Does Clear Cornea Cataract Surgery Influence Conjunctivochalasis?

This is a Letter to the Editor and does not have an abstract

γ-Tocopherol Accelerated Sodium Excretion in a Dose-Dependent Manner in Rats with a High Sodium Intake

We have previously reported that γ-tocopherol (γ-Toc) displays a natriuretic potency in rats fed a NaCl diet and administered 20 mg γ-Toc. In this study, we investigated whether γ-Toc has natriuretic potency at a dose lower or higher than 20 mg in rats given a NaCl diet. Male rats were fed a control diet or a NaCl diet and administered either placebo or 10, 20 or 40 mg of γ-Toc. The rat urine was collected for 24 hours (divided into 6 hour periods) and the 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (γ-CEHC) level, the sodium excretion content, and the urine volume were determined. The 24-hour γ-CEHC and sodium levels in the urine of the NaCl groups given 20 mg or 40 mg γ-Toc were significantly higher than those in the placebo group. The peak levels of urine sodium and γ-CEHC in the NaCl group given 40 mg γ-Toc appeared at 0–6 h, which was a more rapid increase than that seen in the group given 20 mg γ-Toc. The 24-hour urine volumes of the NaCl groups given 10 and 20 mg γ-Toc were significantly higher than the urine volume of the placebo group. Our findings suggested that γ-Toc increased sodium excretion in a dose-dependent manner in rats fed a NaCl diet. Moreover, a high dose of γ-Toc may accelerate its metabolism and cause an increase in the rate of sodium excretion

ERG is required for the differentiation of embryonic stem cells along the endothelial lineage

<p>Abstract</p> <p>Background</p> <p>The molecular mechanisms that govern stem cell differentiation along the endothelial lineage remain largely unknown. Ets related gene (ERG) has recently been shown to participate in the transcriptional regulation of a number of endothelial specific genes including VE-cadherin (CD144), endoglin, and von Willebrand's Factor (vWF). The specific role of the ETS factor ERG during endothelial differentiation has not been evaluated.</p> <p>Results</p> <p>ERG expression and function were evaluated during the differentiation of embryonic stem cells into embryoid bodies (EB). The results of our study demonstrate that ERG is first expressed in a subpopulation of vascular endothelial growth factor receptor 2 (VEGF-R2) expressing cells that also express VE-cadherin. During ES cell differentiation, ERG expression remains restricted to cells of the endothelial lineage that eventually coalesce into primitive vascular structures within embryoid bodies. ERG also exhibits an endothelial cell (EC)-restricted pattern during embryogenesis. To further define the role of ERG during ES cell differentiation, we used a knockdown strategy to inhibit ERG expression. Delivery of three independent shRNA led to 70-85% reductions in ERG expression during ES cell differentiation compared to no change with control shRNA. ERG knockdown was associated with a marked reduction in the number of ECs, the expression of EC-restricted genes, and the formation of vascular structures.</p> <p>Conclusion</p> <p>The ETS factor ERG appears to be a critical regulator of EC differentiation.</p

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy

シェーグレン症候群の新規自己抗原であるREG 蛋白の唾液導管細胞における発現誘導にはIL-6/STAT 経路が重要である

The regenerating gene, Reg, was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named REG Iα. Recently, we reported that REG Iα mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjögren׳s syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of REG Iα in the salivary glands of SS patients. We prepared a reporter plasmid containing REG Iα promoter (−1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of REG Iα was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the REG Iα promoter activity in salivary ductal cells. Deletion analysis revealed that the region of −141 to −117 of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results showed that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the consensus sequence of REG Iα promoter in salivary ductal cells. This IL-6/STAT dependent REG Iα induction might play a role in the pathogenesis of SS.博士（医学）・甲第641号・平成27年11月27日Copyright © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren׳s syndrome patients, in salivary duct epithelial cells

The regenerating gene, Reg, was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named REG Iα. Recently, we reported that REG Iα mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjögren׳s syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of REG Iα in the salivary glands of SS patients. We prepared a reporter plasmid containing REG Iα promoter (−1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of REG Iα was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the REG Iα promoter activity in salivary ductal cells. Deletion analysis revealed that the region of −141 to −117 of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results showed that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the consensus sequence of REG Iα promoter in salivary ductal cells. This IL-6/STAT dependent REG Iα induction might play a role in the pathogenesis of SS

Research and Development of Information and Communication Technology-based Home Blood Pressure Monitoring from Morning to Nocturnal Hypertension

Asians have specific characteristics of hypertension (HTN) and its relationship with cardiovascular disease. The morning surge in blood pressure (BP) in Asians is more extended, and the association slope between higher BP and the risk for cardiovascular events is steeper in this population than in whites. Thus, 24-hour BP control including at night and in the morning is especially important for Asian patients with HTN. There are 3 components of “perfect 24-hour BP control”: the 24-hour BP level, adequate dipping of nocturnal BP (dipper type), and adequate BP variability such as the morning BP surge. The morning BP-guided approach using home BP monitoring (HBPM) is the first step toward perfect 24-hour BP control. After controlling morning HTN, nocturnal HTN is the second target. We have been developing HBPM that can measure nocturnal BP. First, we developed a semiautomatic HBPM device with the function of automatic fixed-interval BP measurement during sleep. In the J-HOP (Japan Morning Surge Home Blood Pressure) study, the largest nationwide home BP cohort, we successfully measured nocturnal home BP using this device with data memory, 3 times during sleep (2, 3, and 4 am), and found that nocturnal home BP is significantly correlated with organ damage independently of office and morning BP values. The second advance was the development of trigger nocturnal BP (TNP) monitoring with an added trigger function that initiates BP measurements when oxygen desaturation falls below a variable threshold continuously monitored by pulse oximetry. TNP can detect the specific nocturnal BP surges triggered by hypoxic episodes in patients with sleep apnea syndrome. We also added the lowest heart rate-trigger function to TNP to detect the “basal nocturnal BP,” which is determined by the circulating volume and structural cardiovascular system without any increase in sympathetic tonus. This double TNP is a novel concept for evaluating the pathogenic pressor mechanism of nocturnal BP. These data are now collected using an information and communication technology (ICT)-based monitoring system. The BP variability includes different time-phase variability from the shortest beat-by-beat, positional, diurnal, day-by-day, visit-to-visit, seasonal, and the longest yearly changes. The synergistic resonance of each type of BP variability would produce great dynamic BP surges, which trigger cardiovascular events. Thus, in the future, the management of HTN based on the simultaneous assessment of the resonance of all of the BP variability phenotypes using a wearable “surge” BP monitoring device with an ICT-based data analysis system will contribute to the ultimate individualized medication for cardiovascular disease

Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft -versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance

Use of vonoprazan for management of systemic sclerosis‑related gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) in systemic sclerosis (SSc) can significantly reduce a patient\u27s quality of life. GERD in SSc is occasionally resistant to conventional anti-acid treatment. Vonoprazan is an H+/K+-ATPase blocker that is approved in Japan for treatment of GERD. The aim of the present study was to evaluate the efficacy of vonoprazan in SSc-related GERD. The frequency scale for symptoms of GERD (FSSG) scores were collected before and after vono-prazan treatment in 15 SSc patients with GERD. Additionally, endoscopic esophagogastroduodenoscopy was performed in select patients. Conventional proton pump inhibitors or hista-mine-2 receptor antagonists had been previously administered in 93% (14/15) of the patients. Although the baseline esophago-gastroduodenoscopy examination did not show severe erosion in the majority of patients,the mean total FSSG score before vonoprazan treatment was notably high (25.2±10.7) compared to a normal score of <8. After vonoprazan treatment, the FSSG score decreased to 9.6±7.0. The mean improvement rate of the total FSSG, acid reflux and dysmotility scores were 60.8±21.2% (P=0.0004), 67.3±24.8% (P<0.0001) and 55.4±26.0% (P=0.0022), respectively.These results suggest that vonoprazan may be a potentially effective treatment for GERD in patients with SSc

Significance of serum palmitoleic acid levels in inflammatory bowel disease

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic intestinal diseases of unknown etiology that present with variable disease extents and outcomes. The use of biomarkers for the diagnosis and management of IBDs is considered beneficial. Palmitoleic acid (PO) is an adipose tissue-derived mono-unsaturated free fatty acid that potentially serves as a lipokine in metabolic and inflammatory diseases. The aim of this study was to investigate the significance of PO levels in the serum of patients with UC and CD. The study included patients with UC (n = 22), patients with CD (n = 35), and controls (n = 22). The levels of serum PO were analyzed using gas chromatography. The association of serum PO levels with the clinical features and disease outcomes in IBD was examined. Serum PO levels were significantly higher in patients with CD than in controls, whereas no difference in these levels was observed between patients with UC and controls. Serum PO levels were significantly associated with the CD activity index. Additionally, high serum PO levels were associated with an increased risk of surgical intervention requirement during follow-up. In a pilot study with a few patients, high PO levels were observed in the mesenteric tissue in the active disease site of patients with CD (n = 7) compared with those with colon cancer (n = 6). Elevated serum PO levels might serve as a marker for local inflammation and prognosis in patients with CD