Association between dynapenia and cognitive decline in community-dwelling older Japanese adults: The IRIDE Cohort Study.

AIM: Muscle mass and strength correlate with cognitive function; however, it remains unclear whether dynapenia (i.e., muscle weakness with preserved muscle mass) is relevant. This study aimed to explore whether dynapenia is associated with global cognitive function in community-dwelling older Japanese adults. METHODS: This cross-sectional study used data from the Integrated Research Initiative for Living Well with Dementia Cohort Study, which pooled data from five community-based geriatric cohorts. Dynapenia was defined as muscle weakness without muscle mass loss according to the Asian Working Group for Sarcopenia criteria. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). An ordered logistic regression analysis was conducted with dynapenia as the exposure and with cognitive decline stages, defined as an MMSE score of 27-30 for normal cognition, 24-26 for possible cognitive decline, and <24 for cognitive decline, as the outcome, stratified by sex and adjusted for age, muscle mass, education, alcohol consumption, smoking habits, living alone, and non-communicable diseases. RESULTS: We analyzed data for 3338 participants (2162 female) with preserved muscle mass. Of these, 449 (13.5%) had dynapenia, and 79 (2.4%) exhibited cognitive decline. Multivariate odds ratios (95% confidence interval) for cognitive decline among those with dynapenia, compared with those without dynapenia, were 1.51 (1.02-2.24) for males and 2.08 (1.51-2.86) for females. CONCLUSIONS: Muscle weakness is associated with cognitive decline, even in individuals with preserved muscle mass. Further studies are needed to better understand the association between muscle weakness and cognitive decline over time in order to develop dementia prevention strategies for those with dynapenia. Geriatr Gerontol Int 2024; 24: 123-129.

Age- and sex-specific associations between sarcopenia severity and poor cognitive function among community-dwelling older adults in Japan: The IRIDE Cohort Study.

Introduction: This study examined whether the association between sarcopenia severity and cognitive function differed according to sex and age in community-dwelling older adults in Japan. Methods: This is a cross-sectional study of older adults (age ≥ 65 years) consisting of five regional cohorts integrated as the Integrated Research Initiative for Living Well with Dementia (IRIDE) Cohort Study. Sarcopenia severity was determined based on the Asian Working Group for Sarcopenia 2019, which assessed grip strength, walking speed, and skeletal muscle mass index. Poor cognitive function was defined as a Mini-Mental State Examination score of ≤ 23. Odds ratios (ORs) and 95% confidence intervals (CIs) for poor cognitive function were calculated by sex and age group (65-74 and ≥75 years) using binomial logistic regression models, which were adjusted for age, educational attainment, history of non-communicable diseases, smoking and drinking habits, living alone, frequency of going outdoors, exercise habits, and depressive symptom. Results: Of the 8,180 participants, 6,426 (1,157 men aged 65-74 and 1,063 men aged 75 or older; 2,281 women aged 65-74 and 1,925 women aged 75 or older) were analyzed. The prevalence ratio of sarcopenia and severe sarcopenia were 309 (13.9%) and 92 (4.1%) among men and 559 (13.3%) and 166 (3.7%) among women, respectively. A total of 127 (5.8%) men and 161 (3.9%) women had a poor cognitive function. Setting non-sarcopenia as a reference, the adjusted ORs (95% CI) of poor cognitive function were 2.20 (1.54, 3.15) for sarcopenia and 3.56 (2.20, 5.71) for severe sarcopenia. A similar trend was observed in analyses stratified by sex and age, with linear associations (P for trend <0.05) in both categories. Furthermore, there was a significant interaction (P < 0.05) between sex and sarcopenia severity, indicating a stronger linear association of sarcopenia severity with poor cognitive function in women compared with men. Discussion and conclusion: Sarcopenia severity was linearly associated with poor cognitive function in adults aged ≥ 65 years, with a stronger association in women compared with men.

Simple screening models for cognitive impairment in community settings: The IRIDE Cohort Study.

AIM: Community settings often need simple screening, rather than detailed tests, to identify cognitive impairment. This study aimed to develop models to screen older adults with cognitive impairment. METHODS: This study used data from the Integrated Research Initiative for Living Well with Dementia Cohort Study and included 5830 older adults. Individuals were considered cognitively impaired if their Mini-Mental State Examination score was less than 24. Three screening models were developed: the simple model (age, sex, and education), the base model comprising 13 candidate variables available in the questionnaire, and the enhanced model, where grip strength and gait speed were added to the base model. We performed binary logistic regression analysis with stepwise backward elimination (P < 0.1 for retention in the model) to develop each model. Then, we calculated integer scores from coefficients to develop score-based models. The area under the receiver operating characteristic curve (AUC) was used to evaluate discrimination. RESULTS: Participants with cognitive impairment accounted for 4.0% (n = 233) of the total. The score-based simple model comprised three variables (AUC = 0.72, sensitivity: 72%, specificity: 61%). The score-based base model included nine variables (AUC = 0.76, sensitivity: 70%, specificity: 67%). The score-based enhanced model comprised eight variables, including grip strength and gait speed (AUC = 0.79, sensitivity: 73%, specificity: 70%). CONCLUSIONS: This study developed three screening models with acceptable discriminant validity for cognitive impairment. These models comprised simple questionnaire-based items and common physical performance measurements. These models could enable screening of older adults suspected of cognitive impairment without the need to conduct cognitive tests in community settings. Geriatr Gerontol Int 2022; 22: 292-297.

Association Between Appetite and Sarcopenia in Patients With Mild Cognitive Impairment and Early-Stage Alzheimer's Disease: A Case-Control Study.

Background: Sarcopenia is frequently seen in patients with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). While appetite loss and physical inactivity, which are also frequently seen in dementia, appear to contribute to sarcopenia, to date, no study has investigated this association. Objective: The aim of this study was to examine factors associated with sarcopenia, including appetite and physical activity, in patients with MCI and early-stage AD. Methods: The study subjects comprised 205 outpatients (MCI, n = 151; early-stage AD, n = 54) who were being treated at the Memory Clinic, National Center for Geriatrics, and Gerontology and had a Mini-Mental State Examination (MMSE) score of 21 or higher. All subjects were assessed for appetite by using the Council on Nutrition Appetite Questionnaire (CNAQ). Confounding variables assessed included physical activity, activities of daily living, mood, body mass index (BMI), nutritional status, and medications. Sarcopenia was defined as low muscle mass and low handgrip strength or slow gait speed. Multivariate logistic regression analyses were performed with adjustment for age, gender, education, and confounding variables to examine the association of sarcopenia with physical activity and appetite. Furthermore, sub-analyses were also conducted to clarify the relationship between CNAQ sub-items and sarcopenia. Results: The prevalence of sarcopenia among the subjects was 14.6% (n = 30). Patients with sarcopenia had lower CNAQ scores (those with sarcopenia, 26.7 ± 3.5; those without, 29.1 ± 2.5). Multivariate analysis showed that BMI (odds ratio [OR], 0.675; 95% confidence interval [CI], 0.534-0.853), polypharmacy (OR, 4.489; 95% CI, 1.315-15.320), and CNAQ (OR, 0.774; 95% CI, 0.630-0.952) were shown to be associated with sarcopenia. Physical activity was not associated with sarcopenia. Of the sub-items of the CNAQ, appetite (OR, 0.353; 95% CI, 0.155-0.805), feeling full (OR, 0.320; 95% CI = 0.135-0.761), and food tastes compared to when younger (OR, 0.299; 95% CI, 0.109-0.818) were shown to be associated with sarcopenia. Conclusions: These results suggest that appetite could be a modifiable risk factor for sarcopenia in patients with MCI and early-stage AD. A comprehensive approach to improving appetite may prove effective in preventing sarcopenia.

Screening Tool for Older Persons' Appropriate Prescriptions for Japanese: Report of the Japan Geriatrics Society Working Group on "Guidelines for medical treatment and its safety in the elderly".

AIM: In 2005, the Japan Geriatrics Society published a list of potentially inappropriate medication that was an extract from the "Guidelines for medical treatment and its safety in the elderly 2005." The 2005 guidelines are due for a revision, and a new comprehensive list of potentially inappropriate medications is required. METHODS: A total of 15 diseases, conditions and special areas related to their clinical care were selected. We originated clinical questions and keywords for these 15 areas, carried out a systematic review using these search criteria, and formulated guidelines applying the Grading of Recommendations Assessment, Development and Evaluation system advocated by Minds2014. If we did not find good evidence despite the drug being clinically important, we looked for evidence of efficacy and for disease-specific guidelines, and incorporated them into our guidelines. RESULTS: We selected 2098 articles (140 articles per area), and extracted another 186 articles through a manual search. We further added guidelines based on disease entity and made two lists, one of "drugs to be prescribed with special caution" and the other of "drugs to consider starting," primarily considering individuals aged 75 years or older or those who are frail or in need of special care. CONCLUSIONS: New lists of potentially inappropriate medications and potential prescribing omissions called "Screening Tool for Older Person's Appropriate Prescriptions for Japanese" were constructed. We anticipate that future studies will highlight more evidence regarding the safety of high-quality drugs, further improving the provision of appropriate medical care for the elderly. Geriatr Gerontol Int 2016: 16: 983-1001.

Japan as the front-runner of super-aged societies: Perspectives from medicine and medical care in Japan.

BACKGROUND: The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare. CURRENT SITUATION AND PROBLEMS: (1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients. CONTENTS OF THE PROPOSAL: The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. Byestablishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).

Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVES: Preventive strategy for falls in demented elderly is a clinical challenge. From early-stage of Alzheimer's disease (AD), patients show impaired balance and gait. The purpose of this study is to determine whether regional white matter lesions (WMLs) can predict balance/gait disturbance and falls in elderly with amnestic mild cognitive impairment (aMCI) or AD. DESIGN: Cross-sectional. SETTINGS: Hospital out-patient clinic. PARTICIPANTS: One hundred sixty-three patients diagnosed with aMCI or AD were classified into groups having experienced falls (n = 63) or not (n = 100) in the previous year. MEASUREMENTS: Cognition, depression, behavior and psychological symptoms of dementia, medication, and balance/gait function were evaluated. Regional WMLs were visually analyzed as periventricular hyperintensity in frontal caps, bands, and occipital caps, and as deep white matter hyperintensity in frontal, parietal, temporal, and occipital lobes, basal ganglia, thalamus, and brain stem. Brain atrophy was linearly measured. RESULTS: The fallers had a greater volume of WMLs and their posture/gait performance tended to be worse than nonfallers. Several WMLs in particular brain regions were closely associated with balance and gait impairment. Besides polypharmacy, periventricular hyperintensity in frontal caps and occipital WMLs were strong predictors for falls, even after potential risk factors for falls were considered. CONCLUSIONS: Regional white matter burden, independent of cognitive decline, correlates with balance/gait disturbance and predicts falls in elderly with aMCI and AD. Careful insight into regional WMLs on brain magnetic resonance may greatly help to diagnose demented elderly with a higher risk of falls.

Relationship between interleukin-6 and cerebral deep white matter and periventricular hyperintensity in elderly women.

AIM: We evaluated the relationships between serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6 with the severity of leukoaraiosis. METHODS: One hundred and thirty-seven elderly women who attended the Center for Comprehensive Care on Memory Disorders at Kyorin University Hospital were enrolled in this study. Leukoaraiosis was assessed by periventricular hyperintensity (PVH) score and deep white matter hyperintensity (DWMH) score. RESULTS: Serum log IL-6 level correlated with PVH and DWMH scores, but hsCRP did not. By multinomial logistic analysis, IL-6 was significantly related to DWMH score, independent of age and systolic blood pressure. CONCLUSION: IL-6 is presumably an important marker of leukoaraiosis, as is the case with silent cerebral infarction.

Plasma sex hormone levels and mortality in disabled older men and women.

AIM: To investigate the relationship between circulating sex hormone levels and subsequent mortality in disabled elderly. METHODS: This prospective observational study was comprised of 214 elderly subjects aged 70-96 years (117 men and 97 women; mean ± standard deviation age, 83 ± 7 years), receiving services at long-term care facilities in Nagano, Japan. All-cause mortality by baseline plasma sex hormone levels was measured. RESULTS: After excluding deaths during the first 6 months, 27 deaths in men and 28 deaths in women occurred during a mean follow up of 32 months and 45 months (up to 52 months), respectively. Mortality rates differed significantly between high and low testosterone tertiles in men, but did not differ significantly between middle and low tertiles. Compared with subjects in the middle and high tertiles, men with testosterone levels in the low tertile (<300 ng/dL) were more likely to die, independent of age, nutritional status, functional status and chronic disease (hazard ratio [HR] = 3.27, 95% confidence interval [CI] = 1.24-12.91). In contrast, the low dehydroepiandrosterone sulfate (DHEA-S) tertile was associated with higher mortality risk in women (multivariate adjusted HR = 4.42, 95% CI = 1.51-12.90). Exclusion of deaths during the first year and cancer deaths had minimal effects on these results. DHEA-S level in men and testosterone and estradiol levels in women were not related to mortality. CONCLUSION: Low testosterone in men and low DHEA-S in women receiving care at facilities are associated with increased mortality risk, independent of other risk factors and pre-existing health conditions.

Effects of dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with mild to moderate cognitive impairment.

AIM: There is little evidence that dehydroepiandrosterone (DHEA) has beneficial effects on physical and psychological functions in older women. We investigated the effect of DHEA supplementation on cognitive function and ADL in older women with cognitive impairment. METHODS: A total of 27 women aged 65-90 years (mean ± standard deviation, 83 ± 6) with mild to moderate cognitive impairment (Mini-Mental State Examination, MMSE; 10-28/30 points), receiving long-term care at a facility in Japan were enrolled. Twelve women were assigned to receive DHEA 25 mg/day p.o. for 6 months. The control group (n = 15) matched for age and cognitive function was followed without hormone replacement. Cognitive function was assessed by MMSE and Hasegawa Dementia Scale-Revised (HDS-R), and basic activities of daily living (ADL) by Barthel Index at baseline, 3 and 6 months. Plasma hormone levels including testosterone, DHEA, DHEA-sulfate and estradiol were also followed up. RESULTS: After 6 months, DHEA treatment significantly increased plasma testosterone, DHEA and DHEA-sulfate levels by 2-3-fold but not estradiol level compared to baseline. DHEA administration increased cognitive scores and maintained basic ADL score, while cognition and basic ADL deteriorated in the control group (6-month change in DHEA group vs control group; MMSE, +0.6 ± 3.2 vs -2.1 ± 2.2, P < 0.05; HDS-R, +2.8 ± 2.8 vs -0.3 ± 4.1, P < 0.05; Barthel Index, +3.7 ± 7.1 vs -2.7 ± 4.6, P = 0.05). Among the cognitive domains, DHEA treatment improved verbal fluency (P < 0.05). CONCLUSION: DHEA supplementation in older women with cognitive impairment may have beneficial effects on cognitive function and ADL.

Association of plasma sex hormone levels with functional decline in elderly men and women.

AIM: We aimed to determine whether plasma sex hormone levels are associated with activities of daily living (ADL), cognition, depression and vitality in elderly individuals with functional decline. METHODS: Two hundred and eight consecutive persons 70 years or older (108 men and 100 women; mean +/- standard deviation, 81 +/- 7 years) with a chronic stable condition, receiving long-term care at a long-term care facilities located in Nagano Prefecture, Japan, were enrolled. Plasma total testosterone, free testosterone (only in men), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and estradiol levels were determined in the morning after an overnight fast. Comprehensive geriatric assessment was performed including basic ADL by Barthel Index, instrumental ADL, cognitive function by Hasegawa Dementia Scale--Revised, mood by Geriatric Depression Scale and ADL-related vitality by Vitality Index. RESULTS: Simple regression analysis showed that, in men, plasma total and free testosterone levels were associated with basic ADL (R = 0.292 and R = 0.282), instrumental ADL (R = 0.261 and R = 0.408), cognitive function (R = 0.393 and R = 0.553) and vitality (R = 0.246 and R = 0.396), while DHEA(-S) was associated with cognitive function, and estradiol with cognitive function as well as vitality. In women, the only significant correlation was between DHEA(-S) and basic ADL. Adjustment for age and nutritional markers did not influence the associations of plasma sex hormone levels with functional scores except for that of free testosterone with Barthel Index. CONCLUSION: These results suggest that sex hormones have sex-specific associations with physical and neuropsychiatric functions in elderly individuals, and that endogenous testosterone is related to global function in elderly men.

Beta2-adrenergic receptor regulates Toll-like receptor-4-induced nuclear factor-kappaB activation through beta-arrestin 2.

Toll-like receptors (TLRs) play an important role in innate immunity while, beta(2)-adrenergic receptors (beta(2)AR) provide the key linkages for the sympathetic nervous system to regulate the immune system. However, their role in macrophages remains uncertain. Here, we demonstrate the cross-talk between beta(2)AR and TLR signalling pathways. Expression of beta(2)AR was down-regulated by TLR4 ligand lipopolysaccharide (LPS) stimulation. To investigate the physiological consequence of this down-regulation RAW264 cells, a macrophage cell line, were transfected with a beta(2)AR expression vector (RAWar). Both LPS-stimulated inducible nitric oxide synthase (NOS II) expression and NO production were markedly suppressed in the RAWar cells. The activation of nuclear factor-kappaB (NF-kappaB) and degradation of the inhibitor of NF-kappaB (IkappaBalpha) in response to LPS were markedly decreased in these cells. The level of beta-arrestin 2, which regulates beta(2)AR signalling, was also reduced in RAW264 cells after stimulation with LPS, but not in RAWar cells. Overexpression of beta-arrestin 2 (RAWarr2) also inhibited NO production and NOS II expression. Furthermore, we demonstrated that beta-arrestin 2 interacted with cytosolic IkappaBalpha and that the level of IkappaBalpha coimmunoprecipitated by anti-beta-arrestin 2 antibodies was decreased in the RAW264 cells but not in RAWar or RAWarr2 cells. These findings suggest that LPS-stimulated signals suppress beta(2)AR expression, leading to down-regulation of beta-arrestin 2 expression, which stabilizes cytosolic IkappaBalpha and inhibits the NF-kappaB activation essential for NOS II expression, probably to ensure rapid and sufficient production of NO in response to microbial attack.

Angiotensin converting enzyme inhibitor attenuates oxidative stress-induced endothelial cell apoptosis via p38 MAP kinase inhibition.

BACKGROUND: The effects of angiotensin converting enzyme (ACE) inhibitors on oxidative stress-induced apoptosis of endothelial cells and the intracellular signaling were investigated. METHODS: Cultured endothelial cells derived from a bovine carotid artery were treated with H2O2 or TNF-alpha to induce apoptosis. Apoptosis was evaluated by DNA fragmentation and cell viability, p38 MAP kinase activity by Western blotting, and oxidative stress by formation of 8-isoprostane. The effects of ACE inhibitors were examined by adding them into the medium throughout the experiments. RESULTS: Apoptosis was attenuated by ACE inhibitors, temocapril and captopril, in a dose-dependent manner (1-100 micromol/l). H2O2 (0.2 mmol/l for 1.5 h) or TNF-alpha (10 ng/ml for 72 h) treatment stimulated the activities of p38 MAP kinase. Temocapril and captopril decreased the activity of p38 MAP kinase as well as 8-isoprostane formation induced by H2O2. A p38 MAP kinase inhibitor, SB203580, partially inhibited the effect of temocapril on apoptosis. CONCLUSIONS: These results suggest that ACE inhibitors protect endothelial cells from oxidative stress-induced apoptosis, and that p38 MAP kinase plays a critical role in the process.

[Incidence of adverse drug reactions in geriatric wards of university hospitals].

Adverse drug reactions (ADR) in elderly people, which have been shown to increase with age, are often attributed to functional decline and polypharmacy. A multi-institutional retrospective survey was undertaken to investigate the current status of ADR in geriatric wards of university hospitals. The inpatient database from 2000 to 2002 in 5 university hospitals was studied, and a total of 1,289 patients were analyzed. The incidence of ADR, as determined by attending physicians, was 9.2% on the whole but varied from 6.3% to 15.8% among the institutions. The factors significantly related to ADR were number of diagnoses, number of geriatric syndromes, number of prescribed drugs, increase of more than two drugs during admission, longer hospital stay, emergency admission, depression and apathy. These results are mostly consistent with previous reports and will provide important information on pharmacotherapy in elderly people.

Effects of oxygen administration on the circulating vascular endothelial growth factor (VEGF) levels in patients with obstructive sleep apnea syndrome.

OBJECTIVE: Repeated nocturnal hypoxia is implicated in the pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS). We hypothesized that circulating vascular endothelial growth factor (VEGF) levels are affected by nocturnal hypoxemia in patients with OSAS. METHODS: We examined the serum VEGF levels in patients with OSAS and in control subjects. We also tested the effects of oxygen or air administration on the subjects' VEGF levels. PATIENTS AND MATERIALS: Twenty-four OSAS patients (mean age 54.2 +/- 3.6 years) and 24 age-matched control subjects (53.2 +/- 3.6 years). Their serum samples were tested. RESULTS: Serum VEGF levels at 8:00 AM were significantly higher in OSAS patients than in controls (p<0.01). VEGF levels decreased from 515 +/- 31 (pg/ml) to 178 +/- 16 (pg/m) (p<0.01) in OSAS patients whose nocturnal hypoxemia was found to be improved by administration of 2 l/min of oxygen during the night. However, the administration of compressed air affected neither the VEGF level nor nocturnal oxygen desaturation in OSAS patients. CONCLUSION: These results indicate that circulating VEGF levels are elevated in OSAS patients, primarily due to nocturnal hypoxemia.