PD-1 deficiency protects experimental colitis via alteration of gut microbiota

Programmed cell death-1 (PD-1) is a coinhibitory molecule and plays a pivotal role in immune regulation. Here, we demonstrate a role for PD-1 in pathogenesis of inflammatory bowel disease (IBD). Wild-type (WT) mice had severe wasting disease during experimentally induced colitis, while mice deficient for PD-1 (PD-1(-/-)) did not develop colon inflammation. Interestingly, PD-1(-/-) mice cohoused with WT mice became susceptible to colitis, suggesting that resistance of PD-1(-/-) mice to colitis is dependent on their gut microbiota. 16S rRNA gene-pyrosequencing analysis showed that PD-1(-/-) mice had altered composition of gut microbiota with significant reduction in Rikenellaceae family. These altered colon bacteria of PD-1(-/-) mice induced less amount of inflammatory mediators from colon epithelial cells, including interleukin (IL)-6, and inflammatory chemokines. Taken together, our study indicates that PD-1 expression is involved in the resistance to experimental colitis through altered bacterial communities of colon.112Ysciescopuskc

Genetic analysis of parathyroid and pancreatic tumors in a patient with multiple endocrine neoplasia type 1 using whole-exome sequencing

Background Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant hereditary disorder characterized by the presence of endocrine tumors affecting the parathyroid, pancreas, and pituitary. A heterozygous germline inactivating mutation in the MEN1 gene (first hit) may be followed by somatic loss of the remaining normal copy or somatic mutations in the MEN1 gene (second hit). Whole-exome sequencing has been successfully used to elucidate the mutations associated with the different types of tumors. Case presentation We performed whole-exome sequencing (WES) on three parathyroid tumors, one pancreatic insulinoma, and a blood sample taken from the same patient with MEN1 to study tumor heterogeneity in MEN1 originating from different tumors. We identified a novel frame-shift deletion (c.1382_1383delAG, p.E461GfsX69) in the MEN1 gene using WES, which was confirmed by Sanger sequencing. WES and the SNP array revealed somatic LOH on chromosome 11 in parathyroid tumors (left upper, left lower, and right upper parathyroid). However, we did not detect a somatic MEN1 gene mutation or LOH in the pancreatic insulinoma. WES revealed two somatic functional variants outside the MEN1 gene in the pancreatic insulinoma. Conclusions This study revealed heterogeneity among tumors in the same patient with MEN1, suggesting that different tumor-specific tumorigenic mechanisms may contribute to the pathogenesis of MEN1 tumors. The present study supports the clinical applicability of the WES strategy to research on multiple tumor samples and blood

Identification of genes modulated by high extracellular calcium in coculuture of mouse osteoblasts and bone marrow cells by oligo chip assay

Calcium concentration in the bone resorption lacunae is high and is in the mM concentration range. Both osteoblast and osteoclast have calcium sensing receptor in the cell surface, suggesting the regulatory role of high extracellular calcium in bone metabolism. In vitro, high extracellular calcium stimulated osteoclastogenesis in coculture of mouse osteoblasts and bone marrow cells. Therefore we examined the genes that were commonly regulated by both high extracellular calcium and 1,25(OH)2vitaminD3 (VD3) by using mouse oligo 11 K gene chip. In the presence of 10 mM [Ca2+]e or 10 nM VD3, mouse calvarial osteoblasts and bone marrow cells were co-cultured for 4 days when tartrate resistant acid phosphatase-positive multinucleated cells start to appear. Of 11,000 genes examined, the genes commonly regulated both by high extracellular calcium and by VD3 were as follows; 1) the expression of genes which were osteoclast differentiation markers or were associated with osteoclastogenesis were up-regulated both by high extracellular calcium and by VD3; trap, mmp9, car2, ctsk, ckb, atp6b2, tm7sf4, rab7, 2) several chemokine and chemokine receptor genes such as sdf1, scya2, scyb5, scya6, scya8, scya9, and ccr1 were up-regulated both by high extracellular calcium and by VD3, 3) the genes such as mmp1b, mmp3 and c3 which possibly stimulate bone resorption by osteoclast, were commonly up-regulated, 4) the gene such as c1q and msr2 which were related with macrophage function, were commonly down-regulated, 5) the genes which possibly stimulate osteoblast differentiation and/or mineralization of extracellular matrix, were commonly down-regulated; slc8a1, admr, plod2, lox, fosb, 6) the genes which possibly suppress osteoblast differentiation and/or mineralization of extracellular matrix, were commonly up-regulated; s100a4, npr3, mme, 7) the genes such as calponin 1 and tgfbi which possibly suppress osteoblast differentiation and/or mineralization of extracellular matrix, were up-regulated by high extracellular calcium but were down-regulated by VD3. These results suggest that in coculture condition, both high extracellular calcium and VD3 commonly induce osteoclastogenesis but suppress osteoblast differentiation/mineralization by regulating the expression of related genes.본 연구는 보건복지부 보건의료기술진흥사업의 지원에 의하여 이루어진 것임(03-PJ1-PG3-20500-0013)

Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy

Recessive mutations in chromosome 10 open reading frame 2 (C10orf2) are relevant in infantile-onset spinocerebellar ataxia (IOSCA). In this study, we investigated the causative mutation in a Korean family with combined phenotypes of IOSCA, sensorimotor polyneuropathy, and myopathy. We investigated recessive mutations in a Korean family with two individuals affected by IOSCA. Causative mutations were investigated using whole exome sequencing. Electrophysiological analyses and muscle and nerve biopsies were performed, along with magnetic resonance imaging (MRI) of the brain and lower extremities. Compound heterozygous mutations c.1460C>T and c.1485-1G>A in C10orf2 were identified as causative of IOSCA. Skeletal muscle showed mitochondrial DNA (mtDNA) deletions. Both patients showed a period of normal development until 12–15 months, followed by ataxia, athetosis, hearing loss, and intellectual disability. Electrophysiological findings indicated motor and sensory polyneuropathies. Muscle biopsy revealed variations in the size and shape of myofibers with scattered, small, and angulated degenerating myofibers containing abnormal mitochondria; these observations are consistent with myopathy and may be the result of mtDNA deletions. Sural nerve biopsy revealed an axonal neuropathy. High-signal-intensity lesions in the middle cerebellar peduncles were correlated with clinical severity, and MRI of the lower legs was compatible with the hypothesis of length-dependent axonal degeneration. We identified novel compound heterozygous mutations of the C10orf2 gene as the cause of IOSCA with sensorimotor polyneuropathy and myopathy. Signs of motor neuropathy and myopathy were discovered for the first time in IOSCA patients with C10orf2 mutations. These results suggest that the clinical spectrum of IOSCA caused by C10orf2 mutations may be more variable than previously reported. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10048-014-0405-1) contains supplementary material, which is available to authorized users

A Survey of Diabetic Educators and Patients for the Revision of Korean Food Exchange Lists

BackgroundFood exchange lists are one of the main methods of nutritional education. However, Korean food exchange lists have not been revised since 1994. Therefore, we surveyed the opinions of diabetes educators and patients with diabetes regarding the need for revision of the current food exchange lists.MethodsFor two weeks beginning on 10 March 2008, a 12-item questionnaire regarding the opinion and need for revision of the current food exchange lists was e-mailed to diabetes educators nationwide. Another 15-question survey was administered to patients with diabetes in 13 hospitals located in the Seoul and Gyeonggi regions of Korea.ResultsWe obtained survey responses from 101 diabetes educators and 209 patients; 65 (64.3%) of the educators answered that the current food exchange lists should be revised. The items that needed revision were the glycemic index, addition of new foods and reaffirmation of exchange standard amounts. The patients demanded specific education about choosing appropriate foods, a balanced meal plan, proper snacks, and dining intake.ConclusionOur survey results demonstrate the need to revise the Korean food exchange lists. This process should focus on glycemic index, the addition of new foods and reconfirmation of one exchange reference unit

Brief Education on Microvasculature and Pit Pattern for Trainees Significantly Improves Estimation of the Invasion Depth of Colorectal Tumors

Objectives. This study was performed to evaluate the effectiveness of education for trainees on the gross findings identified by conventional white-light endoscopy (CWE), the microvascular patterns identified by magnifying narrow-band imaging endoscopy (MNE), and the pit patterns identified by magnifying chromoendoscopy (MCE) in estimation of the invasion depth of colorectal tumors. Methods. A total of 420 endoscopic images of 35 colorectal tumors were used. Five trainees estimated the invasion depth of the tumors by reviewing the CWE images before education. Afterwards, the trainees estimated the invasion depth of the same tumors after brief education on CWE, MNE and MCE images, respectively. Results. The initial diagnostic accuracy for deep submucosal invasion before education and after education on CWE, MNE, and MCE findings was 54.3%, 55.4%, 67.4%, and 76.6%, respectively. The diagnostic accuracy increased significantly after MNE education (P=0.028). The specificity for deep submucosal invasion before education and after education on CWE, MNE, and MCE findings was 47.9%, 45.7%, 65.0%, and 80.7%, respectively. The specificity increased significantly after MNE (P=0.002) and MCE (P=0.005) education. Conclusion. Brief education on microvascular pattern identification by MNE and pit pattern identification by MCE significantly improves trainees’ estimations of the invasion depth of colorectal tumors

Individualized diabetes nutrition education improves compliance with diet prescription

This study was designed to evaluate the effect of individualized diabetes nutrition education. The nutrition education program was open to all type 2 diabetes patients visiting the clinic center and finally 67 patients agreed to join the program. To compare with 67 education group subjects, 34 subjects were selected by medical record review. The education program consisted of one class session for 1-2 hours long in a small group of 4~5 patients. A meal planning using the food exchange system was provided according to the diet prescription and food habits of each subject. Measurements of clinical outcomes and dietary intakes were performed at baseline and 3 months after the education session. After 3 months, subjects in education group showed improvement in dietary behavior and food exchange knowledge. In education group, intakes of protein, calcium, phosphorus, vitamin B2, and folate per 1,000 kcal/day were significantly increased and cholesterol intake was significantly decreased. They also showed significant reductions in body weight, body mass index (BMI), and fasting blood concentrations of glucose (FBS), HbA1c, total cholesterol, and triglyceride. However, no such improvements were observed in control group. To evaluate telephone consultation effect, after the nutrition education session, 34 subjects of the 67 education group received telephone follow-up consultation once a month for 3 months. The others (33 subjects) had no further contact after the nutrition education session. Subjects in the telephone follow-up group showed a decrease in BMI, FBS, and HbA1c. Moreover, the subjects who did not receive telephone follow-up also showed significant decreases in BMI and FBS. These results indicated that our individually planned education program for one session was effective in rectifying dietary behavior problems and improving food exchange knowledge, and quality of diet, leading to an improvement in the clinical outcomes. In conclusion, our individualized nutrition education was effective in adherence to diet recommendation and in improving glycemic control and lipid concentrations, while follow-up by telephone helped to encourage the adherence to diet prescription