Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice

Despite the growing epidemic worldwide, diabetes is an incurable disease. We have been focusing on why diabetes manifests refractoriness to any therapy. We recently found that abnormal bone marrow-derived cells (BMDCs), namely, Vcam-1+ST-HSCs, was a key mechanism for diabetic complications. We then hypothesize that those aberrant BMDCs sustainedly impair pancreatic β cells. Here we show that eliminating abnormal BMDCs using bone marrow transplantation results in controlling serum glucose in diabetic mice, in which normoglycemia is sustained even after cessation of insulin therapy. Alternatively, abnormal BMDCs exhibiting epigenetic alterations are treated with an HDAC inhibitor, givinostat, in diabetic mice. As a result, those mice are normoglycemic along with restored insulin secretion even following the cessation of both insulin and givinostat. Diabetic cell fusion between abnormal BMDCs and resident cells is significantly blocked by the combination therapy in the pancreatic islets and thymus while surgical ablation of the thymus completely eliminates therapeutic protection in diabetic mice. In conclusion, diabetes is an epigenetic stem cell disorder with thymic disturbances. The combination may be applied to patients aiming at complete remission from diabetes in clinical medicine.journal articl

Validating Variational Bayes Linear Regression Method With Multi-Central Datasets.

PurposeTo validate the prediction accuracy of variational Bayes linear regression (VBLR) with two datasets external to the training dataset.MethodThe training dataset consisted of 7268 eyes of 4278 subjects from the University of Tokyo Hospital. The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) dataset consisted of 271 eyes of 177 patients, and the Diagnostic Innovations in Glaucoma Study (DIGS) dataset includes 248 eyes of 173 patients, which were used for validation. Prediction accuracy was compared between the VBLR and ordinary least squared linear regression (OLSLR). First, OLSLR and VBLR were carried out using total deviation (TD) values at each of the 52 test points from the second to fourth visual fields (VFs) (VF2-4) to 2nd to 10th VF (VF2-10) of each patient in JAMDIG and DIGS datasets, and the TD values of the 11th VF test were predicted every time. The predictive accuracy of each method was compared through the root mean squared error (RMSE) statistic.ResultsOLSLR RMSEs with the JAMDIG and DIGS datasets were between 31 and 4.3 dB, and between 19.5 and 3.9 dB. On the other hand, VBLR RMSEs with JAMDIG and DIGS datasets were between 5.0 and 3.7, and between 4.6 and 3.6 dB. There was statistically significant difference between VBLR and OLSLR for both datasets at every series (VF2-4 to VF2-10) (P < 0.01 for all tests). However, there was no statistically significant difference in VBLR RMSEs between JAMDIG and DIGS datasets at any series of VFs (VF2-2 to VF2-10) (P > 0.05).ConclusionsVBLR outperformed OLSLR to predict future VF progression, and the VBLR has a potential to be a helpful tool at clinical settings

Factor analysis for construct validity of a trunk impairment scale in Parkinson’s disease: a cross-sectional study

ObjectivesTo investigate the construct validity of the Trunk Impairment Scale (TIS), which was developed to assess trunk impairment in patients with stroke, in patients with Parkinson’s disease (PD).DesignThis retrospective, cross-sectional study enrolled consecutive PD inpatients. Correlation analysis was performed to clarify whether the TIS assessment was related to other balance functions, lower extremity muscle strength, or walking ability. Factor analysis was performed to see how the background factors of TIS differ from balance function, lower limb muscle strength, and walking ability.ResultsExamining the data of 471 patients with PD, there were relationships between TIS and the Mini-Balance Evaluation Systems Test (r = 0.67), Barthel Index (r = 0.57), general lower limb extension torque (r = 0.51), two-minute walk test (r = 0.54), Hoehn and Yahr stage (r = −0.61), and Movement Disorder Society Unified Parkinson’s Disease Rating Scale part III total points (r = −0.59). Factor analysis showed that TIS items were divided into three factors (an abdominal muscles and righting reflex component; a perception and verticality component; and a rotational component), differing from other scales that included clinical assessment items.ConclusionThe TIS can be useful for assessing the underlying trunk impairment as a basis for activities of daily living, gait function, and balance ability in patients with PD

Aberrant bone marrow-derived microglia in the hypothalamus may dysregulate appetite in diabetes

Bone marrow derived cells (BMDCs) migrate into the hypothalamus, where those cells give rise to microglia to regulate food intake. Given the fact that diabetes functionally impairs BMDCs, we hypothesized that diabetic microglia would fail to exhibit physiological function, accounting for hyperphagia in diabetes. To examine the role of BMDCs, total bone marrow cells from GFP transgenic mice were transplanted into wild type mice in which diabetes was induced by streptozotocin. We first confirmed that bone marrow transplantation could be utilized to examine BMDCs in the brain parenchyma as GFP positive cells could engraft the brain parenchyma and give rise to microglia even when the BBB was intact in the recipient mice. While diabetic mice manifested hyperphagia, BMDCs were in smaller number in the hypothalamus with less response to fasting in the brain parenchyma compared to nondiabetic mice. This finding was also confirmed by examining nondiabetic chimera mice in which BMDCs were diabetic. Those mice also exhibited less response of BMDCs in response to fasting. In conclusion, diabetic BMDCs had less response of microglia to fasting, perhaps accounting for diabetic hyperphagia.journal articl

Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion.

Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy

Approaches to regenerate pancreatic function by converting liver blood flow and transferring specific gene

科学研究費補助金研究成果報告書研究種目: 若手研究(B)研究期間: 2009～2011課題番号: 21791282研究代表者: 藤野 和典（滋賀医科大学・医学部・助教

Variation of Risk Factors for Cause-Specific Reintubation: A Preliminary Study

Unexpected reintubation may occur, even if the risk factors are considered and a spontaneous breathing trial is successful. Reintubation is thought to be caused by various factors. Several studies have investigated the risk factors of reintubation, but most did not classify reintubation by cause. We retrospectively classified patients undergoing reintubation at intensive care unit by cause (respiratory insufficiency vs. nonrespiratory insufficiency) to examine the cause-specific risk factors of reintubation. A total of 262 patients were included; reintubation within 48 hours after extubation was performed in 12 patients (reintubation rate, 4.5%). After classification by cause of reintubation, the pressure of arterial oxygen to fractional inspired oxygen concentration (P/F) ratio exhibited a significant association with reintubation only in the respiratory insufficiency group (odds ratio (OR) 0.989, 95% confidence interval (CI) 0.980 to 0.999, p=0.036, and OR 0.989, 95% CI 0.979 to 0.999, p=0.026, in the univariate and multivariate analyses, respectively). In the propensity score analysis, a P/F ratio ≤ 200 may be a risk factor for reintubation in the respiratory insufficiency group (OR 7.811, 95% CI 1.345 to 45.367, p=0.022). In the nonrespiratory insufficiency group, intubation duration was significantly related to reintubation (OR 1.165, 95% CI 1.012 to 1.342, p=0.033, and OR 1.163, 95% CI 1.004 to 1.348, p=0.044, in the univariate and multivariate analyses, respectively). In conclusion, a low P/F ratio at extubation may be a risk factor for reintubation due to respiratory insufficiency. In the nonrespiratory insufficiency group, intubation duration may be significantly related to reintubation. The risk factors for reintubation may differ by the cause of reintubation. Further large-scale randomized controlled trials are required

The mechanism of liver failure by hyperglycemia in septic state

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2009～2011課題番号: 21592306研究代表者: 松村 一弘（滋賀医科大学・医学部・准教授）研究分担者: 藤野 和典（滋賀医科大学・医学部・助教

Dexmedetomidine attenuates the positive chronotropic effects of intravenous atropine in patients with bradycardia during spinal anaesthesia: a retrospective study

Abstract Introduction Dexmedetomidine is a sedative used during spinal anaesthesia. However, it frequently induces bradycardia. Although intravenous atropine is often used for treating bradycardia during regional anaesthesia, the response to atropine might be attenuated by concomitantly administering sedatives. Methods We examined the effects of atropine used for treating bradycardia during spinal anaesthesia among patients receiving dexmedetomidine (D group), propofol (P group), or neither (nonDnonP group) for sedation, retrospectively. Results A total of 108 patients were included. Heart rate was significantly slower at all time points in the D group (n = 69) than in the nonDnonP group (n = 14) (p <  0.025 for all). On the other hand, heart rate was significantly slower only 60 min after administration of atropine in the P group (n = 25) than in the nonDnonP group (p = 0.002). There were differences in the overall values of heart rate (including all the values from time 0 to 60 min) among the three groups (p = 0.026). Conclusions The positive chronotropic effects of atropine might be attenuated with the use of dexmedetomidine or propofol during spinal anaesthesia. Although atropine may be administered when bradycardia occurs, a dose of atropine might result in an insufficient effect against the bradycardia. The sufficient number of subjects may change the results of the investigation, and large-scale randomised controlled trials will be necessary