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Inborn errors of immunity (IEI) are caused by germline genetic mutations, resulting in defects of innate or acquired immunity. Hematopoietic cell transplantation (HCT) is indicated for curative therapy especially in patients with IEI who develop fatal opportunistic infections or severe manifestations of immune dysregulation. The first successful HCT for severe combined immunodeficiency (SCID) was reported in 1968. Since then, the indications for HCT have expanded from SCID to various non-SCID IEI. In general, HCT for IEI differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution. European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies guidelines recommend reduced-intensity conditioning to avoid treatment-related toxicity, and the optimal conditioning regimen should be considered for each IEI. We review conditioning regimens for some representative IEI disorders in Japanese and worldwide cohort studies, and future strategies for treating IEI.

The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

Aims/Introduction Nucleotide‐binding oligomerization domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL‐18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL‐18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg‐Ay/TaJcl (KK‐Ay) mice against DKD progression. Materials and Methods Suramin or saline was administered i.p. to KK‐Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. Results Suramin treatment significantly suppressed the increase in the urinary albumin‐to‐creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK‐Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome‐related genes and proteins in the renal cortex of KK‐Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK‐Ay mice and mainly distributed in the glomerular mesangial cells of KK‐Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP‐induced NLRP3 complex formation and the downstream expression of caspase‐1 and IL‐18 in MMCs. Conclusions These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD. Suramin, a nonselective antagonist of the P2 receptors, suppresses NLRP3 inflammasome activation and exerts renoprotective effects in diabetic KK‐Ay mice. Suramin protects against DKD development via the inhibition of P2X receptors, and can be expected to be an important drug for the treatment of DKD.

The need for the estimation of the number of microbubbles (MBs) in cardiopulmonary bypass surgery has been recognized among surgeons to avoid postoperative neurological complications. MBs that exceed the diameter of human capillaries may cause endothelial disruption as well as microvascular obstructions that block posterior capillary blood flow. In this paper, we analyzed the relationship between the number of microbubbles generated and four circulation factors, i.e., intraoperative suction flow rate, venous reservoir level, continuous blood viscosity and perfusion flow rate in cardiopulmonary bypass, and proposed a neural-networked model to estimate the number of microbubbles with the factors. Model parameters were determined in a machine-learning manner using experimental data with bovine blood as the perfusate. The estimation accuracy of the model, assessed by tenfold cross-validation, demonstrated that the number of MBs can be estimated with a determinant coefficient R 2  = 0.9328 ( p  < 0.001). A significant increase in the residual error was found when each of four factors was excluded from the contributory variables. The study demonstrated the importance of four circulation factors in the prediction of the number of MBs and its capacity to eliminate potential postsurgical complication risks.

Aims/Introduction To clarify the prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes, we analyzed the baseline data of the Japan Diabetes Complication and its Prevention prospective study. Materials and Methods We used the data of 355 patients with type 1 diabetes and 5,194 patients with type 2 diabetes to evaluate the prevalence of albuminuria and renal dysfunction, and related factors. A binomial logistic regression analysis was used to investigate independent contributing factors for estimated glomerular filtration rate <60 mL/min/1.73 m2 or albuminuria. Results The prevalence of microalbuminuria and macroalbuminuria was 15.2% (54/355) and 3.1% (11/355) in type 1 diabetes patients, and 25.0% (1,298/5,194) and 5.1% (265/5,194) in type 2 diabetes patients, respectively. The proportion of renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2) was 9.9% (35/355) in type 1 diabetes patients, and 15.3% (797/5,194) in type 2 diabetes patients. The proportion of patients with renal dysfunction with normoalbuminuria was 7.3% (26/355) for type 1 diabetes patients, and 9.0% (467/5,194) for type 2 diabetes patients. The factors related to albuminuria in type 2 diabetes patients were glycated hemoglobin, hypertension, age, duration of diabetes, body mass index and estimated glomerular filtration rate. In contrast, factors to related renal dysfunction were age, duration of diabetes, dyslipidemia, hypertension, body mass index, male sex and albuminuria. Conclusions We showed the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese type 1 and type 2 diabetes patients using the baseline data of the Japan Diabetes Complication and its Prevention prospective study. The current results suggest that renal disease in patients with type 2 diabetes is heterogeneous, and different mechanisms might be involved in albuminuria and deterioration of renal function. We clarified the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes using the baseline data of the Japan Diabetes Complication and its Prevention prospective study.

PurposeHematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan.MethodsA cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974–2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).ResultsThe 10-year overall survival (OS) of the patients who received HCT in 2006–2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006–2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01).ConclusionWe showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups. Conclusions The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease. The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Background Although the importance of kinematic evaluation of the sit-to-stand (STS) test of total knee arthroplasty (TKA) patients is clear, there have been no reports analyzing STS during the 30-s chair sit-up test (30 s-CST) with a focus on kinematic characteristics. This study aimed to demonstrate the clinical utility of kinematic analysis of STS during the 30 s-CST by classifying STS into subgroups based on kinematic parameters, and to determine whether differences in movement strategies are expressed as differences in clinical outcomes. Methods The subjects were all patients who underwent unilateral TKA due to osteoarthritis of the knee and were followed up for one year postoperatively. Forty-eight kinematic parameters were calculated using markerless motion capture by cutting STS in the 30 s-CST. The principal components of the kinematic parameters were extracted and grouped by kinematic characteristics based on the principal component scores. Clinical significance was examined by testing whether differences in patient-reported outcome measures (PROMs) were observed. Results Five principal components were extracted from the 48 kinematic parameters of STS and classified into three subgroups (SGs) according to their kinematic characteristics. It was suggested that SG2, using a kinematic strategy similar to the momentum transfer strategy shown in previous studies, performed better in PROMs and, in particular, may be associated with achieving a “forgotten joint”, which is considered the ultimate goal after TKA. Conclusions Clinical outcomes differed according to kinematic strategies used STS, suggesting that kinematic analysis of STS in 30 s-CST may be useful in clinical practice. Trial registration This study was approved by the Medical Ethical Committee of the Tokyo Women’s Medical University (approval number: 5628 on May 21, 2021).