Takayoshi Toyota

Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial

BACKGROUND Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. METHODS In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705. FINDINGS 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. INTERPRETATION Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial

OBJECTIVE—We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS—Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) ≥40 m/s, and HbA1c ≤9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS—Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS—Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Oxidative DNA damage in diabetes mellitus : its association with diabetic complications

Aims/hypothesis. Augmented oxidative stress induced by hyperglycaemia possibly contributes to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine to 8-oxo, 2 ′-deoxyguanosine in DNA. To investigate the possible contribution of oxidative DNA damage to the pathogenesis of diabetic complications, we measured the content of 8-oxo, 2 ′-deoxyguanosine in the urine and the blood mononuclear cells of Type II (non-insulin-dependent) diabetic patients. Methods. We studied 53 Type II diabetic patients and 39 age-matched healthy control subjects. We assayed 8-oxo, 2 ′-deoxyguanosine by HPLC-electrochemical detection method. Results. The content of 8-oxo, 2 ′-deoxyguanosine in the urine and the mononuclear cells of the Type II diabetic patients was much higher than that of the control subjects. Urinary 8-oxo, 2 ′-deoxyguanosine excretion and the 8-oxo, 2 ′-deoxyguanosine content in the mononuclear cells from the diabetic patients with complications were higher than those from the diabetic patients without complications. Urinary excretion of 8-oxo, 2 ′-deoxyguanosine was significantly correlated with the 8-oxo, 2 ′-deoxyguanosine content in the mononuclear cells. The 8-oxo, 2 ′-deoxyguanosine content in the urine and mononuclear cells was correlated with the haemoglobin A1 c value. Conclusion/interpretation. This is the first report of a direct association between oxidative DNA damage and the complications of diabetes. The augmented oxidative DNA damage in diabetes is speculated to contribute to the pathogenesis of diabetic complications. [Diabetologia (1999) 42: 995–998]

Development of Diabetes in the Non-Obese NIDDM Rat (GK Rat)

We produce spontaneously diabetic rats from normal rats by repeating the selective breeding using glucose intolerance as the selection index. The rats are called GK rats and now we have the 37th generation. In this paper, characteristic features, insulin secretion and the effect of obesity will be presented.

Immunologic aspects of the nonobese diabetic (nod) mouse. Abnormalities of cellular immunity.

Experiments were performed on 12-wk-old nonobese diabetic (NOD) mice to investigate the immunologic background of the condition, using ICR mice as controls. The results indicate the following: (1) absolute decreases in number of T lymphocytes, (2) depression of natural killer activity, (3) normal responsiveness in delayed type hypersensitivity and functional depression of killer T cells against allogeneic tumors, (4) diminished resistance to herpes virus infection, and (5) enhanced production of polyclonal antibodies to T cell-dependent antigens. These features are similar to those noted in other autoimmune diseases of man and in their experimental models in laboratory animals. Elucidation of the pathogenetic mechanism of autoimmune diabetes mellitus in NOD mice, therefore, may contribute to the diagnosis, treatment, and prevention of a wide variety of autoimmune diseases.

Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis

OBJECTIVE:Although it is widely accepted that Helicobacter pylori (H. pylori) infection is an important cause of atrophic gastritis, few studies have examined the relationship between H. pylori-induced atrophic gastritis and the occurrence of reflux esophagitis. The present study was aimed to examine the relationship between H. pylori infection, atrophic gastritis, and reflux esophagitis in Japan.METHODS:A total of 175 patients with reflux esophagitis were compared with sex- and age-matched 175 control subjects. Diagnosis of H. pylori infection was made by gastric mucosal biopsy, rapid urease test, and serum IgG antibodies. Severity of atrophic gastritis was assessed by histology and serum pepsinogen I/II ratio.RESULTS:H. pylori infection was found in 59 (33.7%) patients with reflux esophagitis, whereas it was found in 126 (72.0%) control subjects. The grade of atrophic gastritis was significantly lower in the former than in the latter. Among the H. pylori-positive patients, atrophic gastritis was milder in the patients with reflux esophagitis than in the patients without it.CONCLUSIONS:These findings suggest that most cases of reflux esophagitis in Japan occur in the absence of H. pylori infection and atrophic gastritis, and it may also tend to occur in patients with milder gastritis even in the presence of H. pylori infection. Therefore, H. pylori infection may be an inhibitory factor of reflux esophagitis through inducing atrophic gastritis and concomitant hypoacidity.

Oxidative damage to mitochondrial DNA and its relationship to diabetic complications

Increased oxidative stress induced by hyperglycemia may contribute to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine (dG) to 8-hydroxydeoxyguanosine (8-OHdG) in DNA, which is linked to increased mitochondrial DNA (mtDNA) deletions. We investigated mtDNA deletions and 8-OHdG in the muscle DNA of non-insulin-dependent diabetes mellitus (NIDDM) patients. mtDNA deletion of 4977 bp (delta mtDNA4977) and the content of 8-OHdG in the muscle DNA of the NIDDM patients were much higher than those of the control subjects. There was a significant correlation between delta mtDNA4977 and the 8-OHdG content (P < 0.0001). Both delta mtDNA4977 and the 8-OHdG content were also correlated with the duration of diabetes. Delta mtDNA4977 and the 8-OHdG content in muscle DNA increased in proportion to the severity of diabetic nephropathy and retinopathy. This is the first report that an increase in delta mtDNA4977 and 8-OHdG is proportional to the severity of diabetic complications. Oxidative mtDNA damage is speculated to contribute to the pathogenesis of diabetic complications though a defect in mitochondrial oxidative phosphorylation or other mechanisms. 8-OHdG and delta mtDNA4977 are useful markers to evaluate oxidative mtDNA damage in the diabetic patients.

Studies of 13C-urea breath test for diagnosis of Helicobacter pylori infection in Japan

Abstract: In recent years Helicobacter pylori infection has been implicated in the etiology of a variety of upper gastrointestinal diseases. The aim of this multi-center trial was to search for the cut-off value of the simple 13C-urea breath test (13C-UBT) for diagnosis of H. pylori infection, and to examine the sensitivity and specificity of 13C-UBT for culture, the rapid urease test (CLO test), histology, and serological tests. Two hundred and forty-eight patients participated in this study after giving their informed consent. Endoscopic biopsy specimens were taken from gastric antrum and corpus for culture (190 patients), CLO test (222 patients), and histology (98 patients). A serological test was carried out for all patients. H. pylori infection was established when culture was positive or more than two of the tests, histology, CLO test, and serological test, were positive, and non-infection status was established when the all tests more than two tests were negative. After baseline breath samples were taken, the patients (who had fasted) were given 100 mg of 13C-urea in 100 ml water while sitting; they washed out the mouth with water. They were then placed in the left lateral decubitus position for 5 min, and additional breath samples were taken 10, 20, 30, 45, and 60 min after urea administration, with patients in the sitting position. One hundred and sixty-five of the 248 patients were infected, 48 were not infected, and H. pylori infection status was not evaluated in 35 by endoscopic and serological tests. Breath samples at 20 min were employed to determine the cut-off value. Using the receiver operating characteristic (ROC) curve, we determined the cut-off value for a positive UBT at 2.5 Δ‰. The sensitivities of UBT for culture, CLO test, histology, and serological test were 98.4%, 98.6%, 100.0%, and 92.5%, and the specificities were 78.8%, 82.5%, 83.3%, and 87.3%, respectively. The cut-off value of 13C-UBT for the diagnosis of H. pylori infection was 2.5 Δ‰; this test is a simple and non-invasive method for the diagnosis of this infection and has high sensitivity and specificity.

K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas.

Intraductal mucin-hypersecreting neoplasm of the pancreas (IMHN) is a unique tumor that is composed of tumor cells with different cell atypia. K-ras and p53 alterations have been shown to occur in pancreatic duct cell carcinoma (PDC). but they have not been well documented in the individual lesion of IMHN. The aim of this study was to examine the relation of the genetic alterations of K-ras and p53 in IMHN to the tumorigenesis of the pancreas. In 32 microscopically dissected lesions of seven cases of IMHN, the K-ras mutation was investigated by primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism. Mutant p53 expression was examined in the adjacent serial sections by immunohistochemistry. In IMHN, alterations of K-ras and p53 were frequently observed (71.9 and 50%, respectively). The frequency became higher as the grade of cell atypia increased. Simultaneous alterations of the two genes were detected in carcinoma and its accompanying hyperplastic and dysplastic lesions. It is suggested that alterations of K-ras and p53 may be early events in the tumorigenesis of IMHN and may cooperate to produce neoplastic transformation of the pancreatic duct epithelium.

Simultaneous measurements of serum α-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma

Simultaneous measurements of serum α-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma