Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation--double-blind placebo-controlled trial.

BACKGROUND: It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS: Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS: After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. CONCLUSION: These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Successful non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) for Waldenström's macroglobulinemia with severe pancytopenia.

We report a 62-year-old male who underwent non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) because of his life-threatening severe pancytopenia due to refractory Waldenström's macroglobulinemia. This therapy was performed safely and he made a marked recovery from his cytopenia that had not been improved with any other therapy. Bone marrow aspirates showed post-transplant mixed chimerism during engraftment, and became completely donor-derived after a series of GVHD symptoms, without subsequent donor lymphocyte infusion. Our results suggest that non-myeloablative allogeneic PBSCT could be a good alternative for patients suffering from multi-drug resistant Waldenström's macroglobulinemia.

[Intravascular malignant lymphomatosis: an autopsy case with generalized telangiectasia and various neurological manifestations].

We report a 73-year-old woman with intravascular malignant lymphomatosis (IML) who showed generalized telangiectasia as well as various neurological symptoms. In July 1998, she developed fever, dizziness, and confusion followed by left hemiparesis, and was admitted to our hospital on August 11, 1998. Laboratory tests indicated a normochromic normocytic anemia, thrombocytopenia, elevated serum lactic dehydrogenase (LDH), C-reactive protein (CRP), and cerebrospinal fluid protein. Magnetic resonance imaging (MRI) of the brain revealed an infarct-like lesion in the left frontal lobe and multiple white matter lesions. After admission, her neurological status deteriorated and lapsed into coma and quadriplegia. At the end of September 1998, generalized telangiectasia appeared, and she was diagnosed as IML on skin biopsy. Although combination chemotherapy failed to improve her neurological symptoms, telangiectasia disappeared in a few days, and the infarct-like lesion on MRI decreased in size. Serum LDH, CRP, and thrombocyte counts were normalized. Autopsy findings revealed perivascular clustering of B cell type lymphoma cells in the left frontal lobe where abnormal signal intensity was found on MRI, as well as the spleen and the bone marrow. This case emphasizes the importance of early diagnosis and treatment in IML.

Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population.

Familial hypercholesterolemia (FH) is a common genetic disorder caused by mutations of the LDL-receptor gene. In the present study, we investigated four Japanese FH homozygotes and identified five point mutations: a splice site mutation in intron 12 (the 1845 + 2 T-->C mutation), a missense mutation in exon 7 (the C317S mutation), a nonsense mutation in exon 17 (the K790X mutation), a missense mutation in exon 14 (the P664L mutation), and a missense mutation in exon 4 (the E119K mutation). We developed simple methods for detecting these mutations. When we examined the presence of these mutations in 24 unrelated FH homozygotes, the 1845 + 2 T-->C mutation was found in 7 of them, and the other four mutations were unique for each proband. We also screened 120 unrelated FH heterozygotes for these mutations and found that the frequencies of the 1845 + 2 T-->C, C317S, K790X, P664L, and E119K mutations were 13.3% (16/120), 6.7% (8/120), 6.7% (8/120), 3.3% (4/120), and 1.7% (2/120), respectively. These mutations were found in more than 30% of unrelated Japanese FH patients. By using the detection methods developed in this study, the diagnosis of more than 30% of the genetic bases of Japanese FH heterozygotes is expected.

Regression of coronary atherosclerosis by combined LDL-apheresis and lipid-lowering drug therapy in patients with familial hypercholesterolemia: a multicenter study. The LARS Investigators.

The purpose of the LDL-Apheresis Regression Study (LARS) group, which included 13 institutions in Japan, was to investigate the effects on coronary atherosclerosis of LDL-apheresis combined with cholesterol-lowering drugs. Changes in coronary artery stenosis were assessed angiographically in 37 patients with familial hypercholesterolemia (7 homozygotes and 25 heterozygotes) and hypercholesterolemia which had not been defined as familial hypercholesterolemia (5 patients) by visual judgement and computer analysis. Definite regression was observed in 14 cases, including 4 homozygotes and 10 heterozygotes and others. Regression occurred as often in patients with severe coronary artery disease (2 or more vessel disease) as in those having less severe disease. Our results encourage initiation of aggressive cholesterol-lowering therapy to produce regression of coronary atherosclerosis in FH patients at high risk for cardiovascular events.

CA125-positive papillary tumor of the peritoneum.

A 71-year-old female visited our outpatient unit with chief complaints of anorexia and a sense of abdominal distension. The abnormalities found after admission were conspicious increases in CA125 levels in serum and ascites as well as anemia, accelerated erythrocyte sedimentation and increased serum LDH. The patient underwent an emergency operation for ileus. The histological diagnosis was serous papillomatous cancer. Immunohistologic staining of the cancer tissue demonstrated the production of CA125. In this very rare the remnant of the Müllerian duct in the peritoneum is thought to have been cancerous.

Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome, associated with preceding polycythemia vera. A case report and review of the literature.

A case of plasma cell dyscrasia with polyneuropathy and endocrine disorder is reported. Clinically, polycythemia vera, gynecomastia, pigmentation of the skin, hepatosplenomegaly, renal enlargement and severe polyneuropathy in the lower extremities were recognized. The peculiarity of this case was polycythemia vera that had been present for several years before manifestation of the clinical symptoms. Microscopically, retroperitoneal lymph nodes showed angio-follicular lymphoid hyperplasia and plasma cell infiltration in the interfollicular region. By means of the avidin-biotin-peroxidase complex method, plasma cells were positive for lambda light chain, IgA and IgG. Severe segmental demyelination and slight axonal atrophy were found in a sural nerve biopsy.

[Basic studies on an immunoradiometric assay system for human parathyrin (intact PTH1-84)].

Two-site immunoradiometric assay for human parathyrin (PTH1-84) is specific for the intact, secreted, biologically active 84 amino peptide. This system incorporates two-different polyclonal antibodies to human intact PTH and has several technical advantages for use. This assay could detect a wide range of PTH in patients with hypo-, hyperparathyroidism, chronic renal failure and hypercalcemia with malignancy, especially distinguishing the level of human intact PTH in hypoparathyroidism from in normal.

Mutations of the low density lipoprotein receptor in Japanese kindreds with familial hypercholesterolemia.

Mutations of the low density lipoprotein (LDL) receptor in 16 Japanese kindreds with homozygous familial hypercholesterolemia (FH) were studied using an anti-LDL receptor antibody. The LDL receptor mutations in Japanese FH were heterogeneous and included defects in synthesis, post-translational processing, ligand-binding activity, and internalization of the LDL receptor. Of the 16 kindreds, 10 were receptor-negative and 5, receptor-defective types and 1 was an internalization-defective type with respect to LDL binding. The receptor-negative group was further subdivided into four groups: those with cells producing (i) no immunodetectable receptor (five kindreds); (ii) 160-kd mature receptors, which were quite scarce (two kindreds); (iii) receptors that could not be processed to the mature receptor properly (two kindreds); and (iv) receptors with an apparent molecular weight smaller than normal (one kindred). The last kindred synthesized an about 155-kd mature receptor that was rapidly degraded. This finding is compatible with the low concentration of the cell surface LDL receptors and decreased binding activity for LDL in the cells of this kindred. The receptor-defective group, which could produce a residual amount of functional receptors, exhibited a lower tendency to coronary artery disease than the receptor-negative group.

Impaired catecholamine secretion as a cause of diabetic autonomic neuropathy.

Human and animal studies were performed to investigate the causes of diabetic autonomic neuropathy. Human diabetics, with and without autonomic neuropathy, were measured for plasma catecholamine response to insulin hypoglycemia and for urinary catecholamine excretion. In streptozotocin-diabetic rats, plasma catecholamine response and tissue catecholamine concentrations were measured at various stages of the disease. As the duration of the diabetic state lengthens in rats, there is a time-proportional stepwise decrease in plasma catecholamine response. This is similar to the clinical course observed in human diabetics, which also includes a reduction of catecholamine excretion after the appearance of autonomic neuropathy. After 6 weeks of diabetes, rat tissue is found to have an increased concentration of catecholamines; this may represent a compensatory reaction to the difficulties of secretion. At 13 weeks of diabetes, tissue catecholamine concentrations return to almost normal, when plasma responses have disappeared. These results suggest that the impaired secretion of catecholamines in diabetics may be a cause of diabetic autonomic neuropathy.