Kagawa University

Mammalian embryos possess undifferentiated gonads and primordial male and female reproductive tracts. In males, sex-determining region of the Y chromosome (Sry) triggers the differentiation of gonadal supporting cell precursors into Sertoli cells. In C57BL/6N-XYPOS (B6N-XYPOS) mice, a model of disorders of sex development, Sry expression is delayed relative to wild-type B6N mice, and several reproductive tract malformations have been reported. In this study, we investigated the developmental stage and regions at which reproductive tract development fails in B6N-XYPOS. In B6N-XYPOS at 15.5 days post-coitum (dpc), the number of seminiferous tubules showed no difference from B6N, but seminiferous tubules with closed at both ends appeared. In B6N-XYPOS with bilaterally developed ovaries or testes, significant disorders were observed only in the female reproductive tract. B6N-XYPOS ovotestes showed impaired testis differentiation in the cranial and caudal regions, not only in fetuses but also in adults. In female B6N-XYPOS with bilaterally or unilaterally formed ovaries, the Müllerian ducts opened into the urogenital sinus at 15.5 dpc; however, at postnatal day 1, one individual exhibited a uterus with a closed region, and many adult females formed an edematous uterus. These results suggest that impaired cranial testis differentiation may disrupt the connection between the seminiferous tubules and the rete testis. They also suggest that Müllerian duct formation is initially completed even in female B6N-XYPOS with an edematous uterus, but that the duct closes abnormally between 15.5 dpc and birth.

Exercise therapy is important for exercise tolerance, for the prevention of frailty or sarcopenia, and to improve quality of life (QOL). Previous studies, including systematic reviews, have shown the efficacy of exercise therapy for kidney transplant recipients (KTRs), but the optimal types of exercise remain unclear. Therefore, we aimed to synthesize the published evidence and compare the efficacy of types of exercise. We systematically searched for randomized controlled trials of the efficacy of exercise therapy in KTRs on PubMed and Ichushi, then performed a meta-analysis. Exercise was categorized as aerobic training (AT), resistance training (RT), or AT + RT. The risk of bias was assessed using ROB2 and the certainty of the evidence was evaluated using the GRADE approach. Twenty-five studies were included in the study and 18 in the meta-analysis. Exercise was associated with significant improvements in QOL (SF-36 physical functioning score), cardiorespiratory function (VO2peak), physical function (performance in the 6-min walk test (6MWT) and sit/stand test (STS)), and a metabolic index (triglyceride concentration). Kidney function tended to be superior in the exercise group, but the difference was not significant. Other indices of glucose and lipid metabolism and the incidence of hospitalization did not differ between the Exercise and Control groups. AT + RT significantly improved VO2peak, 6MWT performance, and the triglyceride concentration, whereas AT alone did not improve VO2peak and RT alone did not improve 6MWT performance or the triglyceride concentration. The certainty of the evidence was generally "low" or "very low". Exercise therapy improved the QOL, cardiorespiratory function, physical function, and triglyceride concentration of KTRs. The AT + RT combination may be the most effective exercise therapy for such patients.

This study was aimed at assessing the effects of cerebral sympathetic nervous system activity and renal denervation (RD) on the intrarenal renin-angiotensin system (RAS) and salt-induced nocturnal polyuria (NP). To establish a mouse model, NP was induced by Nω-nitro-L-arginine methyl ester and a high-salt diet. Mice were subjected to dietary, pharmacological, and RD interventions, with blood pressure, urine output, renal norepinephrine, kidney protein expression, and c-Fos positive cells in the hypothalamic paraventricular nucleus (PVN) assessed using standardized physiological, biochemical, and histological methods. Renal angiotensinogen (AGT) and PVN c-Fos were significantly increased in NP model mice, indicating sympathetic activation. RD lowered renal AGT and the diurnal polyuria index versus sham (1.070±0.091 vs. 1.595±0.136 arbitrary units, P<0.01; 0.182±0.018 vs. 0.338±0.021, P<0.01). Cerebral sympathetic activation may promote intrarenal RAS activity and salt-induced NP; therefore, RD may be a potential therapeutic strategy to improve NP.

The impact of each factor and the number of positive criteria on pathogenesis and the diagnostic performance of non-invasive tests (NITs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to investigate the association between the cardiometabolic criteria and the clinical features. This retrospective study investigated clinicopathological characteristics and the diagnostic performance of the Enhanced Liver Fibrosis (ELF) test, fibrosis-4 (FIB-4) index, and nonalcoholic fatty liver disease fibrosis score (NFS) according to the factors and the number of positive cardiometabolic criteria in 1,038 patients with biopsy-proven MASLD. Hypertension is a significant risk factor for progression to advanced fibrosis and at-risk metabolic dysfunction-associated steatohepatitis (MASH) in male patients. In contrast, no significant risk factor was identified in female patients. The incidence of advanced fibrosis increased significantly in patients with three or more positive criteria. Similarly, the incidence of at-risk MASH increased significantly in a stepwise manner with the number of positive cardiometabolic criteria. The diagnostic performance of the ELF test for advanced fibrosis exceeded that of the FIB-4 index and NFS for all factors except hypertension. Regardless of the number of positive cardiometabolic criteria, the ELF test demonstrated a superior diagnostic performance for advanced fibrosis. MASLD with hypertension in male patients or a higher number of positive cardiometabolic criteria constitutes a significant risk for advanced fibrosis or at-risk MASH. The ELF test is a valuable tool for diagnosing advanced fibrosis progression regardless of individual factors or the number of positive cardiometabolic criteria.

Bone-avid tracers, such as 99mTc-pyrophosphate (PYP) and 99mTc-hydroxymethylene diphosphonate (HMDP), facilitate the noninvasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA). In this study, we compared these two methods. We retrospectively reviewed 83 patients with suspected or diagnosed cardiac amyloidosis (mean age, 79years; 11 women) who underwent PYP and HMDP scintigraphy. Early (1h) imaging was available for of 72/50 patients with PYP/HMDP, and all patients underwent delayed (3h) imaging. Visual grading (Dorbala score), heart-to-contralateral lung (H/CL) ratios, and relative segmental uptake (RSU) derived from SPECT (3h) polar map analysis using the quantitative perfusion SPECT software were compared. visual scores showed substantial agreement. The H/CL ratio showed a strong correlation. Bland-Altman analysis revealed fixed and proportional biases, with discrepancies increasing at higher uptake levels. The median H/CL values were comparable at 1h, whereas HMDP showed slightly higher delayed values. Receiver operating characteristic analysis indicated excellent and good diagnostic accuracy at 1 and 3h, respectively. Using routine diagnostic criteria, SPECT visual assessment demonstrated comparable diagnostic performance between PYP and HMDP. RSU analysis in 34 patients demonstrated similar segmental uptake distributions for both tracers, with basal and septal predominance, consistent with the apical-sparing patterns described previously. PYP and HMDP demonstrated comparable diagnostic accuracies for ATTR-CA. PYP has been extensively validated and is suitable for early imaging, whereas HMDP has a slightly higher delayed uptake and lower blood pool activity. When interpreted using routine diagnostic criteria, SPECT provided equivalent diagnostic performance for PYP and HMDP. Segmental analyses confirmed the preservation of the characteristic apical sparing across the tracers. Both tracers are clinically interchangeable when standardized acquisition and interpretation protocols are applied.

Glucocorticoids (GC) comprise a cornerstone in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, prolonged GC exposure leads to substantial toxicity and immune system-related complications. Hence, identifying treatment strategies that enable early GC withdrawal while maintaining disease control is of clinical importance. To investigate the proportion and characteristics of patients achieving GC-free clinical remission (GFCR) 48 weeks after treatment initiation in patients with newly diagnosed microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) and examine their long-term clinical outcomes (up to week 96). We conducted a retrospective cohort study using clinical data from a multicenter, nationwide registry in Japan comprising patients with newly diagnosed MPA or GPA and at least 48 weeks of follow-up. GFCR was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 with complete GC withdrawal. Univariable and multivariable logistic regression analyses were used to identify independent predictors of GFCR at week 48, and a sensitivity analysis using a matched cohort was performed to validate robustness. A total of 728 patients were enrolled in the registry, of whom 544 were followed for ≥ 48 weeks; among them, 29 (5.3%) achieved GFCR at week 48. Use of rituximab (RTX) for induction therapy and avacopan within 48 weeks were independently associated with achieving GFCR (multivariable analysis, model 1: RTX: odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.5–10.0; avacopan: OR: 24.3, 95% CI: 5.8–101.9; both p < 0.01). Conversely, methylprednisolone pulse therapy was associated with a lower likelihood of achieving GFCR (multivariable analysis, model 1: OR: 0.08, 95% CI: 0.02–0.44; p < 0.01). Patient’s demographic and baseline disease characteristics were not predictive of GFCR. In the long-term (weeks 48 through 96), the rates of death, relapse, and serious infection were similar regardless of GFCR status at week 48. The use of RTX for induction therapy and avacopan within 48 weeks is independently associated with achieving GFCR at week 48 in patients with MPA and GPA, supporting their potential as key components of GC-sparing strategies in AAV. Prospective studies are needed to confirm these results and optimize treatment algorithms to ensure disease control and minimize GC-related toxicity.