To evaluate regional LV function, regional pre-ejection contraction time (PECT), and pre-ejection contraction velocity (PECV) and early diastolic velocity (Emyo vel) were measured by M-mode tissue color Doppler in normal myocardium of 28 normal patients (pts), hypertrophic myocardium of 18 pts with hypertrophic cardiomyopathy and infarcted myocardium of 11 pts with myocardial infarction. Data were compared with global LV isovolumic contraction time (ICT) and early diastolic mitral flow velocity (Emv) measured by pulsed Doppler. PECT was significantly shorter than ICT in all patients. PECT was uniform in LV of the normal group. However, the mean PECT was shorter in hypertrophic myocardium, and longer in infarcted myocardium than that in normal myocardium. In both hypertrophic and infarcted myocardium, abnormalities of PECV and Emyo vel were detected easily while LV-ICT or Emv was within normal. M-mode tissue color Doppler methods are useful in distinguishing between normal, hypertrophic and infarcted myocardium more sensitively.

View full abstract

 A bolus injection of 5-HT (32μg/kg) into the right atrium immediately induced Bezold-Jarisch reflex (hypotension, bradycardia and apnea) and delayed bronchoconstriction (assumed by decreased air flow and increased intrapleural pressure) in anesthetized, spontaneously breathing rats. This bronchoconstrictor response was mimicked by α-methyl-5-HT (5-HT₂-receptor agonist: 32μg/kg), and 5-methoxytryptamine (5-HT₂-and 5-HT₄-receptor agonist: 32μg/kg), but not by 1-phenylbiguanide (5-HT₃-receptor agonist : 16μg/kg) or cisapride (5-HT₄-receptor agonist: 32μg/kg). To study the effects of 5-HT and α-methyl-5-HT on the airway dynamics, lung conductance (G_L ) and lung compliance (C_L) were calculated from flow rate, tidal volume and intrapleural pressure curves. Dose response curve (DRC) of 5-HT on GL or CL was not affected by granisetron (5 -HT₃-receptor antagonist: 0.05 mg/kg), but DRC of α-methyl-5-HT was significantly shifted to the right. Subsequently, both the DRCs of 5-HT and α-methyl-5-HT were shifted to the right by sarpogrelate (5-HT₂-receptor antagonist: 0.3, 1.0 mg/kg) in a dose-dependent manner. Moreover, the bronchoconstriction of 5-HT and α-methyl-5-HT (respectively 32μg/kg) were either abolished or potently reduced by bilateral, cervical vagotomy, but the bronchoconstriction response to 5-HT was partly recovered at 128μg/kg. Peak response latency of G_L were 9.14±0.39 sec in 5-HT (32μg/kg), suggesting that the response might be originated at the bronchial vascular bed. These results suggest that, at least in the rat, 1) 5-HT-induced bronchoconstriction is mediated by 5-HT₂-receptor, but not by 5-HT₃-or 5-HT₄- receptor, 2) sarpogrelate antagonizes 5-HT-induced bronchoconstriction in a dose-related manner, 3) 5-HT-induced bronchoconstriction is potently augmented by vagal reflex, but is primarily mediated by a direct action in the airway, 4) the possible site of action of intravenous 5-HT is the bronchial, not the pulmonary vascular bed.

View full abstract

Background: LVH is frequently found in diabetic and hypertensive patients at the initiation of dialysis therapy and is highly predictive of future cardiac morbidity and mortality. However, it is unknown whether the blockage of renin-angiotensin system will regress LVH or not in these patients using ACEi or AIIA or both of them in combination.
Method: Twenty four diabetic patients (62±3 years old; F/M: 8/16) with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from 5 dialysis units staffed by the faculty of Saitama Medical School, Saitama, Japan between 1996 and 1998. The study was carried out for 2 years. An ACEi, enalapril 5 mg daily or an AIIA, losartan 50 mg daily was assigned at random. These drugs were administered 30 min after the cessation of dialysis therapy and usually given after lunch when dialysis therapy was not received. The doses of these drugs were adjusted up to 10 mg or 100 mg daily respectively according to the levels of blood pressure. One year after the start of the study, if LVH was not regressed in spite of treatments with enalapril or losartan, add-on each other drug was done.
Results: Using repeated measures analysis of variance, applied to those with four echocardiograms, there were progressive decreases over time in LV mass index (LVMi: g/m2), posterior wall thickness, left ventricle end-diastolic diameter, interventricular thickness. The biggest changes in LVMi and other parameters found between the baseline and year 1 (147±14 vs. 138±12 g/m2). Combination therapy of enalapril and losartan for 7 patients who did not respond the initial therapy produced a significant reduction of LVH at the end of study. There was no significant difference in regression of LVH as well as blood pressure control and other variables between enalapril and losartan. Furthermore, there were significant correlations between the variables obtained from the repeated echocardiography related with LVH and systolic blood pressure in all patients.
Conclusion: Antihypertensive treatment with either ACEi or AIIA is beneficial in the regression of LVH in diabetic patients who started dialysis therapy. Moreover, a combination therapy with ACEi and AIIA would provide a favorable effect on LVH in those patients unless a single administration of ACEi or AIIA is effective.

View full abstract

 Interleukin-4 (IL-4), one of the key regulators of the Th1-Th2 balance, promotes the differentiation of CD4^＋ helper lymphocytes into Th2 cells. It is assumed that the Th1 predominance over Th2 has an important role in the development organ-specific autoimmune diseases, such as type 1 diabetes and Hashimoto’s thyroiditis. In the present study, therefore, we investigated the possible role of the IL-4 gene in type 1 diabetes and autoimmune thyroid disease. First, we screened for variations in the promoter region (position－1,105 to＋38; ＋1－ translation start site) and exons of the IL-4 gene in 24 patients by PCR direct sequencing, and detected five polymorphisms: C(－589)T, C(－144)T, C(－33)T, A363T and A8411C. Among them, A363T and A8411C are located in introns and were not further analyzed. Genotyping of other polymorphisms were performed by PCR-RFLP on 114 patients with type 1 diabetes, 92 patients with Graves’disease, 57 patients with Hashimoto’s thyroiditis and 221 control subjects. C(－144)T is a novel and relatively rare polymorphism, and it was revealed that the distribution of the C(－144)T genotypes was significantly different between type 1 diabetic patients and control subjects (p＝0.0035); the CT genotype was observed in six type 1 diabetic patients and one control subject, and the remainder were all CC genotype. The frequency of the CT genotype was also increased in patients with autoimmune thyroid disease compared to control subjects, but the difference was not significant. No significant difference was observed in the distribution of C(－589)T and C(－33)T genotypes between patients with type 1 diabetes or autoimmune thyroid disease and control subjects. Then, effects of the C(－144)T polymorphism on promoter activity of IL-4 gene were assessed by luciferase reporter gene assays. Transcriptional activity of the －144T allele, both stimulated and unstimulated, was significantly lower than that of the －144C allele. These data suggest that the C(－144)T polymorphism in the IL-4 gene reduces the IL-4 synthesis and contributes to the development of type 1 diabetes.

View full abstract

Background/Purpose: Connective tissue growth factor (CTGF) is a member of CCN family which mediates profibrotic effects of transforming growth factor-β1 (TGF-β1), promoting fibroblast proliferation and extracellular matrix (ECM) production. CTGF has been presumed to involve in a variety of organ fibrogenesis. In the kidney at health and a disease, by using in situ hybridization glomerular parietal and visceral epithelial cells, mesangial cells, and interstitial fibroblasts were shown to express CTGF. Recently, tubular epithelial cells have been also revealed to express CTGF especially in diabetic nephropathy. Therefore, in this study, I evaluated CTGF protein expression in the tubular epithelium of renal biopsy specimens by immunohistochemistry, and the expression regulation and the role of CTGF in the cultured tubular epithelial cells (mPTEC).
Methods: Using an anti-CTGF antibody, I performed catalyzed signal amplification immunohistochemistry on renal biopsy specimens from patients with minimal change nephrotic syndrome (MCNS), diffuse proliferative lupus nephritis (DPLN), IgA nephropathy (IgAN), and diabetic nephropathy (DN). Using mPTEC cultured in monolayer and co-culture with renal fibroblasts (TFB), whether a given humoral factor could induce CTGF mRNA expression and whether CTGF derived from mPTEC could stimulate TFB to produce type I collagen were tested. The expression of mRNA and type I collagen were determined by ribonuclease protection assay and indirect enzyme-linked immunosorbent assay, respectively.
Results: Significant CTGF expression in the tubular epithelium was found in parallel to the interstitial fibrosis in DN samples. In addition, it was revealed that glucocorticoid (GC) therapy resulted in significant induction of tubular CTGF expression in MCNS and DPLN. Among profibrotic growth factors and proinflammatory cytokines employed, only TGF-β1 could induce CTGF mRNA expression in mPTEC in time-and dose-dependent fashion. D-glucose and dexamethasone could also induce CTGF expression in mPTEC. CTGF derived from mPTEC by TGF-β1 and d-glucose could subsequently induce type I collagen production in TFB.
Conclusion: Renal tubular epithelial cells can express CTGF in vivo and in vitro, which is likely involved in renal fibrogenesis at least in DN and other diseases undergoing GC therapy.

View full abstract

Study I: This study was carried out to determine whether non-invasive assessment of cardiovascular system discriminates white coat hypertension (WCH). The major reason is the high prevalence of WCH in these subjects and it remains uncertain whether WCH is associated with cardiovascular risk. Women were required to be naturally menopausal; at least 1 year, but not greater than 5 years, past their menstrual period. Exclusion criteria were past history of preeclampsia or eclampsia, severe illness such as myocardial infarction and stroke within 6 months, having used estrogens or progestins within 3 months, being treated with antihypertensive agents or with non pharmacological therapy such as reduction of daily salt, and proteinuric nephropathy. In addition, secondary hypertension was excluded as possible. WCH was defined if subjects who had BP more than 150/90 mmHg at office had to have both mean systolic and diastolic pressures below 120/80 mmHg at home. Forty-four subjects, mean age 52 years, recruited from the outpatients clinic, were examined. BPs at office and home, pulse wave velocity (PWV), and augmentation index (Aix) were recorded. Left ventricular diameter, septal wall thickness, and left posterior wall thickness were assessed by M-mode echocardiography after selecting the measurement section by B-mode echocardiography. Twenty patients were diagnosed as having WCH based on the criteria in the trial. We found that the patterns of pulse wave were different between subjects with WCH and those with hypertension. The most prominent difference was the levels of Aix. In subjects with WCH, Aixs were 25.6±3.8 compared to 38.6±4.5 mmHg in those with hypertension. Moreover, PWV of subjects with WCH were 6.05±0.53 and those of with hypertension were 8.45±0.72 m/sec (p<0.01). In addition to these findings, there was a significant association between the values of home systolic BP but not those of office systolic BP and PWV, Aix and LV mass index. When we combined the data of LV mass index and Aix, white coat hypertension was easily segregated from hypertension. The combination of self BP monitoring, echocardiographic data and Aix and PWV would be powerful indicators for treatment of hypertension in postmenopausal women.
Study II: To assess the efficacy of the various classes of antihypertensive drugs in postmenopausal women with hypertension. Women were required to be naturally menopausal; at least 1 year, but not greater than 5 years, past their menstrual period. Exclusion criteria were past history of preeclampsia or eclampsia, severe illness such as myocardial infarction and stroke within 6 months, having used estrogens or progestins within 3 months, and proteinuric nephropathy as well as surgically menopausal. 114 women who participated in this study after informed consent were obtained. These women were diagnosed as having hypertension based on BP of more than 140/90 mmHg at clinic as well as on self-reported BP of more than 130/85 mmHg at home. If both levels of BP were not satisfied with the criteria, such patients were also excluded. All antihypertensive medications were withdrawn 6 weeks before the initiation of the study. All patients were randomly assigned in equal numbers to the following therapeutic groups; A) losartan, 50 mg daily and trichlormethiazide 2 mg twice a week and B) cilnidipine, a calcium channel blocker, 5mg and arotinolol, an αβ blocker, 10 mg daily. Three groups were retrospectively segregated according to pulse pressure (PP) at the start of the study: Group I (n＝ 24); more than 65 mmHg: Group II (n＝58); below 64 to more than 45 mmHg and Group III (n＝32); below 44 mmHg. In Group I, combination therapy with B) reduced systolic BP much more compared to that with A) (169±2/88±5 to 133±2/73±5 vs 169±2/88±5 to 149±2/66±5 mmHg, p<0.05).
View PDF for the rest of the abstract

View full abstract