Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.

Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography-tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle-bone relationship.

Discontinuation of Alzheimer Disease Medications in Patients Receiving Home Care Medicine.

There is no consensus on how long antidementia medications should be administered to patients with Alzheimer disease (AD). To clarify this issue, we investigated the discontinuation of antidementia medications in Japanese home care settings, including community-dwelling and institutionalized patients. Using medical records from April 2017 to March 2022 at 3 clinics in Tokyo and Chiba prefectures, we selected patients with AD who started receiving home care medicine. Forty-nine patients discontinued antidementia medications during the observation period, there was no apparent deterioration in cognitive function or new occurrence of behavioral and psychological symptoms of dementia caused by the discontinuation of medications. More aggressive discontinuation of AD medications probably is recommended for patients with activities of daily living dysfunction, such as those receiving home care medicine.

Safety profile of hypnotics or sedatives on community-dwelling older adults aged 75 or older in Japan: A retrospective propensity-matched cohort study.

OBJECTIVE: The purpose of the study is to assess if daily use of hypnotics increases mortality, aspiration pneumonia and hip fracture among relatively healthy individuals aged 75 years or older who lead independent lives in the community. METHOD AND PATIENTS: Of the adults aged 75 years or older residing in Hokkaido prefecture of Japan (n = 705,538), those who did not meet several exclusion criteria were eligible for generating propensity score-matched cohorts (n = 214,723). Exclusion criteria included co-prescribed medications acting on the central nervous system, diagnoses of malignant neoplasm, dementia, depression, etc. We compared 33,095 participants who were prescribed hypnotics for daily use (hypnotic group) with a propensity score-matched cohort without a prescription (control group). Participants were followed for more than 42 months. RESULTS: During the 42-month follow-up period, the incidence of the three outcome measures in the hypnotics group was significantly higher than that in the control group (aspiration pneumonia p < 0.001, hip fracture p = 0.007, and all-cause mortality p < 0.001). Sensitivity analyses utilizing inverse probability weighting demonstrated hazard ratios of 1.083 [1.023-1.146] for mortality, 1.117 [1.014-1.230] for aspiration pneumonia, and 1.720 [1.559-1.897] for hip fracture. Meanwhile, the attribute risk differences were 2.7, 1.5, and 1.0 per 1000 patient-years, respectively. CONCLUSIONS: Although daily use of hypnotics increased the risk of three events, their attribute risk differences were fewer than 3.0 per 1000 patient-years. The results will help provide guidance on whether it is reasonable to prescribe hypnotics to geriatric population aged 75 or older leading independent lives in the community. CLINICAL TRIAL REGISTRATION: UMIN-CTR UMIN000048398.

Early-onset dementia and risk of hip fracture and major osteoporotic fractures.

INTRODUCTION: There is limited knowledge about early-onset dementia (EOD) on fracture risk. METHODS: Individuals ages 50 to 64 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2012 to 2019). The association between EOD and fractures and the association between cholinesterase inhibitors for EOD and fractures were evaluated using logistic regression analyses. RESULTS: We identified 13,614 EOD patients and 9,144,560 cognitively healthy individuals. The analysis revealed that EOD was associated with an increased risk of hip fractures (adjusted odds ratio, 95% confidence interval: 8.79, 7.37-10.48), vertebral fractures (1.73, 1.48-2.01), and major osteoporotic fractures (2.05, 1.83-2.30) over 3 years. The use of cholinesterase inhibitors was significantly associated with a reduction in hip fractures among EOD patients (0.28, 0.11-0.69). DISCUSSION: EOD patients have a higher risk of osteoporotic fractures than cognitively healthy individuals. The use of cholinesterase inhibitors may reduce the risk of hip fracture among EOD patients. HIGHLIGHTS: It is unknown whether early-onset dementia (EOD) increases the risk of fractures. We identified 13,614 individuals with EOD using a nationwide administrative database. Patients with EOD have a higher risk of hip, vertebral, and major osteoporotic fractures. The use of cholinesterase inhibitors may reduce hip fracture among patients with EOD.

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Background: Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones. Methods: A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords. Main Findings Results: Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent. Conclusion: The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

BACKGROUND: Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis. RESULTS: A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36). CONCLUSIONS: In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

Serum IgA augments adhesiveness of cultured lung microvascular endothelial cells and suppresses angiogenesis.

Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, ß1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.

Changes in Polypharmacy and Potentially Inappropriate Medications in Homebound Older Adults in Japan, 2015-2019: a Nationwide Study.

BACKGROUND: With rising worldwide population aging, the number of homebound individuals with multimorbidity is increasing. Improvement in the quality of home medical care (HMC), including medications, contributes to meeting older adults' preference for "aging in place" and securing healthcare resources. OBJECTIVE: To evaluate the changes in drug prescriptions, particularly potentially inappropriate medications (PIMs), among older adults receiving HMC in recent years, during which measures addressing inappropriate polypharmacy were implemented, including the introduction of clinical practice guidelines and medical fees for deprescribing. DESIGN: A cross-sectional study. PARTICIPANTS: Using data from the national claims database in Japan, this study included older adults aged ≥ 75 years who received HMC in October 2015 (N = 499,850) and October 2019 (N = 657,051). MAIN MEASURES: Number of drugs, prevalence of polypharmacy (≥ 5 regular drugs), major drug categories/classes, and PIMs according to Japanese guidelines were analyzed. Random effects logistic regression models were used to evaluate the differences in medications between 2015 and 2019, considering the correlation within individuals who contributed to the analysis in both years. KEY RESULTS: The number of drugs remained unchanged from 2015 to 2019 (median: 6; interquartile range: 4, 9). The prevalence of polypharmacy also remained unchanged at 70.0% in both years (P = 0.93). However, the prescription of some drugs (e.g., direct oral anticoagulants, new types of hypnotics, acetaminophen, proton pump inhibitors, and ß-blockers) increased, whereas others (e.g., warfarin, vasodilators, H2 blockers, acetylcholinesterase inhibitors, and benzodiazepines) decreased. Among the frequently prescribed PIMs, benzodiazepines/Z-drugs (25.6% in 2015 to 21.1% in 2019; adjusted odds ratio: 0.52) and H2 blockers (11.2 to 7.3%; 0.45) decreased, whereas diuretics (23.8 to 23.6%; 0.90) and antipsychotics (9.7 to 10.5%; 1.11) remained unchanged. CONCLUSIONS: We observed some favorable changes but identified some continuous and new challenges. This study suggests that continued attention to medication optimization is required to achieve safe and effective HMC.

Polypharmacy with potentially inappropriate medications as a risk factor of new onset sarcopenia among community-dwelling Japanese older adults: a 9-year Kashiwa cohort study.

BACKGROUND: Clinical evidence demonstrating a longitudinal association between prescribed medications and sarcopenia onset is lacking. We investigated the association of polypharmacy (the use of five or more medications) and potentially inappropriate medications (PIMs) with sarcopenia risk in community-dwelling older adults. METHODS: In this longitudinal population-based cohort study, 2,044 older residents with no long-term care needs were randomly selected from a community in Kashiwa, Japan. Baseline data collection was conducted in 2012, with follow-ups in 2013, 2014, 2016, 2018, and 2021. Prescribed medications and PIMs (drugs listed in the Screening Tool for Older Person's Appropriate Prescriptions for the Japanese or potentially muscle-wasting drugs) were identified through interviews. New-onset sarcopenia was identified according to the 2019 criteria of the Asian Working Group for Sarcopenia over a 9-year period and analyzed. We used Cox proportional hazards models to test the longitudinal association of prescribed medications with sarcopenia onset. RESULTS: Of the 1,549 participants without sarcopenia at baseline (mean age, 72.5 ± 5.5 years; 49.1% women; median and interquartile range, 6.0 [4.0-9.0] years), 230 experienced new-onset sarcopenia during the follow-up. After adjusting for confounders, polypharmacy combined with PIM use was strongly associated with new-onset sarcopenia (adjusted hazard ratio, 2.35; 95% confidence interval, 1.58-3.51; P < 0.001). No significant associations were observed for either PIM use or polypharmacy alone. CONCLUSIONS: Polypharmacy combined with PIM use, but not polypharmacy alone, was associated with an increased risk of new-onset sarcopenia over the 9-year follow-up period among community-dwelling older adults. Limiting polypharmacy and imposing the prescription of appropriate medications may facilitate sarcopenia prevention.

Validation of the questionnaire for medical checkup of old-old (QMCOO) score cutoff to diagnose frailty.

BACKGROUND: Frailty is a state of increased vulnerability to poor resolution of homeostasis following a stress. Early diagnosis and intervention of frailty are essential to prevent its adverse outcomes. However, simple diagnostic criteria have not been established. The Questionnaire for Medical Checkup of Old-Old (QMCOO) is widely used for medical checkups of older adults in Japan. In our previous report, we developed a method to score the QMCOO and showed that frailty can be diagnosed with the highest accuracy when the score cutoff was set at 3/4 points. We aimed to validate the criteria in a larger cohort. METHODS: Participants aged 65 years or over were recruited in the western region of Japan. They answered all the items of the Kihon Checklist (KCL) and the QMCOO. Based on the KCL score, they were diagnosed as robust (3 or lower), prefrail (4 to 7), or frail (8 or over). Then we tested the effectiveness to diagnose frailty using the QMCOO cutoff of 3/4 points. We also aimed to determine the score cutoff to separate robust and prefrail. RESULTS: 7,605 participants (3,458 males and 4,147 females, age 77.4 ± 6.9 years) were recruited. 3,665 participants were diagnosed as robust, 2,448 were prefrail, and 1,492 were frail based on the KCL score. The diagnosis of frailty had a sensitivity of 84.0%, specificity of 82.5%, and accuracy of 82.8% with a QMCOO score cutoff of 3/4 points, suggesting its validity. To separate robust and prefrail, both the accuracy and the Youden index were the highest with the QMCOO cutoff of 2/3 points (sensitivity, specificity, and accuracy were 63.9%, 83.4%, and 75.6%, respectively). All the questions of the QMCOO except Q12 (about smoking) were significantly related to prefrailty status after a logistic regression analysis. CONCLUSION: Diagnosis of frailty using the QMCOO score cutoff of 3/4 points was validated. Prefrailty could be diagnosed using the score cutoff of 2/3 points.

Questionnaires for the Assessment of Cognitive Function Secondary to Intake Interviews in In-Hospital Work and Development and Evaluation of a Classification Model Using Acoustic Features.

The number of people with dementia is increasing each year, and early detection allows for early intervention and treatment. Since conventional screening methods are time-consuming and expensive, a simple and inexpensive screening is expected. We created a standardized intake questionnaire with thirty questions in five categories and used machine learning to categorize older adults with moderate and mild dementia and mild cognitive impairment, based on speech patterns. To evaluate the feasibility of the developed interview items and the accuracy of the classification model based on acoustic features, 29 participants (7 males and 22 females) aged 72 to 91 years were recruited with the approval of the University of Tokyo Hospital. The MMSE results showed that 12 participants had moderate dementia with MMSE scores of 20 or less, 8 participants had mild dementia with MMSE scores between 21 and 23, and 9 participants had MCI with MMSE scores between 24 and 27. As a result, Mel-spectrogram generally outperformed MFCC in terms of accuracy, precision, recall, and F1-score in all classification tasks. The multi-classification using Mel-spectrogram achieved the highest accuracy of 0.932, while the binary classification of moderate dementia and MCI group using MFCC achieved the lowest accuracy of 0.502. The FDR was generally low for all classification tasks, indicating a low rate of false positives. However, the FNR was relatively high in some cases, indicating a higher rate of false negatives.

Breathing irregularities before sleep onset on polysomnography in patients with heart diseases.

PURPOSE: Severe cardiac dysfunction can manifest with diurnal breathing irregularity. However, it remains to be clarified whether or not diurnal breathing irregularity is observed in patients with heart diseases, including relatively mild chronic heart failure (CHF), compared to those without heart diseases. METHODS: In this cross-sectional study, consecutive inpatients who were admitted for evaluation of sleep-disordered breathing were enrolled. We extracted 3.5 min of stable respiratory signals before sleep onset using polysomnography, analyzed the airflow data using fast Fourier transform, and quantified breathing irregularities using Shannon entropy S. RESULTS: A total of 162 subjects were evaluated. Among these, 39 subjects had heart diseases, including ischemic heart disease (IHD), atrial fibrillation (Af), CHF, and a history of aortic dissection. The values of Shannon entropy S of airflow signals in subjects with heart diseases were significantly higher than in those without heart diseases (p < 0.001). After excluding CHF, the Shannon entropy S was also significantly higher in subjects with heart diseases than in those without heart diseases (p < 0.001). The values of Shannon entropy S were significantly correlated with plasma brain natriuretic peptide levels (r = 0.443, p < 0.001). Although the values were also significantly correlated with body mass index, the presence of heart diseases was independently associated with breathing irregularity in the multiple logistic analysis. Matching analysis revealed consistent differences between subjects with heart diseases and without heart diseases. CONCLUSION: Breathing irregularity was observed before sleep onset in subjects with heart diseases who underwent polysomnography to diagnose sleep-disordered breathing.

Influence of oral health on frailty in patients with type 2 diabetes aged 75 years or older.

BACKGROUND: Poor oral health conditions are known to affect frailty in the older adults. Diabetes is a risk factor for both poor oral health and frailty, therefore, oral health status may affect frailty in diabetic patients more than in the general population. The purpose of this study was to evaluate the influence of oral health and other factors on frailty and the relationship among oral health, diabetes and frailty in older adult patients with type 2 diabetes. METHODS: Patients with type 2 diabetes aged 75 years or older were included in this cross-sectional study. Eligible patients were surveyed by questionnaire for frailty, oral health status, and cognitive and living functions. Factors influencing pre-frailty, frailty, and individual frailty screening index (FSI) classes were evaluated. RESULTS: Of the 111 patients analyzed, 66 cases (59.5%) were categorized as robust, 33 cases (29.7%) as pre-frailty, and 12 cases (10.8%) as frailty. The oral frailty index, the cognitive and living functions score, and BMI were found to be factors influencing pre-frailty or frailty. In the evaluation of individual FSI classes, BMI had an influence on those with a FSI ≤2. The cognitive and living functions score was a factor influencing those with FSI ≤3. The oral frailty index was found to have a significant influence on all FSI classes. CONCLUSIONS: Poor oral health has an influence on frailty in patients with type 2 diabetes aged ≥75. In this patient population, as frailty progresses, the impact of oral health on frailty may increase. TRIAL REGISTRATION: This study was retrospectively registered in UMIN-CTR ( UMIN000044227 ).

Malnutrition and depression as predictors for 30-day unplanned readmission in older patient: a prospective cohort study to develop 7-point scoring system.

BACKGROUND: Readmission is related to high cost, high burden, and high risk for mortality in geriatric patients. A scoring system can be developed to predict the readmission of older inpatients to perform earlier interventions and prevent readmission. METHODS: We followed prospectively inpatients aged 60 years and older for 30 days, with initial comprehensive geriatric assessment (CGA) on admission in a tertiary referral centre. Patients were assessed with CGA tools consisting of FRAIL scale (fatigue, resistance, ambulation, illness, loss of weight), the 15-item Geriatric Depression Scale, Mini Nutritional Assessment short-form (MNA-SF), the Barthel index for activities of daily living (ADL), Charlson Comorbidity Index (CCI), caregiver burden based on 4-item Zarit Burden Index (ZBI), and cognitive problem with Abbreviated Mental Test (AMT). Demographic data, malignancy diagnosis, and number of drugs were also recorded. We excluded data of deceased patients and patients transferred to other hospitals. We conducted stepwise multivariate regression analysis to develop the scoring system. RESULTS: Thirty-day unplanned readmission rate was 37.6 %. Among 266 patients, 64.7 % of them were malnourished, and 46.5 % of them were readmitted. About 24 % were at risk for depression or having depressed mood, and 53.1 % of them were readmitted. In multivariate analysis, nutritional status (OR 2.152, 95 %CI 1.151-4.024), depression status (OR 1.884, 95 %CI 1.071-3.314), malignancy (OR 1.863 95 %CI 1.005-3.451), and functional status (OR 1.584, 95 %CI 0.885-2.835) were included in derivation of 7 score system. The scoring system had maximum score of 7 and incorporated malnutrition (2 points), depression (2 points), malignancy (2 points), and dependent functional status (1 point). A score of 3 or higher suggested 82 % probability of readmission within 30 days following discharge. Area under the curve (AUC) was 0.694 (p = 0.001). CONCLUSIONS: Malnutrition, depression, malignancy and functional problem are predictors for 30-day readmission. A practical CGA-based 7 scoring system had moderate accuracy and strong calibration in predicting 30-day unplanned readmission for older patients.

Updated concept of sarcopenia based on muscle-bone relationship.

Sarcopenia is an age-related loss of skeletal muscle mass and strength. It has been widely recognized that low muscle mass was essential in the diagnosis of sarcopenia, whereas recent studies have emphasized the importance of muscle strength. In practice, muscle quality as well as muscle mass might determine the strength and physical performance. A new diagnostic algorithm of sarcopenia has recently been established, in which low muscle strength is a key characteristic factor for the diagnosis of sarcopenia. Although many factors are supposed to be involved in the pathology and development of sarcopenia, precise mechanisms remain to be elucidated. Recent studies have also focused on the crosstalk between muscles and bones, including functional involvement of myokines and osteokines.

Use of Anti-Dementia Drugs Reduces the Risk of Potentially Inappropriate Medications: A Secondary Analysis of a Nationwide Survey of Prescribing Pharmacies.

AIMS: As the number of older people with dementia increases, safe pharmacotherapy in this population has attracted attention in recent years. The aims of this study were to clarify the prescribing patterns in older patients who were prescribed anti-dementia drugs and to investigate the association of potentially inappropriate medications (PIMs) with the use of anti-dementia drugs. METHODS: Adults aged ≥65 years, who were prescribed anti-dementia drugs at 585 pharmacies across Japan (N = 7,953), were surveyed. The percentage of prescriptions of anti-dementia drugs and the effect of those prescriptions on PIMs were investigated. RESULTS: Prescriptions of anti-dementia drugs were found in 4.4% of the entire study population. A multiple logistic regression analysis revealed that the use of anti-dementia drugs reduced the risk of prescribing psychotropic drugs, which represented PIMs, and that a combination of anti-dementia drugs (e.g., cholineesterase inhibitor with memantine) may reduce the risk of prescribing PIMs compared with monotherapy. CONCLUSION: The use of anti-dementia drugs was associated with fewer prescriptions of drugs considered as PIMs.

Low-Intensity Exercise Suppresses CCAAT/Enhancer-Binding Protein δ/Myostatin Pathway Through Androgen Receptor in Muscle Cells.

BACKGROUND: Androgen production following exercise has been suggested to contribute anabolic actions of muscle. However, the underlying mechanisms of the androgen receptor (AR) in androgen's action are still unclear. OBJECTIVE: In the present study, we examined androgen/AR-mediated action in exercise, especially for the suppression of myostatin, a potent negative regulator of muscle mass. METHODS: To examine the effects of exercise, we employed low-intensity exercise in mice and electric pulse stimulation (EPS) in C2C12 myotubes. Androgen production by C2C12 myotubes was measured by enzyme-linked immunosorbent assay. To block the action of AR, we pretreated C2C12 myotubes with flutamide. Quantitative real-time polymerase chain reaction was used to determine the expression levels of proteolytic genes including CCAAT/enhancer-binding protein delta (C/EBPδ), myostatin and muscle E3 ubiquitin ligases, as well as myogenic genes such as myogenin and PGC1α. The activation of 5'-adenosine-activated protein kinase and STAT3 was determined by Western blot analysis. RESULTS: Both mRNA and protein levels of AR significantly increased in skeletal muscle of low-intensity exercised mice and C2C12 myotubes exposed to EPS. Production of testosterone and dihydrotestosterone from EPS-treated C2C12 myotubes was markedly increased. Of interest, we found that myostatin was clearly inhibited by EPS, and its inhibition was significantly abrogated when AR was blocked by flutamide. To test how AR suppresses myostatin, we examined the effects of EPS on C/EBPδ because the promoter region of myostatin has several C/EBP recognition sites. C/EBPδ expression was decreased by EPS, and this decrease was negated by flutamide. IL-6 and phospho-STAT3 (pSTAT3) expression, the downstream pathway of myostatin, were decreased by EPS and this was also reversed by flutamide. Similar downregulation of C/EBPδ, myostatin, and IL-6 was seen in skeletal muscle of low-intensity exercised mice. CONCLUSIONS: Muscle AR expression and androgen production were increased by exercise and EPS treatment. As a mechanistical insight, it is suggested that AR inhibited myostatin expression transcriptionally by C/EBPδ suppression, which negatively influences IL-6/pSTAT3 expression and consequently contributes to the prevention of muscle proteolysis during exercise.

Polysomnographic features of low arousal threshold in overlap syndrome involving obstructive sleep apnea and chronic obstructive pulmonary disease.

PURPOSE: In patients with overlap syndrome (OVS), the pathophysiologies of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease can interact with one another. Focusing on low arousal threshold, the authors evaluated polysomnographic features of OVS patients. METHODS: This retrospective, multicenter study was conducted at three hospitals in Japan. Patients aged ≥ 60 years who underwent polysomnography and pulmonary function testing were reviewed. Severity of airflow limitation (AFL) was classified according to the Global Initiative for Chronic Obstructive Lung Disease criteria. Low arousal threshold was predicted based on the following polysomnography features: lower apnea-hypopnea index (AHI); higher nadir oxygen saturation, and larger hypopnea fraction of total respiratory events. These features were compared among patients with only OSA (n = 126), OVS with mild AFL (n = 16), and OVS with moderate/severe AFL (n = 22). RESULTS: A low arousal threshold was more frequently exhibited by OVS patients with moderate/severe AFL than by those with OSA only (p = 0.016) and OVS with mild AFL (p = 0.026). As forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) decreased in OVS patients, the mean length of apnea decreased (r = 0.388, p = 0.016), hypopnea fractions increased (r = - 0.337, p = 0.039), and AHI decreased (r = 0.424, p = 0.008). FEV1/FVC contributed to low arousal threshold independent of age, sex, smoking history, hospital, or body mass index in all subjects (OR 0.946 [95% CI 0.909-0.984]) and in OVS patients (OR 0.799 [95% CI 0.679-0.940]). CONCLUSIONS: This study first described peculiar polysomnographic features in OVS patients with moderate/severe AFL, suggesting a high prevalence of low arousal threshold.

Sex-related differences in the association between frailty and dietary consumption in Japanese older people: a cross-sectional study.

BACKGROUND: Female sex is an important factor predisposing individuals to frailty. Appropriate nutrition is one of the most effective ways to prevent older adults from developing frailty; Sex-related differences have also been detected in the association between nutritional intervention and health-related outcomes. However, few studies have discussed these sex-related differences. The aim of the present study was to investigate the sex-related differences in the association between frailty and dietary consumption. METHODS: We conducted a cross-sectional study which investigated community-dwelling older adults aged ≥65 years. We surveyed age, sex, body mass index, family arrangement (living alone, living with a partner or living with parent(s) and/or child (ren)), dietary consumption and frailty status. Dietary consumption was surveyed using a food frequency questionnaire that included 13 major food categories (fish, meat, eggs, dairy products, soybean products, vegetables, seaweeds, potatoes, fruits, fats or oils, snacks, salty foods and alcohol). Frailty was defined by the Kihon Checklist score. The Kihon Checklist is composed of 25 simple yes/no questions, and it has been validated as a metric for frailty. A higher score indicates a greater degree of frailty. Multinomial regression analysis was performed to clarify the association between frailty and dietary consumption for each sex. RESULTS: We analyzed 905 older adults (420 (46.4%) were male). After adjusting for cofounders, a low frequency of meat consumption (less than twice/week) was associated with a high prevalence of frailty in men (odds ratio: 2.76 (95%CI: 1.12-6.77), p = 0.027). In contrast, in women, low frequencies of consumption of fish, meat, vegetables, potatoes and snacks were associated with a higher prevalence of frailty compared with those who consumed foods from those categories daily (odds ratios: fish 2.45 (1.02-5.89), p = 0.045; meat 4.05 (1.67-9.86), p = 0.002; vegetables 5.03 (2.13-11.92), p < 0.001; potatoes 3.84 (1.63-9.05), p = 0.002; snacks 2.16 (1.02-4.56), p = 0.043). CONCLUSIONS: More food categories were associated with frailty in women than in men. Nutritional intervention to prevent frailty is presumably more effective for women than for men.

Identifying drug substances of screening tool for older persons' appropriate prescriptions for Japanese.

BACKGROUND: In 2015, the Japan Geriatric Society (JGS) updated "the Guidelines for Medical Treatment and its Safety in the elderly," accompanied with the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J): "drugs to be prescribed with special caution" and "drugs to consider starting." The JGS proposed the STOPP-J to contribute to improving prescribing quality; however, each decision should be carefully based on medical knowledge. The STOPP-J shows examples of commonly prescribed drug substances, but not all relevant drugs. This research aimed to identify substances using such coding, as a standardized classification system would support medication monitoring and pharmacoepidemiologic research using such health-related information. METHODS: A voluntary team of three physicians and two pharmacists identified possible approved medicines based on the STOPP-J, and matched certain drug substances to the Anatomical Therapeutic Chemical Classification (ATC) and the Japanese price list as of 2017 February. Injectables and externally used drugs were excluded, except for self-injecting insulin, since the STOPP-J guidelines are intended to cover medicines used chronically for more than one month. Some vaccines are not available in the Japanese price list since they not reimbursed through the national health insurance. RESULTS: The ATC 5th level was not available for 39 of the 235 identified substances, resulting in their classification at the ATC 4th level. Furthermore, among 26 combinations, 10 products were matched directly to the ATC 5th level of the exact substances, and others were linked to the ATC representing the combination or divided into multiple substances for classification if the combination was not listed in the ATC. CONCLUSION: This initial work demonstrates the challenge of matching ATC codes and the Japan standard commodity classification codes corresponding to STOPP-J substances. Since coding facilitates database analysis, the proposed drug list could be applied to research using large databases to examine prescribing patterns in patients older than 75 years or who are frail. Since ATC is not available for some substances, Japanese medicines need the process to be registered in the ATC for an effective screening tool to be developed for STOPP-J.