Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil

OBJECTIVES: We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I(Ks) gene) defect linked to acquired long QT syndrome (LQTS). BACKGROUND: Agents with an I(Kr)-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP. METHODS: Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. RESULTS: The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I(Kr) blocker under conditions with I(Ks) suppression by chromanol 293B 10 micromol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I(Ks) and I(Kr) suppression. Verapamil (0.1 to 5.0 micromol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. CONCLUSIONS: Subclinical I(Ks) dysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.     

cDNA cloning of thyroid hormone receptor betas from the conger eel,Conger myriaster

Two distinct TRbetas cDNA clones were generated by RACE from a conger eel (Conger myriaster). The deduced amino acid sequences of the conger eel TRbetas (cTRbetas) showed higher homologies to the known TRbetas of other vertebrate animals than to TRalphas. Two cTRbetas possessed an insertion sequence in the hinge region similar to other teleost fish TRbetas. Variation in cTRbeta due to differential splicing in the hinge region of the cTRbetas genes was found using PCR analysis. The determination of TRbeta mRNA levels in eel tissue was performed using competitive RT-PCR. The cTRbeta1 mRNA was widely expressed, whereas cTRbeta 2 mRNA was most highly expressed in the brain and pituitary. The expression pattern of cTRbeta1 and cTRbeta2 in tissues were similar to that of TRbeta1 and TRbeta2 in mammals.     

Carcinoma of duodenal bulb arising from the Brunner’s gland

A 75-year-old man was diagnosed as having a sessile tumor measuring 1.4 x 1.0 cm in size in the duodenal bulb after upper gastroduodenal series. The biopsy specimens revealed a proliferation of the adenomatous glands showing an acinar structure with papillary infolding; type III mucus, which is characteristic of Brunner’s glands. Antral glands and mucus neck cells of the fundic glands were also observed in the adenomatous glands by concanavalin A staining. Thus, it was clear that the tumor had originated from the Brunner’s glands. Three years and four months later, the sessile tumor had developed into a fungating ulcerated tumor via a polypoid form. The biopsy specimens revealed a papillary adenocarcinoma with foci of undifferentiated carcinoma. Retrospectively, the adenomatous glands in the biopsy taken from the sessile tumor should have been regarded as low grade carcinoma. Therefore, we propose that when a polyp or tumor shows an increase in size or change in macroscopic appearance, surgery should be considered.     

Primary cultured T cell vaccine for adjuvant arthritis (AA), collagen-induced arthritis (CA) and arthritis in HTLV-1 pX-transgenic mice as models of rheumatoid-like arthritis: dominancy of the roles of T cells or humoral factors in the pathogenesis of CA and pX-transgenic arthritis

It has been reported that a T cell vaccine is capable of regulating auto-reactive T cells, and may be used for protection against and treatment of adjuvant arthritis (AA), but no reports have appeared regarding other forms of autoimmune arthritis. In this paper, we aimed for protection against and treatment of collagen-induced arthritis (CA) and arthritis induced in HTLV-1 pX-transgenic mice (pX-A) with a T cell vaccine as another model of autoimmune arthritis, in addition to a parallel study on AA. Drained lymph node lymphocytes were cultured in eitherMycobacterium tuberculosis, type II collagen or in an anti-CD3 antibody immobilized dishes for a total of 7 days. These cells were then fixed with 0.5% glutaraldehyde and used as a T cell vaccine. This was applied in the following five groups: protection and treatment of AA, protection (tolerance induction) and treatment of CA, and treatment of pX-a. The effects of a T cell vaccine were examined as: (i) an arthritis score, (ii) a histopathological examination of joint lesions, (iii) serum titers of anti-type II collagen antibodies and (iv) serum levels of several cytokines. In terms of the arthritis score, although the T cell vaccine was effective both in the protection of and treatment against AA, it was not effective for either CA or pX-A. The serum titers of anti-collagen antibodies were unchanged in the four groups examined. The serum levels of interleukin-1 β showed almost no differences in the four groups. Serum levels of tumor necrosis factor-α and interferon-γ were significantly higher in the pX-A treatment group. The T cell vaccine was effective in both protecting against and treating AA; however, it was not effective with regard to CA and pX-A. The possible dominancy of T cells in the pathogenesis of each autoimmune arthritis was discussed.     

Effects of cellular cardiomyoplasty on ventricular remodeling assessed by Doppler echocardiography and topographic immunohistochemistry.

BACKGROUND: Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. Supplementing infarcted myocardium with neonatal myocyte would attenuate deleterious remodeling and so the present study used Doppler echocardiography and histology to analyze the cardiac function and histological regeneration of the damaged myocardium after cellular cardiomyoplasty. METHODS AND RESULTS: Experimental MI was induced by 24-h coronary ligation followed by reperfusion in adult male Lewis rats and neonatal myocytes were injected directly into the infarct and peri-infarct regions. Three groups of animals were studied at 4 weeks after cellular cardiomyoplasty: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI + cell). Ventricular remodeling and cardiac performance were assessed by Doppler echocardiography or contrast echocardiography. At 4 weeks after cellular cardiomyoplasty, MI + cell hearts exhibited attenuation of global ventricular dilation and cardiac function compared with MI hearts not receiving cellular cardiomyoplasty. Immunohistochemically, connexin-43-positive small cells were observed in the vicinity of the infarction in MI + cell heart. By electron microscopy, these cells contained myofilaments with Z-bands and poorly developed intercalated disks, suggesting neonatal myocardial cells. Furthermore, the myocardial cells were often making close contact with interstitial cells. CONCLUSIONS: Implanted neonatal myocytes form viable grafts after MI, resulting in attenuated ventricular dilation and enhanced contractile function. Echocardiography, electron microscopy, and immunohistochemistry are useful methods for assessing the functional and histological regeneration of the damaged myocardium.     

Effect of Diltiazem on Cardiac Function Assessed by Echocardiography and Neurohumoral Factors After Reperfused Myocardial Infarction Without Congestive Heart Failure

The purpose of this study was to examine the effect of diltiazem on cardiac function and neurohumoral factors (BNP, epinephrine, norepinephrine) after reperfused myocardial infarction without congestive heart failure (Killip class I). On the first day after myocardial infarction following reperfusion therapy patients were randomly assigned to diltiazem treatment (group 1, n=33) or no treatment (group 2, n=39). We then performed echocardiographic examinations on the patients and measured heart rate, mean blood pressure and neurohormones (BNP, epinephrine and norepinephrine). Follow-up evaluations of echocardiography were performed at 4 and 12 weeks and of neurohormones at 1 and 4 weeks after acute myocardial infarction. The highest peaks of plasma BNP, epinephrine, and norepinephrine levels were observed before treatment and decreased with time in both groups. After 4 weeks the level of plasma BNP in the diltiazem treatment group was lower than in the no treatment group [55+/-3 pg/mL vs 85+/-5 pg/mL (P < 0.05)]. Other neurohormones did not differ between groups. Fractional shortening (FS) and ejection fraction (EF)improved after myocardial infarction in both groups, but significantly more in the diltiazem group (P < 0.05) after 12 weeks of treatment. Changes in BNP correlated significantly with changes in left ventricular end systolic volumes, FS and EF. In this study, diltiazem significantly improved systolic function and reduced the level of plasma BNP after myocardial infarction, which suggest that diltiazem may have a beneficial effect on myocardial infarction without congestive heart failure.     

Randomized,double-blind,placebo-controlled trial of eight-week course of recombinant α-interferon for chronic non-A,non-B hepatitis

Forty-nine Japanese patients were enrolled in a randomized, placebo-controlled, doubleblind trial of -interferon for chronic non-A, non-B hepatitis: 24 patients received 3 million units of recombinant human alpha -interferon (-2a) thrice weekly for eight weeks, and 25 patients received placebo in a similar schedule. The mean serum alanine aminotransferase (ALT) dropped from 155±91 (sd) to 69±72 during interferon treatment, but remained unchanged (158±140 to 147±130) during placebo treatment (P<0.001). Serum ALT level fell to the normal range in 29% of interferon-treated patients, but in only 4% of placebo-treated patients. Pre- and posttreatment liver biopsies were obtained in all but one case. Average histological activity indices (HAI) were markedly improved in the interferon-treated group (9.5±3.7 to 7.0±4.3), but were unchanged in the placebo group (8.5±4.3 to 8.5±4.9). In addition, we compared the efficacy of interferon treatment between anti-hepatitis C virus (HCV) antibody positive and negative groups. Biochemical and histological improvements were similar and statistically significant in patients with and without antibody to hepatitis C virus. These data indicate that a eight-week course of -interferon induces biochemical and histological improvement in more than half the patients with chronic non-A, non-B hepatitis.This study was supported by a grant from Japanese Ministry of Health and Welfare.     

Prognostic significance of serum uric acid in patients with chronic obstructive pulmonary disease receiving home oxygen therapy]

Home oxygen therapy (HOT) not only prolongs life expectancy but also improves quality of life. Serum uric acid (UA), the final product of purine catabolism, has been shown to be increased in the hypoxic state. To elucidate the prognostic significance of serum UA in patients with chronic obstructive pulmonary disease (COPD) receiving HOT, we assessed the ratio between the serum concentration of UA and creatinine (Cr) in 91 outpatients with COPD. During a mean follow-up period of 31 months, 24 patients died of acute exacerbation of COPD. The delta UA/Cr ratio was calculated as the percent changes in serum UA/Cr during HOT. delta UA/Cr was increased in non-survivors, but not in survivors, and was negatively correlated with the nadir of oxyhemoglobin saturation (r = -0.32, p < 0.01). Of the clinical and laboratory variables, only the delta UA/Cr ratio was found to be independently related to mortality by a multivariate Cox proportional-hazards analysis. The Kaplan-Meier survival curves divided into values below and above the median value (9.7%) of this ratio demonstrated that mortality was significantly higher among patients with high values than among those with low values (log-rank test: p < 0.05). We conclude that the delta UA/Cr ratio appears to be a reliable marker of prognosis, and may be useful for the long-term follow-up of outpatients with COPD receiving HOT.     

Effect of exercise and beer on the plasma concentration and urinary excretion of purine bases

OBJECTIVE: To investigate the effects of exercise and beer ingestion separately and combined on the plasma concentration of purine bases. METHODS: Six healthy men aged 30-39 years participated in 3 different experiments, in which they exercised for 30 min (at 70% of maximum oxygen uptake) and ingested beer (10 ml/kg body weight), or did each activity separately, with each experiment performed at 2 week intervals. RESULTS: The plasma concentration of uric acid was increased by 12% (p < 0.05), 8% (p < 0.01), and 29% (p < 0.01) with exercise, beer ingestion, and a combination of exercise and beer ingestion, respectively, which showed that it increased synergistically in the combination experiment. The fractional excretion of uric acid was decreased by 44% (p < 0.01) and 52% (p < 0.01) with exercise alone and a combination of exercise and beer ingestion, respectively, while it was increased by 15% (p < 0.05) with beer ingestion alone. Creatinine clearance was decreased by 16% (p < 0.01) with both exercise alone and a combination of exercise and beer ingestion, while it was not changed with beer ingestion alone. The increase in the plasma concentration of xanthine during the beer ingestion experiment was 2.1-fold greater than that during the combination (p < 0.05), while the increase in urinary excretion of xanthine caused by beer ingestion was 2.5-fold greater than that caused by a combination of beer and exercise (p < 0.05). Finally, exercise alone as well as a combination of beer and exercise increased the blood concentrations of lactic acid and NH3, whereas beer alone decreased concentration of pyruvic acid. CONCLUSION: These results suggest that the production of uric acid caused by both exercise and beer ingestion, as well as the inhibition of urinary uric acid excretion from a high blood lactic acid concentration, were the main contributors to the synergistic effect on the increase in plasma uric acid concentration. A decrease in creatinine clearance also contributed to the effect. We considered that pyruvic acid and NH3, produced in the muscles following exercise, relieved the beer induced increase of the plasma concentration and urinary excretion of xanthine, which may have played a minor role in the increase in plasma uric acid concentration.