Effect of beta-blockers on the mortality of Japanese patients with myocardial infarction

BACKGROUND: After a myocardial infarction, a higher prevalence of coronary vasospastic response has been reported in the Japanese population than in the Caucasian population. Beta-blockers may exacerbate coronary vasospasm. However, beta-blockers are given to Japanese patients after an acute myocardial infarction, though the mortality benefit is unknown. Thus, we investigated the mortality benefit of beta-blockers given to Japanese patients after an acute myocardial infarction. METHODS: We prospectively studied consecutive patients with a first myocardial infarction admitted to the coronary care unit of Kansai Medical University Hospital, Osaka, Japan from May 1994 through the end of 2001. Patients who died during hospitalization or who were referred for coronary artery bypass graft surgery were excluded. The association of beta-blocker use with mortality after discharge was assessed by a proportional hazards regression analysis. RESULTS: There were 546 patients and 400 (73.3%) patients were treated with beta-blockers at the time of discharge from hospital. During a mean follow-up of 2 years, 46 (8.4%) patients died. Beta-blocker therapy was associated with a reduced mortality after adjustment for age, gender, Q wave myocardial infarction, reperfusion therapy during acute phase, Killip functional class, serum creatinine level, cardiovascular risk factors, and medications (hazard ratio=0.51, 95% confidence interval=0.27 to 0.95). CONCLUSIONS: Contrary to the concern that beta-blocker therapy might induce coronary vasospasm and reduce survival, beta-blocker therapy improved survival after discharge in Japanese patients with a first myocardial infarction.     

Immune responses to Nippostrongylus brasiliensis and tuberculin protein in GATA-3-transgenic mice

GATA-3 appears to be key to the Th2 response. However, few in vivo experiments have examined the function of GATA-3 in Th1 and Th2 immune responses. We developed two lines of GATA-3-transgenic (Tg) mice harboring the SRalpha or lck promoters and examined the Th2 immune responses of mice infected with the intestinal nematode Nippostrongylus brasiliensis and the Th1 responses with purified derivative of tuberculin (PPD) immunization. Numbers of peripheral blood eosinophils in all GATA-3-Tg mice increased 10- to 20-fold after primary infection with N. brasiliensis and 25-100-fold after secondary infection. The number of eosinophils in infected GATA-3-Tg mice was significantly higher than that in infected control littermates. Total IgE levels after primary infection in GATA-3-Tg mice were 8-450-fold increased, which was significantly higher than those of control mice. Mesenteric lymph node cells of infected GATA-3-Tg mice upon stimulation with N. brasiliensis antigen secreted more IL-5 and IL-13 than those of control mice. However, production of IL-4 and IFN-gamma were comparable between GATA-3-Tg and controls. Mice immunized with PPD were intradermally challenged with PPD to induce delayed type hypersensitivity (DTH). The amount of footpad swelling caused by the DTH reaction in GATA-3-Tg mice was significantly smaller than that of control littermates. Inguinal lymph node cells from GATA-3-Tg mice stimulated with PPD in vitro secreted more IL-5, IL-10 and less IFN-gamma than those of control littermates. These results suggested that Th1 and Th2 driven conditions enhance IL-5 production in GATA-3-Tg mice through the direct binding of GATA-3 to the IL-5 promoter region. The influence of GATA-3 on IL-13, IFN-gamma and IL-10 production varied according to the stimulating conditions. However, IL-4 production was not significantly elevated in GATA-3-Tg mice, indicating that IL-4 and IL-5 production was differentially regulated in these mice.     

The impact of new-onset diabetes on arterial stiffness after renal transplantation

New-onset diabetes after renal transplantation (NODAT) is known to be a potent risk factor for cardiovascular events. We therefore investigated the incidence and risk factors for NODAT, and evaluated surrogate endpoints of atherosclerosis in Japanese patients with stable renal function after renal transplantation. Seventy-nine patients were enrolled in the study, and a 75 g oral glucose tolerance test (OGTT) was performed in subjects excluding patients with known NODAT. We evaluated the risk factors for NODAT and the degree of atherosclerosis, determined by brachial-ankle pulse wave velocity (baPWV), ankle-brachial blood pressure index (ABPI) and intima-media thickness (IMT) of the carotid artery. Eleven patients diagnosed as NODAT had significantly higher fasting plasma glucose before transplantation, blood pressure, and incidence of hepatitis C virus (HCV) infection than patients without NODAT. Multivariate regression analysis revealed that the independent determinant of NODAT was fasting plasma glucose pre-transplantation, HCV infection and systolic blood pressure. The baPWV in patients with NODAT was significantly higher compared to that in patients without NODAT. In addition, the independent determinant of baPWV evaluated by multivariate regression analysis was an increase in systolic blood pressure and age, and a decrease of adiponectin levels. In conclusion, we found that high fasting plasma glucose prior to transplantation, HCV infection and high blood pressure are risk factors for NODAT in Japanese patients after renal transplantation. Since NODAT patients have advanced arterial stiffness probably due to high blood pressure, strict control of blood pressure will be important for preventing the development of cardiovascular disease in NODAT.     

A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice

Tight junctions (TJs) maintain cellular polarity between the apical and basolateral region of epithelial cells. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier function of TJs. We previously found that a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), may be a promising candidate for improving the mucosal absorption of drugs. C-CPE is a fragment of enterotoxin, and putative CPE claudin receptors are highly expressed in liver and kidney. The safety and antigenicity of C-CPE must be evaluated for future clinical application. Therefore, we evaluated whether C-CPE administration in mice leads to tissue injury or production of antibodies. Intravenous administration of C-CPE at 5 mg/kg, which is a more than 25-fold higher dose than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury even after 11 injections once a week. Nasal C-CPE administration (2 mg/kg) once a week for 11 administrations also did not increase these biochemical markers, but 6 administrations of C-CPE resulted in elevation of C-CPE-specific serum IgG. These results indicate that development of a less antigenic claudin modulator will be essential for future clinical application of a C-CPE-based mucosal absorption enhancer.     

Comparison of speedy PCR-ssp method and serological typing of HLA-A24 for Japanese cancer patients

Human leukocyte antigen (HLA) typing is essential to carry out HLA-class I restricted antigenic peptide-based cancer immunotherapy. To establish a one-step polymerase chain reaction-sequence-specific primer (PCR-SSP) method, we designed two novel HLA-A24-specific primer sets and determined the optimal conditions for specific amplification. Then, we performed HLA-A24 typing of two healthy donors' and 17 cancer patients' peripheral blood with serological typing and PCR-SSP typing. Eleven of the 19 cases were determined HLA-A24-positive by the PCR-SSP method precisely; however, five cases showed false positive with serological analysis. Thus, for HLA-A24 typing in the Japanese population, the PCR-SSP method is faster and more accurate than serological typing.