Takeshi Tana

Role of HCN4 channel in preventing ventricular arrhythmia.

Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of If channel produced by HCN4 in a computer simulation model and found that the If channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the If channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.

Multiple risk factor clustering of hypertension in a screened cohort.

Objective A family history of hypertension, obesity, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia have all been associated with the risk for hypertension. We evaluated whether the clustering of these risk factors increases the risk for hypertension or whether the accumulation of risk factors is associated with the blood pressure level in non-hypertensive subjects. Methods and subjects We assessed the clinical data and family history of hypertension (in parents and siblings) for 9914 individuals (6163 men and 3751 women, 18–89 years old) who were screened in Okinawa, Japan, in 1997. Results In 9914 subjects (2465 hypertensive and 7449 non-hypertensive subjects), all the five factors were positively associated with hypertension. The odds ratios (95% confidence interval) for the number of risk factors were 1.88 (1.62–2.18) for one risk factor, 3.06 (2.62–3.57) for two, 5.25 (4.37–6.30) for three, 8.71 (6.48–11.72) for four and 24.48 (8.49–70.56) for five, after adjusting for age, sex, alcohol consumption, cigarette smoking and physical exercise habits. In non-hypertensive subjects, multivariate regression analyses showed that the number of risks was positively correlated with blood pressure; the regression coefficient was 1.96 (P < 0.0001) for systolic blood pressure, and 1.47 (P < 0.0001) for diastolic blood pressure after adjusting for age and sex. Conclusions Clustering of risk factors was significantly associated with hypertension. The number of risk factors positively correlated with the blood pressure levels in nonhypertensive subjects. The accumulation of risk factors may play an important role in the pathogenesis of hypertension, and thus the aggregation of risk factors may need to be addressed in primary prevention efforts related to hypertension.

An HLA-binding-motif-aided peptide epitope library: A novel library design for the screening of HLA-DR4-restricted antigenic peptides recognized by CD4 + T cells

AbstractSusceptibility to a series of autoimmune diseases is strongly associated with particular HLA class II alleles. Identification of T cell clones and antigenic epitopes bound by HLA class II molecules involved in autoimmune diseases is critical to understanding the etiology of these HLA class II-associated diseases. However, establishment of T cell clones in autoimmune diseases is difficult because the antigenic peptides are unknown. Peptide library methods which include all possible peptide sequences offer a potentially powerful tool for the detection of cross-reactive antigenic peptides recognized by T cells. Here, we reduced the number of peptides per mixture by utilizing the known binding motifs of peptides for the HLA-DRB1*0405 molecule and evaluated the effectiveness of this library design. Each library mixture evoked a strong proliferative response in the unprimed peripheral blood lymphocytes (PBL) from HLA-DRB1*0405-positive donors but little or no response in the PBL from HLA-DRB1*0405-negative donors. The library also detected antigenic peptides that activated three antigen-specific T cell lines restricted by HLA-DRB1*0405, with different specificities. The motif-based approach thus presents a powerful method for monitoring T cells in large, heterogeneous T cell populations and is useful for the identification of the mimic peptide epitopes of T cell lines and clones.

Identification of an epitope for T cells correlated with antibody response to hepatitis B surface antigen in vaccinated humans

Two antigenic T-cell epitopes of HBsAg, designated HBs 16-31 and HBs 81-99, were identified using synthetic peptides and HBsAg-specific T-cell lines. HBs 16-31 was recognized by five HBsAg-specific T-cell lines from vaccinees with both high and low antibody titers, whereas HBs 81-99 was recognized by two T-cell lines derived from vaccinees with high antibody titers. The antibody titer against HBsAg was correlated significantly with the proliferation of vaccinees PBLs in response to HBs 81-99 (r = 0.47) but not to HBs 16-31, suggesting that HBs 81-99 plays a critical role in anti-HBs antibody production in humans vaccinated with HBsAg.

Effects of xanthine oxidase inhibitors on renal function and blood pressure in hypertensive patients with hyperuricemia

Hyperuricemia may promote the progression of hypertension and renal dysfunction. However, the effects of hyperuricemia treatment on blood pressure and renal function in adult hypertensive patients with hyperuricemia remain unclear. A total of 137 hypertensive patients with hyperuricemia (96 men and 41 women; mean age of 67 years) who recently started taking xanthine oxidase inhibitors (allopurinol or febuxostat) as outpatients were recruited. Serum uric acid level, estimated glomerular filtration rate (eGFR, ml min−1 per 1.73 m2) and blood pressure (mm Hg) were retrospectively compared immediately before and shortly after starting treatment with xanthine oxidase inhibitors. The mean blood pressure and the eGFR immediately before starting treatment were 128/71 mm Hg and 44.6 ml min−1 per 1.73 m2, respectively. Although the eGFR decreased from 46.6 to 44.6 ml min−1 per 1.73 m2 before starting treatment with xanthine oxidase inhibitors, it increased to 46.2 ml min−1 per 1.73 m2 (P=0.001, compared with immediately before treatment) without any significant changes in blood pressure after the administration of xanthine oxidase inhibitors. Multiple regression analysis revealed that the increase in eGFR after starting xanthine oxidase inhibitor treatment positively correlated with the changes in systolic blood pressure and negatively correlated with the changes in uric acid levels and the use of renin–angiotensin system inhibitors. These results suggest that xanthine oxidase inhibitors may delay the progression of renal dysfunction in adult hypertensive patients with hyperuricemia.

Comparative analysis of HLA restriction and cytokine production in hepatitis B surface antigen-specific T cells from low- and high-antibody responders in vaccinated humans.

AbstractIt is well known that individuals with low, or lack of, antibody production in response to hepatitis B surface antigen (HBsAg) exist in the human population. We have previously reported that HLA class I and class II genes are both involved in antibody production to HBsAg, and that specific alleles of HLA are associated with low and high antibody production. To elucidate further the mechanisms by which the diversity of antibody production to HBsAg is generated in humans, a total of 146 T-cell clones specific for HBsAg were produced from six healthy vaccinees (three low- and three high-antibody responders) and were examined for cytokine production and HLA restriction. It was found that the majority of the T-cell clones from the low-antibody responders were Th1- or Th0-like T cells (62% or 19%, respectively), whereas the majority of T-cell clones from the high-antibody responders were Th2-like T cells (77%), suggesting predominant expansion of Th1/Th0- and Th2-like T cells specific for HBsAg in the low- and high-antibody responders, respectively. This is the first evidence that the diversity of the response to HBsAg in humans is controlled by the activation of functionally distinct CD4+ T-cell subsets, i.e., Th0, Th1, or Th2 T cells.

Beneficial Effect of Switching from a Combination of Angiotensin II Receptor Blockers other than Losartan and Thiazides to a Fixed Dose of Losartan/Hydrochlorothiazide on Uric Acid Metabolism in Hypertensive Patients

Among the angiotensin II receptor blockers (ARBs), losartan (LOS) has uricosuric action. The clinical benefits of LOS compared with those of other ARBs may be apparent when it is combined with diuretics, which have an unfavorable influence on serum uric acid (SUA). The effects of switching from combinations of ARBs other than LOS and thiazides to a fixed-dose combination comprising 50 mg LOS and 12.5 mg hydrochlorothiazide on blood pressure (BP), SUA, percent fractional excretion of UA (FEUA), and urine pH were assessed in 57 hypertensive outpatients. A significant reduction in BP was observed after 6 months (P < .01). The switching therapy significantly decreased SUA level (6.0 ± 1.3 vs. 5.7 ± 1.3 mg/dL, P < .01), which was accompanied by increases in FEUA (P < .01) and urine pH (P < .01). The change in SUA was negatively correlated with the changes in FEUA (P < .004) and estimated glomerular filtration rate (P < .05). The change in FEUA was positively correlated with the changes in urine pH (P < .05) but not with BP or estimated glomerular filtration rate. In a separate group of patients treated with ARBs other than LOS (n = 82), a significant BP reduction was observed, but no change in SUA or FEUA was observed. In conclusion, switching therapy decreased SUA level, which was accompanied by an increase in FEUA. This result may depend on the balance between LOS-induced inhibitory action of urate transporter 1 and hydrochlorothiazide-induced plasma volume reduction. The increase in urine pH plays a role in UA urinary excretion.

Switching Therapy from Variable-Dose Multiple Pill to Fixed-Dose Single-Pill Combinations of Angiotensin II Receptor Blockers and Thiazides for Hypertension

The efficacy and tolerability of switching therapy from free combinations of angiotensin II receptor blocker (ARB) and thiazide (A/T) to a fixed-dose of losartan and hydrochlorothiazide (L/H) has not been evaluated in Japan. We examined effects of switching therapy from variable-dose multiple-pill A/T to a fixed-dose L/H on blood pressure (BP) along with medication adherence and the degree of satisfaction in 91 hypertensive outpatients (mean age, 65.2 ± 9.6 years). After 6 months, a significant BP reduction (132 ± 9/76 ± 10 vs. 126 ± 12/72 ± 11 mm Hg), along with an improvement of attaining target BP (44.0 vs. 61.5%) and that of adherence, were observed. The magnitude of BP reduction in the participants increased their degree of satisfaction more significantly than in the participants who worsened their degree of satisfaction. The estimated glomerular filtration rate and the serum uric acid (UA) level decreased slightly but significantly. The hemoglobin A1c of participants with diabetes mellitus increased slightly but significantly. In conclusion, a switch in therapy from variable-dose, multiple-pill A/T combinations to a fixed-dose, single-pill L/H was effective in decreasing BP and serum UA in Japanese clinical practice. Metabolic side effects of L/H in patients with diabetes mellitus remain to be investigated.

MHC class I bound peptides of a colon carcinoma cell line, a Ki-ras gene-targeted progeny cell line and a B cell line

MHC class I associated peptides on cancer cells represent potential targets for CD8+ cytotoxic T cell activity against tumor cells. We eluted the naturally bound MHC class I peptides of a colon carcinoma cell line and compared them to peptides isolated from a B cell line and a slow-growing activated Ki-ras-disrupted colon cancer cell line. While we failed to detect any significant differences in class I associated peptides due to the presence or absence of activated Ki-ras in colon cancer cell lines, the colon cancer cell lines and B cell line presented vastly different peptide repertoires in the context of HLA-A*0201 molecules.

A questionnaire survey to assess lower urinary tract symptoms in patients with chronic stroke

In this study, we evaluated the prevalence of lower urinary tract symptoms and the associated clinical features in patients with chronic stroke.