Transcriptional activation of a hybrid promoter composed of cytomegalovirus enhancer and β-actin/β-globin gene in glomerular epithelial cells in vivo

Transcriptional activation of a hybrid promoter composed of cytomegalovirus enhancer and β-actin/β-globin gene in glomerular epithelial cells in vivo. The aim of this study was to seek a promoter, transactivated selectively in renal cells in vivo by using transgenic (tg) mouse technology. We generated two kinds of tg mouse lines carrying a green fluorescence protein (GFP) cDNA driven either by cytomegalovirus enhancer and β-actin/β-globin promoter (CX-GFP) or by elongation factor la promoter (EF-GFP), and investigated the expression of GFP in the kidney. Microscopic examination of the renal tissues in CX-GFP-tg mice revealed that GFP was expressed only in glomeruli, mainly epithelial cells, but not in tubules, arteries and interstitium. Moreover, in situ hybridization demonstrated that GFP mRNA expression was localized in the glomerular cells. In contrast, GFP was not detectable in the kidney in any of the lines of EF-GFP-tg mouse. To exclude the possible involvement of the GFP cDNA as an enhancer, we constructed tg mice carrying the CX promoter driving a human CD4 cDNA. It was confirmed that the expression patterns of human CD4 in the kidney were quite similar to those of GFP in the kidney of CX-GFP-tg mice. These results strongly suggest that CX promoter could be transactivated in glomerular epithelial cells in vivo

高フェリチン血症を契機に成人Still 病と診断した不明熱症例

　成人Still 病は弛張熱，関節炎，発熱時に増強する発疹（サーモンピンク疹）を３徴とする疾患で，白血球増加，血清CRP やフェリチン値の上昇などの強い炎症所見を認め，しばしば不明熱の原因となる．高フェリチン血症を契機に成人Still 病と診断した症例を経験したので報告する．患者は57歳女性，入院３週間前から発熱とともに咽頭痛，関節痛が出現し，近医にて抗菌薬治療が行われた．抗菌薬不応の発熱で当院を紹介受診し，不明熱精査目的に入院した．入院時より前胸部や背部に淡い紅斑が出現し，採血で，白血球増加（11,480/μL），CRP 高値（12.98 mg/dL），フェリチン著明高値（5,511 ng/mL）を認めた．胸腹部CT 検査では腋窩・鼠径リンパ節の腫脹と脾腫大を認めた．血液培養検査は陰性で，骨髄生検や皮膚生検にて造血器腫瘍を示唆する所見を認めなかった．感染症や悪性腫瘍を除外し，Yamaguchi らの分類基準を満たし，成人Still 病と診断した．プレドニゾロンとメトトレキサートの併用療法を開始したところ，速やかに全身状態は改善した．不明熱の原因検索を行う際に，フェリチン値の測定は有用であると考えられる．　Adult-onset Still\u27s disease (AOSD) is a systemic inflammatory disorder which is responsible for a significant proportion of cases of fever of unknown origin. This disease is characterized by high spiking fevers, musculoskeletal disorders and salmon-colored rash. Here we report the case of a 57-year-old woman with fever of unknown origin who was diagnosed with AOSD. Hyperferritinemia contributed to her diagnosis. The patient was referred to our clinic with persistent spike fevers and arthralgia for 3 weeks despite antibiotic treatment. The patient also had a sore throat, and developed a skin rush on her trunk upon admission. Laboratory data indicated leukocytosis (11,480 /μL), elevated levels of CRP (12.98 mg/dL), and hyperferritinemia (5,511 ng/mL). To exclude infections and malignant diseases, systemic computed tomography scans and biopsy from bone marrow and skin were performed. From these examinations, and based on the criteria set by Yamaguchi et al. , the patient was given a diagnosis of AOSD. She was started on prednisone and methotrexate, and these treatments were effective. Serum ferritin levels should be checked for the evaluation of fever of unknown origin

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases

妊娠を契機に血小板減少を来たし，子宮内胎児死亡に至った全身性エリテマトーデス及び抗リン脂質抗体症候群の一例

　抗リン脂質抗体症候群は，抗リン脂質抗体が産生されることで血栓症を主体とする病態を引き起こす自己免疫疾患である．動静脈血栓症に加え，習慣性流産，早産，妊娠高血圧症候群，胎児発育遅延，胎児機能不全などの妊娠合併症を高率に引き起こすとされている．また患者のうち約半数は全身性エリテマトーデスが併存していると言われている．我々は妊娠を契機に血小板減少を来たし，子宮内胎児死亡に至った全身性エリテマトーデス及び抗リン脂質抗体症候群の症例を経験した．　患者は20歳代女性，未経妊未経産．５年前に全身性エリテマトーデス及び抗リン脂質抗体症候群と診断された．プレドニゾロンとタクロリムス，アザチオプリンによる免疫抑制療法及び低用量アスピリン療法を開始され，数年間に渡りプレドニゾロン５mg/ 日＋タクロリムス３mg/ 日＋アザチオプリン50mg/ 日で病態は安定していた．妊娠を契機にプレドニゾロン10mg/ 日の単独治療に切り替えたが，徐々に血小板減少が進行してきたため入院し，プレドニゾロン30mg/ 日への増量及びタクロリムス３mg/ 日を再開した．また血栓予防治療として，低用量アスピリンに加えヘパリン療法を開始した．しかし妊娠16週５日で子宮内胎児死亡が判明したため，血栓予防治療を中止し児の娩出に至った．　抗リン脂質抗体症候群合併妊娠は，周産期管理に慎重を要する例も存在することを念頭に置き，特にハイリスク症例に対しては妊娠成立前から産婦人科と連携して治療にあたる必要がある．　Antiphospholipid syndrome is an autoimmune disease characterized by episodes of recurrent thrombosis. This syndrome is associated with not only recurrent arteriovenous thrombosis but also recurrent pregnancy loss, premature birth, pregnancyinduced hypertension, and fetal growth restriction. It has been reported that systemic lupus erythematosus coexists with antiphospholipid syndrome in as many as about 50% of patients. We report a case of intrauterine fetal death (IUFD) following thrombocytopenia in a patient with systemic lupus erythematosus and antiphospholipid syndrome. A woman in her 20s had difficulty conceiving and had been diagnosed as having systemic lupus erythematosus and antiphospholipid syndrome 5 years earlier. She was started on immunosuppressive therapy with prednisolone 5 mg/day, tacrolimus 3 mg/day, and azathioprine 50 mg/day, with low-dose aspirin therapy. Her disease was stable for several years. Thrombopenia gradually developed after treatment was changed to prednisolone 10 mg/day during pregnancy. She was admitted to hospital and treatment was started with prednisolone 30 mg/day, tacrolimus 3 mg/day, and heparin therapy in addition to low-dose aspirin therapy. However, IUFD was detected at a gestational age of 16 weeks 5 days, so we discontinued thromboprophylaxis treatment and administered a therapeutic abortion. In patients with antiphospholipid syndrome who need meticulous perinatal management, it is important to consult with the obstetrics and gynecology specialists before proceeding with a potentially high-risk pregnancy

Derivation of Human Differential Photoreceptor-like Cells from the Iris by Defined Combinations of CRX, RX and NEUROD

Examples of direct differentiation by defined transcription factors have been provided for beta-cells, cardiomyocytes and neurons. In the human visual system, there are four kinds of photoreceptors in the retina. Neural retina and iris-pigmented epithelium (IPE) share a common developmental origin, leading us to test whether human iris cells could differentiate to retinal neurons. We here define the transcription factor combinations that can determine human photoreceptor cell fate. Expression of rhodopsin, blue opsin and green/red opsin in induced photoreceptor cells were dependent on combinations of transcription factors: A combination of CRX and NEUROD induced rhodopsin and blue opsin, but did not induce green opsin; a combination of CRX and RX induced blue opsin and green/red opsin, but did not induce rhodopsin. Phototransduction-related genes as well as opsin genes were up-regulated in those cells. Functional analysis; i.e. patch clamp recordings, clearly revealed that generated photoreceptor cells, induced by CRX, RX and NEUROD, responded to light. The response was an inward current instead of the typical outward current. These data suggest that photosensitive photoreceptor cells can be generated by combinations of transcription factors. The combination of CRX and RX generate immature photoreceptors: and additional NEUROD promotes maturation. These findings contribute substantially to a major advance toward eventual cell-based therapy for retinal degenerative diseases

Functional Overview of the RF Power System for the LIPAc RFQ

Design, development, manufacturing, and test activities of the RF power system (RFPS) for Linear IFMIF Prototype Accelerator (LIPAc) were completed in Europe. Installation and commissioning activities were carried out at the International Fusion Materials Irradiation Facility-Engineering Validation and Engineering Design Activities (IFMIF/EVEDA) site in Rokkasho, Japan. Challenging IFMIF requirements led to a number of innovations during design and development. Commissioning required a major effort on calibration and fine setting and led to development of new functionalities. The RFPS was validated under full power and 125-mA deuteron beam loading conditions, in the radio frequency quadrupole (RFQ), demonstrating good performance. This article is an overview about how technical challenges impacted the prototype RFPS design and its functional evolution during commissioning, cavity conditioning, and beam operation of the RFQ

Effects of riluzole on psychiatric disorders with anxiety or fear as primary symptoms: A systematic review

Abstract Aim Previous behavioral pharmacology studies involving rodents suggested riluzole had potential to be an ideal psychotropic drug for psychiatric disorders with anxiety or fear as primary symptoms. Several clinical studies have recently been conducted. The purpose of this study was to gather information about the efficacy and tolerability of riluzole for patients with those symptoms. Methods We searched PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane database from inception until April 2021, and performed manual searches for additional relevant articles. This review included: (1) studies involving participants that were patients with generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, obsessive‐compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, or phobias; and (2) randomized controlled trials (RCTs) or intervention studies (e.g., single arm trials) examining the effects and safety of riluzole. Results Of the 795 identified articles, four RCTs, one RCT subgroup‐analysis, and three open‐label trials without control groups met the inclusion criteria. Most trials evaluated the efficacy of riluzole as an augmentation therapy with selective serotonin reuptake inhibitors and other antidepressants for PTSD, OCD, or GAD. However, there was insufficient evidence to confirm the effects of riluzole for patients with these psychiatric disorders. Most trials demonstrated adequate study quality. Conclusions This review found insufficient evidence to confirm the effects of riluzole for psychiatric disorders with anxiety or fear as primary symptoms. It would be worthwhile to conduct studies that incorporate novel perspectives, such as examining the efficacy of riluzole as a concomitant medication for psychotherapy