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。     

Diffuse cavernous hemangioma of the rectosigmoid colon

Diffuse cavernous hemangioma of the rectosigmoid colon is an uncommon benign vascular lesion. We report 5 cases of diffuse cavernous hemangioma, focusing on the clinical features, diagnosis procedure and treatment. Five patients have undergone sphincter–saving procedures, 3 cases had coloanal sleeve anastomoses and 1 patient each had pull–through anastomosis and lower anterior resection. During the follow–up, which ranged from 3 to 10 years, 3 patients had no further anal bleeding and 2 patients had minor intermittent anal bleeding. Continence for normal stool was satisfactory in all patients. In conclusion, sphincter–saving procedure is most appropriate and curative approach for the treatment of diffuse cavernous hemangioma. Imaging study plays an important role in the diagnosis, preoperative staging and follow–up.     

酪氨酸激酶受体RON在胰腺癌中的表达及意义

目的:研究酪氨酸激酶RON(recepteur d'origine nantais)在胰腺癌组织中的表达及其意义.方法:收集胰腺癌组织及相关癌旁组织31例.正常胰腺组织8例,采用免疫组织化学技术检测组织中RON的表达.结果:RON在正常胰腺组织、癌旁组织、胰腺癌组织中均见阳性表达,胰腺癌及癌旁中的表达强度高于正常胰腺组织,胰腺癌RON的表达强度强于癌旁组织(P＜0.05).RON表达与患者年龄、肿瘤大小、组织学类型和肿瘤部位等均无关,与胰腺癌临床分期、分化程度及淋巴结转移相关(P＜0.05).结论:RON表达量的增多与胰腺癌的发生、发展有关.     

A prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis

Mycophenolate mofetil (MMF) with prednisolone has been associated with high remission rates when used as induction treatment for lupus nephritis. This prospective, multicentre, cohort study investigates the efficacy and safety of this regimen over 24 weeks in 213 Chinese patients with active lupus nephritis (Classes III, IV, V or combination). Baseline activity index (AI) was 6.91+/-3.33 and chronicity index (CI) was 1.9+/-1.2. The remission rate was 82.6% at 24 weeks (complete remission, 34.3%; partial remission, 48.4%). There were significant (P<0.01) improvements in kidney function shown by reductions in proteinuria, serum albumin, serum creatinine and creatinine clearance, as well as in systemic lupus erythematosus disease activity index (SLEDAI) scores. Independent risk factors influencing remission were pathological classification (including Class V and III or Class V and IV nephritis) and elevated serum creatinine at baseline (OR 2.967, 95% CI: 1.479-6.332, P=0.001 and OR 1.007, 95% CI: 1.002-1.011, P=0.001, respectively). Patients with concomitant membranous features on biopsy had a lower remission rate than those with Class III and IV nephritis (66.7% vs 87.3%, P=0.002). Renal biopsy was repeated in 25 patients following treatment. There was a transition to less severe pathological morphologies in majority of subjects. Infections were monitored throughout treatment: eight patients (3.8%) experienced bacterial infections, whereas herpes zoster occurred in seven patients. Nine patients (4.2%) suffered from gastrointestinal upset, which resolved without discontinuation of MMF. One patient became leucopenic, whereas another died from active disease unrelated to kidney symptoms. MMF combined with prednisolone is an effective and well-tolerated induction treatment for patients with active lupus nephritis and for controlling SLE systemic activity.