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A 43-year-old Japanese woman with rheumatoid arthritis treated by infliximab and methotrexate for 11 years was admitted for proteinuria and purpura. A kidney biopsy revealed endothelial damage-dominant nephritis with IgA deposition. Infliximab and methotrexate were discontinued, and tocilizumab was started; however, proteinuria persisted. Therefore, tocilizumab was discontinued, and oral prednisolone and methylprednisolone pulse therapy were administered. After 6 months, urinary protein was less than 0.1 g/day, and purpura subsided. To our knowledge, this is the first case of endothelial damage-dominant nephritis related to IgA vasculitis involving the skin and kidney after long-term use of infliximab and methotrexate.

Background: Multiple treatment protocols have been described in literature for the treatment of terrible triad injury (TTI) of the elbow. We believe that repair of the medial collateral ligament (MCL) should be performed in preference to repair of a small coronoid fracture if the elbow is unstable after fixation/replacement of the radial head and repair of the lateral collateral ligament (LCL). The aim of this study is to report the outcomes of surgical treatment of patients with TTI associated with a small coronoid fracture in whom the coronoid fracture was not addressed. Methods: This study is a retrospective case series of 12 consecutive patients who underwent surgery for acute TTI with a small coronoid fracture (9 Regan–Morrey type I and 3 Regan–Morrey type II). Ten patients had complete MCL injuries. All patients underwent repair of the torn LCL and MCL and treatment of the radial head. The coronoid fracture was not surgically treated. At the final follow-up, the range of motion, degree of flexion contracture, Mayo elbow performance score (MEPS) and Disabilities of the Arm, Shoulder and Hand (DASH) were measured. Results: The mean follow-up period was 13.5 months. At the final follow-up, the mean arc of elbow flexion was 132° and the mean flexion contracture was 10°. The mean arc of forearm rotation was 148°. None of the patients demonstrated elbow instability. The mean MEPS was 92.5 points with seven having excellent results and five having good results. The average DASH score was 11.2 points. Conclusions: Our results showed that good elbow stability, arc of motion and clinical outcomes could be achieved without repair of small coronoid fractures in the treatment of TTI. The repair of MCL injuries should be given priority over the fixation of small coronoid fractures to regain elbow stability. Level of Evidence: Level IV (Therapeutic)

Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.

A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.

Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient's renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.

Treatment of a Monteggia fracture-dislocation primarily includes anatomical reduction and fixation of the ulna. However, in rare cases, reduction of the radial head remains impossible even after performing this standard procedure. We have encountered patients with Monteggia fracture-dislocation whose radial head could be reduced by 'overcorrecting' the ulna. In this retrospective study, we aimed to propose an unreported subtype of Monteggia fracture-dislocation. Data of three patients (age 6, 14, and 16 years) with Monteggia fracture-dislocations whose radial head could not be reduced by anatomical fixation of the ulna were retrospectively reviewed. In all three patients, the radial head could not be reduced by anatomical reduction and internal fixation of the ulna even after confirmation of the absence of interposed tissue such as annular ligament in the radiocapitellar joint. However, the radial head could be reduced by fixation of the ulna in a posterior convex shape at the fracture site. At the final follow-up, stable reduction of the radial head was maintained in all patients. We hypothesized that these patients had simultaneous existence of a fracture and acute plastic deformity of the ulna. To the best of our knowledge, this pathological state has not been reported previously but it may not be extremely rare and may only be unrecognized. We believe that a new subtype, that is, type A + C, should be established based on Letts' classification.

The brain, particularly the ventromedial hypothalamic nucleus (VMH), has been long known for its involvement in glucose sensing and whole-body glucose homeostasis. However, it is still not fully understood how the brain detects and responds to the changes in the circulating glucose levels, as well as brain-body coordinated control of glucose homeostasis. In this review, we address the growing evidence implicating the brain in glucose homeostasis, especially in the contexts of hypoglycemia and diabetes. In addition to neurons, we emphasize the potential roles played by non-neuronal cells, as well as extracellular matrix in the hypothalamus in whole-body glucose homeostasis. Further, we review the ionic mechanisms by which glucose-sensing neurons sense fluctuations of ambient glucose levels. We also introduce the significant implications of heterogeneous neurons in the VMH upon glucose sensing and whole-body glucose homeostasis, in which sex difference is also addressed. Meanwhile, research gaps have also been identified, which necessities further mechanistic studies in future.

When using the extracorporeal capillary membrane oxygenator (sample A) for ECMO treatments of COVID-19 severely ill patients, which is dominantly used in Japan and worldwide, there is a concern about the risk of SARS-CoV-2 scattering from the gas outlet port of the membrane oxygenator. Terumo has launched two types of membranes (sample A and sample B), both of which are produced by the microphase separation processes using polymethylpentene (PMP) and polypropylene (PP), respectively. However, the pore structures of these membranes and the SARS-CoV-2 permeability through the membrane wall have not been clarified. In this study, we analyzed the pore structures of these gas exchange membranes using our previous approach and verified the SARS-CoV-2 permeation through the membrane wall. Both have the unique gradient and anisotropic pore structure which gradually become denser from the inside to the outside of the membrane wall, and the inner and outer surfaces of the membrane have completely different pore structures. The pore structure of sample A is also completely different from the other membrane made by the melt-extruded stretch process. From this, the pore structure of the ECMO membrane is controlled by designing various membrane-forming processes using the appropriate materials. In sample A, water vapor permeates through the coating layer on the outer surface, but no pores that allow SARS-CoV-2 to penetrate are observed. Therefore, it is unlikely that SARS-CoV-2 permeates through the membrane wall and scatter from sample A, raising the possibility of secondary ECMO infection. These results provide new insights into the evolution of a next-generation ECMO membrane.

1.日本製作のTFコイル4号機が2021年1月に完成、三菱重工株から出荷し、3月にITER機構へ到着した。 2.日本製作のTFコイル3機目が到着したこともあり、ITERサイトではITER組立作業が着々と進行している。ITER組立の進捗状況を報告する。 3.量研が長年続けてきた超伝導コイルの研究において、格超伝導マグネット構造規格の原案・改訂案の策定への貢献」が評価され、「日本機械学会標準事業表彰国際功績賞」を受賞した。 4.ITER企業説明会が3月19日にオンライン開催され、ITER 機構の広報担当者、人事担当者、首席戦略官が、ITER 人事部から見たITER プロジェクトに求める人材などの説明を行った。 5.プラ核学会 若手学会発表賞を受賞した業績「ITER ダイバータ外側垂直ターゲット用タングステンの量産化に向けた性能評価」について説明する。

BackgroundMethotrexate is widely used to treat rheumatoid arthritis (RA) but can cause very serious side effects, including pancytopenia, in patients with renal impairment who have an estimated glomerular filtration rate (GFR) of 2. In patients with low muscle volume such as elderly patients, GFR can be measured as higher value when calculated using serum creatinine [eGFR(cre)], so more accurate estimation using cystatin C [eGFR(cys)] is preferred.MethodWe evaluated 173 patients with RA who visited Toranomon Hospital in 2019 for factors that may contribute to the difference between eGFR(cre) and eGFR(cys) [eGFR(cre−cys)]. Activities of daily living (ADL) (walking, 1 point; using a cane, 2 points; using a wheelchair, 3 points) was added as a parameter.ResultsIn univariate analysis using Spearman's rank correlation coefficient, eGFR(cre−cys) was negatively correlated with body weight, height, body surface area (BSA), subcutaneous fat area (SFA)/BSA, albumin, and creatinine kinase, and positively correlated with age, erythrocyte sedimentation rate (ESR), and urinary protein. eGFR(cre−cys) was higher in patients who used a cane or wheelchair than those who could walk unaided. Multiple regression analysis showed that ADL and age contribute significantly to eGFR(cre−cys). ConclusionPatients using a cane or wheelchair are susceptible to the higher eGFR(cre−cys) values and overestimation of eGFR(cre), resulting in failed detect subclinical renal dysfunction. For such patients, eGFR(cys) should be evaluated to prevent serious side effects of methotrexate that are easily developed on patients with renal dysfunction.

ITERではタングステン(W)ダイバータ板等で反射した光の混入によるプラズマ発光計測の精度悪化が問題視されており、この反射特性は壁面の表面状態に依存する。本研究では、様々な熱負荷を与えたITERダイバータ用Wモノブロックに対してゴニオフォトメーターを用いて双方向反射率分布関数(BRDF)を計測した。熱負荷を与える前のWモノブロックでは切削痕によって異方的な反射特性を示す一方、熱負荷を与えたWモノブロックでは再結晶化によって表面が粗くなり、拡散的な反射特性を示した。熱負荷による表面構造変化に応じたBRDFの変化について報告する。, 第38回 プラズマ・核融合学会 年会

ITERダイバータの外側垂直ターゲット（OVT）プロトタイプ及び・実機用のCuCrZr合金-ITERグレード管の量産が、プラズマ対向材料等の他の材料と同様に進行中である。OVT完成後も水漏れ防止や電磁力に対する耐久性の観点から、設計で要求される機械的特性を有し、かつ結晶の異常粒成長を抑えたCuCrZr管を製造することが求められている。そのため，OVTに使用する前に機械的特性の試験を行い，CuCrZr管の量産時の機械的特性と品質を確認している。本論文では、OVTのプロトタイプおよび実機に使用されるCuCrZr管に要求される重要な機械的特性の一つである引張特性について報告する。量産時の抜き取り検査の結果，CuCrZrチューブは，PFU製造時の溶体化や時効などの熱処理を経ても，要求される引張特性を満たすことができた。, The 30th International Toki Conference on Plasma and Fusion Research

ITERダイバータのプラズマ対向機器、特に日本が調達を担当する外側垂直ターゲット(OVT)の調達スケジュールや設計を紹介するとともに、それを実現するための技術開発状況として、アーマ材と冷却管の接合技術、組立、検査の各テーマにおいて、プラズマ対向機器受熱部の製造法や接合部検査、プラズマ対向ユニット製作において重要となるWモノブロック管のギャップ管理に関して計測方法やプロトタイプでの実績を紹介した。合わせて、QSTで整備を進めている高温ヘリウムリーク試験装置の概要を紹介した。, 核融合エネルギーフォーラム スクレイプ・オフ層及びダイバータ物理サブクラスター、炉材料サブクラスター、ブランケットサブクラスター、ダイバータサブクラスター（令和3年度第1回）合同会合

Highlights • We describe a new operative technique for creating a radial artery-second dorsal metacarpal vein AVF in the first interdigital space for hemodialysis patients. • This technique involves the creation of the AVF using the most peripheral site and autologous vein in the upper limb. • This technique has several advantages including preserving many future VA options and providing a long segment of arterialized vein for cannulation. • This technique is a worthwhile option in patients with the proper vessels for the creation of the AVF., Introduction The creation of the first arteriovenous fistula (AVF) as far distally in the upper limb as possible is ideal. We developed a new operative technique for creating a radial artery-second dorsal metacarpal vein AVF in the first interdigital space. This technique involves the creation of the AVF using the most peripheral site and autologous vein in the upper limb. Case presentation We herein describe the steps of this technique and its successful performance in a 71-year-old man with end-stage renal disease. Discussion This technique has several advantages including preserving many future vascular access options and providing a long segment of arterialized vein for cannulation. Conclusion We consider this technique to be a worthwhile option and recommend the use in patients with the proper vessels for the creation of the AVF.

A radiocephalic arteriovenous fistula in the anatomical snuffbox (tabatière region) was first described in 1969 as the most peripheral site for arteriovenous fistula in the upper limb. In cases in which the internal diameter of the first dorsal metacarpal vein under avascularization is ⩾2.0 mm, we have adopted a new operative technique for creating a radial artery-first dorsal metacarpal vein arteriovenous fistula in the first interdigital space of the dorsal hand, which lies between the thumb and the index finger. This technique is the creation of the arteriovenous fistula using the first dorsal metacarpal vein and the most peripheral site in the upper limb. To our knowledge, no previous report has described the creation of a radial artery-first dorsal metacarpal vein arteriovenous fistula. We herein describe the steps of the technique and report its successful performance in a patient with chronic renal failure.

We herein report the case of myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with anti-glomerular basement membrane (anti-GBM) antibody positivity that successfully treated with mizoribine (MZR) as an immunosuppressive drug for remission maintenance therapy after the initiation of dialysis in addition to plasma exchange (PE) and glucocorticoid treatment to control the disease condition. A 79-year-old woman developed serious renal dysfunction and pulmonary alveolar hemorrhaging due to MPO–ANCA and anti-GBM antibody double-positive vasculitis. She was started on hemodialysis and was treated with methylprednisolone (m-PSL) pulse therapy with PE, followed by oral prednisolone (PSL). The pulmonary alveolar hemorrhaging disappeared, and both antibody titers immediately decreased but then rose again. Thus, m-PSL pulse therapy performed again in combination with combined with MZR treatment. Her poor renal function was irreversible; however, this therapy decreased both antibody titers, and they did not increase again. The patient developed pancytopenia and hyperuricemia. It was considered likely that these conditions developed in association with MZR treatment. We, therefore, measured the patient’s blood concentration of MZR, and the maintenance dose was finally set at 50 mg after each dialysis session. The patient’s pancytopenia and hyperuricemia improved and PSL could be smoothly tapered. This is the first case report of the use of MZR for remission maintenance therapy in a patient on hemodialysis who was positive for both ANCA and anti-GBM antibodies. The findings suggest that MZR can be used safely and effectively in such cases.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Neutron irradiation in mixed spectrum reactors is an effective approach to investigate the synergistic effects of solid transmutations and atomic displacement damage in tungsten. In this article the findings and interpretations from a large-scale tungsten irradiation campaign conducted using the High Flux Isotope Reactor of Oak Ridge National Laboratory are summarized. The response of originally-unalloyed tungsten to mixed spectrum neutron irradiation is characterized by enormous hardening, degradation of modulus of toughness eventually leading to embrittlement, and decreased thermal conductivity. These property changes may be attributed primarily to production, segregation, and precipitation of rhenium and osmium and assisted by displacement damage. The stages describing the evolution of the microstructural development and property changes with the neutron dose and the accompanying accumulation of transmutation products are proposed. This manuscript has been co-authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ).

The United States and Japan have collaborated on fusion materials research in a series of agreements reaching back to 1981. The PHENIX collaboration is the latest U.S.-Japan project which s...

Suppressor of cytokine signaling-3 (SOCS3) is a negative regulator of actions of cytokines and the metabolic hormone leptin. In the hypothalamus, SOCS3 is induced in response to several conditions such as inflammation and high-fat diet feeding, modulates cellular signaling of cytokines and leptin, and mediates the effects of these biological conditions. However, signaling mechanisms controlling hypothalamic Socs3 expression remains to be fully established. To facilitate the identification of molecular pathways of Socs3 induction, we generated a real-time gene expression reporter mouse of Socs3 (Socs3-Luc mice). We successfully detected a remarkable increase in luciferase activity in various tissues of Socs3-Luc mice in response to a peripheral injection of lipopolysaccharide, a potent inducer of inflammation, reflecting expression levels of endogenous Socs3 mRNA. Using ex vivo hypothalamic explants of Socs3-Luc mice, we demonstrate that hypothalamic luciferase activity was significantly elevated in slices stimulated with known inducers of Socs3 such as proinflammatory cytokines IL-6, IL-1β, and TNF-α, lipopolysaccharide, and cAMP-inducing agent forskolin. Using the ex vivo model, we found glycogen synthase kinase-3 (GSK3)β-specific inhibitors to be potent inducers of Socs3. Furthermore, pharmacological inhibitors of β-catenin, a downstream mediator of GSK3β signaling, reduced Socs3 luciferase activity ex vivo. Finally, hypothalamic inhibition of GSK3β hindered leptin-induced phosphorylation of signal transducers and activators of transcription 3 in hypothalamic explants. These results suggest that the Socs3-luciferase mouse is useful for in vivo monitoring of Socs3 gene expression and for ex vivo slice-based screening to identify signaling pathways that control Socs3 in the hypothalamus.

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced) obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate glucose metabolism. While having no effect on body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered blood glucose and insulin levels, improved glucose and insulin tolerance, and protected mice against HFD-induced neural leptin resistance and peripheral insulin resistance at the cellular and whole-body levels. Last, acute pharmacological inhibition of brain exchange protein directly activated by cAMP 2, a direct activator of Rap1, corrected glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.

We experienced a case in which improving the renal damage caused by warfarin‐related nephropathy took a long time. It is important to follow up for a long time after the initiation of dialysis due to warfarin‐related nephropathy.

The mass production of CuCrZr alloy - ITER Grade tubes for the ITER divertor outer vertical target (OVT) prototype and series production is now in progress as well as other material. It is required to manufacture the CuCrZr tube with the mechanical properties required by the design and with the grain growth suppressed in terms of prevention of water leakage and durability of electromagnetic load even after the completion of the OVT. Therefore, the mechanical properties are tested prior to a use for the OVT to confirm the mechanical properties and the quality during mass production of the CuCrZr tube. This paper reports the tensile properties, which are one of important mechanical properties required for the CuCrZr tubes used in the prototype and series production of the OVT. As the results of sampling inspection during the mass production, the CuCrZr tube was capable of meeting required values of the tensile properties even after the heat treatment simulated the solution annealing and aging in the PFU manufacturing.

This study investigated the effects of cooling between exercise bouts and post-exercise with a commercially available fan cooling jacket on thermal and perceptual responses during and following exercise in hot-humid environments. Ten male athletes completed two 30 min cycling bouts at a constant workload (1.4 watts⋅kg–1 of body mass) with a 5 min recovery period in between. Exercise was followed by a 10 min recovery period. In an environmental chamber (33°C, 65% relative humidity), participants performed two trials with (FCJ) or without (CON) the fan cooling jacket on a T-shirt during the 5 min inter-exercise and 10 min post-exercise recovery periods. Mean, chest and upper arm skin temperatures, and thermal sensation and comfort were lower in FCJ than CON trial during and following exercise (P < 0.05). Thigh and calf skin temperatures, infrared tympanic temperature and heart rate were lower in FCJ than CON trial during the experimental trials (P < 0.05). The rates of fall in mean, chest and upper arm skin temperatures, infrared tympanic temperature and thermal sensation and comfort were faster in FCJ than CON trial during both recovery periods (P < 0.05). There were faster rates of fall in thigh and calf skin temperatures and heart rate in FCJ than CON trial during the post-exercise recovery period (P < 0.05). No difference was observed between trials in the rating of perceived exertion (P > 0.05). This study indicates that cooling between exercise bouts and post-exercise with the fan cooling jacket would effectively mitigate thermal strain and perception/discomfort during and following exercise in hot-humid environments. This garment would reduce whole-body skin temperature quickly while promoting falls in lower-body as well as upper-body skin temperatures.

We previously described the success and usefulness of two operative techniques for creating a radial artery-first or second dorsal metacarpal vein arteriovenous fistula (AVF) in the first interdigital space of the dorsal hand using the most distal site and autologous veins in the upper limb. These techniques utilize the dorsal metacarpal veins on the radial side of the dorsal hand. Developing these ideas, we devised a novel operative technique for creating a transposed radial artery-third metacarpal vein AVF in the first interdigital space of the dorsal hand using the most distal vein on the ulnar side of the upper limb and most distal site in the upper limb. The distinctive advantage of this technique is that it can be applied to patients whose cephalic vein in the forearm and the dorsal metacarpal veins on the radial side of the dorsal hand are of a poor quality. We herein report the steps of this technique and describe its successful performance in a patient who has been on hemodialysis for 14 months without any additional vascular access interventions or postoperative complications. We consider this technique to be a valuable option in select patients who meet the applicable conditions. The creation of the first AVF as distally as possible is ideal, and it offers a further viable option of distal native vascular access that may be overlooked.

Sufficient feeding is essential for animals’ survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals’ ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT(2C)R), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel β-arrestin/β2-adaptin inhibitor, can prevent 5-HT(2C)R internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT(2C)R in POMC(ARH) neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT(2C)R desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT(2C)R agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT(2C)R desensitization. SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT(2C)R) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT(2C)R agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.

SUMMARY The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage., In brief Yang et al. demonstrate that SRC-2 in POMC neurons coordinates multifaceted adaptive responses to food shortage, including reducing energy expenditure, promoting counterregulation and suppressing satiation and anxiety to engage refeeding. These effects are mediated by SRC-2 functions to regulate POMC gene expression and modulate POMC neuron activities., Graphical Abstract

Hemoconcentration membranes used in cardiopulmonary bypass require a pore structure design with high pure water permeability, which does not allow excessive protein adsorption and useful protein loss. However, studies on hemoconcentration membranes have not been conducted yet. The purpose of this study was to analyze three-dimensional pore structures and protein fouling before and after blood contact with capillary membranes using the tortuous pore diffusion model and a scanning probe microscope system. We examined two commercially available capillary membranes of similar polymer composition that are successfully used in hemoconcentration clinically. Assuming the conditions of actual use in cardiopulmonary bypass, bovine blood was perfused inside the lumens of these membranes. Pure water permeability before and after bovine blood perfusion was measured using dead-end filtration. The scanning probe microscopy system was used for analysis. High-resolution three-dimensional pore structures on the inner surface of the membranes were observed before blood contact. On the other hand, many pore structures after blood contact could not be observed due to protein fouling. The pore diameters calculated by the tortuous pore diffusion model and scanning probe microscopy were mostly similar and could be validated reciprocally. Achievable pure water permeabilities showed no difference, despite protein fouling on the pore inlets (membrane surface). In addition, low values of albumin sieving coefficient are attributable to protein fouling that occurs on the membrane surface. Therefore, it is essential to design the membrane structure that provides the appropriate control of fouling. The characteristics of the hemoconcentration membranes examined in this study are suitable for clinical use.

A brachio-brachial arteriovenous fistula with superficialization of the brachial vein and superficialization of the brachial artery are useful vascular access techniques for hemodialysis patients. However, both typically require a long skin incision from the antecubital fossa toward the axillary fossa. In addition, the brachio-brachial arteriovenous fistula in particular, which is created with not a one-stage but a two-stage procedure, requires a relatively long time of 2–3 months before it can be used for hemodialysis. Furthermore, superficialization of the brachial artery usually requires nonarterialized superficial veins for blood return. In cases where patients have no adequate superficial veins for creating an arteriovenous fistula, we have adopted a one-stage operative technique to create a brachio-brachial arteriovenous fistula with superficialization of not only the brachial vein but also the brachial artery using a short skin incision. This technique of a brachio-brachial arteriovenous fistula with superficialization of the brachial artery has several advantages over traditional approaches, including a minimally invasive procedure and early use for vascular access. To our knowledge, the presently described technique and the related data have not been previously reported in the English literature. We herein report the steps of this technique and the midterm follow-up outcomes.

We report the case of a 69-year-old male patient with extensor pollicis longus (EPL) tendon rupture associated with a scaphoid nonunion advanced collapse (SNAC) wrist. He could not actively extend the left thumb interphalangeal joint and visited our institution for an examination. Plain X-rays revealed advanced stage SNAC and an enlarged soft tissue shadow owing to dorsal ridge growth. The patient was diagnosed with EPL tendon subcutaneous rupture due to SNAC. During surgery, the EPL tendon was found to be absent, a proximal-type scaphoid nonunion was detected, and bone growth to the dorsal part of the dorsal ridge was observed. Considering that the EPL tendon rupture was associated with the bone growth, we performed scaphoid lunate advanced collapse (SLAC) reconstruction and extensor indicis proprius tendon transfer which needed a revision tendon surgery afterward. To the best of our knowledge, EPL tendon ruptures caused by SLAC or SNAC are considered rare and have not yet been reported.

The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-β inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3β in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.

Highlights • We describe a one-sheath inverse method in vascular access intervention therapy (VAIVT) for hemodialysis patients. • It allows VAIVT to be performed using one sheath with one approach site in cases in which lesions are present on the upstream and downstream sides. • Because vascular access location is usually superficial, the technique can be utilized with relative ease., Introduction Vascular access intervention therapy (VAIVT) is an essential interventional therapy in the field of hemodialysis therapy that allows for the long-term vascular access functionality to be maintained. The venous approach is often performed in VAIVT for arteriovenous fistula. When lesions are present on the upstream and downstream sides from the approach site, it is likely that two sheaths will be inserted from two facing punctures. However, we have adopted a one-sheath inverse method using a guidewire in such cases. Case presentation We herein describe the steps of the technique that we have performed and report the successful treatment of a 77-year-old woman who developed arteriovenous fistula failure. Discussion To the best of our knowledge, the concrete and detailed technique has not been reported in the English literature to date. The merit of the technique is that it allows VAIVT to be performed using one sheath with one approach site in cases in which lesions are present on the upstream and downstream sides from the approach site. The other benefits include pain reduction, a shortened operation time, and reduced costs. Because vascular access location is usually superficial, the technique can be utilized with relative ease. Conclusion A one-sheath inverse method is useful. We hope that the technique will be more widely recognized, allowing the technique to be applied to more cases.

When using the extracorporeal capillary membrane oxygenator (sample A) for ECMO treatments of COVID-19 severely ill patients, which is dominantly used in Japan and worldwide, there is a concern about the risk of SARS-CoV-2 scattering from the gas outlet port of the membrane oxygenator. Terumo has launched two types of membranes (sample A and sample B), both of which are produced by the microphase separation processes using polymethylpentene (PMP) and polypropylene (PP), respectively. However, the pore structures of these membranes and the SARS-CoV-2 permeability through the membrane wall have not been clarified. In this study, we analyzed the pore structures of these gas exchange membranes using our previous approach and verified the SARS-CoV-2 permeation through the membrane wall. Both have the unique gradient and anisotropic pore structure which gradually become denser from the inside to the outside of the membrane wall, and the inner and outer surfaces of the membrane have completely different pore structures. The pore structure of sample A is also completely different from the other membrane made by the melt-extruded stretch process. From this, the pore structure of the ECMO membrane is controlled by designing various membrane-forming processes using the appropriate materials. In sample A, water vapor permeates through the coating layer on the outer surface, but no pores that allow SARS-CoV-2 to penetrate are observed. Therefore, it is unlikely that SARS-CoV-2 permeates through the membrane wall and scatter from sample A, raising the possibility of secondary ECMO infection. These results provide new insights into the evolution of a next-generation ECMO membrane.

Aim The effect of tonsillectomy on IgA nephropathy remains controversial. The aim of this study was to compare the effect of tonsillectomy on the outcome, end stage kidney disease (ESKD) and all-cause death in IgA nephropathy patients who did and did not undergo tonsillectomy. Methods All basic data were retrospectively gathered from patients who had undergone renal biopsies at two Japanese clinical centers. Two hundred and twenty-seven patients were eligible for the study, with a median age of 34 (Interquartile range (IQR): 25 to 43) years and median follow-up of 92 (IQR: 40 to 178) months. The primary endpoint was the composite outcome of the onset of ESKD and all-cause death before ESKD. We performed a Cox proportional hazard regression analysis after adjusting for patient characteristics using the inverse probability therapy weighting (IPTW) method and a Cox analysis using the Matching method. Similarly, we analyzed these outcomes in a mild cohort. Results We were unable to find any significant advantages of tonsillectomy in either analysis (IPTW and matching, HR: 0.40 (0.12-1.36) P = 0.072 and 0.78 (0.13-4.64) P = 0.786). However, in the mild cohort analysis, our data showed that the Tonsillectomy group tended to be less likely to reach the composite outcomes than the Not Tonsillectomy group with statistical significance (hazard ratio (HR)

Background Concerns about sodium overload when using sodium polystyrene sulfonate (Na-resin) as an ion-exchange resin for the treatment of hyperkalemia led our institution to gradually shift to the use of calcium polystyrene sulfonate (Ca-resin). However, as serum potassium levels were insufficiently controlled and patients experienced constipation, we returned to using Na-resin and observed better results than previously. Objective As few papers have examined the potassium adsorption ability of Ca-resin compared with Na-resin, we investigated this issue within our institution. Methods We studied potassium adsorption in patients who switched from Ca-resin to an equivalent amount of Na-resin (change group). We also investigated the incidence of sodium loading with Na-resin, including in patients newly commencing Na-resin treatment (new start group). Results Mean (± standard deviation) serum potassium levels decreased significantly, from 5.5 ± 0.6 to 4.9 ± 0.6 mEq/l in the change group and from 5.9 ± 0.4 to 4.7 ± 0.6 mEq/l in the new start group. No changes were observed in blood pressure, weight gain or serum sodium levels in the change group, but serum sodium levels in the new start group increased significantly, from 137.4 ± 2.3 to 139.0 ± 2.5 mEq/l, although they remained within the normal range. Conclusions Our results indicate that Na-resin exhibited an advantage in treating hyperkalemia when used in small amounts. However, when prescribing an ion-exchange resin at a higher dose, physicians should select the type and amount of resin according to the sodium and/or calcium load in each case.