BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

Background: The anti-programmed death 1 (PD-1) antibody has led to durable clinical responses in a wide variety of human tumors. We have previously developed the caninized anti-canine PD-1 antibody (ca-4F12-E6) and evaluated its therapeutic properties in dogs with advance-staged oral malignant melanoma (OMM), however, their therapeutic effects on other types of canine tumors remain unclear. Objective: The present clinical study was carried out to evaluate the safety profile and clinical efficacy of ca-4F12-E6 in dogs with advanced solid tumors except for OMM. Methods: Thirty-eight dogs with non-OMM solid tumors were enrolled prospectively and treated with ca-4F12-E6 at 3 mg/kg every 2 weeks of each 10-week treatment cycle. Adverse events (AEs) and treatment efficacy were graded based on the criteria established by the Veterinary Cooperative Oncology Group. Results: One dog was withdrawn, and thirty-seven dogs were evaluated for the safety and efficacy of ca-4F12-E6. Treatment-related AEs of any grade occurred in 13 out of 37 cases (35.1%).Two dogs with sterile nodular panniculitis and one with myasthenia gravis and hypothyroidism were suspected of immune-related AEs. In 30 out of 37 dogs that had target tumor lesions, the overall response and clinical benefit rates were 6.9% and 27.6%, respectively. The median progression-free survival and overall survival time were 70 days and 215 days, respectively. Conclusions The present study demonstrated that ca-4F12-E6 was well-tolerated in nonOMM dogs, with a small number of cases showing objective responses. This provides evidence supporting large-scale clinical trials of anti-PD-1 antibody therapy in dogs.

A 40-year-old female visited our hospital because of malaise. She had no history of early loss of primary teeth nor family history of skeletal dysplasia. Laboratory examination showed low serum alkaline phosphatase levels of 18 U/L. In addition, hypozincemia was also observed, but alkaline phosphatase level did not increase after zinc replacement. Mediators, including calcium and phosphorus metabolism, were within normal range. X-ray examination showed no evidence of osteomalacia, but mineral bone density was slightly decreased compared with the young adult mean. Urine phosphoethanolamine level was increased, and we then suspected hypophosphatasia. Genetic tests detected ALPL gene heterozygous missense mutation (c.529G>A p.Ala177Thr and c.670A>G p.Lys224Glu) and adult-onset hypophosphatasia was finally diagnosed. It is important to evaluate alkaline phosphatase levels in the screening of patients with non-specific symptoms.

A 48-year-old woman with a history of recurrent alcoholic pancreatitis was found to have a pancreatic pseudocyst. In November 20XX, she visited the emergency department due to sudden abdominal pain. Contrast-enhanced computed tomography showed a pancreatic pseudocyst with a maximum diameter of 67 mm and ascites. A ruptured pancreatic pseudocyst was suspected and abdominal paracentesis was performed. The amylase level in the ascitic fluid was high (3444 IU/L), leading to a diagnosis of acute generalized peritonitis due to rupture of a pancreatic pseudocyst. Intraoperative findings revealed 500 mL of ascites mixed with pancreatic juice and turbid cyst contents, and distal pancreatectomy was performed. The postoperative course was favorable, and the patient was discharged on hospital day 14. Rupture of pancreatic pseudocyst is rare. In this case, it was promptly diagnosed and successfully treated with emergency surgery.

　Few studies have examined medical students' perceptions of community medicine and specialty choice through comparison between students of quotas related to community medicine and regular admission. We conducted a questionnaire survey on students' desire for future work places, types of health facility/hospital, medical specialization, and community medicine involving year 1 to year 5 students in Gifu University School of Medicine (n=335, selective admission: regular admission=81:254) . This study demonstrated that the selected students for community medicine (years 1 to 5) preferred to work at a core/small-sized hospital in a rural area and tended to choose the specialties that were characterized by primary care, such as pediatrics. Moreover, they had positive perceptions of community medicine. Further follow-up study needs to be undertaken in order to explore how students are actually engaging in community medicine after graduation.