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Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease involving multiple organs in which B cells perform important functions such as antibody and cytokine production and antigen presentation. B cells are activated and differentiated by the primary B cell receptor, co-stimulatory molecule signals-such as CD40/CD40L-, the Toll-like receptors 7,9, and various cytokine signals. The importance of immunometabolism in the activation, differentiation, and exerting functions of B cells and other immune cells has been widely reported in recent years. However, the regulatory mechanism of immunometabolism in B cells and its involvement in SLE pathogenesis remain elusive. Similarly, the importance of the PI3K-Akt-mTOR signaling pathway, glycolytic system, and oxidative phosphorylation has been demonstrated in the mechanisms of B cell immunometabolic activation, mainly in mouse studies. However, the activation of the mTOR pathway in B cells in patients with SLE, the induction of plasmablast differentiation through metabolic and transcription factor regulation by mTOR, and the involvement of this phenomenon in SLE pathogenesis are unclear. In our studies using activated B cells derived from healthy donors and from patients with SLE, we observed that methionine, an essential amino acid, is important for mTORC1 activation. Further, we observed that splenic tyrosine kinase and mTORC1 activation synergistically induce EZH2 expression and plasmablasts by suppressing BACH2 expression through epigenomic modification. Additionally, we identified another mechanism by which the glutaminolysis-induced enhancement of mitochondrial function promotes plasmablast differentiation in SLE. In this review, we focused on the SLE exacerbation mechanisms related to the activation of immune cells-especially B cells-and immunometabolism and reported the latest findings in the field., Competing Interests: YT has received speaking fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GlaxoSmithKline, Mitsubishi-Tanabe, Gilead, Janssen, research grants from Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, and Daiichi-Sankyo and consultant fee from Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GlaxoSmithKline, and Abbvie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Iwata, Hajime Sumikawa and Tanaka.)

Background: Worldwide, different strategies have been chosen to face the COVID-19-patient surge, often affecting access to health care for other patients. This observational study aimed to investigate whether the standard of burn care changed globally during the pandemic, and whether country´s income, geographical location, COVID-19-transmission pattern, and levels of specialization of the burn units affected reallocation of resources and access to burn care., Methods: The Burn Care Survey is a questionnaire developed to collect information on the capacity to provide burn care by burn units around the world, before and during the pandemic. The survey was distributed between September and October 2020. McNemar`s test analyzed differences between services provided before and during the pandemic, χ2 or Fisher's exact test differences between groups. Multivariable logistic regression analyzed the independent effect of different factors on keeping the burn units open during the pandemic., Results: The survey was completed by 234 burn units in 43 countries. During the pandemic, presence of burn surgeons did not change (p = 0.06), while that of anesthetists and dedicated nursing staff was reduced (<0.01), and so did the capacity to manage patients in all age groups (p = 0.04). Use of telemedicine was implemented (p < 0.01), collaboration between burn centers was not. Burn units in LMICs and LICs were more likely to be closed, after adjustment for other factors., Conclusions: During the pandemic, most burn units were open, although availability of standard resources diminished worldwide. The use of telemedicine increased, suggesting the implementation of new strategies to manage burns. Low income was independently associated with reduced access to burn care., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: This study aimed to determine the association between serum 25-hydroxyvitamin D (25(OH)D) levels and vascular endothelial function in patients with type 2 diabetes (T2D)., Methods: This retrospective study included 113 patients with poorly controlled T2D who were admitted for in-hospital diabetes educational program and underwent measurements of serum 25(OH)D levels and reactive hyperemia index (RHI)., Results: Serum 25(OH)D levels significantly correlated with RHI in T2D patients. Receiver operating characteristic (ROC) curve analysis showed that serum 25(OH)D level of 16.5 ng/mL is the optimal cutoff level for predicting vascular endothelial dysfunction (RHI＜1.67), with a sensitivity of 68.5%, specificity of 67.9%, and area under the ROC curve of 0.668 (95% confidence interval [CI]: 0.566-0.770, p=0.002). The mean RHI was significantly lower (1.70±0.54) in patients with low 25(OH)D levels (n=56, 25(OH)D levels ＜16.5 ng/mL) than that (1.99±0.58; p＜0.001) in patients with high 25(OH)D levels (n=57, 25(OH)D level ≥ 16.5 ng/mL). The proportion of patients with RHI＜1.67 was higher in the low 25(OH)D group than in the high 25(OH)D group (38% vs. 18%; p＜0.001). Multivariate logistic regression analysis identified that serum 25(OH)D level ＜16.5 ng/mL was associated with increased odds of RHI ＜1.67 (odds ratio 4.598, 95% CI 1.961-10.783, p＜0.001)., Conclusion: The results demonstrated the association of serum 25(OH)D levels with endothelial function in poorly controlled T2D patients and identified serum 25(OH)D level of ＜16.5 ng/mL as a predictor of RHI ＜1.67. Serum 25(OH)D level is a potentially useful marker of vascular endothelial dysfunction in poorly controlled T2D patients.

Objectives: B cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA., Methods: Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms., Results: Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression., Conclusion: mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Recent reports have shown the importance of IFN-γ and T-bet + B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet + CD4 + cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bet hi CXCR3 lo effector cells and T-bet + Foxp3 lo non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet + Foxp3 hi activated-T reg cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated in vitro using memory CD4 + cells obtained from healthy donors and patients with SLE. In memory CD4 + cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet + Foxp3 - cells, and induced T-bet + Foxp3 +(lo/hi) cells. Rapamycin induced IFN-γ-producing T-bet + Foxp3 lo cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet + Foxp3 hi cells. In memory CD4 + cells of SLE patients, inhibition of fatty acid synthesis, but not β-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet + Foxp3 + cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE., Competing Interests: KS is an employee of Mitsubishi Tanabe Pharma. SN has received speaking fees from Bristol Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Pfizer, Takeda, and also research grants from Mitsubishi Tanabe, Novartis, and MSD. YT received research grants from Mitsubishi Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Iwata, Zhang, Hao, Trimova, Hajime, Miyazaki, Ohkubo, Satoh Kanda, Todoroki, Miyata, Ueno, Nagayasu, Nakayamada, Sakata and Tanaka.)

Objective: Plasmablasts play important roles in autoimmune diseases, including systemic lupus erythematosus (SLE). Activation of mechanistic target of rapamycin complex 1 (mTORC1) is regulated by amino acid levels. In patients with SLE, mTORC1 is activated in B cells and modulates plasmablast differentiation. However, the detailed mechanisms of amino acid metabolism in plasmablast differentiation remain elusive. We undertook this study to evaluate the effects of methionine in human B cells., Methods: Purified CD19+ cells from healthy donors (n = 21) or patients with SLE (n = 35) were cultured with Toll-like receptor 7/9 ligand, interferon-α (IFNα), and B cell receptor crosslinking, and we determined the types of amino acids that were important for plasmablast differentiation and amino acid metabolism. We also identified the transcriptional regulatory mechanisms induced by amino acid metabolism, and we assessed B cell metabolism and its relevance to SLE., Results: The essential amino acid methionine strongly committed cells to plasmablast differentiation. In the presence of methionine, Syk and mTORC1 activation synergistically induced methyltransferase EZH2 expression. EZH2 induced H3K27me3 at BTB and CNC homolog 2 (Bach2) loci and suppressed Bach2 expression, leading to induction of B lymphocyte-induced maturation protein 1 and X-box binding protein 1 expression and plasmablast differentiation. CD19+ cells from patients with SLE overexpressed EZH2, which was correlated with disease activity and autoantibody production., Conclusion: Our findings show that methionine activated signaling by controlling immunologic metabolism in B cells and played an important role in the differentiation of B cells into plasmablasts through epigenome modification of Bach2 by the methyltransferase EZH2., (© 2020, American College of Rheumatology.)

It is difficult to detect glycemic excursions using CGM in daily clinical practice. We retrospectively analyzed CGM data in type T2DM to define the correlations between HbA1c and GA levels at admission and the parameters representing glycemic excursions measured by CGM, including the mean amplitude of glycemic excursions (MAGE) and standard deviation (SD). The MAGE correlated significantly with GA and HbA1c, but not with the GA/HbA1c ratio. The SD correlated significantly with GA, HbA1c, and GA/HbA1c. Multivariate analysis identified the GA value to be the most reflective of MAGE. Patients were divided into 2 groups using a MAGE cutoff value of 75 mg/dl, which reflects stable diabetes. There was a significant difference in GA, but not HbA1c, between the groups with low and high mean amplitudes of glycemic excursions. Receiver operating characteristic curve analysis indicated that the cutoff for GA for identifying patients with MAGE of ≤75 mg/dl was 18.1%. Our study identified GA to be the most reflective of glycemic excursions in patients with T2DM. GA can be a useful index of glycemic excursions and treatment optimization to prevent arteriosclerosis.

Human airway trypsin-like protease (HAT) localizes at human bronchial epithelial cells (HBECs). HAT enhanced release of interleukin-8 (IL-8) from HBECs at 10-100 mU/mL and the enhanced release was almost completely abolished by 50 μM leupeptin, a serine protease inhibitor. Previous reports suggested that HAT displays its physiological functions via protease-activated receptor 2 (PAR2). In the present study, we examined the mechanism whereby HAT upregulates IL-8 synthesis in HBECs with a focus on PAR2. Northern blot analysis revealed that HAT enhanced IL-8 mRNA expression at concentrations of 10-100 mU/mL. PAR2 activating peptide (PAR2 AP) also enhanced IL-8 release and IL-8 mRNA expression in HBECs at 50-1,000 μM at similar levels as HAT. Knockdown of PAR2 mRNA by siRNA methods showed that PAR2 mRNA expression was significantly depressed in primary HBECs, and both HAT- and PAR2 AP-induced IL-8 mRNA elevation was significantly depressed in PAR2 siRNA-transfected HBECs. Additionally, HAT cleaved the PAR2 activating site (R 36 -S 37 bond) of synthetic PAR2 N-terminal peptide. These results indicate that HAT stimulates IL-8 synthesis in airway epithelial cells via PAR2 and could help to amplify inflammation in chronic respiratory tract disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Xanthoma disseminatum is a very rare disease classified as a benign non-Langerhans cell histiocytosis, which is rarely associated with osteoarticular lesions. There is only a report of tumor abrasion during treatment of osteoarticular lesions of this disease, artificial joint replacement has not been reported. We describe a patient in whom bilateral total joint replacement was performed for disseminated xanthoma lesions of the hip joints., Case Presentation: A 34-year-old Japanese woman had a chief complaint of bilateral coxalgia. She had been diagnosed as having disseminated xanthoma. Radiographs showed numerous 5-mm radiolucent bands that resembled worm-eaten tracks in the lower part of the femoral heads adjacent to the joint surface. In addition, short tau inversion recovery imaging scans showed high-intensity areas from the femoral head to the neck in both femurs, suggesting bone marrow edema. Total hip arthroplasty was performed for hip arthrosis on both hip joints caused by disseminated xanthoma. Deflection of the implants was a concern from the early stages postoperatively, but both the imaging and clinical findings have been satisfactory for 4 years of follow-up., Conclusions: A very unusual hip joint lesion of xanthoma disseminatum was replaced with a total artificial joint replacement, and the course over 4 years was good. Our patient's course will continue to be followed carefully.

Background: Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM)., Methods: T2DM patients (n = 293) receiving inpatient care were divided into five groups according to HbA1c level on admission (Group 1: ≥ 6 to < 7%, Group 2: ≥ 7 to < 8%, Group 3: ≥ 8 to < 9%, Group 4: ≥ 9 to < 10%, and Group 5: ≥ 10%). The frequency of hypoglycemia and factors associated with hypoglycemia were analyzed., Results: Hypoglycemia occurred in 15 patients (5.1%), including 4 (8%), 4 (6%), and 7 (10%) patients of Groups 1, 2, and 3, respectively, but in none of groups 4 and 5. Patients with hypoglycemia of Groups 1 had low insulin secretion and were high among insulin users, those of Groups 2 had low homeostasis model assessment of insulin resistance (HOMA-IR). Those of Group 2 and 3 had significantly lower mean blood glucose levels, those of Group 3 only had significantly lower maximum blood glucose level and percentage of AUC > 180 mg/dL. In any of the HbA1c groups, variations in blood glucose level were significantly larger in patients with hypoglycemia than without., Conclusions: Hypoglycemia occurred in patients with a wide range of HbA1c on admission (range 6-9%), suggesting that prediction of hypoglycemia based on HbA1c alone is inappropriate. Among patients with low HbA1c, strict control sometimes induce hypoglycemia. Among patients with high HbA1c, the possibility of hypoglycemia should be considered if there is a marked discrepancy between HbA1c and randomly measured blood glucose level. Larger variations in blood glucose level induce hypoglycemia in any of the HbA1c groups. The treatment to reduce variations in blood glucose level is important to prevent hypoglycemia.

Objective Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both complicated by arteriosclerosis, resulting in increased rates of cardiovascular events. No previous studies have compared the index between RA and T2DM. We assessed the vascular endothelial function in early-stage arteriosclerosis for each disease to determine the influential factors and compared the extent to which these two diseases cause vascular endothelial dysfunction. Methods This study is a retrospective study based on medical records. Differences in the reactive hyperemia index (RHI) among the groups and factors affecting the RHI in each group was analyzed. The vascular endothelial function was assessed by measuring the RHI using peripheral arterial tonometry. Patients The study subjects were 114 patients with non-functional thyroid tumors (healthy n=14), T2DM (T2DM n=64), and RA (RA n=36). Results The RHI was 2.29 in the control, 1.85 in the T2DM, and 1.83 in the RA group, with values lower in the T2DM and RA groups than in the control group (p=0.033) but not markedly different between the two disease groups. The RHI distribution (<1.68/1.68 to <2.10/≥2.1) was as follows: control group: 14.3%/28.6%/57.1%; T2DM group: 42.2%/39.1%/18.8%; and RA group: 36.1%/44.4%/19.4% (p=0.031), respectively. A multivariate analysis identified the triglyceride level and dyslipidemia in the control group and the Disease Activity Score in 28 joints with the erythrocyte sedimentation rate and fasting plasma glucose level in the RA group to influence the RHI. Conclusion The vascular endothelial function was impaired in approximately 80% of patients with T2DM and RA, with comparable degrees of impairment between the two diseases. No factors affecting the function were identified in the T2DM group, while the function was more impaired in patients with a higher disease activity in the RA group.

Background: The objective of this study was to determine the risk factors of hypoglycemia by evaluating the glycemic profile using continuous glucose monitoring (CGM) in patients with type 2 diabetes mellitus (T2DM)., Methods: The participants were 294 patients with T2DM who received inpatient diabetes education. The mean blood glucose (MBG), coefficient of variation (CV), mean postprandial glucose excursion, low blood glucose index (LBGI), and percentage of time with blood glucose (BG) at <70 mg/dL were measured on admission using CGM. We predicted the risk of hypoglycemia utilizing transform to Gaussian model. The primary end point was the relationship between CGM parameters and hypoglycemia., Results: Multivariate logistic regression analysis showed that disease duration, MBG, CV, LBGI, and Predicted% of BG correlated significantly with hypoglycemia. Receiver operating characteristic curve analysis showed that the optimal cutoff points for MBG and CV in predicting hypoglycemia were 152 mg/dL and 22%, respectively. The proportion of patients with hypoglycemia was 0% for the group with no hypoglycemia risk factors, 4.2% for the group with one risk factor, and 36.6% for the group with two risk factors, showing a linear increase across the groups (P < 0.001). LBGI was the best predictor of hypoglycemia; and Predicted% BG <70 mg/dL was very useful as an index to predict hypoglycemia., Conclusions: Patients with low MBG levels and large fluctuations in BG were more likely to develop hypoglycemia, suggesting that assessment of these two variables is useful for the prediction of hypoglycemia. To achieve good glycemic control free of hypoglycemia, approaches are needed that do not only lower BG level but also minimize fluctuations in blood and interstitial fluid glucose level.

Aims/introduction: High fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type 2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type 2 diabetes patients., Materials and Methods: Our retrospective study included 294 patients with type 2 diabetes who were divided by HbA1c level into five groups (≥6.0 to <7.0%, ≥7.0 to <8.0%, ≥8.0 to <9.0%, ≥9.0 to <10.0% and ≥10%). The correlation between HbA1c level and CGM data was analyzed. The primary end-point was the difference in blood glucose fluctuations among the HbA1c groups., Results: The mean blood glucose level increased significantly with increasing HbA1c (P trend  < 0.01). The standard deviation increased with increases in HbA1c (P trend  < 0.01). The mean amplitude of glycemic excursions did not vary significantly with HbA1c. The levels of maximum blood glucose, minimum blood glucose, each preprandial blood glucose, each postprandial maximum blood glucose, range of increase in postprandial glucose from pre-meal to after breakfast, the area under the blood concentration-time curve >180 mg/dL and percentage of the area under the blood concentration-time curve >180 mg/dL were higher with higher HbA1c. Mean glucose level and pre-breakfast blood glucose level were significant and independent determinants of HbA1c., Conclusions: In Japanese patients treated for type 2 diabetes, the mean amplitude of glycemic excursions did not correlate with HbA1c, making it difficult to assess blood glucose fluctuations using HbA1c. Parameters other than HbA1c are required to evaluate fluctuations in blood glucose level in patients receiving treatment for type 2 diabetes., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

The aim of this retrospective study was to elucidate the association between glucose profile using the continuous glucose monitoring system (CGMS) and microvascular complications in patients with type 2 diabetes mellitus (T2DM). The subjects were 160 inpatients with T2DM. The mean blood glucose (MBG) level, percentage of time in a 24-hour period spent with blood glucose level higher than 180 mg/dl (time at >180 mg/dl), standard deviation (SD), and mean amplitude of glycemic excursions (MAGE) were measured continuously over 48 hours using the CGMS. The primary outcome was the association between microvascular complications and glycemic variability. The secondary outcome was the association between microangiopathies and MBG. The SD and MAGE were not associated with presence of microangiopathies or number of complications. There were also no associations between abnormal vibratory sensation in the bilateral lower extremities, coefficient of variation of the R-R interval (CVRR), retinopathy stage, nephropathy stage, or microalbuminuria. MBG was associated, however, with retinopathy, retinopathy stage, and number of complications. Time at >180 mg/dl correlated with abnormal vibratory sensation in the bilateral lower extremities and presence or stage of retinopathy. MBG and time at >180 mg/dl were not associated with presence or stage of nephropathy. Our findings suggest that broad glycemic variability was not associated with microvascular complications, the number of which increased in patients with a high mean glucose level and long time spent with hyperglycemia. It is important, therefore, to reduce the mean glucose level and time spent with hyperglycemia to prevent future microangiopathies.

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27 + IgD + unswitched memory B cells into CD27 hi CD38 hi plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27 - IgD - memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27 - IgD - B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19 + B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27 - IgD - memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Purpose To determine trabecular bone analysis values by using tomosynthesis images in determining femoral neck strength in patients with diabetes mellitus and compare its parameters between vertebral compression fracture and nonfracture groups. Materials and Methods The institutional review board approved this study, and written informed consent was obtained from all patients. Forty-nine patients with diabetes mellitus were included. Within 1 week, patients underwent dual x-ray absorptiometry (DXA), tomosynthesis, and computed tomography (CT) covering the T10 vertebral body to the hip joints. The trabecular patterns of tomosynthesis images were extracted, and the total strut length, bone volume per tissue volume, and five textural features (homogeneity, entropy, correlation, contrast, and variance) were obtained as the indices of tomosynthesis images. Failure load of the femoral neck, which was determined with the CT-based finite-element method (FEM), was used as the reference standard for bone strength. A forward stepwise multiple regression analysis for evaluating the availability of the tomosynthesis image indices was performed. The bone mineral density (BMD) at DXA and tomosynthesis image indices were compared between the vertebral compression fracture (n = 16) and nonfracture groups (n = 33) according to Genant semiquantitative morphometry methods by using one-way analysis of variance. Results The combination of BMD with the bone volume per tissue volume at the principal tensile group and the correlation at the principal compressive group showed the highest correlation to the failure load at CT FEM, and the correlation (r 2 = 0.83) was higher than that between the failure load and the BMD alone (r 2 = 0.76; P < .001). The averages of the bone volume per tissue volume and entropy at the principal tensile group in the vertebral compression fracture group were lower than those in the nonfracture group (P = .017 and P = .029, respectively), but there was no difference in BMD. Conclusion Tomosynthesis-based trabecular bone analysis is technically feasible and, in combination with BMD measurements, can potentially be used to determine bone strength in patients with diabetes mellitus. © RSNA, 2016 Online supplemental material is available for this article.

Background: Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to their indirect effects on postprandial glucose and lipid metabolism. GLP-1 analogs are also reported to inhibit postprandial vascular endothelial dysfunction. This study examined whether the GLP-1 analog exenatide inhibits postprandial vascular endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM)., Methods: Seventeen patients with T2DM underwent a meal tolerance test to examine changes in postprandial vascular endothelial function and in glucose and lipid metabolism, both without exenatide (baseline) and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was determined using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide tests., Results: The natural logarithmically-scaled RHI (L&#95;RHI) was significantly lower after the baseline meal test but not in the exenatide test. The use of exenatide resulted in a significant decrease in triglycerides (TG) area under the curve and coefficient of variation (CV). The change in L&#95;RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L&#95;RHI, contributing to 41% of the observed change., Conclusions: Exenatide inhibited postprandial vascular endothelial dysfunction after the meal loading test, suggesting that exenatide has a multiphasic anti-atherogenic action involving not only glucose but also lipid metabolism., Trial Registration: ClinicalTrials.gov: UMIN000015699.

PTH (teriparatide) is used in the treatment of osteoporosis, and can sometimes cause transient hypercalcemia, but to date there have been no reports of persistent hypercalcemia and hypophosphatemia resulting from its use. We describe a case with marked hypophosphatemia and hypercalcemia associated with the use of teriparatide. The patient was a 49-year-old woman who was followed up for acute intermittent porphyria and glucocorticoid-induced osteoporosis (following administration of prednisolone at 22.5 mg/day), and presented with unexplained fracture of the left tibia, for which treatment with teriparatide at 20 μg/day was started. Two weeks after treatment with teriparatide, the patient developed hypophosphatemia, hypercalcemia, hyperalkaline phosphatasemia, low TmP/GFR, FEca, BAP, and urinary NT×, with low intact PTH. These changes were considered to be related to teriparatide. Cessation of teriparatide treatment resulted in normalization of all parameters at 10 weeks (serum P 3.6 mg/dl, corrected Ca 8.8 mg/dl, ALP 273 IU/l, intact PTH 63 pg/ml). The observed abnormalities were considered to be in part related to acute intermittent porphyria, which is known to delay hepatic teriparatide clearance, with subsequent delay of PTH action despite its intermittent use, resulting in hypercalcemia and hypophosphatemia.

Background: Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus, but many of these patients fail to achieve the target LDL-C level. Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin. However, in patients with type 2 diabetes who are already being treated with satins, it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose. Therefore, this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins., Methods: The subjects were type 2 diabetic patients under treatment with rosuvastatin (2.5 mg daily), who had LDL-C levels ≥80 mg/dL. They were randomly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day (combination group, n = 40) or an increase of the rosuvastatin dose to 5 mg/day (dose escalation group, n = 39). These two groups were compared at baseline and after 12 weeks of treatment., Results: The percent change of LDL-C was -31% in the combination group and -12% in the dose escalation group. Both groups showed a significant decrease, but the decrease was greater in the combination group. In both groups, there was a significant decrease in the levels of small dense LDL-C, oxidized LDL and remnant-like lipoprotein cholesterol. For all of these parameters, the percent changes were greater in the combination group. Only the combination group showed a significant decrease of triglycerides. Multivariate analysis was performed to identify factors associated with reaching an LDL-C level <80 mg/dL. As a result, add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C., Conclusions: Compared with increasing the dose of rosuvastatin, the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients, suggesting that this combination could suppress the progression of atherosclerosis., Trial Registration: UMIN000011005.

It has become possible in Japan to use high-dose metformin for patients with type 2 diabetes. The aim of this retrospective study was to determine the effects and safety of metformin in elderly patients with type 2 diabetes. The study subjects (98 patients who were treated with metformin) were assigned into two groups: (Ⅰ) 59 patients who were younger, aged less than 65 years, and (Ⅱ) 39 patients who were elderly, aged more than 65 years. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at 12 weeks. The secondary endpoints were the safety variables, including hypoglycemic events and adverse events. Although HbA1c decreased significantly in both group Ⅰ (-0.5%) and group Ⅱ (-0.9%), the difference between the two groups in the change in HbA1c was not significant. There were no incidences of hypoglycemia or adverse events in either group. Metformin improved glycemic control in the elderly patients as well as in the non-elderly patients. It is necessary to examine what dose of metformin and serum creatinin level (Cre), eGFR is appropriate for elderly patients.

We report the inhibitory effect of 4-methylesculetin (ME), a 4-methylumbelliferone derivative, on hyaluronan (HA) synthesis by pancreatic cancer cells, and its resulting anticancer action. First, HA in cell culture was analyzed using competitive inhibition with hyaluronic acid-binding protein (HABP) to study HA synthesis by the human pancreatic cancer cell line KP1-NK, and cell-surface HA was visualized using a particle-exclusion assay to study the synthesis of extracellular matrix HA. We also analyzed the inhibitory effect of ME on cell adhesion and invasion, which play a role in the invasion, growth and metastasis of human pancreatic cancer. Furthermore, we examined HA in human pancreatic cancer cells transplanted into the hypodermis of nude mice to study the inhibitory effect of ME on HA synthesis. Moreover, pancreatic cancer cells were also transplanted into the abdomen of nude mice to study whether ME would have the potential to prolong the survival of patients with end-stage pancreatic cancer. ME at 10 muM did not inhibit the growth of human pancreatic cancer cells, but inhibited HA synthesis in cell culture by 40%, adhesion by 44% and invasion by 40%. ME inhibited the proliferation of subcutaneous tumors and HA synthesis (by 50%) of pancreatic cancer transplanted into the hypodermis of nude mice. ME also prolonged the survival time of nude mice bearing abdominally transplanted pancreatic cancer cells. ME inhibited pancreatic cancer growth and metastasis by inhibition of HA synthesis. These results suggest that ME may prolong the survival time of patients with end-stage pancreatic cancer.