Involvement of cyclooxygenase, phospholipase C and MAP kinase pathways in human platelet aggregation mediated by the synergistic interaction of adrenaline and PAF

This study was conducted to examine the mechanism(s) of synergistic interaction of adrenaline and platelet-activating factor (PAF) mediated human platelet aggregation. We found that platelet aggregation mediated by subthreshold concentrations of PAF (5-8 nM) plus adrenaline (0.5-2 M) was inhibited by both ₂-adrenoceptor blocker (yohimbine) and PAF receptor antagonist (WEB2086). While examining the role of the downstream signalling pathways, we found that this synergism was inhibited by calcium channel blockers, verapamil, and diltiazem. In addition, platelet aggregation by co-addition of adrenaline and PAF was also inhibited by very low concentrations of phospholipase C (PLC) inhibitor (U73122; IC₅₀ = 0.2 _M), the MAP kinase inhibitor, PD98059 (IC₅₀ = 3 _M) and cyclooxygenase (COX-1) inhibitors including indomethacin (IC₅₀= 0.25 _M), flurbiprofen (IC₅₀ = 0.7 _M) and piroxicam (IC₅₀ = 7 _M). However, the COX-2 inhibitor, nimesulide, was also effective in inhibiting the aggregation. The inhibitors of tyrosine kinase (genistien) and phosphatidylinositol 3-kinase inhibitor (wortmannin) had no significant effects on platelet aggregation. These data suggest that the synergistic effect of adrenaline and PAF on human platelet aggregation is receptor-mediated and involves the activation of PLC/calcium, COX and MAP kinase signalling pathways.     

Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer

Pancreatic cancer cells are usually resistant to apoptosis mediated by tumor necrosis factor (TNF)-alpha or FasL, and their toxicity towards normal cells hampers their application for therapeutic use. TNF-related apoptosis-inducing ligand (TRAIL), a novel member of the TNF family, triggers apoptosis in a variety of malignant cells, but exhibits less cytotoxicity in normal cells. To investigate the therapeutic potential of TRAIL, we analyzed the expression of TRAIL and its apoptosis-inducing receptors (DR4 and DR5) in the normal and cancerous human pancreas, and the sensitivity of pancreatic cancer cells to TRAIL cytotoxicity. TRAIL, DR4 and DR5 mRNA levels were concomitantly increased in pancreatic cancers compared with normal controls (P<0.01), and there were positive correlations between the expression levels of TRAIL and DR4, TRAIL and DR5 and between DR4 and DR5 mRNA (r=0.85, r=0.87, r=0.91; P<0.01). Immunostaining revealed the presence of the corresponding proteins frequently within the same cancer cells. In five pancreatic cancer cell lines, TRAIL, DR4 and DR5 mRNA expression was detectable at various levels. However, independent of the presence of DR4 and DR5, TRAIL cytotoxicity assays revealed that pancreatic cancer cells showed a significantly lower sensitivity (LD(50)>85 ng/ml) to TRAIL treatment than Jurkat T lymphoma cells (LD(50)=7.2 ng/ml). These findings show that pancreatic cancers are insensitive towards TRAIL-mediated apoptosis despite expression of TRAIL and its receptors, suggesting the presence of mediators which inhibit the TRAIL cell-death-inducing pathway in pancreatic cancer cells.     

Cerebellar mutism caused by arteriovenous malformation of the vermis

Transient mutism following posterior fossa tumour resection in children is well known in the literature. To our Knowledge, this phenomenon has never been reported without surgical intervention. We report a case of cerebellar mutism secondary haemorrhage from a vermian arteriovenous malformation (AVM), which resolved to ataxic dysarthria after 6 weeks. Embolization of the AVM was performed and the patient's clinical status continued to improve gradually till she became normal 6 months from the insult. The mutism was due to rupture of the AVM which might correlate the cerebellar mutism with the transient vasospasm of the blood vessels supplying the cerebellum. It is possible for a spontaneus posterior fossa bleed to result in transient mutism similar to post surgical mutism.     

急性冠脉综合征后6个月死亡和心肌梗死的预测：前瞻性的多国观察性研究（GRACE）

目的:发现一种临床上可以用来预测的工具,以预测累计的6个月死亡或心肌梗死的危险,以方便对急性冠脉综合征患者的分类管理。设计:前瞻性的多国观察性研究,采用多变量回归的方法建立一个最终的预测模型。方法:选择GRACE(globalregistryofacutecoronaryevents,全球急性冠脉事件登记)研究中从1999年4月到2005年9月有(或无)ST段抬高的急性冠脉综合征患者43810例,他们来自欧洲、北美洲或南美洲、澳大利亚和新西兰等14个国家的94家医院。主要结果测量:死亡和心肌梗死。结果:1989例患者死于医院,1466例死于出院后的6个月随访期内,2793例发生了新…     

Amelioration of adjuvant-induced arthritis by ursolic acid through altered Th1/Th2 cytokine production.

The objective of the study was to investigate the activity of ursolic acid (UA) on proinflammatory (Th1) and anti-inflammatory (Th2) cytokines in the peripheral blood of arthritic balb/c mice. Ursolic acid is ubiquitous in the plant kingdom and is a constituent of numerous plants which are having diversified phylogenetic origin and taxonomic position. We applied Cytometric bead array (CBA) technology for simultaneously measurement of these cytokines in adjuvant inflammatory arthritis induced mice treated with ursolic acid in graded oral doses. Cytometric bead array uses the sensitivity of amplified fluorescence detection by flowcytometer to measure soluble analytes in a particle based immune assay. This assay can accurately quantitate five cytokines in a 50 microl sample volume. The T-helper (Th1) deviated cells produce detectable level of tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5). Oral administration of UA at doses of 10, 20, 40, 80 and 160 mg kg(-1) per oral dose inhibited the presence of IL-2, IFN-gamma and TNF-alpha in the peripheral blood.     

Medical ethics and Islam: principles and practice.

A minimum level of cultural awareness is a necessary prerequisite for the delivery of care that is culturally sensitive. In this paper we simplify and highlight certain key teachings in Islamic medical ethics and explore their applications. We hope that the insights gained will aid clinicians to better understand their Muslim patients and deliver care that pays due respect to their beliefs.     

Ethical and research dilemmas arising from a questionnaire study of psychological morbidity among general practice managers.

A questionnaire-based research project enquiring into the psychological health of general practice managers found that 5% of managers admitted to suicidal ideas. This paper explores the moral issues raised when research conducted at a distance uncovers information about participants which indicates that they may be at increased risk of harm. It examines whether the authors of such studies have responsibilities towards their research participants beyond those of analysing and properly interpreting the data supplied to them. The paper is an exercise in self-reflection and self-criticism; not all the questions posed and explored by it can be answered definitively. Implications for planning studies of this kind are discussed.     

Is there a sex or race difference in 30-day mortality after interruption of vena cava in a Medicare population?

PURPOSE: Disparities in health care and its outcome often indicate an opportunity for improving the quality of health care. Sex and rare differences in short-term mortality following interruption of vena cava are not known. The objective of this study was to determine such differences. MATERIALS AND METHODS: With use of Medicare administrative data, 1,823 interruption of vena cava procedures performed between 1994 and 1997 were identified among beneficiaries aged 65-99 years residing in Indiana and Kentucky. In Cox proportional hazard regression models, male-to-female and nonwhite-to-white 30-day mortality ratios were adjusted for age, sex or race, weighted Charlson comorbidity score, length of hospital stay, and fatal coexisting conditions (ascertained from death certificate data). RESULTS: Altogether, 277 patients died within 30 days after the procedure. Women were older than men. The comorbidity score was associated with male sex and mortality. There was no significant race difference in unadjusted or adjusted 30-day mortality after interruption of the vena cava. Unadjusted mortality was higher in men than in women (odds ratio, 1.49; 95% confidence interval [CI]=1.15, 1.92). Although adjustment for age, race, Charlson score, and length of hospital stay reduced the magnitude of sex difference, it remained significant. Further adjustment for fatal coexistent conditions reduced the sex difference to an insignificant level (odds ratio, 1.22; 95% CI=0.96, 1.56). CONCLUSIONS: There was no significant sex or race difference in adjusted 30-day mortality after interruption of vena cava procedure in the elderly Medicare beneficiary population of two states.