C3 glomerulopathy and current dilemmas

C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components. Because laboratory detection of complement dysregulation is still uncommon in practice, “dominant C3 deposition by two orders greater than that of immunoglobulins in the glomeruli by immunofluorescence”, as stated in the consensus report, defines C3G. However, this morphological definition possibly includes the cases with glomerular diseases of different mechanisms such as post-infectious glomerulonephritis. In addition, the differential diagnosis between DDD and C3GN is often difficult because the distinction between these two diseases is based solely on electron microscopic features. Recent molecular and genetic advances provide information to characterize C3G. Some C3G cases are found with genetic abnormalities in complement regulatory factors, but majority of cases seem to be associated with acquired factors that dysregulate the alternative complement pathway. Because clinical courses and prognoses among glomerular diseases with dominant C3 deposition differ, further understanding the background mechanism, particularly complement dysregulation in C3G, is needed. This may resolve current dilemmas in practice and shed light on novel targeted therapies to remedy the dysregulated alternative complement pathway in C3G

Realizing Community Invigoration and an Inclusive Society through International Human Resources : Findings from an Open Studies Course at Tokushima University

我が国では，グローバル化及び少子高齢化・人口減少が進む中，外国人労働者の積極的な活用が喫緊の課題となっている。但し外国人材の獲得は，国内の地域間だけでなく国際的な競争にもさらされているため，彼らの我が国及び徳島への定着を促し，産業の維持・発展並びに地域活性化と共生を実現していくには，各地域社会において具体的な方策が求められる。こうした問題意識のもと，JICA 四国と徳島大学は2019 年に連携して公開講座を実施した。本稿は，その講座内容を整理し，実施成果より今後の展望を考察するものである。 本稿での考察を産学官民の観点から整理すると，①産業界においては，外国人と日本人の双方にとって生産性の高い労働環境を整備し，国内外でのビジネス展開強化の意識を持つこと，②学術界においては，地域社会及び経済の発展に資する研究成果の社会実装と，グローバルな視野を有し，地域に貢献できる人材の育成・輩出を促進すること，③行政においては，外国人一人ひとりの生活及び労働面等の異なるニーズに寄り添い，柔軟に対応する姿勢を持つとともに，地域全体で外国人の受入れと共生に向けた意識を育むための環境を醸成していくこと，④市民社会においては，外国人を地域に住む仲間として受入れ，彼らと協働しながら誰にとっても住みやすいまちづくりを促進していくこと，が今後の展望として析出された。今後，それぞれの業界が上記課題を具現化し，かつ効果的に連携できる方途を模索しながら，戦略的な地域活性化及び外国人材との共生に向けた前進が期待される

Awareness-Building Seminar on Aging-Related Issues for the Public in Tokushima : Overview and Report

我が国は2022年現在，世界で最も高齢化が進行しており，中でも徳島県は全国有数の高齢化先進県として，それにまつわる諸問題が全国に先駆けて顕在化しつつある。本稿は，こうした状況を踏まえ，筆者らが「徳島県の高齢化問題を地域で考えよう！」と題するセミナーを徳島大学において実施した結果と，今後地域で高齢化問題に取り組むにあたっての展望を概括するものである。 本セミナーは，高齢化問題への関与の有無にかかわらず，制度・分野ごとの「縦割り」や「支え手」「受け手」という関係性や年代を超えて集まった多様な参加者が，高齢化問題の概略を知り，考えや思いを共有する第一歩となった。参加者からは，今後徳島県が取り組むべき事項として，①「介護者の立場」を考えた支援，②健康寿命を延ばし，認知症の「予防」にもなる地域活動，③高齢者・認知症の人の経済的自立につながる社会的取り組みの展開，④多世代交流や地域の助け合いを促進するしくみの構築，等が挙げられた。 本セミナーにおける課題として，参加者による具体的な活動を導き出す前に，様々に異なる経歴，年代の人々の意見を効果的に集約し，相互の知見を共有する中で，次のステップをどのように見出し，具現化していくかが求められていることが判明した。今後，活動を継続する中で，地域社会での高齢化問題解決に資する，幅広い世代や多様な経歴を持つ参加者への効果的な意識啓発のあり方を徐々に明らかにしていきたい

Molecular characterization of buckwheat major immunoglobulin E-reactive proteins in allergic patients

ABSTRACTBuckwheat extract was analyzed by immunoblotting experiments using sera from nine allergic and three non-allergic individuals. Major IgE-reactive bands were 73, 70, 62, 58 and 54kDa under non-reducing conditions and were detected in allergic subjects, but not in non-allergic ones. Under reducing conditions, the 73, 70, 62 and 58kDa bands split to 56 and 24, 52 and 24, 45 and 24, and 43 and 24kDa, respectively. The 24kDa molecule was the most prominent band recognized with IgE as well as IgG or IgA. The FA02 cDNA clone, encoding the α and β subunits of the legumin-like storage protein, was isolated from a cDNA library made of immature buckwheat seeds. The deduced amino acid sequence of the cDNA clone is substantially identical to the N-terminal amino acid sequence of the 24kDa molecule, which may be identical to that of BW24KD reported by Urisu et al. Consistent with these results, the translation product of the cDNA encoding the putative β subunit was strongly recognized with serum IgE, IgG and IgA from buckwheat-allergic patients. These results suggested that the 24kDa molecule may be the β subunit of the legumin-like storage molecule of buckwheat

Mite-antigen Stimulates MAL Expression in Peripheral Blood T Cells of Mite-sensitive Subjects

ABSTRACTBackgroundDifferential gene expression in CD3+ T cells from allergic patients stimulated with allergen will provide important information on the responses of T cells.MethodsAfter stimulation of peripheral blood mononuclear cells (PBMCs) with mite extracts, levels of gene transcription were examined in CD3+ T cells from allergic patients.ResultsStimulation of PBMCs from mite specific IgE positive subjects resulted in specific upregulation of MAL transcription levels that was mediated by IL-4 secretion. The MAL protein in IL-4 stimulated primary T cells preferentially localized in glycolipid-enriched membrane (GEM) microdomains. When MAL was exogenously expressed in primary T cells, CD3ζ was concomitantly enriched, along with the expression of MAL, in GEM microdomains.ConclusionsGEMs are important for the formation and stabilization of TCR signaling complexes. Therefore, MAL may play a role in the formation of GEMs in activated T cells and the high expression of MAL may contribute to Th2 immune response

Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients

Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7±5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309–449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all-cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29–13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality

Growth hormone-producing pituitary adenomas in childhood and young adulthood : clinical features and outcomes

Purpose Growth hormone (GH)-producing pituitary adenomas (PAs) in childhood or young adulthood are rare, and the details surrounding these tumors remain enigmatic. We present the clinical, pathological and genetic features of this disease. Methods We identified 25 patients aged 20 years or younger with GH-producing PAs who underwent surgery between 2003 and 2016 at Toranomon Hospital in Tokyo. We retrospectively reviewed the clinical data, treatment outcomes and pathological features of these patients to shed light on childhood acromegaly. Results The cohort comprised 14 male and 11 female patients whose average age at the time of surgery was 17.3 years. Germline AIP mutations were present in 5 of 13 patients examined, and Carney complex was identified in 2 of 25 patients. The mean maximum tumor diameter was 26.7 mm, and total resection assessed during surgery was achieved in 17 patients. Based on their respective pathological findings, patients were divided into the following 4 groups: sparsely granulated adenomas (5), densely granulated (DG) adenomas (6), plurihormonal adenomas (9), and silent subtype 3 (SS3) adenomas (5). During the mean follow-up period of 50.3 months, complete endocrinological remission was achieved in 14 of 25 patients (56%) by surgery alone and in 19 patients (76%) after postoperative adjuvant therapy. Conclusions GH-producing PAs in young patients are intriguing and difficult to treat due to their distinct tumor characteristics, including a lower incidence of the DG subtype and a higher incidence of SS3 adenomas and genetic abnormalities. Therefore, multi-modal therapies are essential to achieve optimal clinical outcomes

E3 Ubiquitin Ligase Synoviolin Is Involved in Liver Fibrogenesis

Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis.The expression and localization of synoviolin in the liver were analyzed in CCl(4)-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno(+/-) mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno(+/-) mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno(-/-) mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno(-/-) MEF cells.In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno(+/-) mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno(+/-) mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno(-/-) MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis

Association of dietary fiber intake with subsequent fasting glucose levels and indicators of adiposity in school-age Japanese children

Abstract Objective: To evaluate the relationships of fiber intake with subsequent body mass index SD-score, waist-to-height ratio, and serum fasting glucose levels among school-age Japanese children. Design: A prospective study of school-age Japanese children. Participants were followed from 6–7 to 9–10 years of age (follow-up rate: 92.0%). Fiber intake was assessed using a validated food frequency questionnaire. Serum fasting glucose was measured by a hexokinase enzymatic method. Using a general linear model, the associations between dietary fiber intake at baseline and body mass index SD-score, waist-to-height ratio, and serum levels of fasting glucose at follow-up were evaluated after considering potential confounding factors. Setting: Public elementary schools in a city in Japan Participants: A total of 2,784 students. Results: The estimated means for fasting glucose at 9–10 years of age were 86.45, 85.68, 85.88, and 85.58 mg/dl in the lowest, second, third, and highest quartile of fiber intake at 6–7 years of age, respectively (p= 0.033, trend p= 0.018). Higher fiber intake at 6–7 years of age was associated with lower waist-to-height ratio at 9–10 years of age (trend p= 0.023). The change in fiber intake was inversely associated with concurrent change of body mass index SD-score (trend p= 0.044). Conclusion: These results suggest that dietary fiber intake may be potentially effective to limit excess weight gain and lower glucose levels during childhood