Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan.

Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disorder caused by deficiency of the glycogen-debranching enzyme (AGL). Recent studies of the AGL gene have revealed the prevalent mutations in North African Jewish and Caucasian populations, but whether these common mutations are present in other ethnic groups remains unclear. We have investigated eight Japanese GSD IIIa patients from seven families and identified seven mutations, including one splicing mutation (IVS 14+1G-->T) previously reported by us, together with six novel ones: a nonsense mutation (L124X), a splice site mutation (IVS29-1G-->C), a 1-bp deletion (587delC), a 2-bp deletion (4216-4217delAG), a 1-bp insertion (2072-2073insA), and a 3-bp insertion (4735-4736insTAT). The last mutation results in insertion of a tyrosine residue at a putative glycogen-binding site, and the rest are predicted to cause synthesis of truncated proteins lacking the glycogen-binding site at the carboxyl terminal. Thirteen novel polymorphisms have also been revealed in this study: three amino acid substitutions (R387Q, G1115R, and E1343 K), one silent point mutation (L298L), one nucleotide change in the 5'-noncoding region, and eight nucleotide changes in introns. Haplotype analysis with combinations of these polymorphic markers showed L124X, IVS14+1G-->T, and 4216-4217delAG to be on different haplotypes. These results demonstrate the importance of the integrity of the carboxy terminal domain in the AGL protein and the molecular heterogeneity of GSD IIIa in Japan.

Impact of cigarette smoking on the incidence of Type 2 diabetes mellitus in middle-aged Japanese men: the Osaka Health Survey.

AIMS: To assess the impact of cigarette smoking on the incidence of Type 2 diabetes mellitus (DM) in middle-aged Japanese men. METHODS: The study enrolled 6250 men aged 35-60 years and free of diabetes, impaired fasting glucose and hypertension at entry. Type 2 DM was defined by a fasting plasma glucose level > or =7.0 mmol/l or physician-diagnosed Type 2DM. RESULTS: Four hundred and fifty cases of Type 2 DM were confirmed during the 60904 person-years follow-up. After adjustment for multiple covariates, including age, body mass index, alcohol consumption, physical activity, parental history of diabetes and the level of fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol and haematocrit, the relative risk of Type 2 DM among current smokers compared with non-smokers was 1.47 (95% confidence interval (CI) 1.14-1.92). Men who smoked >30 cigarettes/day had a multivariate-relative risk of 1.73 (95% CI 1.20-2.48) compared with non-smokers. The number of cigarettes smoked daily and the pack-year values were positively related to the development of Type 2 DM in a dose-dependent manner (P for trends = 0.0026 and 0.001, respectively). CONCLUSIONS: A cigarette smoking habit is an independent risk factor for Type 2 DM.

Primary cardiac lymphoma with infiltration of the atrioventricular node: remission with reversal of the atrioventricular block induced by chemotherapy.

We describe a rare case of primary cardiac lymphoma associated with complete atrioventricular block, with recovery following systemic chemotherapy. A 61 year-old woman was admitted because of a massive pericardial effusion and complete atrioventricular block. Echocardiography disclosed several polypoid masses in the right atrium. A diagnosis of primary cardiac lymphoma was made. After three cycles of chemotherapy, the patient achieved a complete remission, the ECG showed first-degree atrioventricular block, and echocardiography revealed disappearance of the right atrial masses. This is the first report of a patient recovering from primary cardiac lymphoma and complete atrioventricular block following systemic chemotherapy. We conclude that aggressive treatment of this malignancy can improve cardiac function and the patient's prognosis.

Implication of parathyroid hormone for the development of hypertension in young spontaneously hypertensive rats.

The purpose of this study is to elucidate the role of parathyroid hormone (PTH) in the development of hypertension in young spontaneously hypertensive rats (SHR). Parathyroidectomy (PTX) or sham surgery was performed on 6-week-old male SHR, and 3 weeks later human PTH (hPTH) or saline was infused subcutaneously over 2 weeks using a minipump. PTX significantly attenuated the development of hypertension and reduced serum vitamin-D concentrations. PTX also augmented the depressor response to acetylcholine before N-nitro-L-arginine (L-NNA), although it remained unchanged after L-NNA. The cardiovascular reactivity to exogenous noradrenaline and angiotensin II was not affected by PTX. The chronic administration of hPTH reversed these effects. We conclude that PTH plays an important role in the development of hypertension, through modulating the release of endothelium-derived relaxing factor, in young SHR.

[A case of dextrocardia concomitant with tetralogy of Fallot, patent ductus arteriosus and bronchiectasia].

We report a case of dextrocardia concomitant with tetralogy of Fallot (TOF), patent ductus arteriosus (PDA), bronchiectasia, and pulmonary tuberculosis. A 24-years-old man without surgical operation for TOF, whose diagnosis had been made at infancy, was admitted to the Osaka City University Hospital because of massive hemoptysis. The diagnosis of pulmonary tuberculosis was made. He received anti-tuberculotic drugs and bronchial arterial embolization improved his symptoms. A case of mirror-image dextrocardia concomitant with TOF, PDA, and bronchiectasia, as seen in our case, has a low incidence rate, and, moreover, such a case concomitant with pulmonary tuberculosis is rarer still.

Chronic parathyroid hormone administration reverses the antihypertensive effect of calcium loading in young spontaneously hypertensive rats.

To investigate the role of parathyroid hormone (PTH) in the development of hypertension, the long-term administration of human PTH (hPTH) was performed in 7-week-old male spontaneously hypertensive rats maintained on a standard calcium diet (1.1% calcium) or a high calcium diet (2.8% calcium). The hPTH was infused subcutaneously at 0.9 U/h over 2 weeks using a minipump. Two weeks after minipump implantation, rat PTH (rPTH) and 1,25-dihydroxy vitamin D (1,25-D) levels were measured and the pressor response to norepinephrine (NE) was examined. Calcium loading both attenuated the development of hypertension and reduced the pressor response to norepinephrine. Chronic hPTH administration accelerated the development of hypertension and increased the pressor response to norepinephrine in rats fed a high calcium diet, but did not affect either parameter in rats fed a standard calcium diet. The serum concentrations of rat PTH and 1,25-D were significantly lower in rats fed a high calcium diet than in those fed a standard calcium diet (rat PTH: 351 +/- 16 v 430 +/- 1 pmol/L; 1,25-D: 125 +/- 19 v 206 +/- 31 pg/mL). Chronic administration of hPTH increased the serum 1,25-D concentration in rats fed a high calcium diet (186 +/- 35 pg/mL), but did not affect that of rats fed a standard calcium diet (165 +/- 16 pg/mL). It is concluded that PTH prevented the antihypertensive effect of calcium loading in young SHR, perhaps by enhancing blood pressure reactivity through causing an increase of 1,25-D.

[Hemodynamic assessment before and after PTMC by using cardiac blood pool scintigraphy].

Rest and exercise cardiac blood pool scintigraphy with 99mTc-RBC were performed in 12 patients with symptomatic mitral stenosis before percutaneous transvenous mitral commissurotomy (PTMC) and at one week, one month after PTMC. Comparison of hemodynamic parameters before and one month after PTMC showed that LVEDV (97.4 +/- 8.9 vs. 111.4 +/- 12.1 ml; p less than 0.01) and diastolic indices (1/3FF: 23.6 +/- 6.5 vs. 30.9 +/- 4.1%; p less than 0.01) both increased, while there was no significant change in LVEF and RVEF. Comparison of symptom-limited bicycle exercise before and one month after PTMC showed that the duration of exercise time (7.6 +/- 1.6 vs. 8.6 +/- 1.4 min; p less than 0.02) and anaerobic threshold (10.6 +/- 3.0 vs. 15.4 +/- 3.2 ml/min/kg; p less than 0.01) increased. In comparison of hemodynamic response before and one month after PTMC, there were significant increases in cardiac output (CO) at the same workload (15 W: 3.9 +/- 0.7 vs. 4.8 +/- 0.8 l/min; p less than 0.05, 30 W: 3.9 +/- 0.7 vs. 5.2 +/- 1.2 l/min; p less than 0.05) despite similar CO at rest (3.5 +/- 0.8 vs. 3.9 +/- 0.7 l/min; NS). We conclude that cardiac blood pool scintigraphy is useful to evaluate improvement of hemodynamic parameters and exercise capacity after PTMC non-invasively.

Cardiac function and exercise capacity of diabetic patients.

To evaluate the relationship between cardiac function at rest and the exercise capacity of diabetic patients, left ventricular function and exercise capacity were evaluated in 15 non-insulin-dependent male diabetic patients. Isovolumic relaxation time (IRT) and the PEP/LVET ratio were obtained by simultaneous echophonocardiograms, electrocardiograms, and recordings of the carotid arterial pulse. VO2 at anaerobic threshold was obtained from a cycle ergometer exercise test with expired gas analysis. Patients were divided into two groups: those with IRT less than 90 msec (Group 1) and those with IRT greater than or equal to 90 msec (Group 2). Group 2 patients had a lower VO2 at anaerobic threshold than Group 1 (Group 1: 17.4 +/- 3.6, Group 2: 12.9 +/- 2.5 ml/min/kg; M +/- SD, p less than 0.05). There was a good correlation between the IRT at rest and delta HR, defined as the change in heart rate from rest to anaerobic threshold (r = 0.666, p less than 0.01), and between delta HR and the beat-to-beat variation in R-R interval at rest (r = 0.637, p less than 0.02). There was also a good correlation between VO2 at anaerobic threshold and IRT (r = 0.555, p less than 0.05), and between VO2 at anaerobic threshold and delta HR (r = 0.858, p less than 0.01). Our data suggests that both left ventricular diastolic function and cardiac sympathetic nervous system reflexes, reflected by delta HR, may affect the exercise capacity of diabetic patients. Thus, IRT obtained by a non-invasive method may provide a useful index for cardiovascular response to exercise in diabetic patients without coronary artery disease.

Effects of parathyroid hormone-related protein on systemic and regional hemodynamics in conscious rats. A comparison with human parathyroid hormone.

PTHrp was discovered as a humoral hypercalcemic factor of malignancy and has been shown to bind the same receptor as PTH in rat bone cells, canine renal membranes, and rabbit renal microvessels. We investigated the global effect of human PTH(hPTH) and PTHrp on systemic and regional hemodynamics in conscious rats. The hypotensive response to PTHrp was more potent than that to hPTH. Although hPTH (15 micrograms/kg/min, i.v.) caused a significant increase in cardiac output, whereas PTHrp (5 micrograms/kg/min, i.v.) caused no change in cardiac output despite a similar hypotensive effect to hPTH, the effects of PTHrp and hPTHrp on regional hemodynamics were quite similar, and both peptides had a prominent vasodilatory effect on the coronary and hepatic arteries. Therefore, PTHrp appears to have an important role in blood pressure and regional hemodynamics as does hPTH.

[Non-supervised home exercise programs in a convalescent phase of acute myocardial infarction: their effectiveness and the usefulness of the heart rate at the anaerobic threshold].

The effectiveness of 2 different exercise programs in the convalescent phase of acute myocardial infarction (AMI) was assessed. One hundred and five patients with AMI were enrolled for one of these 2 non-supervised home exercise programs immediately after discharge from the hospital. Before discharge and one month later, they underwent submaximal graded treadmill exercise tests with the application of expiratory gas analysis. All patients were assigned to perform 2 km of walk-jog exercise daily for one month. The heart rate during exercise, duration of exercise and the total steps during 24 hrs were measured. Eighty patients (group A) underwent the exercise program in which their heart rates were maintained at 100-110 beats/min during exercise; while 25 patients (group B) underwent the other program in which their heart rates were maintained at 90-100% of those obtained at their anaerobic threshold (AT). The ventilatory AT was calculated by the standard technique using the Horizon System. In group A, AT increased from 13.4 ml/min/kg to 15.1 ml/min/kg (p < 0.01) after the exercise program and in group B, from 12.8 ml/min/kg to 14.9 ml/min/kg (p < 0.01). In group B, AT increased in all patients, while it remained unchanged in 30% of the patients in group A (p < 0.01). In conclusion, a non-supervised home exercise program can be effective and easily instituted for rehabilitation in a convalescent phase of AMI. The program using 90-100% of the heart rates at the anaerobic threshold seemed to be more suitable for obtaining better effects on exercise tolerance than that using 100-110/min heart rate.

Management and evaluation of non-supervised home exercise program in a convalescent phase of acute myocardial infarction.

Out of 636 patients with acute myocardial infarction (AMI) admitted to our institution, 183 patients enrolled in our non-supervised home exercise program immediately after their discharge from the hospital. The first 40 patients were randomized to control and training group, while the remaining 143 patients were included in the training group. Before and after the trial, all patients underwent cardiopulmonary exercise testing; submaximal graded treadmill exercise test with the application of expiratory gas analysis. In the training group, patients performed 2 km walk-jog exercise everyday for 1 month, keeping their heart rate (HR) at 90-100% of that in the anaerobic threshold. HR during exercise was monitored by patients themselves, using HR-meter. The anaerobic threshold significantly increased in the training group; while control group had no significant changes. VO2 and HR significantly increased at the same Borg's indices. Psychological improvement was also obtained in the training group compared to control group. It is concluded that non-supervised home exercise program is effective and easily applicable in the convalescent phase of AMI.

[Efficacy of home exercise program in a convalescent phase of acute myocardial infarction evaluated by Borg's indices, expiratory gas analysis and blood lactate].

The Borg's indices, the rate of perceived exertion have been widely accepted to evaluate subjective symptoms semi-quantitatively in exercise tests. We applied the indices to evaluate the efficacy of our home exercise program in patients with acute myocardial infarction. Eighty-five patients were entered in our home exercise program after their discharge from the hospital. This program consisted of everyday 2 km walk-jog exercise for 1 month keeping their heart rate at 100-110/min during the exercise. Before and 1 month after their discharge, they underwent treadmill exercise tests with expiratory gas analysis and a measurement of blood lactate. In the treadmill tests performed before and after the training, VO2 and heart rate increased linearly with Borg's indices, however VE and blood lactate had disproportionate increases after Borg's 13 which is considered to be the anaerobic threshold (AT). In fact, AT measured individually by expiratory gas analysis and blood lactate, appeared at Borg's 13 in 53% of the patients. After 1 month physical training, VO2 and heart rate significantly increased at the same Borg's indices, but there was no significant changes in blood lactate at the same Borg's score before and after the training. These results suggest that, in patients with acute myocardial infarction, exercise performance significantly increased at any score of subjective symptoms and that Borg's indices may reflect the blood lactate levels. It is concluded that Borg's indices, closely related to the dynamics of blood lactate, are not only useful in quantifying subjective symptoms but also to estimate the efficacy of physical training.