Nagara Medical Center

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone’s therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.

Rationale: Patients with noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex pulmonary disease (MAC-PD) are treated intermittently three times per week, although no randomized controlled trials have been conducted comparing three times weekly with daily therapy. Objectives: To assess the tolerability, safety, and efficacy of intermittent versus daily treatment in patients with previously untreated noncavitary NB MAC-PD. Methods: In an open-label study, patients were randomly assigned to the intermittent therapy group receiving clarithromycin 1,000 mg, rifampicin 600 mg, and ethambutol 25 mg/kg (maximum 1,000 mg) three days per week or the daily therapy group receiving clarithromycin 800 mg, rifampicin 450 mg, and ethambutol 15 mg/kg (maximum 750 mg) daily for 1 year. The primary endpoint was the proportion of patients requiring modification of the initial treatment regimen. Results: Twenty-one Japanese hospitals participated in the study, enrolling 141 patients between May 2019 and December 2021. The full analysis set included 138 participants (intermittent therapy = 70; daily therapy = 68). There were no significant differences between the intermittent and daily therapy groups in terms of the regimen modification rate (20.0% [14 of 70] vs. 33.8% [23 of 68]; adjusted odds ratio, 0.48; 95% confidence interval, 0.22 to 1.05; P = 0.06) or culture conversion (70.3% vs. 80.0%; P = 0.53), time to culture conversion (28.0 vs. 28.5 d; P = 0.89), improvement in chest CT findings (60.9% vs. 71.0%; P = 0.30), or clarithromycin resistance development (1.4% vs. 0%; P = 1.00). Elevated aspartate aminotransferase (16.9% vs. 41.2%; P = 0.003) and alanine aminotransferase (18.3% vs. 44.1%; P = 0.002) were more common in the daily treatment group, whereas elevated bilirubin (11.3% vs. 1.5%; P = 0.04) and dysgeusia (14.1% vs. 1.5%; P = 0.01) were more common in the intermittent treatment group. The daily treatment group exhibited a greater absolute change in the 36-Item Short Form Health Survey physical aspect score (-2.5 points) than the intermittent treatment group (2.1 points) (P = 0.01). Conclusions: Intermittent treatment was not significantly better tolerated than daily treatment for noncavitary NB MAC-PD. However, further studies with larger numbers of patients are needed. Clinical trial registered with https://jrct.mhlw.go.jp/en-top (jRCTs031190008).

ObjectivesPropolis possesses antibacterial, anti-inflammatory, and antioxidant properties. While its application in oral care has garnered significant attention, evidence supporting its effectiveness against periodontal bacteria is limited. This study used a randomized double-blind protocol to assess the safety and efficacy of toothpaste containing propolis compared to a placebo in patients undergoing supportive periodontal therapy (SPT).Materials and methodsThirty-two participants in SPT were randomized into two groups: toothpaste containing 2.5% ethanol-extracted propolis (EEP) and a placebo without EEP. Participants brushed twice daily for four weeks, and clinical parameters, bacterial counts, and salivary characteristics were assessed before and after the intervention.ResultsThe propolis group showed a significant reduction in periodontal pocket depth (P = 0.006), with a mean depth of 3.80 mm compared to 4.35 mm in the placebo group. Bleeding on probing was significantly reduced in both groups (P = 0.032 in the propolis group and 0.0498 in the placebo group), but did not differ between groups. Total bacterial and Porphyromonas gingivalis (P. gingivalis) counts did not differ significantly between the groups; however, the number of patients with decreased P. gingivalis was slightly larger than those in the placebo group (not significant). Additionally, saliva acidity decreased significantly in the propolis group (P = 0.041), suggesting a shift toward a less pathogenic oral environment. No adverse events were observed.ConclusionThese findings suggest that propolis may contribute to stabilizing periodontal disease during supportive periodontal therapy by modulating salivary acidity.Clinical relevancePeriodontal pocket depth and the rate of bleeding on probing are reduced, along with decreased saliva acidity. Meanwhile, the levels of P. gingivalis in the periodontal pockets remain low. Propolis-dentifrice may help alleviate gingival inflammation during SPT.Clinical trial registrationRegistered in the University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN000029554).Graphical abstract

Background/AimThe albumin-bilirubin (ALBI) grade is an assessment tool for hepatic function and prognosis in patients with hepatocellular carcinoma (HCC). However, its significance in patients with non-small cell lung cancer (NSCLC) treated with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) remains unclear. We retrospectively investigated the relationship between pre-treatment ALBI grade and hepatotoxicity and treatment efficacy in patients with NSCLC receiving EGFR-TKIs.Patients and MethodsWe analyzed data from 182 patients with NSCLC treated with EGFR-TKIs. Patients were categorized into ALBI grades 1/2a and 2b/3 groups. We examined the association between ALBI grade, hepatotoxicity, and time to treatment failure (TTF) using univariate and multivariate analyses.ResultsIn the univariate Kaplan-Meier analysis, ALBI grade was not associated with hepatotoxicity (log-rank p=0.56). This finding was consistent with the multivariate analysis of patients treated with gefitinib and erlotinib (n=158). However, In the univariate Kaplan-Meier analysis, the median TTF for the ALBI grade 1/2a group was 10.6 months, compared to 5.8 months for the ALBI grade 2b/3 group (hazard ratio=1.66, 95% confidence interval=1.19-2.33, p=0.003). Multivariate analysis confirmed that ALBI grade 2b/3 (hazard ratio=1.64, 95% confidence interval=1.16-2.30, p<0.01) was independently associated with shortened TTF.ConclusionPretreatment ALBI grade classification can predict efficacy in patients with NSCLC treated with EGFR-TKIs.

BackgroundSacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure.MethodsIn this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg).ResultsNinety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026).ConclusionsThese findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure.