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: Although serum carotene may contribute to dementia prevention, there is a lack of longitudinal evidence for early cognitive decline before dementia symptoms. The aim of this study was to examine whether serum carotene levels were associated with annually evaluated cognitive trajectories among the Japanese general population. METHODS: Among 581 baseline participants, 199 individuals (83 males; mean age [min, max], 62.7 [39, 90] years) who underwent cognitive assessments more than twice after baseline were analyzed. "Attention" levels were assessed using one- and three-target Digit Cancellation Tests (D-CAT1 and D-CAT3). "General cognitive ability" was assessed by the short version of Mini-Mental State Examination (SMMSE). Serum carotenes (α-carotene, β-carotene and lycopene) were measured by high-performance liquid chromatography. After the measurements, we calculated total carotene levels by summing up the levels of all measured carotene. Carotene levels were categorized into three groups for analysis (low: 0%-25%, middle: 25%-75%, and high: 75%-100%). A linear mixed model was used to estimate the slope of the D-CAT score trajectory and to compare it between three categories. RESULTS: Compared with the middle carotene group, decline of attention was faster in the D-CAT1 for low β-carotene (β = -3.48, p = 0.035), lycopene (β = -3.10, p = 0.062), and total carotene (β = -4.75, p = 0.003), but not for α-carotene (β = -2.60, p = 0.111). For the D-CAT3, decline of attention was faster in the group of low lycopene (β = -3.17, p = 0.002) and total carotene (β = -2.17, p = 0.037) compared with the middle carotene group, while no clear association for α-carotene (β = -0.67, p = 0.521) and β-carotene (β = -0.64, p = 0.639). There were no clear associations between serum carotene and the SMMSE score. CONCLUSIONS These findings suggest low levels of serum lycopene are associated with a decline of attention in the setting of the general population.
Humans ; Male ; Carotenoids/blood* ; Female ; Longitudinal Studies ; Middle Aged ; Japan ; Aged ; Adult ; Aged, 80 and over ; Attention ; Lycopene ; East Asian People

Methadone, which has unique mechanism of long-acting mu receptor agonism paired with N-Methyl-D-Aspartate（NMDA）antagonism, is thought to have potential to control pain no longer responsive to other opioids. Fatal adverse effects of methadone are respiratory suppression and QT interval prolongation, which leads to ventricular tachycardia. Here we report a case of a patient who benefited from starting on methadone in hospital and increasing methadone safely in a home-based care setting. A 79-year-old Japanese woman, who developed local recurrence after resection for primary retroperitoneal leiomyosarcoma, presented with frequent burning pain in right groin area. After receiving palliative radiation therapy, she took oxycodone and adjuvant analgesics but without relief, and began experiencing somnolence. She underwent opioid switching from oxycodone to methadone with her breakthrough pain remarkably improved. When her breakthrough pain recurred after discharge, escalating dosages of methadone was performed successfully with no serious adverse effects even in a home-based care setting, by forming multidisciplinary collaboration for the management of prescribing methadone among healthcare providers near her home.

Celiac artery aneurysm is very uncommon. We report an even more rare case in which a life threatening ruptured aneurysm was treated successfully by an emergency interventional procedure. A 72-year-old man was transferred to our hospital with a chief complaint of severe epigastralgia. In the emergency room, the patient was already in shock and emergency CT scan suggested severe intraperitoneal bleeding. The diagnosis of ruptured celiac artery aneurysm was confirmed by subsequent angiographic examinations and immediate hemostasis was successfully achieved by transcatheter arterial embolization. One year after the embolization, the patient remains asymptomatic and follow-up CT scans revealed reduction in size and thrombotic occlusion of the aneurysm.

Using various types of monoclonal antibodies and flow cytometer, whole blood analysis were conducted on subsets of lymphocytes taken from peripheral blood samples of healthy persons and umbilical cord blood samples of mature babies.
The findings were as follows:
(1) Normal values of healthy persons (Mean ± SD) were: T-cell phenotypes-OKT3⁺: 66.2 ± 9.4%, OKT4⁺: 40.9±8.3%, OKT8⁺: 28.2±6.6%, OKT11⁺: 80.1±4.8%, OKT4/OKT8 ratio: 1.57±0.60; B-cell phenotype-SmIg (polyvalent) ⁺: 15.9±6.5%; others-OKTal⁺: 12.9±3.2%, Leu7⁺: 16.2±8.9%.
(2) Of the healthy persons, 17% showed 1.0 or below and 6.5% showed 2.5 or above, in the OKT4/OKT8 ratio.
(3) The OKT4+ OKT8/OKT3 ratio was significantly high (P<0.001) in the babies and persons of 40 years and over.
(4) Physiologic variations were noted in some degree in children and the aged, and between men and women. The individual values of the lymphocyte subsets were almost constant, but the difference between individuals was large. It is suggested that the difference of the immune response of each individual or each family partly depends on the different values of the lymphocyte subsets.

We have established NICU (Neonatal Intensive Care Unit) in our hospital and concentrated our efforts on improving the contents of medical treatment since 1976 in order to accomplish a regionalization of neonatal medical treatment in our district.
Thereafter, the mortality rate of low birth weight infants at different weight have decreased markedly. During this period, we have gathered information by means of questinnaire concerning the prognosis of low birth weight (below 2, 000 g) infants whowere admitted in our hospital in the preimprovement period of five years (1971 through 1975, Group 1; N =110) and in the post-improvement period of five years (1976 through 1980, Group 2; N = 96).
The results were as follows:
1, In terms of height and weight, both groups revealed to be no less than those of normal infants.
2. The occurrence of cerebral palsy in Group 2 (2.2%) decreased to below one third of Group 1 (7.5%).
3. There were two infants with blindness resulting from retrolental fibloplasia in Group 1 and one in Group 2.
4. As regards the occurrence rate of epilepsy, there were two children with it in Group 1 (1.98%) and one in Group 2 (1.1%), whereas four children in Group 1 had episodes of afebrile convulsion.
5. Five (5.4%) of 92 grade-school pupils in Group 1 were attending a clss for handicapped.
From these results, it may be concluded that the improvement of neonatal medical treatment brought about a decrease of death rate of low birth weight infants and the improvement of theirprognosis as well.

We have established NICU (Neonatal Intensive Care Unit) in our hospital and have made efforts to improve the contents of medical treatment since 1976 in order to establish a regionalization of neonatal medical treatment.
Thus are main items of the improvement:
1. Completed the apparatuses and equipments needed in Intensive Care.
2. Promoted the communication with regional facilities of delivery so as to enable immature or stressed mature babies to be transported to our hospital at all hours.
3. Made Pediatrician attend all the deliveries with high risk factors and treat the asphyxiated newborn right after the delivery.
We have recorded the results of comparison of the death rate of immature babies at different birth weight treated in our hospital, and of the perinatal mortality in our Obstetric Department in the pie-improvement period of 5 years (1971-1975) and in the post-improvement period of 4 years (1976-1979) respectively.
The results are as follows:
1. A comparison of the death rate of immature babies at different birth weight.
In comparison of pre and post improvement, under 1, 000 g we haven't had enough cases to compare, besides most of the babies have died. However, at the weight between 1, 001-1, 500 g, the death rate has decreased from 39.4% down to 14.3%, at between 1, 501-2, 000g it has decreased from 11.4% down to 8.9%, and at between 2, 001-2, 500 g, from 6.9% to 1.1%.
2. A comparison of the perinatal mortality in our Obstetric Department.
The perinatal mortality has decreased from 18.5% down to 11.8% when we compare pre and post improvement. This result of the decrease depends on the decrease of fetal death at delivery and baby's death in the early neonatal period. Items of the causes of early neonatal death reveals that the deaths of immature babies and asphyxiated mature babies have decreased significantly.
From these results, we are fully realized the benefit of the regionalization of the neonatal medical treatment and I think we ought to promote such regionalization especially in rural area.