Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis

We analyzed gene expression patterns in human gastric cancers by using cDNA microarrays representing approximately equal 30,300 genes. Expression of PLA2G2A, a gene previously implicated as a modifier of the Apc(Min/+) (multiple intestinal neoplasia 1) mutant phenotype in the mouse, was significantly correlated with patient survival. We confirmed this observation in an independent set of patient samples by using quantitative RT-PCR. Beyond its potential diagnostic and prognostic significance, this result suggests the intriguing possibility that the activity of PLA2G2A may suppress progression or metastasis of human gastric cancer.     

蒿甲醚和青蒿琥酯对感染曼氏血吸虫小鼠治疗作用的初步研究

目的了解蒿甲醚和青蒿琥酯对小鼠曼氏血吸虫作用的效果.方法将小鼠随机分成12个实验组及1个对照组,以皮下注射的方法,每鼠接种约80条尾蚴,接种尾蚴46 d后,分别以蒿甲醚或青蒿琥酯灌胃治疗,第1天,分别以400、300、200 mg/kg的剂量1次灌胃;第2～7天,则每天分别按以上剂量的半量灌胃,7 d灌胃的总剂量分别为1 600、1 200、800 mg/kg.总量1剂组,在第7天,分别按1 600、1 200、800 mg/kg剂量1次灌胃.另设感染阳性对照组,不加治疗. 结果蒿甲醚7日疗法1 600、1 200、800 mg/kg剂量组减虫率分别为53.0%、49.0%和53.0%,减雌率为78.0%～82.0%,总量1剂组效果与7日疗法基本相同.青蒿琥酯7日疗法相应剂量减虫率分别为16.0%、37.0%和49.0%.结论蒿甲醚和青蒿琥酯对小鼠曼氏血吸虫具有一定的杀虫效果,蒿甲醚在疗效和毒性方面稍佳.     

Trends in cardiovascular drug utilization and drug expenditures in Canada between 1996 and 2001

BACKGROUND: There is increasing interest in studying trends in drug utilization because drug costs are the fastest growing sector of the health care system. OBJECTIVES: To focus on the trends in the utilization of and expenditures for cardiovascular drugs in Canada by drug class and by province over a six-year period. METHODS: Data from the IMS Health Canada CompuScript Audit database were used for this study from the period of February 1996 to January 2002. Patterns of drug utilization and expenditures in Canada were described for cardiovascular drug classes, individual agents within classes and by provincial analyses. RESULTS: Substantial increases in both the utilization of and the expenditures for cardiovascular medications have occurred in Canada over the last six years. Newer medication classes such as angiotensin converting enzyme inhibitors and statins now comprise the majority of cardiovascular drugs prescribed, along with continued high use of diuretics. Increases in some drug classes, such as angiotensin converting enzyme inhibitors, statins and beta-blockers, appear to be based on trial evidence or guidelines. However, marketing may play a larger role in the increases in use of angiotensin receptor blockers and specific drugs, such as amlodipine besylate and atorvastatin, because their increased utilization cannot be explained by major clinical trial evidence and/or practice guidelines. CONCLUSIONS: Changes in patterns of cardiovascular drug utilization and expenditures in Canada may be associated with clinical trial evidence, clinical practice guidelines, policy changes and/or marketing initiatives.     

Trends in heart failure outcomes and pharmacotherapy: 1992 to 2000

PURPOSE: To review trends in drug therapy and concomitant outcomes of elderly heart failure patients in Ontario, Canada. METHODS: Utilization of drug therapies, mortality, and rehospitalization rates from April 1992 to March 2000 were determined in 77,421 elderly (aged >/=65 years), community-based heart failure patients using linked administrative databases. Treatment effects were identified from published meta-analyses and randomized trials. The effect of drug trends on mortality and morbidity were assessed based on their absolute treatment effects. RESULTS: From 1992 to 2000, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use increased from 58% to 62% (P = 0.001) while beta-blocker use increased from 6% to 22% (P <0.001). There was a decrease in the use of treatments for which no survival advantage had been demonstrated in randomized trials, such as digitalis (49% to 35%, P <0.001), Vaughan-Williams class I antiarrhythmic agents (3.5% to 1.4%, P <0.001), and first-generation calcium antagonists (21.3% to 9.6%, P <0.001). The trends in drug therapy were associated with a 2.8% reduction in age-, sex-, and comorbidity-adjusted 1-year mortality and a 4.1% reduction in 1-year hospitalization rates. The observed trends in therapy over time explained 37% of the decrease in mortality and 30% of the decrease in rehospitalization rates. The treatment effect from beta-blockers was most pronounced, explaining 30% of the decrease in mortality and 10% of the decrease in rehospitalization rates. CONCLUSION: During 1992 to 2000, mortality and morbidity improved among elderly patients with heart failure, with increased utilization of beta-blockers contributing most to the beneficial trends in outcomes.     

GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans

GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABA_AR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.

Innate immunity, an evolutionally conserved behavior, constitutes the first defense line of multiple organisms to prevent microbial infections (1). The nematode Caenorhabditis elegans has been used as a model host for human opportunistic pathogen Pseudomonas aeruginosa infection (2) to identify evolutionarily conserved mechanisms of innate immunity. Typically, p38/PMK-1 mitogen-activated protein kinases (MAPKs) (3) and insulin/insulin-like signaling (IIS)/DAF-2 signaling cascades are recognized as two key components of the C. elegans intestinal innate immune response upon P. aeruginosa strain PA14 infection (4), as they are in mammals (3, 4). Moreover, increasing evidence has revealed several neural mechanisms as also being involved in the regulation of innate immunity. For example, G protein–coupled receptor (GPCR) NPR-1– and soluble guanylate cyclase GCY-35–expressing sensory neurons actively suppress the immune response of nonneuronal tissues (5). Additionally, a putative octopamine GPCR, OCTR-1, which is expressed and functions in the C. elegans sensory neurons ASH and ASI (6), down-regulates the unfolded protein response genes pqn/abu to further suppress the immune response of nonneuronal tissues (5, 6).Recent studies demonstrate that dopaminergic signaling inhibits innate immunity (7) whereas neuronal acetylcholine stimulates muscarinic signaling in the epithelium and activates the epithelial canonical Wnt pathway to promote the ability to defend against bacterial infection (8). Moreover, insulin-like peptide INS-7 secreted by the nervous system functions in a cell-nonautonomous manner to activate the IIS/DAF-2 pathway and modulate the intestinal innate immunity of C. elegans (9).GABAergic signaling constitutes a major inhibitory neurotransmission system that plays crucial roles in the central nervous system, especially for maintaining the balance between excitation and inhibition of neuronal networks (10). Disruption of this balance is not only linked to several neuropsychiatric disorders including schizophrenia, autism, and epilepsy (11) but also implicated in autoimmune disease (12). Up to date, multiple lines of evidence have shown that GABAergic signaling cell-autonomously modulates the immune response in immune cells (13–15). However, the roles of GABAergic synapses in innate immunity remain unknown.Here, we found that the nematode C. elegans harboring a deficiency in GABAergic neuromuscular junctions (NMJs) exhibits enhanced resistance to pathogens. P. aeruginosa PA14 infection increases synaptic expression of GABAergic synaptic components at the nerve cord of worms and enhances the strength of GABAergic transmission. Moreover, we identified an insulin-like peptide, INS-31, acting downstream of GABAergic NMJs and in body wall muscle (BWM) to control intestinal innate immunity in a cell-nonautonomous manner. This work reveals a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.     

Protection by nitecapone against sodium taurocholate-induced damage to cultured gastric cells

The goal of this study was to observe if nitecapone protected against taurocholate-induced damage in primary cultured rat gastric mucosal cells, as well as in a well-differentiated human gastric epithelial cell line (MKN 28). Prostaglandins were measured to analyze the protection mechanism. In primary rat gastric mucosal cell culture, nitecapone 125–250 M protected the cells significantly against damage induced by sodidum taurocholate, increasing cell viability by 31–38%. In the human gastric epithelial cell line, in which mitochondrial activity was measured as an indication of cell viability, nitecapone (62.5–250 M) protected the cells against sodium taurocholate-induced damage by 12–20%. Prostaglandin E₂, thromboxane B₂, and 6-keto-prostaglandin F₁ measurements in the primary cultured rat gastric mucosal cells showed that nitecapone (125 M and 250 M) significantly stimulated prostaglandin E₂ production (84.7% and 61.0%, respectively), and inhibited thromboxane B₂ formation (50% at 250 M), while the 6-keto-prostaglandin F₁ formation was unaffected. Nitecapone had no effect on prostaglandin E₂ production in the MKN 28 epithelial cell line. Indomethacin or aspirin, at concentrations that did not affect cell viability, antagonized the stimulative effect of nitecapone on prostaglandin E₂ formation in the primary cultured rat gastric mucosal cells. Although the prostaglandin E₂ synthesis was blocked, nitecapone still protected against cell damage induced by taurocholate. These results demonstrated the direct and efficacious protection of nitecapone on gastric cell level and suggest that the cytoprotection by nitecapone against taurocholate may not be mediated through the mechanism of stimulated synthesis of prostaglandin E₂.     

Correlation of Chlamydia pneumoniae infection with primary biliary cirrhosis

AIM: To evaluate the association between Chlamydia pneumoniae (Cpn) infection and primary biliary cirrhosis (PBC). METHODS: Cpn IgG and IgM were determined by enzyme-linked immunosorbent assay (ELISA) in 41 well-established PBC patients and two race-matched control groups (post-hepatitis cirrhosis, n = 70; healthy controls, n = 57). RESULTS: The mean level and seroprevalence of Cpn IgG in PBC group and post-hepatitis cirrhosis (PHC) group were significantly higher than those in healthy controls (46.8+/-43.4 RU/mL, 49.5+/-45.2 RU/mL vs 28.3+/-32.7 RU/mL; 68.3%, 71.4%, 42.1%, respectively; P<0.05). There was a remarkably elevated seroprevalence of Cpn IgM in patients with PBC (22.0%) compared to the PHC and healthy control (HC) groups. For the PBC patients versus the HCs, the odds ratios (ORs) of the presence of Cpn IgG and IgM were 2.7 (95% CI 0.9-6.1) and 5.1 (95% CI 1.4-18.5), respectively. Though there was no correlation in the level of Cpn IgG with total IgG in sera of patients with PBC (r = -0.857, P = 0.344>0.05), Cpn IgM was related with the abnormally high concentrations of total IgM in PBC group. CONCLUSION: The results of this study do not support the hypothesis that infection with Chlamydia pneumoniae may be a triggering agent or even a causative agent in PBC, but suggest that Chlamydia pneumoniae infection probably contributes to the high level of IgM present in most patients with PBC.     

Low incidence of deep venous thrombosis after laparoscopic cholecystectomy

The effects of the increased intraabdominal pressure that occurs during laparoscopic cholecystectomy and the effects of the reverse Trendelenburg position adopted for the procedure on deep venous thrombosis (DVT) were investigated prospectively. Thirty patients who underwent laparoscopic and 13 who underwent open cholecystectomy for symptomatic cholelithiasis were investigated for postoperative DVT. Lower extremity venous blood flow was examined by color Doppler ultrasonography before and after operations. Thrombus formation was not found in the femoral, popliteal, or iliac veins of any of the patients who underwent either open or laparoscopic cholecystectomy. None of the patients in either group displayed signs of DVT or pulmonary embolus. We concluded that the incidence of DVT does not increase with laparoscopic cholecystectomy.     

核内胞质性自噬体导致肝癌细胞和肝细胞特殊性核溶解与细胞死亡

探索核内胞质性自噬体的结构和性能,从肝组织内选择17例肝细胞癌和患有其他疾病的肝细胞。核内胞质会被核膜隔离和降解,被破坏的胞质会损伤自身胞膜和除核膜以外的周围核组织,导致特殊性核溶解和细胞死亡。