Increased insulin sensitivity and hypoinsulinemia in APS knockout mice

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.     

Postoperative chemotherapy for patients with advanced gastric cancer.

The relationship between postoperative chemotherapy and survival time after gastric resection in patients with advanced gastric cancer was examined by retrospectively reviewing data on 916 patients treated in our clinics between 1965 and 1985. Of these patients, 738 were treated postoperatively with antitumor drugs. Postoperative chemotherapy was more often prescribed for those in the advanced stages of malignancy. Univariate analysis revealed that the survival time of patients given postoperative chemotherapy was shorter than for those not receiving chemotherapy, but there was no statistical significance. Multivariate analysis using the Cox regression analysis adjusted for sex, age, and other covariants indicated that operative curability, liver metastasis, serosal invasion, lymph node metastasis, peritoneal dissemination, and tumor size were the important prognostic factors. There was no correlation with postoperative chemotherapy. Our findings rule out any relationship between postoperative chemotherapy and length of survival time for patients with advanced gastric cancer undergoing gastric resection.     

Pancreas-Sparing Duodenectomy for a Recurrent Retroperitoneal Liposarcoma: Report of a Case

Pancreas-sparing duodenectomy (PSD), which allows preservation of the pancreas in its entirety, is a promising procedure for low-grade malignancies of the duodenum, the periampullary region, and the neighboring retroperitoneum. We report a case of recurrent retroperitoneal liposarcoma involving the second and third parts of the duodenum, which was extirpated using PSD, after a right hemicolectomy for tumor invasion of part of the colonic hepatic flexura. The Roux-en-Y jejunal limb was sutured to the duodenal bulb in an end-to-end fashion, and the biliary and pancreatic duct systems were reconstructed with end-to-side anastomoses, placing the jejunal limb distal to the bulbo-jejunostomy after a septoplasty to repair the adjacent pancreatic and biliary ducts. Because retroperitoneal liposarcoma has a low incidence of lymph node metastasis, pancreaticoduodenectomy may be inappropriate, especially if minimally extensive surgery can ensure organ preservation. Pancreas-sparing duodenectomy could be the most appropriate procedure for nonepithelial malignant tumors located around the duodenum distal to the pylorus, which have no involvement with the pancreatic parenchyma or periduodenal lymph nodes.     

Japanese orthopaedic association cervical myelopathy evaluation questionnaire (JOACMEQ): Part 5. Determination of responsiveness

Background

In 1999, the Japanese Orthopaedic Association decided to develop a new Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). The final version of the JOACMEQ, comprising 24 questions and five domains (cervical spine function (CF); upper extremity function (UF); lower extremity function (LF); bladder function (BF); and quality of life (QOL)), was established after three nationwide investigations. The fourth investigation, reported in this paper, was performed to confirm the responsiveness of the questionnaire.

Cholesterol crystal embolization (CCE) after cardiac catheterization: a case report and a review of 36 cases in the Japanese literature

Cholesterol crystal embolization (CCE) is a complication of atherosclerosis. A 67-year-old Japanese man underwent coronary artery bypass grafting. After the surgery, he underwent coronary angiography via the right femoral artery. Twelve days later, he suddenly developed acalculous cholecystitis and was treated with antibiotics. Gradual deterioration in renal function, purplish discoloration of the distal portion of his toes, and eosinophilia were noted. We performed a skin biopsy and made a diagnosis of CCE. Cilostazol and intravenous heparin improved the symptoms and decreased the creatinine level. We retrospectively studied the clinical features of 36 cases registered with a diagnosis of CCE in the Japanese literature.     

Surgical palliation for Taussig-Bing anomaly with multiple lesions

A successful surgical palliative procedure, consisting of an arterial switch operation, pulmonary artery banding, and arch repair, was performed in a neonate with Taussig-Bing anomaly and aortic arch interruption, subaortic stenosis, and multiple muscular ventricular septal defects. Such anatomical complexity made treatment difficult. This palliative procedure allows future biventricular repair.     

Bone mineral density in Japanese prostate cancer patients under androgen-deprivation therapy

Androgen-deprivation therapy (ADT) of patients with prostate cancer (PCa) is known to reduce bone mineral density (BMD). However, the most studies examined Caucasian or black patients and the effects of ADT on the bone metabolism of East Asians are unclear. Therefore, we performed a cross-sectional study to elucidate the influence of ADT on bone metabolism in Japanese patients. In total, 101 native Japanese patients with PCa were enrolled. They consisted of 58 ADT-treated and 43 hormone-naive patients. The BMD in the lumbar spine, total hip, and femoral neck was measured by dual energy X-ray absorptiometry and expressed in s.d. units relative to young adult men (T-score) or age-matched men (Z-score). Serum levels of bone metabolism markers were also measured. The BMDs at the three sites revealed that 2.3% (1/43) and 8.6% (5/58) of the hormone-naive and ADT-treated PCa patients had osteoporosis respectively, but this difference failed to achieve statistical significance (P=0.294). The two groups also did not differ significantly in their Z-scores of the three sites, and univariate and multivariate analyses indicated that ADT was not a significant risk factor for decreased BMD. In addition, a significant correlation between the duration of ADT and BMD was not observed for all three sites measured. However, the ADT-treated patients had significantly higher serum levels of N-terminal telopeptide of type I collagen (NTx) than the hormone-naive patients (P=0.017). To our knowledge, this is the first study to demonstrate the low prevalence of osteoporosis in both ADT-treated and hormone-naive Japanese PCa patients. Moreover, ADT did not significantly increase the prevalence of osteoporosis in this Japanese population.     

A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy.

Familial hypertrophic cardiomyopathy (HC) can be caused by mutations in 9 different genes encoding sarcomere proteins expressed in cardiac muscle. To date, only 13 different mutations in the cardiac troponin T (cTnT) gene have been reported to cause HC. Clinical characteristics and prognosis associated with mutations of this gene have not been well characterized owing to the small size and composition of affected families. The aim of this study was to determine the characteristic phenotype of patients with HC caused by a novel cTnT gene mutation, Lys273Glu. Two hundred Japanese probands with HC were screened for mutations in the cTnT gene. The Lys273Glu missense mutation was present in 9 persons from 2 unrelated pedigrees. They exhibited different cardiac morphologies: 1 had a dilated cardiomyopathy-like feature, 7 had left ventricular hypertrophy with normal left ventricular systolic function, and the 6 of them had asymmetric septal hypertrophy. A 1-year-old boy was not evaluated with echocardiography. The mean maximum wall thickness was 18.0 +/- 5.5 mm (range 8 to 24). There were 7 histories of sudden death in 1 of the 2 families. The Lys273Glu substitution in the cTnT gene shows a high degree of penetrance (100% in persons aged >20 years), a high incidence of sudden death, and a partial transition from hypertrophic to dilated cardiomyopathy. Because the location of a mutation appears to influence the development of a phenotype, we suggest that the precise definition of the disease-causing mutation can provide important prognostic information about affected members.     

Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability

We demonstrated recently that chronic administration of aldosterone to rats induces glomerular mesangial injury and activates mitogen-activated protein kinases including extracellular signal-regulated kinases 1/2 (ERK1/2). We also observed that the aldosterone-induced mesangial injury and ERK1/2 activation were prevented by treatment with a selective mineralocorticoid receptor (MR) antagonist, eplerenone, suggesting that the glomerular mesangium is a potential target for injuries induced by aldosterone via activation of MR. In the present study, we investigated whether MR is expressed in cultured rat mesangial cells (RMCs) and involved in aldosterone-induced RMC injury. MR expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. Cell proliferation and micromechanical properties were determined by [3H]-thymidine uptake measurements and a nanoindentation technique using an atomic force microscope cantilever, respectively. ERK1/2 activity was measured by Western blotting analysis with an anti-phospho-ERK1/2 antibody. Protein expression and immunostaining revealed that MR was abundant in the cytoplasm of RMCs. Aldosterone (1 to 100 nmol/L) dose-dependently activated ERK1/2 in RMCs with a peak at 10 minutes. Pretreatment with eplerenone (10 micromol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation and decreased the elastic modulus, indicating cellular proliferative and deforming effects of aldosterone, respectively. These aldosterone-induced changes in cellular characteristics were prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor, PD988059 (100 micromol/L). The results indicate that aldosterone directly induces RMC proliferation and deformability through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.