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We present a new technique for carotid artery reconstruction using a modified bifurcated saphenous vein graft in a patient with a malignant neck tumor. This technique can optimize the size match between the SVG and common carotid artery, as well as the internal and external carotid arteries. Post operative computed tomography performed a year after the operation demonstrated excellent graft alignment and patent carotid arteries., (@ 2024 The Editorial Committee of Annals of Vascular Diseases.)

Purpose: The significance of thyroglobulin antibodies (TgAbs) and thyroid peroxidase antibodies (TPOAbs) in Graves' disease (GD) remains unclear. Therefore, this study aimed to clarify the clinical significance of TgAbs and TPOAbs in GD., Methods: A total of 442 patients with GD were recruited and divided into four groups based on TgAb and TPOAb positivity. Their clinical parameters and the characteristics of the groups were compared. Cox proportional hazard regression analysis was performed to assess risk factors for GD remission., Results: The free triiodothyronine (FT3) level was significantly higher in groups positive for TgAbs and TPOAbs than in the other groups. The FT3 to free thyroxine (FT4) (FT3/FT4) ratio was significantly higher and thyrotropin-stimulating hormone (TSH) receptor antibodies (TRAbs) were significantly lower in the TgAb+/TPOAb- group. Time to FT4 recovery was significantly shorter for groups negative for TPOAbs, whereas time to TSH recovery was significantly longer for groups positive for TPOAbs. Cox proportional hazard regression analysis revealed that TgAb positivity, prolonged treatment duration with antithyroid drugs, and Graves' ophthalmopathy treated with methylprednisolone were significantly associated with GD remission and that a smoking history, elevated FT3/FT4 ratio, and treatment with propylthiouracil hindered GD remission., Conclusion: The contributions of TgAbs and TPOAbs to GD pathogenesis differ. Patients positive for TgAbs develop GD with lower TRAb titers and undergo earlier remission than those negative for TgAbs. Patients positive for TPOAbs develop GD with high TRAb titers and need a long time to achieve remission., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of type 1 diabetes (T1D). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of T1D was investigated using PTP1B-deficient (knockout [KO]) mice and a PTP1B inhibitor. T1D wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared with non-T1D WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-T1D WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in T1D WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in T1D WT mice improved glucose metabolism to the same level as non-T1D WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle through the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of T1D with leptin, PTP1B deficiency, or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for T1D., (© 2022 by the American Diabetes Association.)

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin., Competing Interests: Declaration of competing interest The authors declare that they have no conflict interests., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABA B R) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABA B R-deficient knockout (KO) mice compared to WT mice. Treatment with the GABA B R agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABA B R signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice., (© 2021. The Author(s).)

Objective: To evaluate patient acceptability and bowel preparation efficacy of sodium picosulfate-magnesium citrate (PICOPREP) for colonoscopy., Methods: A questionnaire survey regarding the patient acceptability of bowel preparation agent PICOPREP was administered to 54 patients, and its efficacy was evaluated using the Ottawa Bowel Preparation Scale (OBPS)., Results: Eighteen (33.3%) participants reported that PICOPREP is very easy to drink, 30 (55.5%) easy, four (7.4%) acceptable, one (1.9%) difficult, and one (1.9%) very difficult. The flavor was very good as reported by eight (14.8%) participants, good by 25 (46.3%), neutral by 20 (37.0%), bad by one (1.9%), and very bad by none. The number of patients who requested PICOPREP was 42 (77.7%), indicating its high acceptability. Evaluation of the OBPS score showed that the rectosigmoid colon had significantly better polyethylene glycol (PEG) scores than PICOPREP, but the entire colon did not show a significant difference between PICOPREP and PEG scores (1.09 ± 0.65 vs. 1.17 ± 0.76, p  = 0.632 in the right colon; 0.48 ± 0.52 vs. 0.72 ± 0.66, p  = 0.079 in the mid colon, 0.93 ± 0.49 vs. 0.63 ± 0.52, p  = 0.012 in the rectosigmoid colon, and 3.28 ± 1.70 vs. 3.20 ± 1.90, p  = 0.836 in the entire colon)., Conclusion: PICOPREP is considered as one of the important options due to its good patient acceptability and high efficacy similar to PEG., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4 + T cells and partially prevented by depleting CD8 + T cells. The frequencies of central and effector memory CD4 + T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4 + T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4 + T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4 + T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4 + T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.

The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective We investigated the muscle cramp status of patients with liver cirrhosis by focusing on the degree of liver damage, skeletal muscle mass, and nutritional status. Methods All enrolled patients completed a questionnaire about muscle cramps. The degree of liver damage was examined using the Child-Pugh classification and the albumin-bilirubin (ALBI) grade. The nutritional status and skeletal muscle mass were examined using the Controlling Nutritional Status (CONUT) method and the psoas muscle index (PMI). Results Among the respondents, 55.7% of the patients reported experiencing muscle cramps. An analysis of the two patient groups-those who experienced muscle cramps and those who did not-revealed significant differences in Child-Pugh classification (muscle cramp-positive vs. muscle cramp-negative: A/B/C, 54.1%/32.4%/13.5% vs. 90.0%/10.0%/0.0%; p=0.004), ALBI grade (1/2/3, 20.5%/71.8%/7.7% vs. 54.8%/38.7%/6.5%; p=0.011), modified ALBI grade (1/2a/2b/3, 20.5%/20.5%/51.3%/7.7% vs. 54.8%/22.6%/16.1%/6.5%; p=0.008), CONUT score (normal/mild/moderate/severe, 25.6%/28.2%/41.0%/5.1% vs. 22.6%/61.3%/12.9%/3.2%; p=0.024), and PMI (3.85±1.13 cm 2 /m 2 vs. 4.94±1.86 cm 2 /m 2 ; p=0.012). Conclusion Our findings suggest that muscle cramps occur more frequently in patients with liver cirrhosis due to their decreased liver function and poorer nutritional status.

Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFD-fed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Uncomplicated type B acute aortic dissection (UTBAAD) has traditionally been treated medically. Although patients are treated based on the rehabilitation program established by the Japanese Circulation Society, we sometimes encounter patients with complications related to the long duration of bed rest. We performed novel fast-track rehabilitation for UTBAAD, which consisted of short-duration bed rest and the early initiation of walking under secure blood pressure control., Methods and Results: From April 2009 to February 2017, there were 73 consecutive cases of UTBAAD. Conventional medical treatment was administered to 39 patients (group G) during the early period. From August 2013, 34 patients (group F) received our 'fast-track' rehabilitation program, which consisted of the following: oral intake and assuming a sitting position from day 1 after the onset, standing by the bed from day 2, walking in their room from day 4, and discharge from day 16 if all goes smoothly. Group F had a significantly earlier initiation of standing and walking, first defecation, and weaning from oxygen and intravenous antihypertensive agents than group G. The pneumonia complication rate was significantly lower in group F than in group G. The hospitalization duration was markedly shorter and the in-hospital expense lower in group F than in group G. There were no significant differences in the rate of late adverse aortic events within 12 months after onset., Conclusions: Our fast-track rehabilitation program for patients with UTBAAD resulted in a better in-hospital clinical course and lower expense than conventional medical treatment without any adverse aortic events.

A 60-year-old male, who exhibited finger tremors, obnubilation, and hyperammonemia (409 μg/dL), was admitted to our hospital. Initially, we suspected that a portosystemic shunt had caused his hyperammonemia. However, his symptoms did not improve after balloon-occluded retrograde transvenous obliteration. He was subsequently found to have some peculiar eating habits, including a fondness for bean curd and peanuts, and an aversion to alcohol and sweets. Furthermore, marked citrullinemia (454.2 nmol/mL) was revealed, which led us to suspect adult-onset type II citrullinemia (CTLN2). DNA analysis of the patient and his mother, son, and daughter confirmed that he was homozygous for the c.852_855del mutation in the SLC25A13 gene, and his relatives were heterozygous for the c.852_855del mutation, which led to a definitive diagnosis. A low-carbohydrate diet and the administration of L-arginine ameliorated his symptoms. It is important to be aware that CTLN2 can occur in elderly patients. Thus, patients who exhibit symptoms of CTLN2 should be interviewed about their dietary habits and subjected to plasma amino acid analysis.In this report, we consider the metabolic disorders seen in citrin deficiency and the associated compensatory mechanisms in relation to the clinical features and treatment of CTLN2.

Background: Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM)., Methods: A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint., Results: Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05)., Conclusions: In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone., Clinical Trials Registration: UMIN000019024., Competing Interests: Competing interests: SI receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. TO receives personal fees from MSD K.K. HT receives grants from MSD K.K. YI receives grants from Sanwa Kagaku Kenkyusho, Kowa Pharmaceutical, MSD K.K., Dainippon Sumitomo, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, Nihon Medi-Physics Co., Ltd., and personal fees from Astellas Pharma, Daiichi Sankyo, and Ono Pharmaceutical Company. KY receives personal fees from Ono Pharmaceutical Company, MSD K.K., and Bristol-Myers Squibb. TH received personal fees from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Company, and Bristol-Myers Squibb while the study was being conducted. TH also received grants from Boehringer Ingelheim, Taiho Pharmaceutical Co., Ltd., and personal fees from Boehringer Ingelheim outside the submitted work. MMS receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. MA receives grants from Kyowa Kirin Co., Ltd. YA receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co. Ltd. as well as personal fees from Bristol-Myers Squibb. MA receives grants and personal fees from Ono Pharmaceutical Company, MSD K.K., and personal fees from Bristol-Myers Squibb. YH receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, MSD K.K., and Pfizer; grants from Novartis and Taiho Pharmaceutical Co., Ltd., and personal fees from Astra Zeneca. HA receives grants from Ono Pharmaceutical Company, MSD K.K., Chugai Pharmaceutical Co. Ltd., and personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, and MSD K.K., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Glial cells can mediate hypothalamic inflammatory processes induced in response to a high-fat diet (HFD). We used magnetic-activated cell sorting (MACS) to isolate microglia and astrocytes from hypothalamus of mice fed HFD and examined changes in expression of inflammation-related cytokines and markers related to glial cell activation status. Hypothalamus from male C57BL6 mice fed a chow diet (chow) or HFD for 1, 3, or 28 days were collected and microglia and astrocytes were isolated by MACS. After confirming cell viability by fluorescence activated cell sorting, mRNA expression levels of inflammation-related cytokines and markers of glial cell activation status were examined by qRT-PCR, which revealed that both glial cell types isolated by MACS retained specificity. On day 3 of HFD, both CD86 and TNFα mRNA expression was significantly increased in microglia relative to the chow group. In astrocytes, TNFα mRNA expression levels were similar between the chow and HFD groups on day 3, but anti-inflammatory cytokine IL-10 levels were significantly increased. On day 7 of HFD, TNFα expression in microglia decreased to levels comparable to the chow group while that in astrocytes remained unchanged. On day 28 of HFD, TNFα levels were significantly increased in both microglia and astrocytes, which had increased mRNA expression of CD86 and MAO-B, respectively. For both glial cell types, results for TNFα expression assessed by RT-PCR and immunohistochemical analysis were similar. These results indicate that the role of microglia and astrocytes in hypothalamic inflammation under HFD conditions changed with time and these changes were accompanied by changes in the activation status of glial cells. Our data suggest that early after initiating HFD, hypothalamic astrocytes suppress diet-induced inflammation at least in part by secreting IL-10, whereas continued HFD feeding impairs this suppressive function such that both microglia and astrocytes promote hypothalamic inflammation., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The present study aimed to evaluate the effects of flash glucose monitoring (FGM) and conventional self-monitoring of blood glucose (SMBG) on glycemic control in patients with non-insulin-treated type 2 diabetes., Research Design and Methods: In this 24-week, multicenter, open-label, randomized (1:1), parallel-group study, patients with non-insulin-treated type 2 diabetes at five hospitals in Japan were randomly assigned to the FGM (n=49) or SMBG (n=51) groups and were provided each device for 12 weeks. The primary outcome was change in glycated hemoglobin (HbA1c) level, and was compared using analysis of covariance model that included baseline values and group as covariates., Results: Forty-eight participants in the FGM group and 45 in the SMBG group completed the study. The mean HbA1c levels were 7.83% (62.1 mmol/mol) in the FGM group and 7.84% (62.2 mmol/mol) in the SMBG group at baseline, and the values were reduced in both FGM (-0.43% (-4.7 mmol/mol), p<0.001) and SMBG groups (-0.30% (-3.3 mmol/mol), p=0.001) at 12 weeks. On the other hand, HbA1c was significantly decreased from baseline values in the FGM group, but not in the SMBG group at 24 weeks (FGM: -0.46% (-5.0 mmol/mol), p<0.001; SMBG: -0.17% (-1.8 mmol/mol), p=0.124); a significant between-group difference was also observed (difference -0.29% (-3.2 mmol/mol), p=0.022). Diabetes Treatment Satisfaction Questionnaire score was significantly improved, and the mean glucose levels, SD of glucose, mean amplitude of glycemic excursions and time in hyperglycemia were significantly decreased in the FGM group compared with the SMBG group., Conclusions: Glycemic control was better with FGM than with SMBG after cessation of glucose monitoring in patients with non-insulin-treated type 2 diabetes., Trial Registration Number: UMIN000026452, jRCTs041180082., Competing Interests: Competing interests: HA reports grants and speaker honoraria from Abbott Japan outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare different configurations of the bilateral internal thoracic arteries for the left coronary system and examine early and late outcomes, including mid-term graft patency., Methods: We reviewed 877 patients who underwent primary isolated coronary artery bypass grafting using in situ bilateral internal thoracic arteries [in situ right internal thoracic artery (RITA)-to-left anterior descending artery (LAD) grafting, n = 683; in situ left internal thoracic artery (LITA)-to-LAD grafting, n = 194]. We compared mid-term patency between the grafts. Propensity score matching was performed to investigate early and long-term outcomes., Results: The 2-year patency rate for RITA-to-LAD and LITA-to-LAD grafts were similar. Multivariate analysis revealed that RITA-to-non-LAD anastomosis (P = 0.029), postoperative length of stay (P = 0.003) and chronic obstructive pulmonary disease (P = 0.005) were associated with graft failure. After statistical adjustment, 176 propensity-matched pairs were available for comparison. RITA-to-LAD grafting enabled a more distal anastomosis. Kaplan-Meier analysis revealed that the incidences of death, repeat revascularization and myocardial infarction were significantly higher in the LITA-to-LAD group among both the unmatched and matched samples (P = 0.045 and 0.029, respectively)., Conclusions: The mid-term patency and outcomes of RITA-to-LAD grafting are good and reduces future cardiac event, in contrast to LITA-to-LAD grafting., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.

Background: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified., Methods: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline., Results: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period., Conclusions: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline., Trial Registration: UMIN000019024.

Background: Previously, we showed that serum malondialdehyde (MDA) was significantly higher in patients with neovascular age-related macular degeneration (nAMD) than in those without AMD. The Diacron reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests are known markers of oxidative stress. The aim of this study was to use d-ROMs and BAP tests to evaluate changes in systemic oxidative stress in patients with nAMD., Methods: Blood serum samples were collected from 34 patients with nAMD (mean age: 76.5 ± 7.7 years; 22 men) and 20 control subjects (mean age: 62.9 ± 14.0 years; 10 men), and d-ROMs and BAP tests were examined., Results: In men, the mean level of d-ROMs for the nAMD patients was significantly higher than that for the controls (312.0 ± 52.4 vs. 275.1 ± 45.5 U.CARR, respectively; P < .05). There was a significant correlation between d-ROM level and CNV lesion area in the male nAMD group (r = .42, P = .05). There were no significant differences in mean BAP test results between the nAMD patients and controls for either sex (men: 2241 ± 549 vs. 2136 ± 246 μmol/L; women: 2263 ± 292 vs. 2335 ± 161 μmol/L)., Conclusion: The d-ROMs test may provide a useful indicator of nAMD in men but not in women.

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport., Competing Interests: Yoshiaki Morishita, Yusuke Seino, and Yoji Hamada belonged to the Department of Metabolic Medicine, which was established by a donation from the Sanwa Kagaku Co. Ltd. Yoshihiro Ito belongs to the Department of Nephrology/CKD initiatives, which receives donations from the Sanwa Kagaku Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABA B R) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABA B R-deficient mice compared with wild-type mice. Furthermore, the GABA B R agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABA B R-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABA B R signaling suppresses binge-like eating of HFD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

High differentiation efficiency is one of the most important factors in developing an in vitro model from pluripotent stem cells. In this report, we improved the handling technique applied to mouse-induced pluripotent stem (iPS) cells, resulting in better differentiation into hypothalamic vasopressin (AVP) neurons. We modified the culture procedure to make the maintenance of iPS cells in an undifferentiated state much easier. Three-dimensional floating culture was demonstrated to be effective for mouse iPS cells. We also improved the differentiation method with regards to embryology, resulting in a greater number of bigger colonies of AVP neurons differentiating from mouse iPS cells. Fgf8, which was not used in the original differentiation method, increased iPS differentiation into AVP neurons. These refinements will be useful as a valuable tool for the modeling of degenerative disease in AVP neurons in vitro using disease-specific iPS cells in future studies., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Based on the hypothesis that silicone oil (SO) with a higher refractive index than water induces unexpected vignetting effects during surgeries, we aimed to investigate the relationship between the volume of SO and light intensity using a surgical microscope., Methods: Using a light-sensitive paper and model eye filled with varying volumes (0%, 50%, 62.5%, 75%, 87.5% and 100%) of SO, the light intensity of intraocular lens (IOL) with various refractive powers (0, 10 and 20 dioptres) illuminated by a surgical microscope was measured., Results: Light exposure density with 1.0% coaxial and oblique light was approximately 22-fold higher than that with 0.1% coaxial and oblique light. Further, it was approximately 34-fold higher in eyes with +20 D IOL than in those with no IOL. The density in eyes with 75% SO was the highest among all groups followed by that with 0% SO. Light exposure densities in the eyes with 75% and 0% SO were significantly higher than those with other volumes of SO. In SO-filled eyes, a microscope set with only an oblique light and a filter successfully reduced light exposure., Conclusion: Silicone oil-related vision loss (SORVL) during SO removal surgeries might be due to increased light exposure on the macular retina caused by the SO-associated vignetting effect. SORVL could be prevented by placing a filter in the microscope during SO removal surgeries., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Tanycytes have recently been accepted as neural stem/progenitor cells in the postnatal hypothalamus. Persistent retina and anterior neural fold homeobox (Rax) expression is characteristic of tanycytes in contrast to its transient expression of whole hypothalamic precursors. In this study, we found that Rax+ residual cells in the maturation phase of hypothalamic differentiation in mouse embryonic stem cell (mESC) cultures had similar characteristics to ventral tanycytes. They expressed typical neural stem/progenitor cell markers, including Sox2, vimentin, and nestin, and differentiated into mature neurons and glial cells. Quantitative RT-PCR analysis showed that Rax+ residual cells expressed Fgf-10, Fgf-18, and Lhx2, which are expressed by ventral tanycytes. They highly expressed tanycyte-specific genes Dio2 and Gpr50 compared with Rax+ early hypothalamic progenitor cells. Therefore, Rax+ residual cells in the maturation phase of hypothalamic differentiation were considered to be more differentiated and similar to late progenitor cells and tanycytes. They self-renewed and formed neurospheres when cultured with exogenous FGF-2. Additionally, these Rax+ neurospheres differentiated into three neuronal lineages (neurons, astrocytes, and oligodendrocytes), including neuropeptide Y+ neuron, that are reported to be differentiated from ventral tanycytes toward the arcuate nuclei. Thus, Rax+ residual cells were multipotent neural stem/progenitor cells. Rax+ neurospheres were stably passaged and retained high Sox2 expression even after multiple passages. These results suggest the successful induction of Rax+ tanycyte-like cells from mESCs [induced tanycyte-like (iTan) cells]. These hypothalamic neural stem/progenitor cells may have potential in regenerative medicine and as a research tool., (Copyright © 2019 Endocrine Society.)

Purpose: To examine the characteristics of the foveal vascular structure of patients with retinopathy of prematurity (ROP) by optical coherence tomography angiography., Methods: Ten patients with a history of laser photocoagulation or cryopexy treatment for Stage 3 (Zone ≥ II) ROP and 10 normal subjects (controls) were included. Foveal avascular zone, vessel density, vessel length, and vascular diameter index were measured by optical coherence tomography angiography using the 3 × 3-mm Early Treatment Diabetic Retinopathy Study (ETDRS) sectors., Results: The median foveal avascular zone values of the patients with ROP and controls were 0.103 mm and 0.260 mm, respectively (P = 0.0025). The medians of the vessel density, vessel length, and vascular diameter index of the patients with ROP were 0.218 mm/mm, 11.75 mm/mm, and 18.00 μm, respectively, in ETDRS Sector 1 and did not significantly differ from those of the controls (P = 0.940, 0.733, and 0.705, respectively). For the average of ETDRS Sectors 2 to 5, the medians of the vessel density, vessel length, and vascular diameter index for the patients with ROP were 0.347 mm/mm, 18.95 mm/mm, and 18.28 μm, respectively; vessel density and vessel length were significantly smaller than those of the controls (P = 0.002 and 0.003, respectively), but there was no significant difference in vascular diameter index (P = 0.286)., Conclusion: Optical coherence tomography angiography-guided foveal avascular zone was significantly smaller in patients with ROP than in controls. Our results indicate that foveal vascular development may be altered in patients with a history of treatment-requiring ROP.

Background: This study compared the diagnostic value of myocardial perfusion imaging (MPI) between the rest-stress 99 m Tc-tetrofosmin protocol (Tc/Tc protocol) and simultaneous acquisition rest 99 m Tc-tetrofosmin/stress 201 Tl dual-isotope protocol (SDI protocol) with a semiconductor camera.Methods and Results: We retrospectively studied 147 patients who underwent stress MPI using a cadmium-zinc-telluride camera and invasive coronary angiography within a 3-month interval. The Tc/Tc and SDI protocols were used in 59 and 88 patients, respectively. The sensitivity, specificity, and accuracy of the summed difference score in per-patient analysis were 56%, 85%, and 69%, respectively, for the Tc/Tc protocol and 89%, 82%, and 85%, respectively, for the SDI protocol. The area under the receiver operating characteristic curve was significantly better for the SDI than Tc/Tc protocol for the left anterior descending artery (0.836 vs. 0.674; P=0.0380), the left circumflex artery (0.754 vs. 0.599; P=0.0441), and in per-patient analysis (0.875 vs. 0.707; P=0.0135). There was no significant difference in the diagnostic accuracy of the summed stress score for any vessel or in per-patient analysis between the 2 protocols., Conclusions: The SDI protocol had a higher diagnostic accuracy for the detection of coronary ischemia than the Tc/Tc protocol.

The traditional classification of hypertensive retinopathy was based on the Keith-Wagener-Barker (KWB) grading, which is a subjective scaling system, and it is difficult to distinguish between the first and second grades. Retinal and choroidal vasculatures are affected by systemic hypertension, although retinal vasculature changes with age, axial length, intraocular pressure, and retinal diseases. It is necessary to establish a new objective method to assess hypertensive vascular changes. In the present study, we have examined the vasculature of the macular choriocapillaris in order to establish a new objective method to assess hypertensive vascular changes using optical coherence tomography angiography (OCTA). Choriocapillaris vessel density (VD), vessel length, and vessel diameter index in a 3 × 3 mm macular area were measured by OTCA in a total of 567 volunteers (361 healthy subjects and 206 subjects with systemic hypertension) who attended a basic health check-up. Ocular factors, systemic factors, and medications were evaluated. We detected significant differences in normative choriocapillaris vasculature between the left and right eyes in 53 healthy subjects and revealed correlations between age, intraocular pressure, axial length, and choriocapillaris vasculature in 308 healthy subjects. Normative foveal VD was correlated with age only and the efficiency was weak. The analysis of 206 right eyes (KWB grade 0, 159 eyes; grade 1, 35 eyes; and grade 2, 12 eyes) revealed that foveal VD was strongly correlated with KWB grade only (P < 0.001). This is the first report suggesting that OCTA for foveal choriocapillaris measurement by OCTA would might provide the advantage of evaluating be objective method for evaluating the progression of systemic hypertension.

Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To investigate the refractive characteristics of Japanese children with Down syndrome., Study Design: Retrospective study., Methods: The clinical records of refractive errors and ocular manifestations in children with Down syndrome who visited the Aichi Children's Health and Medical Center between November 2001 and January 2016 were retrospectively reviewed. The children were divided into the 3 following groups depending on their age: group 1 (≤ 6 years), group 2 (7-12 years), and group 3 (13-19 years). The collection of refractive error data was performed only for the right eyes and only once for each child, when the children were last examined with their pupils dilated., Results: The study included 416 children (224 boys, 192 girls; average age, 6.1 ± 4.1 years). Group 3 had significantly stronger myopia than did groups 1 and 2. The mean cylindrical power in all the children was - 2.1 ± 1.2 diopters (D), and cylindrical power ≤ - 1.0 D (stronger than - 1.0 D) was seen in 366 eyes (88%). No significant difference in cylindrical power was found among the 3 groups., Conclusions: The spherical equivalent refraction showed an age-dependent myopic shift. Given that the amount of astigmatism did not show age-dependent differences, the age-dependent myopic shift could be due mainly to the change in spherical power.

Context: Immune checkpoint inhibitors, including anti-programmed cell death-1 (PD-1) antibodies, have become promising treatments for a variety of advanced malignancies. However, these medicines can cause immune-related adverse events (irAEs), including endocrinopathies., Objective: This study examined the incidence of endocrine irAEs induced by nivolumab., Patients and Main Outcome Measured: Sixty-six patients treated with nivolumab at Nagoya University Hospital were prospectively evaluated for pituitary hormones, thyroid function, antithyroid antibodies (Abs), and glucose levels every 6 weeks after the initiation of nivolumab for 24 weeks., Results: Four out of 66 patients developed destructive thyroiditis, and three patients developed hypothyroidism requiring levothyroxine replacement. The prevalence of positive anti-thyroglobulin Abs (TgAbs) and/or anti-thyroid peroxidase Abs (TPOAbs) at baseline was significantly higher in the group that developed destructive thyroiditis (3/4) compared with the group that did not develop thyroiditis (3/62; P = 0.002). There were no significant differences in other clinical variables between the groups. There were no endocrine irAEs other than destructive thyroiditis during the 24 weeks. The prevalence of TgAbs and/or TPOAbs at baseline was not associated with the development of other irAEs, including pneumonitis, colitis, or skin reactions., Conclusions: Our real-world data showed that destructive thyroiditis was an endocrine irAE that was frequently induced by nivolumab and was significantly associated with positive TgAbs and/or TPOAbs before treatment. Our findings indicate that evaluating these Abs before treatment may help identify patients with a high risk of thyroidal irAEs and may have important clinical benefit.

Intracranial cerebral atherosclerosis is a significant predictor of stroke after coronary artery bypass grafting (CABG). However, there is limited information on intracranial occlusive lesions in patients undergoing CABG. The purpose of the study was to elucidate the precise prevalence and distribution of occlusive lesions of the extracranial and intracranial arteries in patients undergoing CABG. Between 2009 and 2016, 205 patients underwent preoperative magnetic resonance angiography and elective CABG. The prevalence and the distribution of occlusive lesions were retrospectively examined by preoperative magnetic resonance angiography. Association between postoperative central nervous system (CNS) complications and the occlusive lesions was analyzed. Fifty-six patients (27.3%) and 60 patients (29.3%) had occlusive lesions of the extracranial and intracranial arteries, respectively. Twenty-eight patients (13.7%) had both extracranial and intracranial occlusive lesions. Thirty-one (15.1%) and 45 (22.0%) patients had severe stenosis or occlusion of the extracranial and intracranial arteries, respectively. The intracranial internal carotid artery was the most commonly affected intracranial artery (60 vessels; 62.5%), followed by the middle cerebral arteries (20 vessels; 20.8%). Sixteen patients (7.8%) suffered from postoperative CNS complications, including 2 permanent strokes. The etiology of the stroke was attributable to a predefined intracranial lesion in 1 patient. In multivariate analysis, the presence of intracranial occlusive lesions was found to have an independent association with the development of CNS complications (odds ratio 4.05; 95% confidence interval 1.13-14.6). The prevalence of intracranial occlusive lesions was higher than that of extracranial lesions in patients undergoing CABG. There was a solid trend toward the anterior distribution of the intracranial occlusive lesions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-eIF2α protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Open repair for infra-renal abdominal aortic and iliac artery aneurysms (AAAs) is a robust treatment. On the other hand, endovascular aneurysm repair (EVAR) has been widespread because of its less invasiveness. However, patients after EVAR frequently require postoperative radiographic examinations and may feel anxiety for their endoleaks. We prospectively evaluated Health-related Quality of Life of the patients with these two fashions using the 8-item Short Form (SF-8). From 2011 to 2013, 89 consecutive elective cases of AAAs were treated. They were prospectively divided into EVAR and open repair groups but not randomly. The exclusion criteria were as follows: perioperative status for other surgeries, infectious aneurysm, severely deteriorated conditions, and patients who cannot answer for these questionnaire or show their consent. The SF-8 questionnaire was completed through interviews preoperatively, and at 1, 3, 6, and 12 months after treatment. The SF-8 questionnaire was completed for 55 cases [EVAR group (ER): 25, open repair group (OR): 30]. There was no significant difference between these groups regarding patients' characteristics except congestive heart disease. The preoperative scores of the SF-8 were similar in both groups except physical function and social function, which were lower in ER (p < 0.05). There was no operative death in both groups. Operative duration and hospital stay in EVAR were significantly shorter than those in OR (p < 0.05). Follow-up rate at 1, 3, 6, and 12 months was 100, 100, 68.0, and 64.0% in ER, and 100, 90.0, 80.0, and 66.6% in OR, respectively. During follow-up, both groups had no AAAs associated death. Regarding changes of the SF-8 scales, there were some trends at physical component summary score (PCS) and mental component summary score (MCS) in ER. The PCS decreased at 1 month, gradually increased at 3 months, and levelled off until 12 months. The MCS increased at 1 and 3 months, but gradually went down and almost stayed at the same level as preoperative one at 12 months. In OR, PCS and MCS decreased at 1 month and after that increased gradually at 3 and 6 months, and stayed the same at 12 months. The MCS recovered to preoperative score earlier than the PCS. In this study, EVAR did not show any significant mental disturbance based on the SF-8 for 1-year comparing to open repair.

Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti-related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor β (IRβ) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IRβ and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Silicone oil (SO) is an intraocular surgical adjuvant that reduces the surgical complications in refractory retinal diseases, although membrane and cellular proliferation is often seen even in SO-filled eyes. We hypothesised that the fluid in the space between the SO and the retina, named the "sub-silicone oil fluid (SOF)", enhances these biological responses. We proposed a safe method for SOF extraction. We also analysed inflammatory cytokine expressions and SOF osmotic pressures from eyes with rhegmatogenous retinal detachment (RRD), proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and macular hole-associated retinal detachment (MHRD). Interleukin (IL)-10, IL-12p40, IL-6, monocyte chemotactic protein-1, and vascular endothelial growth factor (VEGF) in the SOF with PVR were significantly higher than in those with RRD or MHRD. Fibroblast growth factor-2, IL-10, IL-12p40, IL-8, VEGF, and transforming growth factor beta 1 levels in eyes with exacerbated PDR indicated a significantly higher expression than those with simple PDR. IL-6 and tumour necrosis factor alpha in eyes with exacerbated PVR demonstrated a significantly higher expression than in those with simple PVR. However, there was no difference in SOF osmotic pressure between group of each disease. These studies indicate that disease-specific SOF is a significant reflection of disease status.

Polypoidal choroidal vasculopathy (PCV) is characterized by polyp-like choroidal neovascularization and a branching vascular network. Intravitreal aflibercept injection (IAI) or photodynamic therapy (PDT) is used for treatment. We retrospectively compared the 1-year outcomes of IAI monotherapy and its combination with initial PDT for PCV. Twelve eyes with naïve PCV received three IAIs and a single PDT after the first IAI and as needed injection (combination group); 11 eyes with naïve PCV received three IAIs and as needed injections (IAI group). Significant improvements in visual acuity after 2 months and in CRT after 1 month were maintained at 12 months in both groups (both P < 0.05); groups did not differ significantly at any time point. CCT significantly reduced after 3 and 12 months in the combination group (both P < 0.05) but not in the IAI group. A mean of 3.7 ± 0.9 and 5.6 ± 2.0 injections was administered to the combination and IAI groups, respectively (P = 0.013). Within a 1-year period, combination therapy was found to yield similar visual acuity and retinal structure improvements and maintenance as IAI monotherapy while requiring fewer IAIs.

Regarding to coronary artery bypass grafting (CABG), the end-to-side anastomosis (ESA) has been performed as a gold standard. Recently, the effectiveness of the distal side-to-side anastomosis (SSA) in CABG using internal mammary artery has been reported. The benefit of SSA comparing to ESA also has been disclosed by computing simulation. However, use of SSA by venous conduit for individual CABG has not been reported. In this study, we investigated feasibility of SSA. From January 2013 to October 2014, we conducted 114 CABGs. There were 92 venous distal anastomoses without sequential anastomotic site (61 SSA and 31 ESA). The anastomosis was evaluated before discharge and at 1 year after the procedure by angiography or multi-detector row computed tomographic coronary angiography. The median values for time to anastomosis were 13 min in the two group (p = 0.89). There was no revision of anastomosis in both groups. Additional stitches for hemostasis were required significantly less in SSA than ESA (18.0 vs 45.2 %, respectively, p < 0.05). Early angiographic patency; 96.6 % for SSA vs 93.5 % for ESA (p = 0.50), and percentage of good anastomotic figure; 91.2 % for SSA vs 87.1 % for ESA (p = 0.54) were similar in both groups. The angiographic patency at 1 year were 92.9 % for SSA and 81.0 % for ESA (p = 0.16). There was no predictive factor for early and late graft failure. Our study showed feasibility of SSA using venous conduit in individual CABG based on early and mid-term angiographic results. This anastomotic fashion is easy to perform and maybe beneficial in blood flow pattern.

Objectives: To identify factors that determine early saphenous vein graft failure (VGF) within 1 month after coronary artery bypass grafting (CABG)., Methods: Seven hundred forty-nine consecutive patients underwent primary isolated CABG with saphenous vein grafts at three Japanese centres from 1 January 2005 to 31 December 2014. According to angiographic findings within 1 month of CABG surgery, 63 patients (8.4%) developed early VGF. We examined the relationships between variables and early VGF by using multivariable logistic regression analysis., Results: The preoperative clinical characteristics were similar between patients with and without early VGF, except for median preoperative haemoglobin A1c levels, which were significantly higher among patients with early VGF (6.7 vs 6.4%, P = 0.046). Additionally, anastomosis to the vessel with chronic total obstruction was performed more frequently among patients with early VGF (22/63 [34.9%] vs 140/686 [20.4%], P = 0.007), and myocardial infarction during the hospital admission occurred more frequently among patients with early VGF (4/63 [6.3%] vs 2/686 [0.3%], P < 0.0001). Results of multivariable analysis showed that the preoperative haemoglobin A1c level was associated with early VGF (odds ratio per unit increase, 1.30; 95% confidence interval, 1.06-1.60; P = 0.013)., Conclusions: An increased preoperative haemoglobin A1c level was strongly associated with early VGF after CABG. Thus, VGF happened more frequently in patients with poorly controlled diabetes mellitus., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Ocular trauma is one of the leading causes of visual impairment worldwide. Because of the popularity of cataract surgeries, aged individuals with ocular trauma commonly have a surgical wound in their eyes. The purpose of this study was to evaluate the visual outcome of cases that were coincident with intraocular lens (IOL) ejection in the eyes with ruptured open-globe ocular injuries. Consecutive patients with open-globe ocular injuries were first reviewed. Patients' characteristics, corrected distance visual acuities (CDVAs) over 3 years after the trauma, causes of injuries, traumatic wound patterns, and coexistence of retinal detachment were examined. The relationships between poor CDVA and the other factors, including the complications of crystalline lens and IOL ejection, were examined. A total of 105 eyes/patients [43 eyes with rupture, 33 with penetrating, 28 with intraocular foreign body (IOFB), and 1 with perforating injuries] were included. Rupture injuries were common in aged patients and were mostly caused by falls, whereas penetrating and IOFB injuries were common in young male patients. CDVAs of the eyes with rupture injuries were significantly worse than those of the eyes with penetrating or IOFB injuries. CDVA from more than 50% of the ruptured eyes resulted in no light perception or light perception to 20/500. CDVA of the ruptured eyes complicated by crystalline lens ejection was significantly worse than that of those complicated by IOL ejection. The wounds of the ruptured eyes complicated by IOL ejection were mainly located at the superior corneoscleral limbus, whereas those of the eyes complicated by crystalline lens ejection were located at the posterior sclera. There were significant correlations between poor CDVA and retinal detachment and crystalline lens ejection. These results proposed a new trend in the ocular injuries that commonly occur in aged patients; history of cataract surgery might affect the final visual outcome after open-globe ocular injuries., Competing Interests: The authors have declared that no competing interests exist.

Purpose. To compare serum levels of malondialdehyde (MDA) in patients with wet age-related macular degeneration (wAMD), patients with dry AMD (dAMD), and patients without AMD and to evaluate the efficacy of nutritional supplementation for treating elevated serum MDA in patients with wAMD. Methods. MDA levels were measured in sera from 20 patients with wAMD, 20 with dAMD, and 24 without AMD. Patients with wAMD were randomized to receive or not receive nutritional supplementation (10 patients in each group), and MDA levels were measured after 3 months of treatment. Results. MDA levels in patients with wAMD were significantly greater compared with patients without AMD. In eyes with wAMD, there was a significant correlation between MDA levels and choroidal neovascularization lesion area. Serum MDA levels decreased in most patients that received supplementation and significantly increased in those who did not. Conclusion. Baseline serum MDA levels were elevated in patients with wAMD, and MDA levels were directly correlated with choroidal neovascularization lesion area. In addition, nutritional supplementation appeared to exert a protective effect against oxidative stress in patients with wAMD., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Purpose. We had earlier reported positive hsa-miR-148a-3p expression in eyes with rhegmatogenous retinal detachment (RRD) and its involvement in the epithelial-mesenchymal transition of retinal pigment epithelium in vitro. Here we investigated the association of hsa-miR-148a-3p expression levels in the vitreous fluid of patients with RRD with severity of RRD. Methods. The hsa-miR-148a-3p expression levels in the vitreous fluid, range (degree) of retinal detachment (RD), and pixels of retinal break were measured in 27 eyes with RRD. The association of hsa-miR-148a-3p expression levels with other factors was evaluated by multiple regression analysis. Results. The hsa-miR-148a-3p expression levels, time from onset of RRD to vitrectomy, range of RD, and pixels of retinal breaks were 23.68 ± 43.00, 12.07 ± 15.36 days, 155.85 ± 86.67 degrees, and 37000 ± 67100 pixels, respectively. Five eyes with RRD had vitreous hemorrhage preoperatively. The hsa-miR-148a-3p expression levels were significantly associated with pixels of retinal breaks ( β = 0.699) and the time from onset of RRD to vitrectomy ( β = 0.358) but not with the range of RD or presence of vitreous hemorrhage. Conclusion. The hsa-miR-148a-3p expression levels in the vitreous fluid were significantly associated with the size of retinal break and disease duration., Competing Interests: The authors declare that they have no competing interests.

To evaluate, using pupillography, the difference between eyes affected by age-related macular degeneration and their contralateral normal eyes with regard to the mean relative afferent pupillary defect (RAPD) score. Also, to ascertain any correlations between this difference in RAPD score and differences in visual acuity or age-related macular degeneration (AMD) dimensions. Measurements were made using the RAPDx pupillographer (Konan Medical, Nishinomiya, Japan), which analyzes pupil response to light stimulation. Both best corrected visual acuity (converted to logMAR) and greatest linear dimension (GLD; calculated on the basis of fluorescence angiography images) were measured. The correlations between RAPD difference and logMAR difference, and GLD difference were then analyzed. The study included 32 patients (18 men, 14 women; mean age = 74.8 ± 9.7 years) who had AMD in 1 eye and a normal fundus in the contralateral eye. Mean resting pupil diameter, mean latency onset of constriction, mean velocity of constriction, and recovery were not significantly different in AMD eyes compared with normal eyes. The mean amplitude of constriction was smaller (P = 0.028), and the mean latency of maximum constriction was shorter (P = 0.0013) in AMD eyes than in normal eyes. Regarding RAPD scores, there was a significant correlation between visual acuity difference and RAPD score differences of both amplitude (P < 0.001, r = 0.53) and latency (P = 0.034, r = 0.33). GLD difference was also significantly correlated with differences in both amplitude (P = 0.021, r = 0.36) and latency (P = 0.033, r = 0.33) scores. RAPD outcomes were correlated with visual acuity and AMD dimension. Automated pupillography may be a useful tool in monitoring the progression of AMD and assessing changes in retinal function that result from novel interventions., Competing Interests: The authors report no conflicts of interest.

Age-related macular degeneration (AMD) is a major cause of blindness in developed countries and is closely related to oxidative stress, which leads to lipid peroxidation. Malondialdehyde (MDA) is a major byproduct of polyunsaturated fatty acid (PUFA) peroxidation. Increased levels of MDA have been reported in eyes of AMD patients. However, little is known about the direct relationship between MDA and AMD. Here we show the biological importance of MDA in AMD pathogenesis. We first confirmed that MDA levels were significantly increased in eyes of AMD patients. In ARPE-19 cells, a human retinal pigment epithelial cell line, MDA treatment induced vascular endothelial growth factor (VEGF) expression alternation, cell junction disruption, and autophagy dysfunction that was also observed in eyes of AMD patients. The MDA-induced VEGF increase was inhibited by autophagy-lysosomal inhibitors. Intravitreal MDA injection in mice increased laser-induced choroidal neovascularization (laser-CNV) volumes. In a mouse model fed a high-linoleic acid diet for 3 months, we found a significant increase in MDA levels, autophagic activity, and laser-CNV volumes. Our study revealed an important role of MDA, which acts not only as a marker but also as a causative factor of AMD pathogenesis-related autophagy dysfunction. Furthermore, higher dietary intake of linoleic acid promoted CNV progression in mice with increased MDA levels., (Copyright © 2016 Elsevier Inc. All rights reserved.)