松山 泰

Objective: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement. Methods: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage. Results: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs. Conclusion: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.

Background and objectives: Previous studies support the notion that East Asian medical students do not possess sufficient self-regulation for postgraduate clinical training. However, some East Asian physicians who are employed in geographically isolated and educationally underserved rural settings can self-regulate their study during the early phase of their postgraduate career. To explore the contextual attributes that contribute to self-regulated learning (SRL), we examined the differences in self-regulation between learning as an undergraduate and in a rural context in East Asia. Methods: We conducted interviews and diary data collection among rural physicians (n = 10) and undergraduates (n = 11) in Japan who undertook self-study of unfamiliar diseases. We analyzed three domains of Zimmerman’s definition of SRL: learning behaviors, motivation, and metacognition using constructivist grounded theory. Results: Rural physicians recognized their identity as unique, and as professionals with a central role of handling diseases in the local community by conducting self-study. They simultaneously found themselves being at risk of providing inappropriate aid if their self-study was insufficient. They developed strategic learning strategies to cope with this high-stakes task. Undergraduates had a fear of being left behind and preferred to remain as one of the crowd with students in the same school year. Accordingly, they copied the methods of other students for self-study and used monotonous and homogeneous strategies. Conclusions: Different learning contexts do not keep East Asian learners from being self-regulated. Awareness of their unique identity leads them to view learning tasks as high-stakes, and to initiate learning strategies in a self-regulated manner. Teacher-centered education systems cause students to identify themselves as one of the crowd, and tasks as low-stakes, and to accordingly employ non-self-regulated strategies.

Background: Progress testing (PT) is used in Western countries to evaluate students' level of functional knowledge, and to enhance meaning-oriented and self-directed learning. However, the use of PT has not been investigated in East Asia, where reproduction-oriented and teacher-centered learning styles prevail. Here, we explored the applicability of PT by focusing on student perceptions. Methods: Twenty-four students from Years 2, 3, and 5 at Jichi Medical University in Japan attended a pilot PT session preceded by a brief introduction of its concept and procedures. Variations in obtained test scores were analyzed by year, and student perceptions of PT were explored using focus groups. Results: Formula scores (mean +/- standard deviation) in Years 2, 3, and 5 were 12.63 +/- 3.53, 35.88 +/- 14.53, and 71.00 +/- 18.31, respectively. Qualitative descriptive analysis of focus group data showed that students disfavored testing of medical knowledge without tangible goals, but instead favored repetitive assessment of knowledge that had been learned and was tested on a unit basis in the past in order to achieve deep learning. Further, students of all school years considered that post-test explanatory lectures by teachers were necessary. Conclusions: East Asian students' perceptions indicated that, in addition to their intensive memorization within narrow test domains compartmentalized by end-of-unit tests, the concept of PT was suitable for repetitive memorization, as it helped them to integrate their knowledge and to increase their understanding. Post-test explanatory lectures might lessen their dislike of the intangible goals of PT, but at the expense of delaying the development of self-directed learning. Key issues for the optimization of PT in East Asia may include administration of PT after completed end-of-unit tests and a gradual change in feedback methodology over school years from test-oriented post-test lectures to the provision of literature references only, as a means of enhancing test self-review and self-directed learning.

We herein report the findings of 2 cases of normotensive scleroderma renal crisis (SRC) that developed soon after the commencement of a glucocorticoid therapy. We also review 8 cases of normotensive SRC reported in Japan, including our cases. The common characteristics of these 8 cases are as follows: the recent onset of systemic sclerosis, the presence of diffuse skin sclerosis, the presence of myositis and/or serositis, a high titer of antinuclear antibody and positivity for anti-Scl-70 antibody. In 7 of the 8 patients, thrombotic microangiopathy developed within one month of starting the glucocorticoid treatment. We should be careful with the use of glucocorticoids in systemic sclerosis patients exhibiting these features in order to avoid cases of normotensive SRC.

Soluble ST2 (sST2) is a soluble form of the transmembrane receptor for interleukin (IL)-33, ST2L, and is a member of the IL-1 receptor family. sST2 antagonizes IL-33-ST2L signaling by competing with ST2L as a decoy receptor for IL-33. We investigated the sST2 and IL-33 levels in the sera and bullous fluid of bullous pemphigoid patients and compared these with the corresponding levels in normal healthy controls. As controls, we used the bullous fluid of burn patients and that from suction blisters induced in normal healthy volunteers. The serum sST2 concentrations of bullous pemphigoid patients were higher than those of healthy controls. Serum sST2 levels correlated with the area of skin involvement and serum lactate dehydrogenase levels, suggesting that serum sST2 levels reflect disease severity. The sST2 concentrations in bullous fluid from bullous pemphigoid patients were higher than those from controls. The concentration of IL-33 ligand was below the detectable limits in all enzyme-linked immunosorbent assay samples. Thus, our study suggested that the serum sST2 level may be a useful marker of disease severity and that sST2 functions as a negative regulator in the pathophysiology of bullous pemphigoid.

IL-33, a member of the IL-1 family, activates MAPK and NF-kappa B through its receptor ST2L and IL-1RAcP. ST2, a member of the IL-1R superfamily, is a secreted form of ST2 gene products, which has been shown to act as a decoy receptor for IL-33 and to inhibit the IL-33/ST2L/IL-1RAcP signaling pathway. In this work, we generated ST2 transgenic mice. In control mice, intraperitoneal administration of IL-33 caused an increased number of eosinophils in blood and in peritoneal cavity, an increased number of peritoneal M Phi, splenomegaly, accumulation of periodic acid-Schiff-positive material in the lung, and high concentrations of serum IL-5 and IL-13. However, these alterations were hardly detectable in ST2 Tg mice. In peritoneal M Phi from IL-33-stimulated mice, mRNA expression of M2 M Phi marker genes were increased compared with thioglycollate-elicited peritoneal M Phi. The IL-33-stimulation also increased the secretion of IL-6 from M Phi. However, when the IL-33 was preincubated with ST2 prior to its addition to the M Phi cultures, the secretion of IL-6 was attenuated. These data suggest that, though IL-33 induced the Th2-type immune responses and infiltration of M2 type M Phi into the peritoneal cavity, ST2 can downregulate these reactions both in vivo and in vitro.

症例は55歳男性。15年前より関節症性乾癬に対して治療を受けておりコントロール良好であった。2007年2月に自己判断にて治療薬を中止したところ,皮膚および関節症状が再燃し,著しい疼痛により離床不能となり臀部に褥創を形成するに至った。シクロスポリンA,経口プレドニゾロンによる治療を行ったが効果不充分であり副作用を認めた。血清β-D-glucanの上昇を認め,本邦の生物学的製剤の使用ガイドラインに基づけばインフリキシマブの適応外となるが,臨床所見や他の検査によって活動性の真菌感染症は否定的であったことから同意取得後にインフリキシマブを開始した。結果,皮膚および関節症状は著明に改善し,真菌感染症を発症することなく血清β-D-glucanは正常化した。現在,インフリキシマブを継続して通常の生活を送ることができている。ガイドラインは一つの指針に過ぎず,重要なことは患者の全体像を臨床的に判断することである。

Objective. To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33. Methods. Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1 beta and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting. Results. Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS. Conclusion. IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA. (First Release Nov 15 2009; J Rheumatol 2010;37;18-25; doi:10.3899/jrheum.090492)

Interleukin (IL)-33 is a novel member of the IL-1 family. IL-33 is primarily synthesized as a 30-kDa precursor (pro-IL-33). Pro-IL-33 is cleaved by caspase-1 into an 18-kDa mature form (mature IL-33) in vitro. Recombinant mature IL-33 has been known to induce T-helper type-2 (Th2)-associated cytokines and inflammatory cytokines via its receptor, ST2L However, processing of pro-IL-33 in vivo has not been clarified yet. Here, we report that calpain mediates pro-IL-33 processing in vivo. Pro-IL-33 was expressed by stimulating human epithelial cells with phorbol 12-myristate 13-acetate. Calcium ionophore induced pro-IL-33 cleavage and mature IL-33 production. This cleavage was inhibited by treatment with a calcium and calpain inhibitors. Moreover, short interfering RNA-mediated knockdown of calpains chelator suppressed pro-IL-33 cleavage. These results indicate that calpains play a critical role in pro-IL-33 processing in vivo. (C) 2009 Elsevier Inc. All rights reserved.

強皮症では消化管への膠原線維の沈着、腸内細菌の過剰増殖などにより、著しい消化吸収不全を呈することがある。在宅中心静脈栄養にいたる症例も存在する。吸収不全症候群の診断として、Sudan III染色による便中の脂肪測定が行われる。蠕動障害の早期発見には、Sitzmarksが有用と考えられる。根本的な治療法はないが、対症療法に加え、十分な栄養管理を行う。早期に介入することにより、腸内細菌の過剰増殖や腸液貯留による二次的な粘膜障害を抑制することが期待できる。不可逆的に進行していく疾患であるため、患者のほか、家族や介護協力者との連携をとりながら診療に取り組む。(著者抄録)

75歳女.発熱と両下肢のしびれを契機に他院にて結節性動脈炎との診断にてステロイドの投与を受け,軽快したためにステロイドが中止された.その約6年後に間欠的に下腹部痛と発熱が出現するようになった.腹部CTにて小腸壊死が疑われ,緊急手術が行われ,回腸遠位部が約70cmにわたって壊死を起こしていた.切除標本に腸間膜動脈の壊死性血管炎を認め,結節性多発動脈炎の再発と診断した.入院時の胸部X線写真にて右上肺野に浸潤性陰影を認めたが,それは生検により気道内浸出物の器質化と肺胞壁への炎症細胞浸潤によるものであることが判明した.ステロイドの投与により消化器症状と共に胸部陰影も消失した.臨床経過,画像,生検の結果から,結節性多発動脈炎に伴うBOOPの1例と考えられた

28歳女.腹痛,粘血便が出現し,潰瘍性大腸炎と診断された.prednisolone,salazosulfapyridineの投与にて寛解状態となった.発熱が出現し,次第に全身倦怠感と食欲不振を伴うようになったため,精査加療目的で入院した.末梢血異型リンパ球の出現,脾腫,肝酵素の上昇を認め,CMV-IgM抗体の上昇,アンチゲネミア陽性により,サイトメガロウイルスによる伝染性単核球症と診断した.対症療法を行ったが,第19病日にいたっても解熱せず,全身倦怠感や食欲不振が続いた.ganciclovirの点滴投与を1週間行った.投与翌日より解熱し,倦怠感と食欲不振も速やかに改善し,サイトメガロウイルスアンチゲネミアも陰性化した.経過中,ganciclovirによる副作用は生じず,退院した

アスピリン喘息(AIA)では,好酸球性胃腸炎,好酸球性中耳炎,好酸球性肺炎などの全身病変(副鼻腔気管支外病変)を合併しやすいことが報告されている.当院通院中AIA 11例中5例に副鼻腔気管支外病変(好酸球性胃腸炎3例,好酸球性中耳炎2例,好酸球性肺炎1例,1例は好酸球性胃腸炎と好酸球性中耳炎の両者を合併)の合併を認めた.これらの全身病変は,高用量吸入ステロイド薬やロイコトリエン受容体拮抗薬による喘息症状改善および全身ステロイド薬離脱後に末梢血好酸球増加を伴って発症することが多く,短期間のステロイド薬投与により改善した.AIAに伴う好酸球性胃腸炎は,他の原因(食物アレルギーなど)による好酸球性胃腸炎と比較して上部消化管症状(心窩部痛,腹満感,嘔吐など)を主症状とし,症状の改善に短期間のステロイド薬投与が必要であった.全身病変(副鼻腔気管支外病変)を合併しやすいことが,全身疾患としてのAIAの特徴的臨床像であり,AIAの病因・病態を解明していく上での1つの重要な着眼点であると考えられる(著者抄録)

74歳男.夜間に多い乾性咳嗽,喘鳴が出現した.非アトピー型気管支喘息の診断でキュバール,プランルカスト,ツロブテロールテープの投与を受け,症状の改善を認めた.咳嗽が増悪したため,キュバールを増量し改善した.咳嗽,呼吸困難,発熱が出現した.胸部単純X線写真上,右上肺野に浸潤影を認め,精査加療を目的に入院となった.気管支鏡検査を施行し,メチルプレドニゾロン点滴投与およびプレドニゾロンの後療法を行い,症状,胸部画像所見の改善を認めた.以後,プレドニゾロンを漸減中止した.TBLB病理組織では有意な所見が認められなかったが,BALでリンパ球,好酸球の増加を認め,胸部高分解能CTで小葉間隔壁肥厚や胸水を認めたことより,好酸球性肺炎(CEP)と診断した.喘息症状もなく,CEPの再燃も認めていない

96歳男.朝食後,庭の掃除中,嘔気,腹痛が出現し,受診した.腹部CTを施行し上腸間膜動脈(SMA)閉塞を確認した.超音波ドプラでSMA起始部から約4cm末梢で血流途絶を認めたがSMA中枢側に狭窄および壁硬化などの所見は認めなかった.発症3時間後に中等量の下血を認め,SMAの急性閉塞で二次血栓が進展していると診断し緊急手術を行った.術後,再虚血防止のためヘパリン,ワーファリンによる抗凝固療法を施行した.その後,術後譫妄,生活リズムの崩壊などもあり回復には時間を要したが,第41病日に退院した