutathione precursor) and MnTMPyP (a superoxide dismutase mimetic), suggesting a role for cellular redox states. The oxalate-induced increase in ceramide was also attenuated by pretreatment with AACOCF3, suggesting a role for PLA2. Pretreatment with FB1 produced a small but statistically insignificant attenuation of the response to oxalate. CONCLUSIONS: Oxalate exposure produces a marked accumulation of ceramide in renal epithelial cells by a process that is redox sensitive and mediated in part by activation of PLA2. Since cellular sphingomyelin decreased as ceramide increased, it seems likely that oxalate actions are mediated, at least in part, by an increase in sphingomyelinase activity, although alterations in ceramide synthase are also possible. Further study is required to define the steps involved in oxalate actions and to determine the extent to which ceramide signaling mediates oxalate actions.     

Multimodal fusion of structural and functional brain imaging in depression using linked independent component analysis

Previous structural and functional neuroimaging studies have implicated distributed brain regions and networks in depression. However, there are no robust imaging biomarkers that are specific to depression, which may be due to clinical heterogeneity and neurobiological complexity. A dimensional approach and fusion of imaging modalities may yield a more coherent view of the neuronal correlates of depression. We used linked independent component analysis to fuse cortical macrostructure (thickness, area, gray matter density), white matter diffusion properties and resting‐state functional magnetic resonance imaging default mode network amplitude in patients with a history of depression (n = 170) and controls (n = 71). We used univariate and machine learning approaches to assess the relationship between age, sex, case–control status, and symptom loads for depression and anxiety with the resulting brain components. Univariate analyses revealed strong associations between age and sex with mainly global but also regional specific brain components, with varying degrees of multimodal involvement. In contrast, there were no significant associations with case–control status, nor symptom loads for depression and anxiety with the brain components, nor any interaction effects with age and sex. Machine learning revealed low model performance for classifying patients from controls and predicting symptom loads for depression and anxiety, but high age prediction accuracy. Multimodal fusion of brain imaging data alone may not be sufficient for dissecting the clinical and neurobiological heterogeneity of depression. Precise clinical stratification and methods for brain phenotyping at the individual level based on large training samples may be needed to parse the neuroanatomy of depression.     

The brain‐derived neutrophic factor val66met polymorphism and sudden unexpected infant death

Aim: Findings of hypoxia prior to death and involvement of a dysregulation of the serotonergic network in sudden infant death syndrome (SIDS) may indicate that brain‐derived neutrophic factor (BDNF) also is of importance with regard to sudden unexpected infant death. Based on this, the purpose of this study was to investigate the BDNF val66met polymorphism in SIDS cases, cases of infectious death and controls. Methods: The polymorphism was investigated in 163 SIDS cases, 34 cases of infectious death and 121 controls, using real‐time PCR and fluorescence melting curve analysis. Results: There were no differences in val66met genotype distribution between neither the SIDS cases nor the cases of infectious death and controls (p = 0.95 and p = 0.52, respectively). Conclusion: The study indicates that the val66met polymorphism is not important for sudden unexpected infant death. However, several other SNPs in the BDNF gene, as well as in other genes involved in this pathway, including G‐protein, have to be investigated to fully exclude any involvement of BDNF in SIDS.     

国产利培酮（索乐）治疗精神分裂症多中心开放性临床研究

目的：评价国产利培酮（索乐）治疗精神分裂症的疗效和安全性。方法：通过对全国45家精神病医院的962例精神分裂症患者进行多中心,大样本,开放性的为期8周的治疗观察。采用PANSS、CGI、SAS和TESS评定疗效和不良反应。结果：国产利培酮（索乐）对精神分裂症总有效率84.3%,临床总体疗效肯定,不良反应轻,主要是轻度的锥体外系反应,体重增加,因其程度轻,病人基本能耐受。结论：国产利培酮（索乐）对精神分裂症阳性症状及阴性症状均有效,起效快,安全性高,患者对该药依从性好,可作为精神分裂症的首选药物之一。     

发挥科研优势 促进学科发展

<正> 暨南大学医学院第一附属医院,又名广州华侨医院,经过20年的发展已成为一所集医、教、研为一体的大型三级甲等医院。医院的科研发展始终坚持"以学科建设为基础,人才培养是关键"的科研办院思路,从建院初期以调入人才为主到目前的以人才引进为辅、培养人才为主,20年来培养了一批中青年学术带头人,形成了一批技术力量强大的学科群。从建院初期仅有眼科学、内科学(血液病专业)2个硕士学位授与点发展到现在拥有眼科学、内科学、妇产科学3个博士学位、14个硕士学位授权点,1998年还被国家教委批准为临床医学专业学位授与点的试点单位。在各类学术期刊上发表文章3089篇,主编及参与编写171部专著,承担各级科研课题695项,获国家科技进步奖1项,省部级成果奖25项,厅局级科技进步奖69项,获专利9项。医院在培育科研优势的同时更注意发挥学科优势促进学科的发展。     

Sodium chloride as regulator of renal prostaglandin E2 production in patients with essential hypertension

Summary The effect of dietary sodium intake (5 days' low salt, 4 days' high salt) on 24-h urinary prostaglandin E₂ (PGE₂) and prostaglandin F₂ (PGF₂) excretion, blood pressure (BP), and plasma renin activity (PRA) was evaluated in 16 patients with essential hypertension. Sodium restriction significantly increased urinary PGE₂ excretion (p<0.05) from 151±76 to 328±94 ng/24 h, while high salt intake reduced renal PGE₂ production to 114±41 ng/24 h (p<0.05). There was a moderate but not significant increase in urinary PGF₂ excretion on the low salt regimen, which was reversed under high salt diet. Systolic and diastolic blood pressure fell from 162±11 to 145±10 mm Hg, i.e., 102±6 to 90±9 mm Hg on low sodium intake (35 mEq/day) and returned to levels close to control after 4 days on a high salt diet (250 mEq/day). Under low salt conditions, PRA increased significantly (p<0.001) from 0.83±0.33 to 2.82±1.12 ng AI/ml/h and fell to 0.45±0.31 ng AI/ml/h on high salt regimen (p<0.001).The results demonstrate that dietary sodium chloride intake modulates renal PGE₂ production in patients with essential hypertension. The depressed PGE₂ production under high salt conditions may play a role in regulation of renal vascular resistance and influence sustainment of chronic hypertensive disease.Supported by Deutsche Forschungsgemeinschaft     

Increased apical targeting of renal epithelial sodium channel subunits and decreased expression of type 2 11beta-hydroxysteroid dehydrogenase in rats with CCl4-induced decompensated liver cirrhosis

It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11beta-hydroxysteroid dehydrogenase (11betaHSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl(4) (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of alpha-ENaC was unchanged, whereas beta-ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The gamma-ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of alpha-, beta-, and gamma-ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.