Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population.

OBJECTIVE: To assess whether eldecalcitol, an active vitamin D analogue2, can reduce the development of type 2 diabetes among adults with impaired glucose tolerance. DESIGN: Double blinded, multicentre, randomised, placebo controlled trial. SETTING: Three hospitals in Japan, between June 2013 and August 2019. PARTICIPANTS: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level. INTERVENTIONS: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 µg per day; n=630) or matching placebo (n=626) for three years. MAIN OUTCOMES: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed. RESULTS: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed. CONCLUSIONS: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000010758.

Incidence of type 2 diabetes in pre-diabetic Japanese individuals categorized by HbA1c levels: a historical cohort study.

OBJECTIVE: Reported incidence of type 2 diabetes estimated at the pre-diabetic stage differs widely (2.3-18.1% per year). Because clinicians need to know the risk of incident diabetes after a diagnosis of pre-diabetes, our objective was to estimate precise incidence of diabetes using baseline HbA1c levels. METHODS: A historical cohort study using electronic medical record data obtained between January 2008 and December 2013. A total of 52,781 individuals with HbA1c < 6.5% were assigned to one of six groups categorized by baseline HbA1c level: ≤ 5.5% (n=34,616), 5.6-5.7% (n=9,388), 5.8-5.9% (n=4,664), 6.0-6.1% (n= 2,338), 6.2-6.3% (n=1,257), and 6.4% (n=518). Participants were tracked until a subsequent diagnosis of diabetes or end of follow-up during a period of 5 years. RESULTS: During the follow-up period (mean 3.7 years), 4,369 participants developed diabetes. The incidence of diabetes in the first year was 0.7, 1.5, 2.9, 9.2, 30.4, and 44.0% in the six HbA1c groups, respectively. At five years the incidence was 3.6, 8.9, 13.8, 27.5, 51.6, and 67.8%, respectively (p < 0.0001 comparing the HbA1c ≤5.5% group to the other groups). After adjustment for confounding factors, the hazard ratios compared with the HbA1c ≤5.5% group were significantly elevated: 2.3 (95%CI 2.0-2.5), 3.4 (95%CI 2.9-3.7), 8.8 (95%CI 8.0-10.1), 26.3 (95%CI 23.3-30.1), and 48.7 (95%CI 40.8-58.1) in the five HbA1c groups (p < 0.0001). CONCLUSION: By fractionating baseline HbA1c levels into narrower HbA1c range groups, accuracy of estimating the incidence of type 2 diabetes in subsequent years was increased. The risk of developing diabetes increased with increasing HbA1c levels, especially with the HbA1c level ≥ 6.2% in the first follow-up year.

Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial.

BACKGROUND: Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. METHODS AND RESULTS: A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, -16.4 to -11.3) and 12.3% (95% confidence interval, -14.9 to -9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, -0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (-11.4%) than in the atorvastatin group (-0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). CONCLUSIONS: Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

[Study on dilemma and strategy of community support network by community organization for prevention of isolated death in an urban area].

OBJECTIVES: Isolated death of elderly is recognized as a severe social problem in public health and it is an urgent requirement that a supportive community network be organized so that its occurrence is minimized. The purpose of this research was to analyze actual issues of a supportive community network for elderly within the community and to obtain clues for useful actions to prevent isolated death of elderly individuals in the future. METHODS: The subjects were 14 representatives of a supportive community network for elderly in A City, B Ward and C District (as a junior high school segment). The research was conducted with a qualitative inductively approach using the Focus Group Interview (FGI). Interviews were focused on difficulties and perspectives within their daily support activities in the community, and were held three times during October 2009 to March 2010. The FGI records were then analyzed with meaningful minimal words and sentences, categorized codes, and then those codes were classified into subcategories or categories. RESULTS: Three categories, Individual, Neighborhood and Community network for elderly resulted from the analysis. Regarding difficulties, "Refusing supports or indifference", "Isolation or Tojikomori in the youth generation", "Lack of family support", "Relationships among their residents weakening gradually", "Unfamiliar newcomers and residents", "Residence feels burden on association with neighborhood", "Limitation of support activities under personal security", "Lack of resources for persons and places of gathering" were identified. On the other hand, perspectives in the community network for elderly were "Building relationships personally", "Invitation to community meetings as companions", "Development of safety confirmation", "Helping each other in the neighborhood", "Stimulate enforcement of bonding in daily life", "Making arrangements for regional administration and residents for supportive activites", "Fostering the trust and connection of residence". CONCLUSION: To further promotion and effective activities for community network for elderly by community residents, it is necessary that information be exchanged among resident organizations regarding their activities in achievement of social cooperation.

Reduced progression to type 2 diabetes from impaired glucose tolerance after a 2-day in-hospital diabetes educational program: the Joetsu Diabetes Prevention Trial.

OBJECTIVE: We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance (IGT) to type 2 diabetes, including analysis of changes in serum lipids, body weight, and blood pressure after the program. RESEARCH DESIGN AND METHODS: A total of 426 subjects (51 +/- 9 years, BMI 24.6 +/- 3.9 kg/m(2)) with newly diagnosed IGT were randomly assigned to three groups, 143 as the short-term hospitalization with diabetes education and support (STH) group, 141 as the nonhospitalization but diabetes education and support (DES) group, and 142 as the neither hospitalization nor education (control) group. RESULTS: The average follow-up was 3.1 years. The incidence of diabetes was 8.0, 10.7, and 13.2 cases per 100 person-years for STH, DES, and control groups, respectively. The incidence of diabetes was 42% lower (95% CI 33-51%) in the STH group and 27% lower (15-37%) in the DES group than in the control group. The incidence of diabetes was 21% lower (10-31%) in the STH group than in the DES group. CONCLUSIONS: The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months.

Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus.

Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy.

Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus.

Increased monocyte recruitment into subendothelial space in atherosclerotic lesions is one of the hallmarks of diabetic angiopathy. The aim of this study was to determine the state of peripheral blood monocytes in diabetes associated with atherosclerosis. Diabetic patients treated with/without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n=106). We also included 24 non-diabetic control subjects. We measured serum levels of monocyte chemoattractant protein (MCP)-1, fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, body mass index (BMI), high sensitivity CRP (hs-CRP) and evaluated CCR2, CD36, CD68 expression on the surface of monocytes. Serum MCP-1 levels were significantly (p<0.05) higher in diabetic patients than in normal subjects. In diabetic patients, serum MCP-1 levels correlated significantly with FPG, HbA1c, triglyceride, BMI, and hs-CRP. The expression levels of CCR2, CD36, and CD68 on monocytes were significantly increased in diabetic patients and were more upregulated by MCP-1 stimulation. Our data suggest that elevated serum MCP-1 levels and increased monocyte CCR2, CD36, CD68 expression correlate with poor blood glucose control and potentially contribute to increased recruitment of monocytes to the vessel wall in diabetes mellitus.

Glycated albumin and cross-linking of CD44 induce scavenger receptor expression and uptake of oxidized LDL in human monocytes.

Functional role of CD44, a principal receptor of hyaluronan, and glycated albumin for differentiation of resting human monocytes isolated by counterflow centrifugal elutriation was investigated. Flow cytometric analysis revealed that amadori-modified glycated albumin induced expression of CD44 as well as macrophage scavenger receptors (MSRs) such as CD36 and CD68 on resting monocytes. Crosslinking of CD44 on monocytes also induced MSR expression. Furthermore, CD44 crosslinking and/or glycated albumin enhanced the uptake of oxidized-low density lipoprotein in monocytes and foam cell formation. Taken together, engagement of CD44 (e.g., hyaluronan) and glycated albumin induced the differentiation of resting monocytes into foam macrophages through the induction of MSRs, implying that CD44 could be involved in atherosclerotic lesions of those such as diabetic patients.

Laminar analysis of movement direction information in local field potentials of the rat motor cortex.

Local field potentials (LFPs) have been proposed for use in controlling neural prosthetic devices because they can provide reliable motor and sensory-related information, and can easily be recorded over long periods of time. While studies have shown that directional information about motor movements can be inferred from LFPs, it is not known at what depth these signals should be recorded from in order to maximize the amount of movement information. Towards this end, we used a directional motor task in Long Evans rats, while sampling LFPs with an electrode consisting of 16 vertical recording sites that were evenly-spaced 100 microm apart. This allowed for simultaneous recording of all layers of the motor cortex. The frequency components of LFPs were then analyzed using k-means clustering to determine directional information as a function of depth. Here we report our initial findings that superficial layers (II/III) of motor cortex may provide more information about movement directions then deeper layers (V).

Adult-onset idiopathic progressive acro-osteolysis with proximal symphalangism.

We experienced a 57-year-old female with adult-onset non-congenital idiopathic acro-osteolysis combined with proximal symphalangism. At the age of 36, she developed severe pain and swelling of the toe base of both feet and underwent Clayton surgery. However, the size of her toes diminished progressively over the 5-year period after surgery. At the age of 41, she suffered pain and swelling of the proximal interphalangeal (PIP) joints of fingers of both hands. These PIP joints became rigid and inflexible. Subsequently, she noticed shortening of the little finger of both hands, followed later by shortening of the index, middle, and ring fingers. At the age of 57, the thumbs began to shorten. Laboratory and endocrinological examinations were not abnormal. Finally, we diagnosed her with acro-osteolysis combined with proximal symphalangism by radiological examination. In this case, previously unreported mutations of the Noggin gene were identified. This is the first case report of adult-onset, non-congenital idiopathic acro-osteolysis combined with proximal symphalangism.

Baroreflex control of heart rate during heating in subjects with low orthostatic tolerance.

BACKGROUND: Heat stress induces a reduction of orthostatic tolerance. The cardiovascular responses, including the cardiac baroreflex response to heat stress, were examined to test the hypothesis that subjects with orthostatically low tolerance demonstrate an impaired baroreflex control of heart rate (HR) during heat stress. METHODS: There were 44 healthy young volunteers who underwent whole body heat stress produced by a hot-water-perfused suit during supine rest for 45 min and 75 degrees head-up tilt (HUT) for 6 min. Esophageal temperature, HR, arterial pressure, and skin blood flow in the forearm and palm were measured continuously throughout the experiment. The sensitivity of the arterial baroreflex control of HR was calculated from the spontaneous changes in beat-to-beat arterial pressure and HR. RESULTS: The HUT was uneventful for 22 volunteers (higher tolerance group), but 22 volunteers (lower tolerance group) reached presyncope after 195 +/- 19 s. Esophageal temperature, HR, arterial pressure, and skin blood flow changed similarly in the two groups during heating. In the preheating condition, the sensitivity of the baroreflex control of HR did not differ significantly between the two groups. Heating did not alter the sensitivity of baroreflex control of HR in the higher tolerance group, but decreased it significantly in the lower tolerance group. Heating increased the number of heartbeats used for analysis of the baroreflex sensitivity in the higher tolerance group, but did not change it in the lower tolerance group. CONCLUSIONS: These results suggest that the impairment of vagal baroreflex control of HR during heat exposure aggravates the orthostatic intolerance in heat-stressed humans.

Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44.

For cancer metastasis, tumor cells present in the circulation must first adhere to the endothelium. Integrins play a central role in leukocyte adhesion to the endothelium and subsequent migration into tissues. The majority of tumor cells derived from solid cancers, including breast cancer, do not express integrins. We investigated the mechanisms of adhesion and transendothelial migration of cancer cells using breast carcinoma cell lines. Our results showed the following features of breast cancer cells: (1) HGF stimulated breast cancer cells by up-regulating CD44 expression in a concentration-dependent manner. (2) the maximum level of HGF-induced CD44 up-regulation on breast cancer cell lines occurred within 3 h. (3) HGF-induced up-regulation of CD44 was mediated by the tyrosine kinase signaling pathway. (4) HGF induced CD44-mediated adhesion of tumor cell lines to bone marrow-derived endothelial cells. (5) HGF did not change rolling of breast cancer cell lines on bone marrow-derived endothelial cells, but enhanced firm adhesion of cancer cells on endothelial cells under shear stress conditions. (6) HGF increased transendothelial migration of cancer cells. Our results indicate that HGF stimulates CD44-mediated adhesion of breast cancer cells to bone marrow-derived endothelial cells, which subsequently results in transendothelial migration of tumor cells. These results suggest that CD44 may confer the metastatic properties of breast cancer cells and, therefore, could be used as a target in future molecular cancer therapy.

Virilizing adrenocortical adenoma with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia in a middle-aged woman.

We report a rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450sec, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing's syndrome, thyroid papillary carcinoma, and hypergastrinemia.

Monocyte chemoattractant protein-1 induces scavenger receptor expression and monocyte differentiation into foam cells.

Accumulation of monocytes and the entrapment of oxidized-low-density lipoprotein (ox-LDL) in monocytes are important in the differentiation into "foam" macrophages and the pathogenesis of atherosclerosis. We investigated the role of monocyte chemoattractant protein-1 (MCP-1) in the expression of scavenger receptor (SCR) by using resting monocytes prepared by counterflow centrifugal elutriation. Our results showed that: (1) MCP-1 increased the expression of CD36 SCR by flow cytometric analysis. (2) MCP-1 increased incorporation of 125I-labeled ox-LDL and oil red O staining. (3) MCP-1 and ox-LDL enhanced in vitro transendothelial monocyte migration. (4) These functions were mediated at least in part via extracellular signal-regulated kinase (ERK) pathway. (5) MCP-1 and ox-LDL did not induce monocyte proliferation. Our results imply that MCP-1 is involved in the inflammatory process of atherosclerosis through the induction of SCR expression via the ERK pathway and differentiation of monocytes into foam macrophages, as well as induction of monocyte migration.