Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual.

We present a case of cryptococcosis with adrenal insufficiency and meningitis in a healthy host without any risk factors. Antifungal therapy did not reduce the cryptococcal antigen titers of the cerebrospinal fluid and serum or the bilateral adrenal gland enlargement. It was suggested that the adrenal glands were the focus of persistent fungemia. Removal of both adrenal glands brought about a response to antifungal therapy. We conclude that if antifungal therapy is ineffective, bilateral adrenalectomy is an effective measure for treatment of such patients. Cryptococcosis is a possible cause of primary adrenal insufficiency in immunocompetent patients.

Usefulness of urinary glucose excretion after oral glucose tolerance testing to detect insulin secretion failure before the onset of diabetes mellitus.

Sodium-glucose cotransporter 2 inhibitors are commonly used to promote urinary glucose excretion (UGE). However, it remains unclear how UGE reflects glucose metabolism in the natural history of diabetes. Thus, we retrospectively reviewed the prediabetes medical records of 64 patients who had undergone 75-g oral glucose tolerance testing (OGTT) with measurements of UGE at 0 min, 60 min, and 120 min. The mean age and glycated hemoglobin levels were 46 ± 10 years and 5.6 ± 0.3%, respectively. The median UGE (60 min + 120 min) value was 16.8 mg ([interquartile range]: [10.5-150.0 mg]). Thus, we categorized 16 patients as having high UGE (≥150.0 mg) and 48 patients as having low UGE (<150.0 mg). As compared with the low UGE group, the high UGE group exhibited a significantly lower median insulinogenic index (0.23 [0.12-0.35] vs. 0.56 [0.31-1.06], p = 0.001) and homeostasis model assessment of ß-cell function value (46 [26-67] vs. 66 [41-85], p = 0.028). The log-transformed insulinogenic index exhibited a significant inverse association with log-transformed UGE (60 min + 120 min) (r = -0.50, p < 0.001). The association between higher UGE and lower insulinogenic index was also observed in a subgroup analysis of patients with plasma glucose levels of ≥160 mg/dL during the OGTT. Therefore, UGE measurements after OGTT may provide a useful clinical marker for detecting insulin secretion failure and advancing preventive and therapeutic interventions among populations with a high risk of developing diabetes.

Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells.

AIMS: Mesenchymal stem cells (MSC) have the potential to differentiate into various cell lineages, including adipocytes and osteoblasts. The formation of adipose tissue involves the commitment of MSC to the preadipocyte lineage and the differentiation of preadipocytes into mature adipocytes. In the present study, we investigated the involvement of reactive oxygen species (ROS) in adipocyte differentiation from MSC. MAIN METHODS: ROS signaling was evaluated by the effects of antioxidant N-acetyl-l-cysteine (NAC) or shRNA against NAD(P)H oxidase in the multipotent mesenchymal stem cell line 10T1/2 cells. Intracellular ROS was measured using an H(2)DCF dye. KEY FINDINGS: We found that NAC blocked adipocyte differentiation in MSC. An H(2)DCF assay revealed that differentiation-inducing agents induced ROS generation. These data suggest that ROS is involved in adipocyte differentiation in MSC. Next, we examined the source of ROS. Knockdown of NAD(P)H oxidase 4 (Nox4) by RNA interference inhibited ROS production and adipocyte differentiation by differentiation-inducing agents. Furthermore, treatment with NAC blocked the transcriptional activation of CREB, and the expression of dominant-negative mutants of CREB inhibited adipocyte differentiation. SIGNIFICANCE: The findings suggest that the increase in the intracellular ROS level via Nox4 mediates adipocyte differentiation through CREB in MSC. This data will provide new insight into the drug development for obesity.

Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells.

Previous reports have shown that the paracrine system may be an important mediator in bone-marrow-derived mesenchymal stem cell (MSC) therapy for ischemic diseases. Hyperglycemia and hypoxia have been associated with increased levels of reactive oxygen species; oxidative stress may therefore influence the paracrine effects of MSCs under hypoxic conditions in diabetic patients, although the mechanism underlying this effect remains unknown. Hypoxia-inducible factor 1α (HIF-1α) regulates the transcription of hypoxia-inducible genes. We determined the effect of high-glucose concentrations on the production of angiogenic growth factors via HIF-1α induction in hypoxic MSCs. MSCs were cultured with different glucose concentration (5.6, 11, 20, or 30 mM) for 24 h. The cells were then incubated in a hypoxic chamber (5% O2) or under normoxia (21% O2) for 6 or 24 h. Protein levels of HIF-1α, vascular endothelial growth factor A165 (VEGF-A165), and platelet-derived growth factor B (PDGF-B) were attenuated by glucose in hypoxic MSCs in a dose-dependent manner. Treatment with MG132, a specific inhibitor of proteasome activity, significantly reversed the inhibitory effect of high-glucose concentrations in hypoxic MSCs. 4-Hydroxyl-tetramethylpiperidin-oxyl (a cell-permeable superoxide scavenger) or Apocynin (a NADPH oxidase inhibitor) significantly reversed glucose-induced attenuation of VEGF-A165, PDGF-B, and HIF-1α protein levels. Stimulation with a high-glucose concentration (30 mM) significantly increased intracellular superoxide levels in hypoxic MSCs. Our results suggest that in hypoxic MSCs the increase in intracellular superoxide levels induced by high-glucose concentrations may attenuate hypoxia-induced HIF-1α expression, which in turn attenuates hypoxia-induced VEGF-A165 and PDGF-B transcription.

Optical near-field analysis of spherical metals: Application of the FDTD method combined with the ADE method.

The time-average energy density of the optical near-field generated around a metallic sphere is computed using the finite-difference time-domain method. To check the accuracy, the numerical results are compared with the rigorous solutions by Mie theory. The Lorentz-Drude model, which is coupled with Maxwell's equation via motion equations of an electron, is applied to simulate the dispersion relation of metallic materials. The distributions of the optical near-filed generated around a metallic hemisphere and a metallic spheroid are also computed, and strong optical near-fields are obtained at the rim of them.