RESUMEN
Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis in monoaminergic neurons, phenylalanine metabolism in hepatocytes, and nitric oxide synthesis in endothelial and immune cells. BH4 is consumed as a cofactor or is readily oxidized by autooxidation. Quinonoid dihydropteridine reductase (QDPR) is an enzyme that reduces quinonoid dihydrobiopterin (qBH2) back to BH4, and we have previously demonstrated the significance of QDPR in maintaining BH4 in vivo using Qdpr-KO mice. In addition to the levels of BH4 in the cells, the ratios of oxidized to reduced forms of BH4 are supposed to be important for regulating nitric oxide synthase (NOS) via the so-called uncoupling of NOS. However, previous studies were limited due to the absence of specific and high-affinity inhibitors against QDPR. Here, we performed a high-throughput screening for a QDPR inhibitor and identified Compound 9b with an IC50 of 0.72 µM. To understand the inhibition mechanism, we performed kinetic analyses and molecular dynamics simulations. Treatment with 9b combined with methotrexate (MTX), an inhibitor of another BH4-reducing enzyme, dihydrofolate reductase (DHFR), significantly oxidized intracellular redox states in HepG2, Jurkat, SH-SY5Y, and PC12D cells. Collectively, these findings suggest that 9b may enhance the anticancer and anti-autoimmune effects of MTX.
Asunto(s)
Biopterinas , Dihidropteridina Reductasa , Sinergismo Farmacológico , Metotrexato , Metotrexato/farmacología , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Humanos , Dihidropteridina Reductasa/metabolismo , Inhibidores Enzimáticos/farmacología , Oxidación-Reducción/efectos de los fármacos , Animales , Simulación de Dinámica MolecularRESUMEN
AIM: In Japan, an additional system for patients with suspected or diagnosed dementia during hospitalization for physical illness began in 2016. We examined the clinical characteristics of older patients with suspected or diagnosed dementia during hospitalization. METHODS: The study participants consisted of 569 patients. Current age, sex, comorbidities, causative disease for admission, body mass index (BMI), blood tests, environment before admission, prescription history before admission and rate of delirium were examined. Simple regression analysis for high-frequency diseases was carried out with the respective risk factors as independent variables. Multiple regression analysis was then carried out. RESULTS: Infection had the highest frequency in the causative diseases for admission. A total of 48% of patients had delirium during hospitalization. The delirium group had the highest frequency of being at home. In the infection group, BMI and serum albumin were lower in the non-infection group (BMI 19.0 ± 3.7 vs 20.4 ± 4.1; P < 0.001, albumin 2.1 ± 0.7 vs 3.3 ± 0.6 g/dL; P < 0.001 respectively). White blood cell count and C-reactive protein were higher than in the non-infection group, respectively (white blood cell count 11181.4 ± 6533.3 vs 8765.8 ± 111 424.3/µL; P = 0.007, C-reactive protein 8.6 ± 8.6 vs 3.0 ± 5.2 mg/dL; P < 0.001 respectively). Using independent factors associated with infection, multiple regression analysis was performed. BMI (P = 0.013), serum albumin (P < 0.001) and nursing home care before admission (P < 0.001) had significant correlations. CONCLUSIONS: Assessment of delirium and the environment before admission of older patients with suspected or diagnosed dementia when hospitalized are necessary. Furthermore, evaluation of nutrition might also contribute to reducing deterioration due to physical illness. Geriatr Gerontol Int 2024; 24: 641-645.
Asunto(s)
Demencia , Hospitalización , Humanos , Femenino , Masculino , Demencia/diagnóstico , Demencia/epidemiología , Anciano , Anciano de 80 o más Años , Japón/epidemiología , Factores de Riesgo , Delirio/diagnóstico , Delirio/epidemiología , Índice de Masa Corporal , Evaluación Geriátrica/métodos , ComorbilidadRESUMEN
Background: Because dementia is a long-term condition, the appropriate involvement of health-care professionals is considered important. However, little is known about the factors associated with changes in family caregiver burden. Objective: To clarify changes in family caregiver burden and associated factors during follow-up at a memory clinic. Methods: A retrospective cohort study was conducted, enrolling 495 pairs of patients with dementia or mild cognitive impairment and their family caregivers. A total of 120 pairs completed the second evaluation. The caregiver burden was assessed using the Zarit Burden Interview (ZBI). Data at the initial visit and after an average follow-up of about 2 years were compared and analyzed. Results: At initial visit, the patients' mean age, Mini-Mental State Examination (MMSE) and ZBI scores were 78.6±5.6 years, 23.3±3.5, and 22.6±16.7, respectively. At follow-up, MMSE scores decreased (21.4±4.5, pâ<â0.001), but ZBI scores remained similar (22.5±13.6). When the difference in ZBI scores between the two time points was defined as ΔZBI, and the related factors were analyzed by multiple regression analysis, ZBI scores at the initial visit, start of psychotropic drug, and decrease of neuropsychiatric symptoms were identified as significant factors (pâ<â0.001, pâ=â0.003, pâ<â0.001, respectively). A significant negative correlation was found between ZBI scores at the initial visit and ΔZBI (râ=â-0.588, pâ<â0.001). Conclusions: These findings suggest the importance of assessing changes in the burden experienced by family caregivers during the disease follow-up.
RESUMEN
Fungal contamination in the indoor air of prefabricated temporary houses at the site of the Great East Japan Earthquake revealed extremely high levels compared to those found in conventional residences. We experimentally investigated fungal growth levels on different interior materials to support fungal overgrowth in prefabricated temporary houses. Three species each of allergenic fungi and invasive fungi observed in temporary housing were selected for inoculation tests with various interior materials. The experiments with fungal inoculation were conducted in conformance with standards for industrial products described in the Japanese" JIS Z 2911:2018 Methods of test for fungus resistance" with small modifications. After incubation, visual and stereomicroscopic assessments were performed to determine fungal growth levels. The viability of the fungi varied according to the interior material type. Our findings demonstrate the importance of antifungal measures in indoor environments and the need for additional research on the growth levels of fungal species on various interior materials.
Asunto(s)
Terremotos , Japón , ViviendaRESUMEN
Residents themselves are responsible for controlling their living environment, and their perception of coldness is important to protect their health. Although previous studies examined the association between perceived coldness and indoor temperature, they did not consider the spatial-temporal differences in indoor temperatures. This study, conducted in Japan, measured indoor temperatures in 1,553 houses across several rooms (living room, changing room, and bedroom) and heights (at 1 m above the floor and near the floor) over two weeks and obtained the perceived coldness from 2,793 participants during winter. Results showed substantial temperature differences between rooms (horizontal differences): 3.8 °C between living and changing rooms, and 4.1 °C between living rooms and bedrooms. The average vertical and diel (evening-morning) temperature differences in the living room were 3.1 °C and 3.0 °C, respectively. Regional analysis revealed that the Tohoku region experienced larger horizontal and diel indoor temperature differences, primarily due to its practice of intermittent and partial heating in living rooms only, in contrast to Hokkaido's approach of heating the entire house continuously. Despite Hokkaido's comprehensive heating system, it exhibited the largest vertical temperature difference of 5.1 °C in living rooms, highlighting the insufficiency of heating alone and the necessity for enhanced thermal insulation. The multivariate logistic regression analyses showed that average temperatures and vertical temperature differences were associated with perceived coldness, while horizontal and diel differences did not show a significant association, further emphasizing the importance of improved thermal insulation. Moreover, factors like individual attributes (age and gender), and lifestyle choices (meal quantity, exercise habits, alcohol consumption, and clothing amount) were significantly associated with coldness perception. Notably, older adults were less likely to perceive coldness but more vulnerable to the health impacts of low temperatures, underscoring the necessity of not solely relying on human perception for indoor temperature management to protect cold-related health problems.
Asunto(s)
Frío , Vivienda , Estaciones del Año , Japón , Humanos , Estudios Transversales , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Adulto Joven , Temperatura , Calefacción , PercepciónRESUMEN
BACKGROUND: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice. METHODS: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival. RESULTS: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively. CONCLUSION: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice.