Role of Thrombin in Soluble Thrombomodulin-Induced Suppression of Peripheral HMGB1-Mediated Allodynia in Mice

High mobility group box 1 (HMGB1), a nuclear protein, once released into the extracellular space under pathological conditions, plays a pronociceptive role in redox-dependent distinct active forms, all-thiol HMGB1 (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), that accelerate nociception through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4), respectively. Thrombomodulin (TM), an endothelial membrane protein, and soluble TM, known as TMα, promote thrombin-mediated activation of protein C and also sequester HMGB1, which might facilitate thrombin degradation of HMGB1. The present study aimed at clarifying the role of thrombin in TMα-induced suppression of peripheral HMGB1-dependent allodynia in mice. Thrombin-induced degradation of at-HMGB1 and ds-HMGB1 was accelerated by TMα in vitro. Intraplantar (i.pl.) injection of bovine thymus-derived HMGB1 in an unknown redox state, at-HMGB1, ds-HMGB1 or lipopolysaccharide (LPS), known to cause HMGB1 secretion, produced long-lasting mechanical allodynia in mice, as assessed by von Frey test. TMα, when preadministered i.pl., prevented the allodynia caused by bovine thymus-derived HMGB1, at-HMGB1, ds-HMGB1 or LPS, in a dose-dependent manner. The TMα-induced suppression of the allodynia following i.pl. at-HMGB1, ds-HMGB1 or LPS was abolished by systemic preadministration of argatroban, a thrombin-inhibiting agent, and accelerated by i.pl. co-administered thrombin. Our data clearly indicate that TMα is capable of promoting the thrombin-induced degradation of both at-HMGB1 and ds-HMGB1, and suppresses the allodynia caused by either HMGB1 in a thrombin-dependent manner. Considering the emerging role of HMGB1 in distinct pathological pain models, the present study suggests the therapeutic usefulness of TMα for treatment of intractable and/or persistent pain.     

A point mutation of the ED1 gene in a Japanese family with X-linked hypohidrotic ectodermal dysplasia

X-linked hypohidrotic ectodermal dysplasia (EDA) is characterized by the hypoplasia or absence of hair, teeth and sweat glands. In this study, the authors investigated the ED1 gene in a Japanese family with X-linked hypohidrotic ectodermal dysplasia. The only affected male fulfils the diagnostic criteria for this disorder. His parents were not consanguineous and both of them were healthy. After informed consent, genomic DNA was isolated from the peripheral blood lymphocytes or oral buccal epithelial cells of all members of the family. A polymerase chain reaction fragment containing exon 9 of the ED1 gene was amplified using primers. The patient's amplified fragment, as well as those from his father, mother and sister, were directly sequenced. The sequence from the patient revealed a point mutation (G1149A) in exon 8 of the ED1 gene, which changes codon 291 from glycine to arginine. Heterozygosity was demonstrated in his mother and sister. This mutation has not been reported previously. The amino acid substitution is predicted to disrupt the transmembrane domain, which strongly implies that this is the disease-causing mutation in the family.     

儿童口腔科患儿家长对儿童牙齿排列与咬合关注情况的调查

目的:了解目前儿童口腔科就诊的初诊患儿家长对子女牙齿排列与咬合情况,即儿童早期错畸形的关注现状.方法:采用填写问卷方法对2007-03～09期间来第四军医大学口腔医院儿童口腔科就诊的初诊患儿家长进行调查,最终获得有效问卷783 份.结果:783 例患儿中, 因龋病及其并发症就诊者占51.3%,以牙齿排列和咬合异常为主诉就诊患儿占35.0%.注意到孩子的牙齿排列和咬合问题的家长有510 名,其中希望治疗者474 名,不希望治疗者36 名;从未关注过孩子牙齿排列和咬合情况者273 名.对上前牙和下前牙排列不齐的关注率分别为56.6%和47.4%,注意到前牙咬合异常者占50.5%.有71.5%的家长是通过自己注意的途径得知子女的牙齿排列和咬合异常.48.7%的家长填写了个人资料,其中大学及大学以上文化程度者占73.9%. 结论:越来越多家长关注到自己孩子的牙齿排列与咬合状况,有必要通过各种途径进一步加强对社会及家长相关知识的普及.     

New-onset psychiatric disorders after corticosteroid therapy in systemic lupus erythematosus: an observational case-series study

The objective of this study was to clarify the incidence, clinical characteristics, and courses of new-onset psychiatric manifestations after corticosteroid therapy in patients with systemic lupus erythematosus (SLE), including possible ways of differentiating between corticosteroid-induced psychiatric disorders (CIPDs) and central nervous system manifestations of SLE (CNS-SLE). We prospectively followed for 8 weeks 139 consecutive episodes in 135 in-patients who had a non–CNS-SLE flare treated with corticosteroids. Psychiatric events were evaluated once a week using DSM-IV criteria. We then conducted a post hoc etiological analysis of any newly developed psychiatric events during this follow-up period. In the 8 weeks of corticosteroid administration, new psychiatric events occurred in 20 (14.4 %) of the 139 episodes. The mean dosage of corticosteroids administered was prednisolone at 0.98 (range 0.24–1.39) mg/kg/day. Of the 20 psychiatric events, 14 (10.1 %) were suitable for the strict definition of CIPDs, accompanied by mood disorders in 13 (depressive in 2, manic in 9, and mixed in 2) and psychotic disorder in one. Two (1.4 %), both presenting delirium, were diagnosed as CNS-SLE on the basis of evidence of abnormal CNS findings even before psychiatric manifestations, all of which improved in parallel with these patients’ recoveries through augmentation of immunosuppressive therapy. The other four events (2.9 %) could not be etiologically identified. This study suggests that corticosteroid therapy triggers CIPDs and CNS-SLE in patients with SLE. Delirium may be suggestive of CNS-SLE, while mood disorders may be more suggestive of CIPDs. Electroencephalographic abnormalities may possibly be predictive of CNS-SLE.     

Fatigue and relating to others 3 months after the 2011 Great East Japan Earthquake

Most inhabitants of Tohoku district suffer from chronic fatigue after the 2011 Great East Japan Earthquake. Chronic fatigue following disasters may lead to serious illness, even death. Posttraumatic growth appears to counteract fatigue. We predicted that the chronic fatigue would be inversely related to the posttraumatic growth factor “relating to others,” as represented by mutual helping and a strong sense of connection with humanity. Young 59 healthy volunteers, residing in Miyagi prefecture, were recruited 3 months after the disaster. We measured the subjects? total scores on the Japanese version of the Checklist Individual Strength questionnaire (CIS), the Trait Anxiety (T-A) subscale of the State–Trait Anxiety Inventory (STAI), the Center for Epidemiologic Studies Depression Scale (CES-D), and four subscores on the posttraumatic growth inventory (PTGI). Stepwise regression analyses were conducted with score on the CIS as the dependent variable and other scores as independent variables. Scores on the “relating to others” factor of the PTGI showed a significant negative relationship with the CIS score, whereas the scores on the T-A subscale of the STAI and the CES-D were positively related to the CIS score. Human ties and mutual help were negatively related to the degree of the chronic fatigue.     

Fibrosing Cholestatic Hepatitis Developing within One Month after Living Donor Liver Transplantation for Chronic Hepatitis C-related Cirrhosis: A Case Report

Fibrosing cholestatic hepatitis (FCH) is a life-threatening consequence of hepatitis C virus (HCV) infection occurring in a small minority of liver transplantation (LT) recipients. We herein report a case of early-onset FCH after living donor LT in a 47-year-old woman with HCV-related cirrhosis. The patient underwent balloon-occluded retrograde transvenous obliteration of a splenorenal shunt to treat an impaired portal flow on the sixth postoperative day (POD 6) and a bypass operation for hepatic artery thrombosis on POD 12. Thereafter, the serum bilirubin levels increased gradually; however, computed tomography revealed no evidence of biliary stricture. The serum HCV-RNA level on POD 27 was >7.8 log IU/mL. Histopathology of a needle graft biopsy performed on POD 28 revealed FCH with extensive portal fibrosis accompanied by mild inflammation, hepatocyte ballooning, and ductular proliferation with cholestasis. The patient received combination therapy with pegylated interferon, ribavirin, and double-filtration plasmapheresis for the treatment of early-onset FCH. Both the recipient and the donor carried the major genotype single nucleotide polymorphism (TT) at rs8099917 near the interleukin-28B gene. Furthermore, the HCV genotype was treatment-sensitive 2a. Nonetheless, the recipient died of hepatic failure on POD 211. Thus far, few cases of FCH occurring within 1 month after LT have been reported. In addition, the early onset of FCH may be an adverse prognostic factor.