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Abstract HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiated from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiated from control hiPSCs. Further analysis of hiPSC-derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results demonstrate that abnormal cell maturation possibly contribute to the development of myopathy and DCM. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.

Abstract Background Thyroid storm can be complicated by liver dysfunction, which may occasionally progress to acute liver failure. We herein report a case of acute liver failure following thyroid storm that was treated with living donor liver transplantation after resuscitation from cardiopulmonary arrest. Case report The patient was a woman in her 40 s who had been diagnosed with an abnormal thyroid function. She suffered from fatigue and vomiting, and was found to have consciousness disorder, a fever, and tachycardia with a neck mass. She was diagnosed with thyroid storm and was referred to our hospital. After arrival, she went into cardiopulmonary arrest and veno-arterial extracorporeal membrane oxygenation was initiated. In addition to treatment for thyroid storm with antithyroid drugs, steroids, and plasma exchange, extracorporeal life support was required for 5 days. However, despite improvements in her thyroid function, her liver function deteriorated. We planned living donor liver transplantation for acute liver failure after ensuring the recovery and control of the thyroid function following total thyroidectomy. The donor was her husband who donated the right lobe of his liver. Although she experienced acute cellular rejection after surgery, and other complications—including intra-abdominal hemorrhaging and ischemic changes in the intestine—her liver function and general condition gradually improved. One year after living donor liver transplantation, the patient was in a good condition with a normal liver function. Conclusions To our knowledge, this is the first report of living donor liver transplantation in a patient with acute liver failure following thyroid storm. Liver transplantation should be recognized as an effective treatment for acute liver failure following thyroid storm.

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease, thrombosis, and all-cause death. However, few studies have examined the association between CKD and the prognosis of patients with essential thrombocythemia (ET). We collected ET patients who met the WHO classification 2017 and performed a retrospective clinical study to clarify the association between the presence and onset of CKD and prognosis. Of 73 patients who met the diagnostic criteria, 21 (28.8%) had CKD at the time of ET diagnosis. The age of patients with CKD was significantly higher, and a high proportion of these patients had the JAK2V617F gene mutation. The presence of CKD was a risk factor for the prognosis (hazard ratio (HR): 3.750, 95% confidence interval (CI): 1.196–11.760, P=0.023), and the survival curve was significantly poorer. Furthermore, we analyzed patients without CKD at the time of ET diagnosis using the onset of CKD as a time-dependent variable and identified the onset of CKD as a risk factor for the prognosis (HR: 9.155, 95% CI: 1.542–54.370, P=0.005). In patients with renal hypofunction at the time of ET diagnosis or those with a reduction in the kidney function during follow-up, strict renal function monitoring at regular intervals is necessary.

ABSTRACT Aims/Introduction In addition to absolute insulin deficiency, dysregulated glucagon in type 1 diabetes is considered pathophysiologically important. Previously, we confirmed the presence of dysregulated glucagon in Japanese patients with type 1 diabetes, and found a significant correlation between plasma glucagon and blood urea nitrogen levels, suggesting an association between glucagon and amino acid metabolism. In this study, we evaluated plasma amino acid levels in Japanese patients with type 1 diabetes in the context of their functional relationship with glucagon. Materials and Methods We assessed plasma free amino acid levels using liquid chromatography–mass spectrometry in 77 Japanese patients with type 1 diabetes, and statistically analyzed their characteristics and relationships with clinical parameters, including glucagon. Results Participants with type 1 diabetes showed a large decrease in glutamate levels together with a characteristic change in plasma free amino acid profiles. The network structural prediction analyses showed correlations between each amino acid and glucagon in type 1 diabetes. Conclusions Participants with type 1 diabetes showed characteristic changes in plasma glutamate levels and free amino acid profiles compared with controls and type 2 diabetes patients. Glucagon showed a closer correlation with amino acids than with parameters of glucose metabolism, suggesting that type 1 diabetes includes dysregulation in amino acids through dysregulated glucagon from remaining pancreatic α‐cells, together with that in glucose by insulin deficiency.

Background Can Background be changed from bold to normal text?: Chemically-induced liver progenitors (CLiPs) have promising applications in liver regenerative medicine. We aimed to clarify the efficacy of CLiPs for ameliorating fibrosis in a diet-induced nonalcoholic steatohepatitis rat model, since nonalcoholic fatty liver disease is currently recognized as the most common form of chronic liver disease in developed countries. Methods: Primary mature hepatocytes were isolated from 7-week-old male Wistar rats. To establish CLiPs, isolated hepatocytes were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). As an animal model that reproduces NASH pathophysiology, 6-week-old severe combined immunodeficient (SCID) mice were carefully selected and prepared and fed with choline-deficient, L-amino acid-defined, high-fat diet (HFD). After 12 weeks’ HFD feeding, the mice were assigned to continue HFD with or without the administration of rat CLiPs (HFD + CLiPs and HFD-CLiPs, respectively). Rat CLiPs were administered from the spleen. Hepatic fibrosis was semi-quantitatively evaluated according to histology. Liver parenchyma and blood samples were collected for biochemical analyses. Results: Rat CLiPs were positive for CK19 and EpCAM were successfully delivered to the liver. At 8 weeks after CLiPs transplantation, the HFD + CLiPs group showed significantly less positive staining than the HFD-CLiPs group. Alanine aminotransferase significantly improved in the HFD + CLiPs group, as demonstrated by Azan staining and αSMA immunostaining. RT qPCR showed that the liver expression of MMP2 and 9 tended to be higher in the HFD + CLiPs group. Conclusions: The anti-fibrotic effect of CLiPs was demonstrated in the immunodeficient NASH animal model and may have therapeutic applications in humans.

Abstract Background Hospital-acquired disability (HAD) in patients who undergo living donor liver transplantation (LDLT) is expected to worsen physical functions due to inactivity during hospitalization. The aim of this study was to explore whether a decline in activities of daily living from hospital admission to discharge is associated with prognosis in LDLT patients, who once discharged from a hospital. Methods We retrospectively examined the relationship between HAD and prognosis in 135 patients who underwent LDLT from June 2008 to June 2018, and discharged from hospital once. HAD was defined as a decline of over 5 points in the Barthel Index as an activity of daily living assessment. Additionally, LDLT patients were classified into four groups: low or high skeletal muscle index (SMI) and HAD or non-HAD. Univariate and multivariate Cox proportional hazard models were used to evaluate the association between HAD and survival. Results HAD was identified in 47 LDLT patients (34.8%). The HAD group had a significantly higher all-cause mortality than the non-HAD group (log-rank: p

Abstract Background and Aim Treatment for small hepatocellular carcinoma (HCC) is determined based on the results of a liver function test and the tumor location and spread. The present study compared the outcomes among local therapy, hepatic resection (HR), and living‐donor liver transplantation (LDLT) for small HCC in a single institute. Methods We compared the overall survival, recurrence‐free survival, and cancer‐specific survival rates in patients with three HCC nodules

Portal vein thrombosis following liver transplantation is generally managed by endovascular treatment. Although several techniques are available for portal venous access, trans-splenic access is of interest because it avoids damage to the liver graft. However, the spleen cannot be punctured to access the portal vein after splenectomy. We herein report a case of portal vein thrombosis following living donor liver transplantation with simultaneous splenectomy successfully treated by percutaneous intervention with direct puncture of the retropancreatic splenic vein. The splenic vein was punctured under computed tomography guidance in the prone position. Portal venography revealed a contrast defect due to a thrombus in the extrahepatic to intrahepatic portal vein. The portal vein was reopened after thrombectomy, and the portal vein thrombosis did not recur for 2 y. The technique and advantages of our approach are described.

PurposeUpregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature.MethodsThe type I IFN signature was measured in patients’ whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature.ResultsA total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling.ConclusionsHalf of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Abstract Patients with hematological disorders are treated with multiple cycles of chemotherapy. As a result, they often require multiple insertions of the peripherally inserted central catheter (PICC) for prolonged periods of time. Although PICCs have been widely used worldwide in various patients, the safety and feasibility of the multiple insertions of the PICC in this population have not been fully verified. We performed a retrospective analysis to clarify the relationship between complications and multiple PICC insertions in patients with hematological disorders who were treated with either chemotherapy or immunotherapy. A total of 651 PICCs were inserted in 261 patients with a median age of 66 years. Acute myeloid leukemia (AML) and non-Hodgkin's lymphoma were the most common diseases in our patient cohort. The total catheter days (CDs) was 29,485 days, with a median catheter duration of 30 days. The rate of catheter-related bloodstream infection (CRBSI) in our patient cohort at high rate of re-insertion was 2.0/1000 CDs. Although multiple PICC insertions were not a risk factor of CRBSI, our findings suggest that a prolonged catheter dwell time may be associated with CRBSI. AML was an important risk factor of CRBSI. While the PICC dwell time depends on the treatment cycle, our findings indicate that it should be limited to approximately 30 days and catheters may be removed and re-inserted as needed.

Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease that causes recurrent fever, arthritis, and serositis. The diagnosis of FMF is based on the presentation of typical clinical symptoms and the Mediterranean fever gene (MEFV) test. However, the challenge lies in diagnosing atypical cases. In this report, we have described a pediatric patient with complex FMF whose diagnosis required trio-whole exome sequencing (WES) and functional validation of a rare MEFV variant. A 3-year-old boy presented with recurrent episodes of elevated liver enzymes and arthralgia. He was diagnosed with autoimmune hepatitis (AIH), and his liver enzymes improved rapidly with steroid treatment. However, he exhibited recurrent arthralgia and severe abdominal attacks. Trio-WES identified compound heterozygous mutations in MEFV (V726A and I692del). Ex vivo functional assays of the patient’s monocytes and macrophages, which had been pre-treated with Clostridium difficile toxin A (TcdA) and colchicine, were comparable to those of typical FMF patients, thereby confirming the diagnosis of FMF. Although he was intolerant to colchicine because of liver toxicity, subsequent administration of canakinumab successfully ameliorated his abdominal attacks. However, it was ineffective against liver injury, which recurred after steroid tapering. Therefore, in this case, the pathogenesis of AIH was probably interleukin-1β (IL-1β)-independent. In fact, AIH might have been a concurrent disease with FMF, rather than being one of its complications. Nevertheless, further studies are necessary to determine whether FMF-induced inflammasome activation contributes to AIH development. Moreover, we must consider the possibility of mixed phenotypes in such atypical patients who present distinct pathologies simultaneously.

Purpose: This study reports a case of the spontaneous avulsion of primary pterygium with anterior segment optical coherence tomography (AS-OCT) findings. Observation: A 72-year-old woman complained of acute pain of the left eye. Primary pterygia were noted in both eyes on the initial examination 4 months ago. Slit-lamp microscopy revealed a nasal corneal epithelial defect, and the rolled elevated lesion in the corneal limbus of the left eye. She was diagnosed with a spontaneous avulsion of the corneal pterygium head. Then the avulsed pterygium head slowly recurred. The pterygium head of the fellow eye had a yellow-whitish elevated lesion beneath the epithelium with poor vascularity. AS-OCT revealed hyper-reflective foci beneath the epithelium corresponding to the yellow-whitish elevated lesion. Conclusions/importance: The present case revealed the spontaneous avulsion of the pterygium head leading to the corneal epithelial defects and ocular pain, while the pterygium head of the fellow eye showed subepithelial hyper-reflective foci suspicious of spheroidal degeneration on AS-OCT. In this case, the cause of spontaneous avulsion of the pterygium head might be potentially weak adhesion to the cornea due to spheroidal degeneration. Precis: This case is a primary pterygium leading to spontaneous avulsion, in which hyper-reflective foci were noted in OCT.

The concept of autoinflammation, first proposed in 1999, refers to a seemingly unprovoked episode of sterile inflammation manifesting as unexplained fever, skin rashes, and arthralgia. Autoinflammatory diseases are caused mainly by hereditary abnormalities of innate immunity, without the production of autoantibodies or autoreactive T cells. The revolutionary discovery of induced pluripotent stem cells (iPSCs), whereby a patient’s somatic cells can be reprogrammed into an embryonic pluripotent state by forced expression of a defined set of transcription factors, has the transformative potential to enable in vitro disease modeling and drug candidate screening, as well as to provide a resource for cell replacement therapy. Recent reports demonstrate that recapitulating a disease phenotype in vitro is feasible for numerous monogenic diseases, including autoinflammatory diseases. In this review, we provide a comprehensive overview of current advances in research into autoinflammatory diseases involving iPSC-derived monocytes/macrophages. This review may aid in the planning of new studies of autoinflammatory diseases.

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The reactivity of expanded porphyrins is highly influenced by their scaffold architecture. Here, the authors construct two nonaromatic dumbbell-shaped benzene- and pyridine-incorporating octaphyrins via Suzuki-Miyaura cross-coupling; depending on the framework, different coordination modes are obtained upon metallation with Pd(II).

Abstract Background Congenital absence of portal vein (CAPV) is a rare structural anomaly in which the portal vein (PV) blood that normally flow into the liver directly drains into the systemic venous system through other collateral circulation. Congenital portal vein shunts (CPSs) is classified into types I and II according to the absence or presence of the intrahepatic portal vein, respectively. The CPS type I is also known as CAPV. The liver transplantation may be the only treatment option for CAPV. The key point of liver transplantation for CAPV is the reconstruction of the PV. Case presentation A 29-year-old man was diagnosed with CAPV with splenomegaly and gastroesophageal varix when being treated for pancytopenia and liver dysfunction. A living donor liver transplantation was performed for him using the right lobe which had been donated by his mother. The PV was reconstructed using his own great saphenous vein (GSV) as a graft vein. The end of the GSV graft was anastomosed to the inferior mesenteric vein while the other end was anastomosed to the vein graft of the right hepatic vein from the explanted liver. Conclusion Using the patient’s own GSV for PV reconstruction during living donor transplantation in the patient with CAPV seems to be an effective method.

In the fields of control engineering and robotics, either the Lagrange or Newton–Euler method is generally used to analyze and design systems using equations of motion. Although the Lagrange method can obtain analytical solutions, it is difficult to handle in multi-degree-of-freedom systems because the computational complexity increases explosively as the number of degrees of freedom increases. Conversely, the Newton–Euler method requires less computation even for multi-degree-of-freedom systems, but it cannot obtain an analytical solution. Therefore, we propose a partial Lagrange method that can handle the Lagrange equation efficiently even for multi-degree-of-freedom systems by using a divide-and-conquer approach. The proposed method can easily handle system extensions and system reconstructions, such as changes to intermediate links, for multi-degree-of-freedom serial link manipulators. In addition, the proposed method facilitates the derivation of the equations of motion-by-hand calculations, and when combined with an analysis algorithm using automatic differentiation, it can easily realize motion analysis and control the simulation of multi-degree-of-freedom models. Using multiple pendulums as examples, we confirm the effectiveness of system expansion and system reconstruction with the partial Lagrangians. The derivation of their equations of motion and the results of motion analysis by simulation and motion control experiments are presented. The system extensions and reconstructions proposed herein can be used simultaneously with conventional analytical methods, allowing manual derivations of equations of motion and numerical computer simulations to be performed more efficiently.

Instrumented wheelsets are widely utilized in the railway industry for the purpose of the measurement of the wheel-rail interaction force. In the conventional instrumented wheelset, the measurement accuracy of the lateral force is reduced due to the bending moment induced by the wheel load. The authors have proposed a new configuration of the instrumented wheelset to reduce the influence of the wheel load on the measurement of the lateral force. This proposed configuration utilizes the shear strains of the wheel web as a measure of the lateral force. This paper describes the accuracy verification of the proposed configuration under the wheel rotating condition. The single-wheelset roller-rig tests are carried out and the test results show that the proposed method can reduce the influence of the wheel load even under the rotating condition.

Vps13 family proteins are proposed to function in bulk lipid transfer between membranes, but little is known about their regulation. During sporulation of Saccharomyces cerevisiae, Vps13 localizes to the prospore membrane (PSM) via the Spo71-Spo73 adaptor complex. We previously reported that loss of any of these proteins causes PSM extension and subsequent sporulation defects, yet their precise function remains unclear. Here, we performed a genetic screen and identified genes coding for a fragment of phosphatidylinositol (PI) 4-kinase catalytic subunit and PI 4-kinase noncatalytic subunit as multicopy suppressors of spo73Δ. Further genetic and cytological analyses revealed that lowering PI4P levels in the PSM rescues the spo73Δ defects. Furthermore, overexpression of VPS13 and lowering PI4P levels synergistically rescued the defect of a spo71Δ spo73Δ double mutant, suggesting that PI4P might regulate Vps13 function. In addition, we show that an N-terminal fragment of Vps13 has affinity for the endoplasmic reticulum (ER), and ER-plasma membrane (PM) tethers localize along the PSM in a manner dependent on Vps13 and the adaptor complex. These observations suggest that Vps13 and the adaptor complex recruit ER-PM tethers to ER-PSM contact sites. Our analysis revealed that involvement of a phosphoinositide, PI4P, in regulation of Vps13, and also suggest that distinct contact site proteins function cooperatively to promote de novo membrane formation.