Causes of death in Japanese diabetics: A questionnaire survey of 18,385 diabetics over a 10-year period.

We collated and analysed data from hospital records regarding the cause of death of 18,385 patients with diabetes who died in 282 medical institutions throughout Japan over the 10-year period between 1991 and 2000. Autopsy was carried out in 1750 cases. The most frequent cause of death in all 18,385 cases was malignant neoplasia, accounting for 34.1% of cases, followed by vascular diseases (including diabetic nephropathy, ischemic heart diseases and cerebrovascular diseases) in 26.8%, infections in 14.3%, and then diabetic coma in 1.2%. The most common malignancy was liver cancer, accounting for 8.6% of all the deaths. Of the deaths from vascular diseases, diabetic nephropathy was the cause of death in 6.8% of cases, and the frequency as cause of death for ischemic heart diseases and cerebrovascular diseases were similar at 10.2% and 9.8%, respectively. Myocardial infarction accounted for almost all the deaths from ischemic heart diseases, whereas deaths from cerebral infarction were 2.2-fold as common as those from cerebral hemorrhage. In the analyses of the relationship between age and causes of death in diabetic patients who underwent autopsy, the overall mortality rate as a result of vascular diseases increased with age, although the mortality rates from diabetic nephropathy and cerebrovascular diseases increased little from the fifth decade of life. The mortality rate from ischemic heart diseases increased with age, however, and was higher than the other forms of vascular diseases from the sixth decade of life, accounting for approximately 50% of vascular deaths in the eighth decade. Malignant neoplasia was the most frequent cause of death from the fifth decade of life, and was extremely common in the seventh decade, accounting for 46.3% of all the deaths. The mortality rate from infections varied little between age groups from the fifth decade of life. In the analyses of glycemic control and the age at the time of death, lifespans were 2.5 years shorter in males, and 1.6 years shorter in female diabetics with poor glycemic control than in those with good or fair glycemic control. This difference was greater for deaths as a result of infections and vascular diseases, particularly diabetic nephropathy, than for malignant neoplasia. Analysis of the relationship between glycemic control and the duration of diabetes and deaths as a result of vascular diseases showed no correlation between the level of glycemic control and death from diabetic nephropathy, ischemic heart diseases or cerebrovascular diseases. In diabetics with disease durations of less than 10 years, the mortality rate from macroangiopathy was higher than that as a result of diabetic nephropathy, a form of microangiopathy. Treatment for diabetes comprised of diet alone in 21.5%, oral hypoglycemic agents in 29.5%, and insulin with or without oral hypoglycemic agents in 44.2%, which was the most common. In particular, 683/1170 (58.4%) diabetics who died from diabetic nephropathy were on insulin therapy, a higher proportion than the 661/1687 (39.2%) who died from ischemic heart diseases, or the 659/1622 (40.6%) who died from cerebrovascular diseases. The average age at the time of death in the survey population was, 68 years for males and 71.6 years for females. These were 9.6 and 13 years, respectively, short of the average life expectancy for the Japanese general population. In comparison with the previous survey (1981-1990), the average age at the time of death had increased 1.5 years for males, and 3.2 years for females. The average life expectancy for the Japanese general population had also increased 1.7 and 2.7 years, respectively, over that period, showing that advances in the management and treatment of diabetes have not led to any improvement in patients' life expectancies. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00019.x, 2010).

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.

Granulocyte-colony stimulating factor- and interleukin 6-producing diffuse deciduoid peritoneal mesothelioma.

An autopsy case of granulocyte colony-stimulating factor (G-CSF)- and interleukin-6 (IL-6)-producing diffuse deciduoid peritoneal mesothelioma is reported. The patient was a 70-year-old man with abdominal distension and weight loss in the year prior to his death. Laboratory data suggested severe inflammation with marked leukocytosis, thrombocytosis and elevated serum levels of C-reactive protein, G-CSF and IL-6. Imaging studies showed an expansive mass occupying the entire abdomen and pelvic cavity. Histological diagnosis of tissue taken by needle biopsy was difficult due to the unusual sarcomatoid-appearance of the tumor. In addition, there was severe infiltration of numerous neutrophilic leukocytes. An autopsy revealed that the diffuse peritoneal tumor had a fresh fishmeat-like appearance with focal mucinous degeneration and entirely encased the abdominal organs. Histological examination showed a sheet-like proliferation of tumor cells with large ovoid or polygonal cytoplasm, large atypical nuclei and obvious nucleoli. The tumor cells showed abundant glycogen and hyaluronic acid, and were immunoreactive to cytokeratin, calretinin, epithelial membrane antigen (EMA), CA-125, and focally to vimentin. The tumor cells were immunoreactive to G-CSF and IL-6. Electron microscopy revealed long, slender microvilli on the tumor cell surface. This tumor was diagnosed as a G-CSF- and IL-6-producing, diffuse deciduoid mesothelioma. We report this case with special reference to the differential diagnosis of deciduoid peritoneal mesothelioma with paraneoplastic syndrome.

Comparison between a new 13C-urea breath test, using a film-coated tablet, and the conventional 13C-urea breath test for the detection of Helicobacter pylori infection.

BACKGROUND: In Japan, urea breath-testing includes mouth rinsing with water immediately after the ingestion of (13)C-urea solution, to prevent false-positive results that are caused by oral bacteria with urease activity. Our objective was to evaluate the diagnostic performance of a urea breath test using a film-coated (13)C-urea tablet and omitting mouth rinsing. METHODS: The study was a multicenter trial comparing the solution- and tablet-based urea breath tests (UBTs). Helicobacter pylori status was determined by histology, culture, and rapid urease testing. RESULTS: Of the 255 subjects who completed the study, evaluation of the tablet-based UBT was possible in 254, and comparison of the tablet-based UBT and the solution-based UBT was possible in 250 patients. When the assessment achieved by a combination of biopsy-based methods was used as a reference standard, the sensitivity, specificity, and accuracy of the tablet-based method were determined to be 97.7%, 98.4%, and 98.0%, respectively. When the results of the solution-based UBT were used as a reference standard, the sensitivity, specificity, and accuracy of the tablet-based UBT were determined to be 96.9%, 97.6%, and 97.2%, respectively. CONCLUSIONS: The (13)C-urea tablet-based method proved to be a simple and accurate test for the diagnosis of H. Pylori infection. Mouth rinsing was not required.

DNA fragmentation and detachment of enterocytes induced by anti-CD3 mAb-activated intraepithelial lymphocytes.

To elucidate the role of intraepithelial lymphocytes (IEL) and enterocytes in the defense mechanism of the small intestine, we designed experiments to stimulate the IEL by anti-CD3epsilon, anti-TCRalphabeta, or anti-TCRgammadelta monoclonal antibodies (mAbs), and to examine the subsequent changes to the enterocytes. The enterocytes of the duodenum and jejunum, but not of the ileum, showed massive DNA fragmentation 30 min after intraperitoneal injection of anti-CD3 mAb. These responses were also induced by anti-TCRgammadelta mAb, but not by anti-TCRalphabeta mAb, and were completely inhibited by cyclosporin A. Nearly half of the enterocytes of the villi in the duodenum and jejunum were exfoliated into the lumen 4 h after the injection of the mAb. Administration of anti-CD3 mAb also induced DNA fragmentation in Fas-deficient MRL/lpr mice, indicating that the Fas-Fas ligand system was not involved in these events. The anti-CD3 mAb treatment also induced massive DNA fragmentation in the intestinal epithelium of the duodenum and jejunum in TNF-receptor-1-deficient mice, whereas TNF-alpha induced only the detachment of intestinal epithelium of wild-type mice, implying the dissociation of two independent factors and/or mechanisms for DNA fragmentation and the subsequent epithelial cell detachment in the murine duodenum and jejunum. The mAb failed to exfoliate the epithelium in TNF-R1-deficient mice. Thus, TCRgammadelta(+) IEL, when treated with anti-CD3 or anti-TCRgammadelta mAbs, induced rapid DNA fragmentation and subsequent detachment of the duodenal and jejunal epithelia, but not in the ileum ("the silent ileum"), partly because of the paucity of TCRgammadelta(+) IELs in the ileum.

The possible role of tumor necrosis factor-alpha in diabetic polyneuropathy.

In this review, the authors provide evidences that imply the role of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of diabetic complications, especially diabetic polyneuropathy. Under chronic hyperglycemia, endogenous TNF-alpha production is accelerated in microvascular and neural tissues, which may undergo an increased microvascular permeability, hypercoagulability, and nerve damage, thus initiating and promoting the development of characteristic lesions of diabetic microangiopathy and polyneuropathy. Enhanced TNF-alpha production may also promote atherosclerosis due to increased insulin resistance and the expression of adhesion molecules. Clinical application of specific agents that suppress production and/or activity of TNF-alpha may inhibit the development and exacerbation of chronic diabetic complications.