Work-related allergy in medical doctors: atopy, exposure to domestic animals, eczema induced by common chemicals and membership of the surgical profession as potential risk factors

Purpose To investigate the risk factors associated with work-related allergy-like symptoms in medical doctors. Methods Self-administered questionnaire survey and CAP test were conducted among medical school students in the 4th grade of their 6-year medical course in 1993–1996 and 1999–2001. Follow-up questionnaires were sent in 2004 to the graduates. These questionnaires enquired into personal and family history of allergic diseases, lifestyle, history of allergy-like symptoms including work-relatedness and occupational history as medical doctors. Relationships between allergy-like symptoms and relevant factors were evaluated by multivariate logistic regression analysis. Results Of 261 respondents at the follow-up survey, 139 (53.3%) and 54 (20.7%) had a history of any allergy-like symptoms and any work-related allergy-like symptoms, respectively. Female gender and family history of allergic diseases were signiWcantly associated with any allergy-like symptoms. Personal history of allergic disease, exposure to domestic animals, eczema caused by rubber gloves, metallic accessories, or cosmetics during schooling days, and membership of the surgical profession were signiW- cant risk factors for work-related allergy-like symptoms. On the contrary, to work-related allergy-like symptoms, gender, age, and smoking status were not signiWcantly related, and consumption of prepared foods was inversely related. Conclusions Personal history of atopy and eczema induced by common goods and the history of keeping domestic animals may be predictors of work-related allergy-like symptoms in doctors. After graduation from medical school, physicians start with exposure to various allergens and irritants at work, which relate to work-related allergy-like symptoms, especially for surgeons

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia

Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits

CCR2の阻害はdb/dbマウスにおけるインスリン抵抗性と肝脂肪蓄積を改善する。

京都大学0048新制・課程博士博士(医学)甲第15218号医博第3418号新制||医||979(附属図書館)27696京都大学大学院医学研究科医学専攻(主査)教授 稲垣 暢也, 教授 中尾 一和, 教授 清水 章学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

The vestibular system is critical for the changes in muscle and bone induced by hypergravity in mice

Gravity changes concurrently affect muscle and bone as well as induce alterations in vestibular signals. However, the role of vestibular signals in the changes in muscle and bone induced by gravity changes remains unknown. We therefore investigated the effects of vestibular lesions (VL) on the changes in muscle and bone induced by 3 g hypergravity for 4 weeks in C57BL/6J mice. Quantitative computed tomography analysis revealed that hypergravity increased muscle mass surrounding the tibia and trabecular bone mineral content, adjusting for body weight in mice. Hypergravity did not affect cortical bone and fat masses surrounding the tibia. Vestibular lesions blunted the increases in muscle and bone masses induced by hypergravity. Histological analysis showed that hypergravity elevated the cross‐sectional area of myofiber in the soleus muscle. The mRNA levels of myogenic genes such as MyoD, Myf6, and myogenin in the soleus muscle were elevated in mice exposed to hypergravity. Vestibular lesions attenuated myofiber size and the mRNA levels of myogenic differentiation markers enhanced by hypergravity in the soleus muscle. Propranolol, a β‐blocker, antagonized the changes in muscle induced by hypergravity. In conclusion, this study is the first to demonstrate that gravity changes affect muscle and bone through vestibular signals and subsequent sympathetic outflow in mice

Effects of Age and Gonadal Steroids on the Localization of T Cell Subsets in the Epididymis of Male Chickens, Gallus domesticus

The aim of this study was to examine the effects of age and gonadal steroids on the localization of T cell subsets in the epididymis of roosters in order to determine the factors affecting their populations. Immature and matured White Leghorn male birds were used, and some of the immature birds were i.m. injected daily with 1mg testosterone propionate (TP), 1mg estradiol benzoate (EB) or 100&mu;l of sesame oil (control) for 3 or 6 days. Cryostat sections of their epididymis were immunostained for CD4 or CD8 antigens. Many of the CD4+ and CD8+ T cells were found in the subepithelial layer of efferent ductules and epididymal duct and also in the interstitum in matured and immature birds. The frequencies of CD4+ and CD8+ T cells in the subepithelial layer of efferent ductules and interstitum was significantly greater in matured birds than in immature ones. The ratios of CD4+/CD8+ T cells in the efferent ductules and interstitum were not different between matured and immature birds. In the subepithelial layer of efferent ductules of immature birds, the frequencies of CD4+ and CD8+ T cells were significantly increased by Day 3 of TP-injection, followed by a decrease to the level of Day 0 by Day 6. Their frequencies were increased by EB-injection on Day 3 and 6 compared with Day 0. In the interstitum of TP-injected birds, the frequency of CD4+ T cells were not changed until Day 6, whereas CD8+ T cells increased on Day 3 and Day 6 compared with Day 0. Injection with EB caused a significant increase of both CD4+ and CD8+ T cells on Day 3 and Day 6 compared with Day 0. The CD4+/CD8+ T cells ratio in the epididymal subepithelial layer and interstitum were not significantly different among treatment days within control, TP- and EB-injected groups. These results suggest that the populations of CD4+ and CD8+ T cells in the epididymis are increased in the matured birds compared with immature ones, and luminal contents and gonadal steroids may be responsible in the increase of those T cells

鶏の卵管漏斗部の局所構造, とくに卵子の取り込み機構との関連において

排卵卵子は卵管腹腔口を通って卵管に取り込まれるのであるが、その機構はほとんど知られていない。本研究は鶏卵子が卵管内に取り込まれる機構を形態学的観点から明らかにするために、卵管漏斗部の構造を調べた。所見は以下のとおりであった。1.卵管近位端の漏斗部は狭義の漏斗部と基部の2部分に区別された。狭義の漏斗部はラッパ状に拡張し、極めて薄い壁構造を呈していた。漏斗部遊離端は約1.5～2㎜幅の漏斗釆と名付けられる肥厚して皺の多い壁によって額取られていた。この釆部は2重の粘膜を具えており、臓側の粘膜が遊離端を越えて漿膜側に伸びて形成されていた。2.釆部の粘膜は低くい縦走ヒダによって被われていた。粘膜ヒダは漏斗基部に移行するにつれて幅と高さを増した。粘膜上皮は卵管の他の部とは異なり、繊毛細胞のみから成っていた。さらに、釆部の粘膜下織は疎性の結合組繊であって、少量の筋線維束を含んでいた。筋線維は漏斗部の長軸と平行に、あるいは斜め方向に走っていた。3.卵管漏斗部には卵巣動脈に由来する前卵管動脈が分布していた。前卵管動脈からの分枝は漏斗釆部に極めて密性な毛細血管網を形成していた。また、釆部には豊富なリンパ管の分布を示唆するリンパ様嚢胞がしばしば認められた。このリンパ様嚢胞は排卵前の漏斗部に多く認められる傾向があった。4.卵管漏斗部ほ卵巣神経叢に由来する豊富な神経によって支配されていた。上記の卵管漏斗部とくに漏斗釆の構造的特徴に基いて、卵子の取り込み機構が漏斗部の形態学的見地から論議された。The infundibulum of the hen's oviduct was examined morphologically in connection with the action of engulfing the ovulated ovum. It was a funnel-shaped, thin-walled structure. Its abdominal ostium was edged by a specialized structure named the fimbrial lip. It was well-defined and had an enlarged wall 1.5-2.0 mm thick, consisting of a double-layered mucosa. In the ostium, the infundibular mucosa turned over the free margin of the fimbrial lip to the parietal side and merged into the serosa. The mucosa of the fimbrial lip and its vicinity was thrown into low, longitudinal folds lined by ciliated epithelial cells only. Nearing to the neck region, mucous folds increased in height and nonciliated cells began to appear. The musculature of the infundibulum looked poorly developed, although its arrangement was characteristic. The fimbrial lip contained a few muscle bundles running parallel or obliquely to the long axis of the infundibulum, but no circular musculature was seen. The infundibular wall below the level of the fimbrial lip had a considerable amount of circular muscle fibers arranged in sheet-like bundles. The infundibulum was abundantly supplied by blood vessels that originated in the ovarian artery. The fimbrial lip had a particularly dense network of capillaries and seemed to be furnished well with lymph vessels. The infundibulum was richly innervated by nerve bundles deriving from the ovarian plexus. On the bais of these structural findings of the infundibulum, discussions were held on the mechanism by which the ovulated ovum was engulfed by the oviduct through the infundibulum from a morphological point of view