Nateglinide and mitiglinide, but not sulfonylureas, induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum

Nateglinide and mitiglinide (glinides) are characterized as rapid-onset and short-acting insulinotropic agents. Although both compounds do not have a sulfonylurea structure, it has been postulated that insulin secretion is preceded by their binding to Kir6.2/SUR1 complex, and a mechanism of insulin secretion of glinides has been accounted for by this pathway. However, we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides, and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions. Dose-dependent effects of tolbutamide, glibenclamide, nateglinide, and mitiglinide were observed. Insulin secretion induced by 3 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil, although the latter half-component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents. Glinides enhanced insulin secretion even in Ca2+-depleted medium, and its pattern of secretion was same as the pattern with existence of verapamil. The latter half was suppressed by 1 microM dantrolene, and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide. Thus, we conclude that glinide action is demonstrated through two pathways, dependently and independently, from the pathway through K(ATP) channels. We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation.     

Serologically HLA-DR—Mismatched Unrelated Donors Might Provide a Valuable Alternative in Allogeneic Transplantation: Experience from a Single Japanese Institution

To clarify the clinical significance of a serologic HLA-DR mismatch after unrelated-donor transplantation, we evaluated for hematologic malignancies 123 cases of unrelated bone marrow transplantation carried out in a single institution between 1995 and 2004. Of the patients in these cases, 12 were serologically mismatched at the single HLA-DR locus. Eighty-two patients who received HLA-matched transplantations were used as controls. Conditioning consisted of a conventional total body irradiation-based regimen or a fludarabine-based reduced-intensity regimen. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus plus short-term methotrexate. Graft failure did not develop. With a median follow-up of 42 months (range, 11-99 months), rates of overall survival, nonrelapse mortality, and relapse at 4 years were 63%, 38%, and 0%, respectively, all of which were comparable with those after HLA-matched transplantation. The frequency of acute GVHD of grades II to IV was 75%, significantly higher than after HLA-matched transplantation (42%, P = .046), and there was a trend toward an increased incidence of acute GVHD of grades III to IV after serologically HLA-DR-mismatched unrelated transplantation (27% versus 10%, P = .093). Chronic GVHD developed in 4 of 11 evaluable patients, an incidence comparable with that after HLA-matched transplantation. In summary, serologically HLA-DR-mismatched unrelated transplantation is feasible and might be an acceptable alternative for the Japanese population, although the higher incidence of acute GVHD is notable.     

Effectiveness of Comprehensive Health Education Combining Lifestyle Education and Hot Spa Bathing for Male White-Collar Employees: A Randomized Controlled Trial with 1-Year Follow-Up

Background

Physical activity is known to prevent obesity and metabolic syndrome in middle-aged and elderly people; however, the effectiveness of a comprehensive health education program for male white-collar employees is uncertain.

Methods

Forty-three men volunteered to participate in this study and were randomly assigned into 2 groups. The intervention group participated in a 2-hour program comprising comprehensive health education and hot spa bathing, offered once every 2 weeks, in addition to individualized programs once a week, for 24 weeks. The control group received only general health guidance. We compared their lifestyle characteristics and physical and mental health criteria at baseline, immediately after the intervention, and 1 year after the end of the intervention.

Results

Rates of adherence to individualized programs were 60.0 ± 27.2% and 30.5 ± 29.6% at the end of the intervention and at 1 year after the end of the intervention, respectively. Significant (P < 0.05) interaction of criteria was observed for cluster of differentiation 4+ (CD4+) cells and the ratio of cluster of differentiation 4+ to 8+ (CD4/8) cells, which were used to represent the participants'' immunological function. We divided the intervention group into 2 subgroups on the basis of their attendance. Among the resulting 3 groups, significant interaction of criteria was observed for CD4+ and CD4/8 cells. In addition, the high attendance group had the highest CD4+ count and CD4/8 ratio.

Conclusions

Participants who attended classes and/or performed the supplementary individualized programs tended to maintain their immunological function and to experience a decrease in body fat percentage. However, few effects were noted in participants with poor adherence, even in the intervention group.Key words: male, white-collar-employees, randomized controlled trial, lifestyle education, hot spa, and exercise     

Aneuploid mosaicism in the developing and adult cerebellar cortex

Neuroprogenitor cells (NPCs) in several telencephalic proliferative regions of the mammalian brain, including the embryonic cerebral cortex and postnatal subventricular zone (SVZ), display cell division "defects" in normal cells that result in aneuploid adult progeny. Here, we identify the developing cerebellum as a major, nontelencephalic proliferative region of the vertebrate central nervous system (CNS) that also produces aneuploid NPCs and nonmitotic cells. Mitotic NPCs assessed by metaphase chromosome analyses revealed that 15.3% and 20.8% of cerebellar NPCs are aneuploid at P0 and P7, respectively. By using immunofluorescent analysis of cerebellar NPCs, we show that chromosome segregation defects contribute to the generation of cells with an aneuploid genomic complement. Nonmitotic cells were assessed by fluorescence-activated cell sorting (FACS) coupled with fluorescence in situ hybridization (FISH), which revealed neuronal and nonneuronal aneuploid populations in both the adult mouse and human cerebellum. Taken together, these results demonstrate that the prevalence of neural aneuploidy includes nontelencephalic portions of the neuraxis and suggest that the generation and maintenance of aneuploid cells is a widespread, if not universal, property of central nervous system development and organization.     

Postoperative changes in mandibular prognathism surgically treated by intraoral vertical ramus osteotomy

This study investigated short- and long-term postoperative skeletal changes following intraoral vertical ramus osteotomy (IVRO) for mandibular prognathism, as determined from lateral cephalograms. The subjects were 20 patients with mandibular prognathism who had undergone surgical orthodontic treatment combined with IVRO. Lateral cephalograms were taken at six time points: 1 month before surgery, and 1 day, 3 months, 6 months, 1 year, and approximately 2 years after surgery. Intermaxillary fixation (IMF) with four monocortical screws was maintained for 1 week in all patients. Mean posterior movement of the menton (Me) was 5.9 mm at surgery. 3 months after surgery, the FMA and FH-CorMe angles had increased 6.3 and 6.2 degrees, respectively, indicating clockwise rotation of the distal segment of the mandible. This rotation was observed in all 20 patients, suggesting that postoperative rotation of the mandible in the postoperative short term is likely to occur after IVRO and could be considered an adaptation of the mastication system newly established by surgery. In the long term after IVRO, Me had moved anteriorly by only 0.9 mm and the relapse ratio was 15.3%. These findings suggest the excellent long-term stability of surgical orthodontic treatment combined with IVRO in patients with mandibular prognathism.     

Possible induction of systemic lupus erythematosus by zonisamide.

An epileptic male to whom zonisamide and ethosuximide had been administered exhibited fever, pericarditis, pleuritis, arthralgia, and elevated titers of antinuclear antibody and anti-DNA-antibody at 5 years, 11 months of age. It was suggested that zonisamide induced the systemic lupus erythematosus symptoms because the antinuclear antibody titers began to rise after zonisamide was administered, and clinical recovery and a decrease in the anti-DNA-antibody levels promptly followed the discontinuation of the drug. The positive lymphocyte transformation test results against zonisamide further supports the etiologic relationship of the male's lupus and the drug. This first case of zonisamide-induced lupus should alert physicians to the possibility of this serious unwanted effect in patients receiving zonisamide.