Visceral fat accumulation contributes to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged non-obese Japanese men.

Visceral fat accumulation plays an important role in the occurrence of coronary artery disease (CAD) associated with a cluster of multiple risk factors, such as glucose intolerance, insulin resistance and hyperlipoproteinemia. To clarify the detailed features of these factors, based on visceral fat accumulation, the present study examined the relationship between fat distribution and the characteristics of glucose metabolism and serum lipoproteins in middle-aged non-obese Japanese men. First, the influence of visceral fat accumulation on glucose metabolism, insulin sensitivity, and the extent and severity of coronary artery lesions was investigated in 50 subjects with CAD and compared with 15 control subjects without CAD (Study 1) and with the lipoprotein characteristics in 44 subjects without CAD who were not treated with lipid-lowering drugs (Study 2). Body fat distribution was determined by abdominal computed tomography. In Study 1, the visceral fat area (VFA), blood pressure, fasting immunoreactive insulin (FIRI), and the plasma insulin area (PIA) obtained by oral glucose tolerance test in the subjects with CAD were all significantly higher than in the control subjects. The VFA was significantly correlated with FIRI, the homeostasis model of insulin resistance, PIA and steady state plasma glucose (SSPG) concentration as an index for insulin resistance (r=0.57, p<0.001, r=0.49, p<0.01, r=0.36, p<0.01, and r=0.50, p<0.05, respectively). Although the SSPG concentration did not correlate with the coronary atherosclerosis index as a score of the extent and severity of coronary lesions, the VFA was significantly correlated with this index (r=0.43, p<0.01). In Study 2, the VFA had significant positive correlations with serum total cholesterol, triglyceride, and apolipoprotein B and E levels and the cholesterol and triglyceride concentrations of very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein (LDL) fractions. There was a negative correlation between the VFA and LDL particle size (r=-0.34, p<0.05). In conclusion, visceral fat accumulation may contribute to the development of CAD through the progression of insulin resistance and the increase of apo B-containing lipoproteins and small-sized LDLs in middle-aged non-obese Japanese men.

CD36 deficiency associated with insulin resistance.

No major genes responsible for insulin resistance have yet been identified. CD36 is a multifunctional receptor, which plays a part in mediating intracellular signalling as well as in taking up biologically active substances such as long-chain fatty acids. We looked for insulin resistance in genetic CD36 deficiency, which is common in Asian and African populations. The euglycaemic hyperinsulinaemic clamp technique showed insulin resistance in the five CD36-deficient people tested. We conclude that CD36 could be responsible for insulin resistance.

Proliferation and differentiation of bone marrow cells on titanium plates treated with a wire-type electrical discharge machine.

For successful dental implants, it is necessary to obtain satisfactory osteointegration at the site of both the cortical and trabecular bones in the jaw. Bone marrow stromal cells differentiate into osteoblast-lineage cells and have an important role in bone remodeling. In this experiment, the responsiveness of bone marrow cells to a titanium plate with a rough surface was compared with that of a titanium plate with a smooth surface. The rough surface was created by treating with a wire-type electrical discharge machine, and the smooth plate was produced by polishing with 1.500-grade emery paper. The results indicated that, though bone marrow cells proliferated on both plates, the proliferation pattern and cell growing time on the plates were different. While the cells on the smooth plate proliferated along the grooves produced by polishing, the cells on the rough plate proliferated randomly and more rapidly. As bone marrow cells consisted of heterogeneous cell populations involving hematopoietic cells, we collected bone marrow mesenchymal stromal cells that proliferated on plastic dishes and studied the proliferation and differentiation of these cells. Stromal cells on the rough plate more actively proliferated than those on the smooth plate. In long-term culture, the cells on the rough plate showed higher alkaline phosphatase activity and produced cell nodules. The cells on the smooth plate were stripped off the plate without nodule formation. These results indicated that bone marrow stromal cells on the rough plate could more rapidly proliferate and differentiate into osteoblast-lineage cells compared with those on the smooth plate.

Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.

We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.

Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation.

The liver plays a central role in lipoprotein metabolism. In particular, very-low density lipoprotein (VLDL) is assembled in the hepatocytes and secreted into the blood circulation. The VLDL is then catabolized to low-density lipoprotein by lipoprotein lipase and hepatic triglyceride lipase. Obese subjects, especially those with visceral fat accumulation, are frequently associated with hyperlipidemia, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension. The mechanism of hyperlipidemia in visceral fat obesity has not yet been elucidated. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of NIDDM, characterized by obesity with visceral fat accumulation, hyperlipidemia, and late-onset insulin resistance. To elucidate the mechanism of hyperlipidemia observed in OLETF rats, we focused on the production of VLDL by the liver and investigated hepatic messenger RNA (mRNA) levels of microsomal triglyceride transfer protein (MTP), acyl-coenzyme A synthetase (ACS), and apolipoprotein B (apo B), which play important roles in VLDL synthesis and secretion. In 6-week-old OLETF rats, in which insulin resistance had not been manifested, visceral fat weight was already higher and portal free fatty acid (FFA) and VLDL-triglyceride levels were elevated compared with the control rats. Hepatic ACS activity and mRNA levels, and MTP mRNA levels were also increased in OLETF rats, whereas apo B mRNA levels were similar; these results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation before developing insulin resistance may be involved in the pathogenesis of hyperlipidemia in obese animal models with NIDDM.

Plasma leptin levels and body fat distribution.

The relation between body fat distribution and plasma leptin levels in the human was investigated in 51 obese and 41 non-obese subjects. Plasma levels of leptin showed a positive correlation with body mass index and subcutaneous fat area at the umbilicus level. However, a significant correlation between its plasma levels and visceral fat area was found in neither non-obese nor obese subjects. These results suggest that plasma leptin levels might be attributed mainly to the extent of subcutaneous adiposity in human obesity.

Clinical aspects of B-cell malignancy involving the BCL1/PRAD1 locus.

BCL1/PRAD1 is the gene locus involved in the t(11;14)(q13;q32) translocation, which often occurs in a proposed subtype of non-Hodgkin's lymphoma of B-cell phenotype (B-NHL), named mantle cell lymphoma (MCL). When 67 Japanese patients with B-NHL were examined using two separate probes composed of the BCL1 MTC probe and the PRADI cDNA probe, rearrangement of BCL1/PRAD1 or overexpression of PRAD1 was detected in 11 patients. Among 13 patients with MCL, 8 had the abnormalities (61%) and the MTC probe detected the BCL1 rearrangement in 5 (38%). Five of the 6 MCL patients studied (83%) showed PRAD1 overexpression. These frequencies were compatible with those reported for Western patients. Although the remaining three with BCL1/PRAD1 abnormalities were diagnosed as having other histologies, 11 patients had advanced diseases, with dissemination to the extranodal sites. Except for one with diffuse large cell lymphoma, they had a slowly progressive disease, and none of the patients displayed clinical or pathological transformation. The tumor cells usually expressed CD5 and lacked CD10. The cells were completely uniform in the expression of IgM and/or IgD, and in the absence of C mu gene deletion. It thus appears that B-malignancies involving the BCL1/PRAD1 locus constitute a refined disease entity.

[Pharmacokinetic study of etoposide in aged patient with non Hodgkin lymphoma receiving hemodialysis].

A 78 year old patient with non Hodgkin Lymphoma receiving hemodialysis was treated with etoposide at a dose of 50 mg per body and its plasma pharmacokinetics were studied. The patient was dialyzed for 4 hours three times weekly. Etoposide was given by 60 minutes infusion on day 1 and 3, and hemodialysis was performed on day 2. The pharmacokinetic curve was found to fit to two compartment model. T 1/2 beta was 11.29 hours. Total body clearance was 13.65 mg/min/m2 on day 1 and 12.83 mg/min/m2 on day 3 respectively. AUC was 41.53 micrograms.h/ml on day 1 and 44.18 micrograms.h/ml on day 3 respectively. When these results were compared to those reported in patients with normal renal function, half life were longer while total body clearance was lower. In addition, AUC was higher. Hematologic toxicities were severe at this low dose. Hemodialysis did not influence on the decay of concentration during the elimination phase. These results suggest that it is necessary to reduce the dose of etoposide in hemodialysis patients.

[Phase II study of prednimustine in follicular lymphoma and chronic lymphocytic leukemia].

A phase II study of Prednimustine (PMN) was conducted for follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). PMN at a dose of 40-60 mg/body, p.o. every day, was administered to 17 patients with FL and 4 with CLL. The dose and schedule of PMN was modified according to hematological toxicity. Among the 17 patients with FL, there were 6 (35.3%) CRs and 7 (41.2%) PRs, with a high response rate of 76.5%. Among the 4 patients with CLL, there were 2 PRs and one case which showed clinical improvement. PMN was effective for cases of FL and CLL refractory to alkylating agents, and therefore the result suggested a lack of clinical cross-resistance to these agents. As to the side effects observed in patients with FL, mild leukopenia (median of lowest count 3,150/mm3) occurred. One case experienced anorexia, while increased appetite was observed in 4 cases. We conclude that PMN is effective for FL and CLL, and that in addition, it has an advantage in that its mild side effects allow long-term administration through outpatient clinics, so that the quality of life for patients is not impaired.

[Combination chemotherapy of cis-diamminedichloroplatinum (CDDP) and 5-fluorouracil (5-FU) in gastrointestinal tumors].

Twenty-five patients with gastrointestinal tumors (stomach 13, colon 8, pancreas 2, liver 2) were treated with a combination chemotherapy regimen consisting of CDDP (30 mg/m2/day d 1, 2) and 5-FU (500 mg/m2/day d 1-3), repeated every 3 or 4 weeks. The patients comprised 14 males and 11 females with a median age of 50 years (range 24-69), and a median performance status of 80% (range 40-100%). Thirteen patients had had prior chemotherapy. Partial response was observed in 2 patients (colon and liver), which lasted for 2 months each, respectively. No objective response was observed in 11 patients evaluable for gastric cancer. Non-hematological toxicities were nausea (92%), vomiting (56%), proteinuria (17%), transient elevation of BUN (8%), and hepatotoxicity (11%). Leukopenia and thrombocytopenia were observed in 71% and 25%, respectively. However, these toxicities were mild to moderate, and generally well tolerated.

[Brain metastasis from breast cancer].

Thirty-seven patients with breast cancer who developed brain metastasis were analyzed. At the diagnosis of brain metastasis, all patients had widespread metastasis, and 36 patients were receiving chemotherapy. Thirty patients were treated by radiotherapy to the brain at doses of 4,000 rads. There were 6 CRs (20%) and 5 PRs (17%). The median survival time for all patients was 53 months (8-177+) from diagnosis of the primary tumor, 24 months (7-126+) from the first recurrence, and 6 months (1-47+) from diagnosis of brain metastasis. Patients who achieved CR or PR survived longer than non-responders (11+ months vs. 6 months: p less than 0.01). Several backgrounds factors were analyzed, and the results indicated that patients with better performance status survived significantly longer than those with poorer performance status (11 months vs. 4 months: p less than 0.001).