Association between metabolic syndrome, diabetes mellitus and prostate cancer risk.

BACKGROUND: The worldwide incidence of diabetes mellitus is rapidly increasing. There is recent interest in the influence of glucose metabolism on oncogenesis. We investigated the role of diabetes mellitus and the metabolic syndrome (MS) on prostate cancer development. METHODS: This study consisted of 11 541 men with coronary heart disease screened to participate in a secondary cardiac prevention trial. MS was defined according to modified NCEP/ATP III criteria. Multivariable regression analysis accounting for competing risks was performed using a modified Cox proportional hazard model in order to assess the association between diabetes, the MS and the subsequent development of prostate cancer. RESULTS: At baseline, subjects were classified into one of the four groups: (1) 6119 (53%) with neither diabetic mellitus nor MS, (2) 3376 (29%) with the MS but without diabetes, (3) 560 (5%) with diabetes mellitus but without MS and (4) 1486 (13%) with both conditions. Median follow-up was 12.7 years (range 0-15.7 years). During follow-up, 459 new cases of prostate cancer were recorded. The age-adjusted hazard ratio (HR) for prostate cancer was reduced in diabetic patients compared with those without diabetes, 0.54 and 95% confidence interval of 0.40-0.73. No significant association was noted between the presence of MS and prostate cancer development. On multivariate analysis, diabetes mellitus continued to protect against the development of prostate cancer, this was more pronounced in the absence of MS (HR=0.43, P=0.01 for diabetes in the absence of MS; HR=0.64, P=0.08 in the presence of MS). CONCLUSIONS: The results of this study indicate an inverse association between type 2 diabetes mellitus and prostate cancer risk.

Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis.

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E(2) (proapoptotic) and lipoxin (LX)A(4) (pronecrotic). Although PGE(2) protects against necrosis, virulent Mtb induces LXA(4) and inhibits PGE(2) production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.

C-reactive protein distribution and correlates among men and women with chronic coronary heart disease.

BACKGROUND: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. METHODS: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. RESULTS: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. CONCLUSIONS: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.

Cardiovascular risk factors and clinical presentation in acute coronary syndromes.

OBJECTIVE: To investigate the hypothesis that risk factors may be differently related to severity of acute coronary syndromes (ACS), with ST elevation used as a marker of severe ACS. DESIGN: Cross sectional study of patients with ACS. SETTING: 103 hospitals in 25 countries in Europe and the Mediterranean basin. PATIENTS: 10,253 patients with a discharge diagnosis of ACS in the Euro heart survey of ACS. MAIN OUTCOME MEASURES: Presenting with ST elevation ACS. RESULTS: Patients with ACS who were smokers had an increased risk to present with ST elevation (age adjusted odds ratio (OR) 1.84, 95% confidence interval (CI) 1.67 to 2.02). Hypertension (OR 0.65, 95% CI 0.60 to 0.70) and high body mass index (BMI) (p for trend 0.0005) were associated with less ST elevation ACS. Diabetes mellitus was also associated with less ST elevation, but only among men. Prior disease (infarction, chronic angina, revascularisation) and treatment with aspirin, beta blockers, or statins before admission were also associated with less ST elevation. After adjustment for age, sex, prior disease, and prior medication, smoking was still significantly associated with increased risk of ST elevation (OR 1.53, 95% CI 1.38 to 1.69), whereas hypertension was associated with reduced risk (OR 0.75, 95% CI 0.69 to 0.82). Obesity (BMI > 30 kg/m2 versus < 25 kg/m2) was independently associated with less risk of presenting with ST elevation among women, but not among men. CONCLUSION: Among patients with ACS, presenting with ST elevation is strongly associated with smoking, whereas hypertension and high BMI (in women) are associated with less ST elevation, independently of prior disease and medication.

Improved prognosis of patients presenting with clinical markers of spontaneous reperfusion during acute myocardial infarction.

OBJECTIVE: To describe the clinical features, management, and prognosis of patients presenting with clinical markers of spontaneous reperfusion (SR) during acute myocardial infarction (AMI). DESIGN: Cohort study. SETTING: National registry of 26 coronary care units. PATIENTS: 2382 consecutive patients with AMI. MAIN OUTCOME MEASURES: Patient characteristics, management, and mortality. RESULTS: The incidence of SR was 4% of patients (n = 98) compared with thrombolytic treatment (n = 1163, 49%), primary angioplasty (n = 102, 4%), and non-reperfusion (n = 1019, 43%). SR patients were more likely to develop less or no myocardial damage as indicated by a higher percentage of non-Q wave AMI (58% v 32%, 47%, and 44%, respectively, p < 0.0001), aborted AMI (25% v 9%, 8%, and 12%, p < 0.001), and lower peak creatine kinase (503 v 1384, 1519, and 751 IU, p < 0.0001). SR patients, however, were more likely to develop recurrent ischaemic events (35% v 17%, 12%, and 16%, respectively; p < 0.001) and subsequently were more likely to be referred to coronary angiography (67%), angioplasty (41%), or bypass surgery (16%, p < 0.001). Mortality at 30 days (1% v 8%, 7%, and 13%, respectively, p < 0.0001) and one year (6% v 11%, 12%, and 19%, p < 0.0001) was significantly lower for SR patients than for the other subgroups. By multivariate analysis, SR remained a strong determinant of 30 day survival (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.01 to 0.74). At one year, the association between SR and survival decreased (OR 0.49, 95% CI 0.18 to 1.13). CONCLUSIONS: Clinical markers of SR are associated with greater myocardial salvage and favourable prognosis. The vulnerability of SR patients to recurrent ischaemic events suggests that they need close surveillance and may benefit from early intervention.

A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).

AIMS: To better delineate the characteristics, treatments, and outcomes of patients with acute coronary syndromes (ACS) in representative countries across Europe and the Mediterranean basin, and to examine adherence to current guidelines. METHODS AND RESULTS: We performed a prospective survey (103 hospitals, 25 countries) of 10484 patients with a discharge diagnosis of acute coronary syndromes. The initial diagnosis was ST elevation ACS in 42.3%, non-ST elevation ACS in 51.2%, and undetermined electrocardiogram ACS in 6.5%. The discharge diagnosis was Q wave myocardial infarction in 32.8%, non-Q wave myocardial infarction in 25.3%, and unstable angina in 41.9%. The use of aspirin, beta-blockers, angiotensin converting enzyme inhibitors, and heparins for patients with ST elevation ACS were 93.0%, 77.8%, 62.1%, and 86.8%, respectively, with corresponding rates of 88.5%, 76.6%, 55.8%, and 83.9% for non-ST elevation ACS patients. Coronary angiography, percutaneous coronary interventions, and coronary bypass surgery were performed in 56.3%, 40.4%, and 3.4% of ST elevation ACS patients, respectively, with corresponding rates of 52.0%, 25.4%, and 5.4% for non-ST elevation ACS patients. Among patients with ST elevation ACS, 55.8% received reperfusion treatment; 35.1% fibrinolytic therapy and 20.7% primary percutaneous coronary interventions. The in-hospital mortality of patients with ST elevation ACS was 7.0%, for non-ST elevation ACS 2.4%, and for undetermined electrocardiogram ACS 11.8%. At 30 days, mortality was 8.4%, 3.5%, and 13.3%, respectively. CONCLUSIONS: This survey demonstrates the discordance between existing guidelines for ACS and current practice across a broad region in Europe and the Mediterranean basin and more extensively reflects the outcomes of ACS in real practice in this region.

Effect on survival of acute myocardial infarction in Killip classes II or III patients undergoing invasive coronary procedures.

The purpose of the present study was to determine whether patients with acute myocardial infarction (AMI) in Killip class II or III are likely to benefit from catheterization and coronary revascularization performed within 30 days of AMI. The study population was drawn from 2 national surveys performed during 1996 and 1998 in 26 coronary care units operating in Israel. Our analysis included 3,113 patients with AMI who were divided into 2 groups according to their admission Killip class: 2,484 patients (80%) in Killip class I, of whom 1,408 (57%) underwent cardiac catheterization and 1,076 were treated noninvasively; and 629 patients in Killip class II or III, of whom 314 (50%) underwent cardiac catheterization and 315 were managed conservatively. Patients in Killip class II or III who were treated invasively had lower mortality rates than their counterparts who were treated noninvasively at 30 days: 7.6% versus 15.6%, respectively (adjusted odds ratio [OR] 0.52, 95% confidence interval [CI] 0.28 to 0.92), and thereafter from 30 days to 6 months, 4.3% versus 13.6%, respectively (OR 0.34, 95% CI 0.16 to 0.68). In Killip class I patients, an invasive versus noninvasive management was not associated with a better outcome at 30 days: 1.6% versus 3.2%, respectively (OR 0.58, 95% CI 0.32 to 1.05), but with similar mortality rates at 30 days to 6 months, 1.9% versus 2.0%, respectively (OR 1.46, 95% CI 0.79 to 2.74). Thus, the present study suggests that patients with AMI in Killip class II or III on admission may benefit from cardiac catheterization and revascularization performed within 30 days from admission, whereas patients with AMI in Killip class I are less likely to benefit from this approach.

Long-term diuretic therapy in patients with coronary disease: increased colon cancer-related mortality over a 5-year follow-up.

OBJECTIVES: Recent studies have suggested that long-term diuretic therapy may be associated with increased risk of renal cell carcinoma. This carcinoma is not a common malignancy, but it shares risk factors with the considerably more widespread colon cancer (CC). However, there are no data whether or not a relationship between long-term diuretic therapy and CC mortality exists. In this study we tested the hypothesis that long-term diuretic therapy may be associated with increased CC mortality over a 5.6-year follow-up period. SUBJECTS AND METHODS: The study sample comprised 14 166 patients aged 45 to 74 years with a previous myocardial infarction and/or stable anginal syndrome, screened for participation in the bezafibrate infarction prevention (BIP) study. There were 2153 patients receiving diuretics and 12 013 patients receiving no diuretics. RESULTS: During the follow-up 139 (6.5%) new cases of cancer were diagnosed in the diuretic-treated group compared with 622 (5.2%) in the group receiving no diuretics (P = 0.02). Colon cancer mortality was significantly higher in the diuretic-treated patients (0.1 vs 0.5%, P = 0.001), whereas mortality differences for other cancer types were not documented. Multivariate analysis identified diuretics as an independent predictor of increased colon cancer incidence and colon cancer mortality with a hazard ratio (HR) of 2.0 (95% CI 1.2-3.2) for colon cancer incidence and 3.7 (95% CI 1.7-8.3) for mortality. However, the association between diuretic therapy and higher incidence of colon cancer was observed only among non-users of aspirin. A relatively lower colon cancer incidence was observed in the furosemide subgroup, and higher in the small combined amiloride/hydrochlorthiazide subgroup (HR 3.15, 95% CI 1.15-8.65). CONCLUSION: Long-term exposure to diuretic therapy may be associated with an increased colon cancer-related mortality.

Prognosis of patients with a recurrent acute myocardial infarction before and in the reperfusion era--a national study.

BACKGROUND: Patients with recurrent acute myocardial infarction (AMI) are at increased risk for morbidity and mortality. We compared the outcome of patients with recurrent AMI hospitalized in coronary care units in the prereperfusion and reperfusion eras. METHODS: The study population comprised 2 large-scale cohorts with recurrent AMI: (1) 1415 (24%) of 5839 consecutive patients with AMI hospitalized in 1981 to 1983 (Secondary Prevention Reinfarction Israeli Nifedipine Trial [SPRINT] Registry) and (2) 1093 (25%) of 4317 patients with AMI from three national surveys performed in 1992 to 1996. RESULTS: Patients in the 1990s had significantly lower rates of heart failure and cardiogenic shock. The 7-day mortality declined from 18% in 1981-1983 to 10% in 1992-1996 (adjusted odds ratio [OR] 0.57 [0.44-0.75]), the 30-day mortality rate from 26% to 16% (OR 0.56 [0.44-0.71]), and the 1-year mortality rate from 39% to 26% (adjusted hazard ratio [HR] 0.64 [0.54-0.75]), respectively. In the 1992-1996 cohort, the adjusted risk of 7-day, 30-day, and 1-year mortality for patients with recurrent AMI treated with thrombolysis in comparison to patients without thrombolysis was OR 1.69 (1.07-2.65), 1.52 (1.03-2.23), and HR 1.18 (0.90-1.55), respectively. The mortality rate among patients treated with early percutaneous transluminal coronary angioplasty/coronary artery bypass grafting was 3% versus 12% at 7 days (OR 0.36 [0.16-0.73]), 7% versus 18% at 30 days (OR 0.45 [0.25-0.77]), and 16% versus 29% at 1 year (HR 0.64 [0.46-0.96]), in comparison to patients without revascularization. CONCLUSION: The prognosis of patients with recurrent AMI improved significantly during the reperfusion era. Although thrombolysis may have a limited therapeutic effect among patients with recurrent AMI, an interventional approach seems more appropriate when indicated. A randomized trial of thrombolysis versus early revascularization is needed in patients with recurrent AMI.

Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S.

NK1.1(+) T cells develop and function through interactions with cell surface CD1 complexes. In I-A(b) mice lacking the invariant chain (Ii) processing enzyme, cathepsin S, NK1.1(+) T cell selection and function are impaired. In vitro, thymic dendritic cells (DCs) from cathepsin S(-/-) mice exhibit defective presentation of the CD1-restricted antigen, alpha-galactosylceramide (alpha-GalCer). CD1 dysfunction is secondary to defective trafficking of CD1, which colocalizes with Ii fragments and accumulates within endocytic compartments of cathepsin S(-/-) DCs. I-A(k), cathepsin S(-/-) mice do not accumulate class II-associated Ii fragments and accordingly do not display CD1 abnormalities. Thus, function of CD1 is critically linked to processing of Ii, revealing MHC class II haplotype and cathepsin S activity as regulators of NK T cells.

Sex differences in management and outcome after acute myocardial infarction in the 1990s: A prospective observational community-based study. Israeli Thrombolytic Survey Group.

BACKGROUND: Previous studies have suggested that women with acute myocardial infarction (AMI) are less aggressively managed than are men. The aim of this study was to assess sex differences in medical and invasive coronary procedures (angiography, PTCA, and CABG) in AMI patients admitted to cardiac care units (CCUs) in Israel in the mid 1990s and their association with early and 1-year prognosis. METHODS AND RESULTS: We studied 2867 consecutive AMI patients (2125 men, 74%) hospitalized in all 25 CCUs in Israel from 3 prospective nationwide surveys conducted in 1992, 1994, and 1996. Women were, on average, older than men (69 versus 61 years, P:<0.0001) and had a higher prevalence of hypertension, diabetes, Killip class >/=II on admission, and in-hospital complications. Women received aspirin and beta-blockers less often than did men, but these differences were not significant after age adjustment. The unadjusted rates of thrombolysis, angiography, and PTCA/CABG use were lower in women than in men but not after covariate adjustment: 42% versus 48% (adjusted odds ratio [OR] 0.92, 95% CI 0.77 to 1.11), 23% versus 31% (OR 0.88, 95% CI 0.70 to 1.09), and 15% versus 19% (OR 0.93, 95% CI 0.72 to 1.19), respectively. The 30-day mortality was higher in women than in men (17.6% versus 9.6%, respectively; OR 1.39, 95% CI 1.06 to 1.82), but the 30-day to 1-year mortality rate was not (9.1% versus 5.6%, respectively; hazard ratio 1.18, 95% CI 0.84 to 1.66). CONCLUSIONS: This prospective nationwide observational community-based study of consecutive AMI patients hospitalized in the CCUs in the mid 1990s indicates that women fare significantly worse than do men at 30 days but not thereafter at 1-year. The difference in 30-day outcome was not influenced by the use of different therapeutic modalities, including thrombolysis and invasive coronary procedures, but was rather due to the older age and greater comorbidity of women; these findings seem also to explain the less frequent use of invasive procedures in women.

Murine CD1d-restricted T cell recognition of cellular lipids.

NKT cells are associated with immunological control of autoimmune disease and cancer and can recognize cell surface mCD1d without addition of exogenous antigens. Cellular antigens presented by mCD1d have not been identified, although NKT cells can recognize a synthetic glycolipid, alpha-GalCer. Here we show that after addition of a lipid extract from a tumor cell line, plate-bound mCD1d molecules stimulated an NKT cell hybridoma. This hybridoma also responded strongly to three purified phospholipids, but failed to recognize alpha-GalCer. Seven of sixteen other mCD1d restricted hybridomas also showed a response to certain purified phospholipids. These findings suggest NKT cells can recognize cellular antigens distinct from alpha-GalCer and identify phospholipids as potential self-antigens presented by mCD1d.

Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up.

Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45-74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10-1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90-1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients.

Long-term (three-year) prognosis of patients treated with reperfusion or conservatively after acute myocardial infarction. Israeli Thrombolytic Survey Group.

OBJECTIVES: This survey sought to assess the frequency of the use of thrombolytic therapy, invasive coronary procedures (ICP) (angiography, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting [CABG]), variables associated with their use, and their impact on early (30-day) and long-term (3-year) mortality after acute myocardial infarction (AMI). BACKGROUND: Few data are available regarding the implementation in daily practice of the results of clinical trials of treatments for AMI and their impact on early and long-term prognosis in unselected patients after AMI. METHODS: A prospective community-based national survey was conducted during January-February 1994 in all 25 coronary care units operating in Israel. RESULTS: Among 999 consecutive patients with an AMI (72% men; mean age 63+/-12 years) acute reperfusion therapy (ART) was used in 455 patients (46%; thrombolysis in 435 patients [44%] and primary angioplasty in 20 [2%]). Its use was independently associated with anterior AMI location and hospitals with on-site angioplasty facilities, whereas advancing age, prior myocardial infarction (MI) and prior angioplasty or CABG were independently associated with its lower use. The three-year mortality of patients treated with ART was lower than in counterpart patients (22.0% vs. 31.4%, p = 0.0008), mainly as the result of 30-day to 3-year outcome (12.4% vs. 21.1%; hazard ratio = 0.73, 95% confidence interval [CI] 0.52 to 1.03). Independent predictors of long-term mortality were: age, heart failure on admission or during the hospitalization, ventricular tachycardia or fibrillation and diabetes. The outcome of patients not treated with ART differed according to the reason for the exclusion, where patients with contraindications experienced the highest three-year (50%) mortality rate. After ART, coronary angiography, angioplasty and CABG were performed in-hospital in 28%, 12% and 5% of patients, respectively. Their use was independently associated with recurrent infarction or ischemia, on-site catheterization or CABG facilities, non-Q-wave AMI and anterior infarct location. In the entire study population, and in patients with a non-Q-wave AMI, performance of ICP was associated with lower 30-day mortality (odds ratio [OR] = 0.53, 95% CI 0.25 to 0.98, and OR = 0.21, 0.03 to 0.84, respectively), but not thereafter. CONCLUSIONS: This survey demonstrates the extent of implementation in daily practice of ART and ICP and their impact on early and long-term prognosis in an unselected population after AMI.

Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis.

Cellular immunity against Mycobacterium tuberculosis controls infection in the majority of infected humans. Studies in mice have delineated an important role for CD4(+) T cells and cytokines including interferon gamma and tumor necrosis factor alpha in the response to infection with mycobacteria. Recently, the identification of CD8(+) CD1-restricted T cells that kill M. tuberculosis organisms via granulysin and the rapid death after infection of beta2 microglobulin deficient mice in humans has drawn attention to a critical role for CD8(+) T cells. The nature of mycobacterial-specific CD8(+) T cells has been an enigma because few have been identified in any species. Here, we delineate the contribution of class I MHC-restricted T cells in the defense against tuberculosis as transporter associated with antigen processing (TAP)1-deficient mice died rapidly, bore a greater bacterial burden, and had more severe tissue pathology than control mice. In contrast, CD1D-/- mice were not significantly different in their susceptibility to infection than control mice. This data demonstrates a critical role for TAP-dependent peptide antigen presentation and provides further evidence that class I MHC-restricted CD8(+) T cells, the major T cell subset activated by this antigen processing pathway, play an essential role in immunity to tuberculosis.

Diverse TCRs recognize murine CD1.

Human and murine T cells that specifically recognize CD1d and produce IL-4 and IFN-gamma play a role in immunoregulation and tumor rejection. In the mouse, most CD1d1-reactive T cells described express an invariant Valpha14-Jalpha281 TCR associated with TCR beta-chains of limited diversity. Similarly, human CD1d-reactive T cells express a highly restricted TCR repertoire. Here we report the unexpected result that in mice immunized with CD1d1-bearing transfectant cells, a diverse repertoire of TCRs was expressed by CD1d1-reactive T cell clones isolated by limiting dilution without preselection for NK1 expression. Only 3 of 10 CD1d1-reactive T cell clones expressed the invariant Valpha14-Jalpha281 TCRalpha rearrangement. T cells expressing Valpha10, -11, -15, and -17, and having non-germline-encoded nucleotides resulting in diverse V-J junctions were identified. Like CD1d1-reactive T cells expressing the invariant Valpha14-Jalpha281 TCR alpha-chain, CD1d1-reactive clones with diverse TCRs produced both Type 1 (IFN-y) and Type 2 (IL-4, IL-10) cytokines. This establishes the existence of significant diversity in the TCRs directly reactive to the CD1d1 protein. Our findings reveal that CD1d interacts with a broad array of TCRs, suggesting substantial redundancy and flexibility of the immune system in providing T cells serving the role(s) mediated by CD1d reactivity.

Prognosis of patients with a first non-Q-wave myocardial infarction before and in the reperfusion era. SPRINT and the Israeli Thrombolytic Survey Groups. Secondary Prevention Reinfarction Israeli Nifedipine Trial.

BACKGROUND: The reported incidence of non-Q-wave acute myocardial infarction (AMI) has increased in the thrombolytic era. Data comparing prognosis among these patients before and after the advent of the thrombolytic era are scarce. METHODS: We compared the early and late prognosis among 2 cohorts of consecutive patients with a first non-Q-wave AMI hospitalized in the coronary care units operating in Israel: 610 patients from 1981 to 1983 and 225 patients in 1994. RESULTS: The proportion of patients with non-Q-wave AMI increased from 14% in 1981 to 1983 to 32% in 1994. Baseline characteristics in both periods were comparable. In-hospital management of patients differed during the last decade. Patients in 1994 received aspirin, angiotensin-converting enzyme inhibitors, beta-blockers, and nitrates more frequently than in the period 1981 to 1983. Thrombolytic therapy, coronary angiography, and percutaneous transluminal coronary angioplasty or coronary artery bypass grafting were not used during the index hospitalization in the early 1980s, whereas in 1994 these procedures were used in 28%, 38%, 19%, and 6% of patients, respectively. In-hospital complications, including arrhythmias, conduction disturbances, and heart failure, were less frequent in 1994 compared with the period 1981 to 1983. The 7- and 30-day crude mortality rates were significantly lower in 1994 compared with the early 1980s (5% vs 9% and 5% vs 13%, respectively, P < .05 for both), whereas the 1-year crude mortality rate decreased slightly (15% vs 19%, P = .13). Multivariate analyses adjusting for pertinent variables revealed a decreased risk for death in 1994 versus 1981 to 1983; for 7-day (odds ratio = 0.49, 95% confidence interval 0.23 to 0.94), 30-day (odds ratio = 0.36, 95% confidence interval 0.18 to 0.69) and for 1-year (odds ratio = 0.65, 95% confidence interval 0.44 to 0.96). CONCLUSION: The prognosis of patients with a first non-Q-wave AMI has improved considerably during the last decade. The introduction of new therapeutic modalities, including invasive cardiac procedures and new medications, probably played a major role in the favorable outcome of these patients.

Nifedipine and cancer mortality: ten-year follow-up of 2607 patients after acute myocardial infarction.

Recent publications contended that the use of short-acting calcium antagonists may double the risk of cancer incidence and possibly increase mortality in hypertensive patients. The purpose of this study was to assess the risk ratio for cancer mortality associated with nifedipine in a large population of patients post-myocardial infarction. Cancer mortality data, over a 10-year period, were obtained on 2607 hospital survivors of acute myocardial infarction who were screened, but not included, in the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT I) study. In this group of patients, 526 (20%) were on nifedipine, according to their treating physicians' decision. In the cohort of screened patients not included in SPRINT I, there were 22 (4.2%) cancer-related deaths in the patients on nifedipine compared with 114 (5.5%) in the group not treated with nifedipine (P = 0.23). In multivariate analysis, the 10-year cancer mortality risk ratio associated with nifedipine therapy was 1.06 (95% CI 0.52-2.18). The current analysis shows no evidence of an increased risk of cancer mortality in a large number of patients treated at baseline with nifedipine.

The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage.

Helicobacter pylori infection is associated with gastric epithelial damage, including apoptosis, ulceration, and cancer. Although bacterial factors and the host response are believed to contribute to gastric disease, no receptor has been identified that explains how the bacteria attach and signal the host cell to undergo apoptosis. Using H. pylori as "bait" to capture receptor proteins in solubilized membranes of gastric epithelial cells, class II major histocompatibility complex (MHC) molecules were identified as a possible receptor. Signaling through class II MHC molecules leading to the induction of apoptosis was confirmed using cross-linking IgM antibodies to surface class II MHC molecules. Moreover, binding of H. pylori and the induction of apoptosis were inhibited by antibodies recognizing class II MHC. Since type 1 T helper cells are present during infection and produce interferon (IFN)-gamma, which increases class II MHC expression, gastric epithelial cell lines were exposed to H. pylori in the presence or absence of IFN-gamma. IFN-gamma increased the attachment of the bacteria as well as the induction of apoptosis in gastric epithelial cells. In contrast to MHC II-negative cell lines, H. pylori induced apoptosis in cells expressing class II MHC molecules constitutively or after gene transfection. These data describe a novel receptor for H. pylori and provide a mechanism by which bacteria and the host response interact in the pathogenesis of gastric epithelial cell damage.