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Polypharmacy is an extremely important problem, because it increases the risk of adverse drug reactions. The aim of the current study was to create a clinical medication review tool to detect inappropriate medication use, and assess this new method with elderly Japanese patients.The new method involves optimizing prescription drugs from indications, based on the chronic disease-anatomical therapeutic class code list. The present study investigated the prevalence of potentially inappropriate medications in 5667 Japanese patients aged ≥65 years with polypharmacy (≥5 drugs) in comparison with the Beers criteria 2012.We propose a new method called the Mapping Approach for Pharmacotherapeutic Classifications: (i) identify the chronic disease-anatomical therapeutic class code assigned to the prescription drugs; (ii) identify the chronic disease-anatomical therapeutic class code corresponding to the patient's chronic disease; (iii) compare the prescription drug and patient's chronic disease chronic disease-anatomical therapeutic class codes; and (iv) identify the appropriateness of medication use based on the comparison (appropriate use is defined as matching codes). The mean number of potentially inappropriate medications detected was significantly different between the mapping approach and Beers criteria 2012 (3.1 ± 2.6 vs 0.6 ± 0.8 drugs, respectively; P0.001).The Mapping Approach for Pharmacotherapeutic Classifications is highly dependent on the chronic condition. Pharmacists should confirm the chronic condition with the treating physician before reducing a patient's medications. We hope this process will further influence prescribing patterns, and decrease the inappropriate use of medications and associated adverse drug reactions in older adults. Geriatr Gerontol Int 2017; 17: 2025-2033.

Sarcopenia was recently classified a geriatric syndrome and is a major challenge to healthy aging. Affected patients tend to have worse clinical outcomes and higher mortality than those without sarcopenia. Although there is general agreement on the principal diagnostic characteristics, initial thresholds for muscle mass, strength, and physical performance were based on data from populations of predominantly Europid ancestry and may not apply worldwide. The Asian Working Group for Sarcopenia (AWGS) issued regional consensus guidelines in 2014, and many more research studies from Asia have since been published; this review summarizes recent progress. The prevalence of sarcopenia estimated by the AWGS criteria ranges between 4.1% and 11.5% of the general older population; however, prevalence rates were higher in Asian studies that used European Working Group on Sarcopenia in Older People cut-offs. Risk factors include age, sex, heart disease, hyperlipidemia, daily alcohol consumption, and low protein or vitamin intake; physical activity is protective. Adjusting skeletal muscle mass by weight rather than height is better in showing the effect of older age in sarcopenia and identifying sarcopenic obesity; however, some Asian studies found no significant skeletal muscle loss, and muscle strength might be a better indicator. Although AWGS 2014 diagnostic cut-offs were generally well accepted, some may require further revision in light of conflicting evidence from some studies. The importance of sarcopenia in diverse therapeutic areas is increasingly evident, with strong research interest in sarcopenic obesity and the setting of malignancy. Pharmacologic interventions have been unsatisfactory, and the core management strategies remain physical exercise and nutritional supplementation; however, further research is required to determine the most beneficial approaches.

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.

We investigated the relationships among nocturnal polyuria, sleep apnea and body fluid volume to elucidate the pathophysiology of nocturia in sleep apnea syndrome.We enrolled 104 consecutive patients who underwent polysomnography for suspected sleep apnea syndrome. Self-assessed symptom questionnaires were administered to evaluate sleep disorder and lower urinary tract symptoms, including nocturia. Voiding frequency and voided volume were recorded using a 24-hour frequency-volume chart. Body fluid composition was estimated in the morning and at night using bioelectric impedance analysis. Frequency-volume chart data were analyzed in 22 patients after continuous positive airway pressure therapy.Patients with nocturnal polyuria showed a higher apnea-hypopnea index (33.9 vs 24.2, p = 0.03) and a larger circadian change in extracellular fluid adjusted to lean body mass (0.22 vs -0.19, p = 0.019) than those without nocturnal polyuria. These relations were more evident in patients 65 years old or older than in those 64 years or younger. A multivariate linear regression model showed an independent relationship of nocturnal polyuria with the apnea-hypopnea index and the circadian change in extracellular fluid adjusted to lean body mass (p = 0.0012 and 0.022, respectively). Continuous positive airway pressure therapy significantly improved nocturnal polyuria and nocturia only in patients with nocturnal polyuria.This study identified sleep apnea and the circadian change in extracellular fluid as independent factors for nocturnal polyuria.

Many drugs have been reported to induce not only delirium but also cognitive impairment. Some types of drugs are reported to induce dementia, and prolonged hypotension or hypoglycemia induced by overuse of antihypertensive drugs or oral antidiabetic drugs could result in dementia. Recently, taking multiple drugs with anticholinergic activity are reported to cause cognitive decline and anticholinergic burden should be avoided especially in patients with dementia. Drug-induced dementia can be prevented by avoiding polypharmacy and adhering to the saying 'start low and go slow' . Early diagnosis of drug-induced dementia and withdrawal of the offending drug is essential to improve cognitive function.

Aim: The aim of this study was to examine how geriatricians decide the indication of tube feeding in the elderly with eating difficulty as a result of several disorders, and to determine the factors associated with their decision making and interventions for dysphagia. Methods: The design was a cross-sectional study. All board-certified geriatricians in the Japan Geriatrics Society were recruited to this study in September 2010. We sent questionnaires to 1469 geriatricians. Among them, 629 agreed to participate. The survey consisted of self-administered questionnaires regarding demographic information, indications of tube feeding and interventions for dysphagia before tube feeding. Results: We analyzed the remaining 555 questionnaires after excluding incomplete ones. Over 90% of geriatricians answered that “neurological disorder” and “stroke” are indications, whereas 46.8% of them answered that “dementia” is an indication for tube feeding. Geriatricians who organize a multidisciplinary team conference tended to carry out more “interventions for dysphagia before the prescription of tube feeding” compared with the reference group (odds ratio 2.1–8.7) after multivariate adjustment. Conclusions: The results show that approximately half of the geriatricians prescribe tube feeding when the patient has dementia with loss of appetite or apraxia for eating. There is no consensus among Japanese geriatricians about the indication of tube feeding for demented people. We suggest that guidelines for tube feeding in the elderly should be established. Furthermore, a multidisciplinary approach would be desirable for decision making for tube feeding. Geriatr Gerontol Int 2012; ••: ••–••.

An increase in short-term blood pressure (BP) variability is a characteristic feature in the elderly. It makes the management of hemodynamics more difficult, because it is frequently seen disturbed baro-reflex function and increased arterial stiffness, leading to isolated systolic hypertension. Large BP variability aggravates hypertensive target organ damage and is an independent risk factor for the cardiovascular (CV) events in elderly hypertensive patients. Therefore, appropriate control in BP is indispensable to manage lifestyle-related diseases and to prevent subsequent CV events. In addition, accumulating recent reports show that excessive BP variability is also associated with a decline in cognitive function and fall in the elderly. In the clinical settings, we usually evaluate their health condition, mainly with single point BP measurement using cuff inflation. However, unfortunately we are not able to find the close changes in BP by the traditional way. Here, we can show our advantageous approach of continuous BP monitoring using newly developing device `wearable BP sensing' without a cuff stress in the elderly. The new device could reflect systolic BP and its detailed changes, in consistent with cuff-based BP measurement. Our new challenge suggests new possibility of its clinical application with high accuracy.

In older people, the therapeutic importance for hypertension is different from young people because of wide interindividual variability in organ failure or dysfunction. The association with the severity and mortality of hypertension is known to be attenuated by aging Here, we describe the therapeutic strategy for hypertension of old people in frailty.

To describe medication use including potentially inappropriate medication (PIM) and examine the association between adverse outcomes and patient factors including PIM use in Japanese elderly patients in long-term care facilities.This was a retrospective cohort study of 470 patients in 53 Geriatric Health Service Facilities and 44 Sanatorium Type Medical Care Facilities for the Elderly Requiring Long Term Care. Standardized forms were used to collect information including oral and parenteral medication use on admission, and 1 month and 3 months after admission. PIMs were determined by the 2003 or 2012 Beers criteria. Adverse outcomes were any medical events leading to emergency department transfer, hospitalization to acute care hospitals or death.A total of 2,227 oral medications and 197 parenteral medications were prescribed for 470 patients on admission. PIM exposure based on the 2003 and 2012 Beers criteria was observed in 11.9% and 37.5%, respectively. Adverse outcomes within 3 months after admission were observed in 8.9% of the entire cohort, and were associated with age, sex, facility type and number of parenteral medications on admission. Adverse outcomes between one and three months after admission were associated with age, sex, number of parenteral medications at one month, and a change in the number of oral and parenteral medications within one month after admission. PIM exposure was not associated with adverse outcomes in any models.Use of PIM was prevalent in long-term care facilities. Our findings support the importance of comprehensive assessment of medication regimens including parenteral medication. Geriatr Gerontol Int 2017; 17: 591-597.

Objective: To investigate the predictors of falls, such as comorbidity and medication, in geriatric outpatients in a longitudinal observational study. Methods: A total of 172 outpatients (45 men and 126 women, mean age 76.9 ± 7.0 years) were evaluated. Physical examination, clinical history and medication profile were obtained from each patient at baseline. These patients were followed for up to 2 years and falls were self-reported to their physicians. The factors associated with falls were analyzed statistically. Results: A total of 32 patients experienced falls within 2 years. On univariate analysis, older age, osteoporosis, number of comorbid conditions and number of drugs were significantly associated with falls within 2 years. On multiple logistic regression analysis, the number of drugs was associated with falls, independent of age, sex, number of comorbid conditions and other factors that were significantly associated in univariate analysis. A receiver-operator curve evaluating the optimal cut-off value for the number of drugs showed that taking five or more drugs was a significant risk. Conclusion: In geriatric outpatients, polypharmacy is associated with falls. Intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidity and falls. Language: en

Objective— Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis. Aged vascular cells manifest some morphological features of a senescent phenotype. Recent studies have demonstrated that mammalian sirtuin 1 (SIRT1), a histone deacetylase, is an exciting target for cardiovascular disease management. Here, we investigated the role of SIRT1 in a calcification model of vascular smooth muscle cells (SMCs). Methods and Results— In adenine-induced renal failure rats with hyperphosphatemia, massive calcification was induced in the aortic media. Senescence-associated β-galactosidase (SAβ-gal) activity, a marker of cellular senescence, in medial SMCs was significantly increased, and its induction was positively associated with the degree of calcification. In cultured SMCs, inorganic phosphate (Pi) stimulation dose-dependently increased SAβ-gal-positive cells, and Pi-induced senescence was associated with downregulation of SIRT1 expression, leading to p21 activation. The activation via SIRT1 downregulation was blunted by inhibition of Pi cotransporter. Activation of SIRT1 by resveratrol significantly reduced the senescence-associated calcification. Conversely, SIRT1 knockdown by small interfering RNA accelerated the Pi-induced SMC senescence and subsequent calcification. In addition, SIRT1 knockdown induced phenotypic change from a differentiated state to osteoblast-like cells. The senescence-related SMC calcification was completely prevented by p21 knockdown. In addition to Pi-induced premature senescence, SMCs with replicative senescence were also more sensitive to Pi-induced calcification compared with young SMCs, and this finding was attributable to augmented p21 expression. Conclusion— SIRT1 plays an essential role in preventing hyperphosphatemia-induced arterial calcification via inhibition of osteoblastic transdifferentiation. In addition, Pi-induced SMC calcification may be associated with both premature and replicative cellular senescence.

Aim: To investigate the association of fall risk with comorbidities and medications in geriatric outpatients in a cross-sectional design. Methods: A total of 262 outpatients (84 men and 178 women, mean age 76.2 ± 6.8 years) were evaluated. Physical examination, clinical histories and medication profile were obtained from each patient. History of falls in the past year, 22-item fall risk index, 13-point simple screening test for fall, and time interval of one-leg standing test were examined as markers of fall risk. Results: On univariate analysis, older age, female sex, hypertension, osteoporosis, history of stroke, number of comorbidities, use of antihypertensives, aspirin, bisphosphonates, hypnotics and number of prescribed drugs were significantly associated with either of four indices. On multiple regression analysis, the number of drugs was associated with all of the four indices, independent of other factors associated in the univariate analysis. The association of number of drugs with fall risk indices was stepwise. Conclusion: In geriatric outpatients, polypharmacy rather than number of comorbidities was associated with fall risk. Prospective and intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidities and fall risk. Geriatr Gerontol Int 2011; 11: 438-444. Language: en

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. Geriatr Gerontol Int 2011; 11: 328–332.

Aim: The Japan Geriatrics Society (JGS) developed the guidelines for medical treatment and its safety in the elderly and the list of potentially inappropriate medication use, a Japanese version of the Beers list, in 2005. The JGS working group in collaboration with the Japan Broadcasting Corporation conducted the survey to geriatricians to investigate their experiences of adverse drug reactions (ADR) caused by potentially inappropriate medications. Methods: In September 2008, the survey mails were sent to all the JGS certified geriatricians (n = 1492). The questionnaire consisted of 1 year of experiences of ADR of any type, past experiences of ADR by the use of antipsychotic benzamides, hypnotic benzodiazepines, digoxin (≥0.15 mg/day), vitamin D3 (alfacalcidol ≥1.0 µg/day) and additional drugs, and their attitudes to reduce the dose/number of drugs for the prevention of ADR. Results: A total of 425 geriatricians responded (response rate 29%). Seventy-two percent experienced ADR within 1 year. Past experiences of ADR were reported by 79% for antipsychotic benzamides, 86% for hypnotic benzodiazepines, 70% for digoxin and 37% for vitamin D3. Free responses included frequent ADR by non-steroidal anti-inflammatory, antihypertensive, antiplatelet, anti-arrhythmic, antidiabetic and antidepressant drugs. Reduction of drugs for ADR prevention was attempted by 93%. Conclusion: This survey showed that most geriatricians experience ADR and take preventive measures for ADR. The results can be used for education and the development of new guidelines. Geriatr Gerontol Int 2011; 11: 3–7.

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 (

OBJECTIVES: To examine the relationship between visceral fat area (VFA) evaluated using computed tomography (CT) scans and the number of metabolic risk factors in older adults. DESIGN: Cross-sectional study SETTING: A community clinic in Tokyo, Japan. PARTICIPANTS: Two hundred eighteen individuals aged 65 and older without impairments in activities of daily living who underwent geriatric health examination (63 men, mean age 74.5 ± 7.1; 155 women, mean age 75.3 ± 6.7). MEASUREMENTS: VFA was obtained from a cross-sectional image at umbilical level in the supine position using CT scanning. Metabolic syndrome components except waist circumference were measured using the criteria of the International Diabetes Federation. RESULTS: There was a positive correlation between VFA and number of metabolic risk factors in men and women. Multiple regression analysis demonstrated that only VFA was significantly correlated with number of risk factors in men, whereas age and VFA were significantly correlated in women; body mass index was not correlated with number of metabolic risk factors in men or women. Dyslipidemia and high blood glucose were associated with higher VFA, but high blood pressure was not. There was a negative correlation between VFA and serum adiponectin level and a positive correlation between VFA and homeostasis model assessment of insulin resistance. CONCLUSION: Visceral fat accumulation is associated with metabolic risk factor clustering even in the elderly population. These results have clinical implications for the management of obesity in older adults.

The aim is to investigate the relationship between a positive outcome on rehabilitation after hip fracture and behavioral psychological symptoms of dementia (BPSD) transition during rehabilitation. This study is a retrospective cohort study based on the Japan Rehabilitation Database. We recruited 756 subjects 65 years of age or older from 31 hospitals in the database. All subjects were in the hospital as patients undergoing rehabilitation for hip fracture. Functional independence measure (FIM), walking ability, Mini-Mental State Examination (MMSE), and BPSD were measured both at the beginning and at the end of rehabilitation. MMSE for 23 or under was defined as the cognitive-impaired group. MMSE for 24 or over was used as the cognitively intact group. Cognitive impaired participants were divided into four groups: participants presented no BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (-/-)), participants presented BPSD at the beginning of rehabilitation but resolved at the end of rehabilitation (Group (+/-)), participants had no BPSD at the beginning of rehabilitation but appeared at the end of rehabilitation (Group (-/+)) and participants had sign of BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (+/+)). The endpoints were waking ability, FIM gain. As results, one hundred thirty-seven cognitive-impaired older people patients out of 471 (29.1%) suffered from BPSD at the beginning of rehabilitation. FIM gains in cognitively intact group, Group (-/-), Group (+/-), Group (-/+) and Group (+/+) were 24.8 ± 18.7, 17.5 ± 16.9, 27.3 ± 19.7, 17.8 ± 12.2 and 12.2 ± 17.2, respectively. The Group (+/-) was significantly connected to a positive outcome for rehabilitation. The present study suggested that the management of BPSD can lead to better functional recovery during rehabilitation.

It is known that dehydroepiandrosterone (DHEA) inhibits a phenotypic switch in vascular smooth muscle cells (VSMC) induced by platelet-derived growth factor (PDGF)-BB. However, the mechanism behind the effect of DHEA on VSMC is not clear. Previously we reported that low molecular weight-protein tyrosine phosphatase (LMW-PTP) dephosphorylates PDGF receptor (PDGFR)-beta via a redox-dependent mechanism involving glutathione (GSH)/glutaredoxin (GRX)1. Here we demonstrate that the redox regulation of PDGFR-beta is involved in the effect of DHEA on VSMC. DHEA suppressed the PDGF-BB-dependent phosphorylation of PDGFR-beta. As expected, DHEA increased the levels of GSH and GRX1, and the GSH/GRX1 system maintained the redox state of LMW-PTP. Down-regulation of the expression of LMW-PTP using siRNA restored the suppression of PDGFR-beta-phosphorylation by DHEA. A promoter analysis of GRX1 and gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of GSH synthesis, showed that DHEA up-regulated the transcriptional activity at the peroxisome proliferator-activated receptor (PPAR) response element, suggesting PPARalpha plays a role in the induction of GRX1 and gamma-GCS expression by DHEA. In conclusion, the redox regulation of PDGFR-beta is involved in the suppressive effect of DHEA on VSMC proliferation through the up-regulation of GSH/GRX system., Biochemical and biophysical research communications, 396(2), pp.489-494; 2010

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

Recent epidemiological studies have found that testosterone deficiency is associated with higher mortality largely due to cardiovascular (CV) disease in community-dwelling older men. We investigated whether a low plasma testosterone level could predict cardiovascular events in middle-aged Japanese men with coronary risk factors.One hundred and seventy-one male outpatients (30-69 years old, mean+/-SD=48+/-13 years) who had any coronary risk factor (hypertension, diabetes, dyslipidemia, smoking, and obesity) without a previous history of CV disease were followed up. At baseline, the subjects underwent examination of coronary risk factors, measurement of flow-mediated dilation (FMD) of the brachial artery as an indicator of vascular endothelial function and assays of plasma total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), estradiol and cortisol.During the mean follow-up period of 77 months, a total of 20 CV events occurred. Kaplan-Meier survival analysis by tertile of plasma hormone levels revealed that the subjects with the lowest testosterone tertile were more likely to develop CV events than those with the highest tertile (P0.01 by log-rank test). Cox proportional hazards models showed that the subjects with the lowest tertile of plasma testosterone (14.2 nmol/L) had an approximately 4-fold higher CV event risk compared to those with the higher testosterone tertiles after adjustment for coronary risk factors including medication and FMD (unadjusted hazard ratio, 3.61; 95% CI, 1.47-8.86: multivariate-adjusted hazard ratio, 4.61; 95% CI, 1.02-21.04). Multivariate analysis did not show any significant association of DHEA-S, estradiol or cortisol with CV events.A low plasma testosterone level is associated with CV events in middle-aged Japanese men, independent of coronary risk factors and endothelial function. This is the first report to show the relationship between endogenous testosterone and CV events in Asian population.

Epidemiological studies have shown that low testosterone is associated with metabolic syndrome (MetS) in Caucasian men. We investigated whether testosterone level is related to the prevalence of MetS in middle-aged Japanese men. A cross-sectional survey was conducted in 194 men aged 30-64 years (49+/-9). Blood sampling was performed in the morning after a 12-h fast, and the relationship between plasma hormone and MetS was analyzed. Low total testosterone was associated with MetS according to the Japanese criteria (HRs of 2.02 by quartile of testosterone; 95% CI=1.43-2.87) and the International Diabetes Federation criteria (HRs of 1.68 by quartile of testosterone; 95% CI=1.25-2.25). Age-adjusted regression analyses revealed that testosterone was significantly related to the MetS parameters of obesity (beta=-0.365 and -0.343 for waist circumference and body mass index, respectively), hypertension (beta=-0.278 and -0.157 for systolic and diastolic blood pressure, respectively), dyslipidemia (beta=-0.242 and 0.228 for triglycerides and high-density lipoprotein cholesterol, respectively), insulin resistance (beta=-0.253 and -0.333 for fasting plasma glucose and homeostasis model assessment of insulin resistance, respectively) and adiponectin (beta=0.216). Inclusion of waist circumference into the model largely weakened the association of testosterone with other metabolic risk factors. In contrast, high estradiol was associated with MetS and its parameters, mostly attributing to the positive correlation between estradiol and obesity. Dehydroepiandrosterone sulfate was not associated with MetS or its parameters. These results suggest that low testosterone is associated with MetS and its parameters in middle-aged Japanese men. The association between estradiol and MetS needs further investigation.

We report the findings regarding a 70-year-old man with paraneoplastic limbic encephalitis. He presented with a chief complaint of inability to recall any events. He had been well until one month before admission, and then he abruptly began to show progressive amnesia. At admission, the patient's score on the Revised Hasegawa Dementia Scale (HDS-R) showed a decline to 13/30, thus indicating the existence of severe disorientation and an impaired memory. The brain CT and EEG showed no specific abnormalities and an analysis of cerebrospinal fluid showed only a mild increase in the total protein level. A chest X-ray film revealed a mass in the right hilum, while a histological analysis of the biopsied specimen finally established a diagnosis of small cell lung carcinoma. The FDG-PET and the enhanced brain MRI showed a single small metastatic lesion in the cerebellum. After the 1st course of chemotherapy and whole brain radiation, cognitive function, especially the short-term memory, remarkably improved and the HDS-R score increased to 21/30. However, the tumor again increased in size during the 3(rd) and 4(th) courses of chemotherapy. Interestingly, cognitive function also worsened again and the score of HDS-R declined to 15/30, 20 weeks after the start of chemotherapy. Limbic encephalitis can be associated with malignant tumors, such as small cell lung carcinoma, and some reported cases have shown a cognitive improvement after tumor therapy. In our case, we also observed a reworsening of the cognitive function in association with the acquired chemoresistence.

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.

Tumor necrosis factor (TNF-alpha) is a pleiotropic cytokine exerting both inflammatory and cell death activity and is thought to play a role in the pathogenesis of atherosclerosis. The present study was designed to examine whether the raloxifene analogue, LY117018 could inhibit TNF-alpha-induced apoptosis in vascular endothelial cells and to clarify the involved mechanisms. Apoptosis of endothelial cells was determined by DNA fragmentation assay and the activation of caspase-3. LY117018 significantly inhibited TNF-alpha-induced caspase-3 activation and cell DNA fragmentation levels in bovine carotid artery endothelial cells. The inhibitory effect of LY117018 was abolished by an estrogen receptor antagonist ICI 182,780. p38 MAPK, JNK, ERK1/2 and Akt have been shown to act as apoptotic or anti-apoptotic signals. TNF-alpha stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-alpha-induced apoptosis was significantly decreased by SB203580, a p38 MAPK inhibitor or SP600125, a JNK inhibitor, but was enhanced by an ERK1/2 pathway inhibitor, PD98059 or a PI3-kinase/Akt pathway inhibitor, wortmannin. The anti-apoptotic effect of LY117018 was abrogated only by PD98059 but was not affected by the inhibitors for p38 MAPK, JNK, or Akt. LY117018 stimulated the further increase in phosphorylation of ERK1/2 in TNF-alpha treated endothelial cells but it did not affect phosphorylation levels of p38 MAPK, JNK or Akt. These results suggest that LY 110718 prevents caspase-3 dependent apoptosis induced by TNF-alpha in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway.

Objectives The aim of this study was to compare the effects of paclitaxel, sirolimus, and everolimus on the senescent phenotype in human endothelial cells, and to further investigate possible involvement of mammalian sirtuin 1 (Sirt1) down-regulation as a mechanism. Background Endothelial cell senescence may play a role in impaired re-endothelialization after drug-eluting stent (DES) implantation. Recently, the down-regulation of Sirt1 has been shown to mediate oxidative stress-induced endothelial senescence. Methods Senescent human umbilical vein endothelial cells (HUVEC) were judged by senescence-associated β-galactosidase assay (SA-βgal), morphological appearance, and plasminogen activator inhibitor (PAI)-1. Results Treatment with paclitaxel, sirolimus, and everolimus significantly caused a senescent phenotype and PAI-1 up-regulation, associated with a decrease in endothelial nitric oxide synthase (eNOS) and Sirt1 expression. Overexpression of Sirt1 or Sirt1 activation reversed the sirolimus- or everolimus-induced senescent phenotype. Interestingly, paclitaxel-induced senescence was not suppressed by Sirt1 overexpression, suggesting the existence of a different mechanism. Cilostazol markedly inhibited the sirolimus- or everolimus-induced senescent phenotype (sirolimus or everolimus [2.5 nmol/l]; 49.2% or 53.0% SA-βgal positive vs. only 13.6% or 14.6% with cilostazol [100 μmol/l]) and PAI-1 up-regulation, but had no influence on the effects of paclitaxel. Finally, aspirin significantly blunted sirolimus- or everolimus-induced senescence, but neither ticlopidine nor clopidogrel had any effects. Conclusions Sirolimus and everolimus induce endothelial senescence involving down-regulation of Sirt1. In contrast, the development of endothelial senescence by paclitaxel involves a Sirt1-independent pathway. Because sirolimus and everolimus are involved in Sirt1 modulation, cilostazol rescues HUVEC from sirolimus- or everolimus-induced senescence. These results may have therapeutic implications in the clinical sequelae after DES implantation.

Aim: We investigated whether mental stress-induced blood pressure elevation was related to cognitive function in the elderly, and further examined the effects of the dual-type calcium channel blocker, cilnidipine, on stress induced hypertension in subjects with mild cognitive impairment. Methods: In study I, 39 consecutive outpatients (mean age ± standard deviation, 77 ± 8 years), who were referred to our memory clinic and were not taking any medications, were studied. They were divided into three groups according to cognitive function on the Hasegawa Dementia Scale-Revised (HDSR): group 1 (n = 8), 28 points or more; group 2 (n = 18), 21–27 points; and group 3 (n = 13), 20 points or less. In study II, 14 outpatients with hypertension and mild cognitive impairment (aged 79 ± 8 years; HDSR score, 24 ± 4) were assigned to receive cilnidipine (10–20 mg/day). The control group (n = 10) matched for age, HDSR and blood pressure was followed without cilnidipine. Results: In study I, although age and basal blood pressure were similar among the three groups, the blood pressure response to a mental arithmetic test was twice as large in group 2 (26 ± 12 mmHg in systolic pressure and 11 ± 8 mmHg in diastolic pressure) as those in groups 1 and 3. In study II, after 4 weeks, cilnidipine treatment significantly decreased the blood pressure responses to the mental arithmetic test compared to the baseline as well as to those of the control group. Conclusions: Stress-induced blood pressure elevations are exaggerated in subjects with mild cognitive impairment. Cilnidipine may have inhibitory effects on stress-induced hypertension.

A selective estrogen receptor modulator, raloxifene, has been shown to reduce cardiovascular events in relatively high-risk postmenopausal women with osteoporosis. However, the mechanisms by which raloxifene exerts a pharmacological effect on cardiovascular organs have not been fully elucidated. The present study was designed to examine whether the raloxifene analogue, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b) thien-3-yl-p-(2-(pyrrolidinyl)ethoxy phenyl ketone (LY117018), could inhibit apoptosis and to clarify the signaling pathway in vascular endothelial cells. LY117018 significantly inhibited hydrogen peroxide-induced apoptosis in bovine carotid artery endothelial cells. The anti-apoptotic effect of LY117018 was abolished by an estrogen receptor antagonist, 7α,7β-(9[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl) estra-1,3,5(10)-triene-3,17-diol (ICI 182,780). Mitogen-activated protein kinases (MAPK), including p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase1/2 (ERK1/2), and Akt, have been shown to act as apoptotic or anti-apoptotic signals. Phosphorylation of p38, JNK, ERK1/2 and Akt was examined. LY117018 increased ERK1/2 phosphorylation but did not enhance the phosphorylation of p38, JNK, or Akt. The anti-apoptotic effect of LY117018 was prevented by treatment with 2-[2′-amino-3′-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. LY117018 stimulated an increase in ERK1/2 phosphorylation, which was diminished by ICI 182,780. The activation of ERK/1/2 by LY117018 was not inhibited by the transcription inhibitor, actinomycin D. These results suggest that estrogen receptors and the ERK1/2 signaling pathway are involved in the anti-apoptotic action of LY117018 in vascular endothelial cells.

Aim: White matter lesions (WML) are common findings on magnetic resonance imaging (MRI) in elderly persons. In this study, we analyzed the relation of WML with global cognitive function, depression, vitality/volition, and 19 symptoms of geriatric syndrome in Japanese elderly patients who attended three university geriatric outpatient clinics. Methods: Two hundred and eighty-six subjects (103 men and 183 women; mean ± standard deviation age, 74.5 ± 7.8 years) were included in this study. MRI scans were performed for the diagnosis of WML, and the severity of periventricular and deep white matter hyperintensities (PVH and DWMH) was rated semiquantitatively. Concurrently, all subjects underwent tests of cognitive function, depressive state and vitality, and were examined for 19 symptoms of geriatric syndrome. Results: The study subjects showed cognitive decline, depression and low vitality, all to a mild extent. Univariate linear regression analysis showed a negative correlation between the severity of WML and cognitive function or vitality. Multiple logistic analysis revealed that the severity of WML was a significant determinant of cognitive impairment and low vitality, after adjustment for confounding factors such as age, sex and concomitant diseases. PVH and/or DWMH score was significantly greater in subjects who exhibited 13 out of 19 symptoms of geriatric syndrome. Logistic regression analysis indicated that WML were associated with psychological disorders, gait disturbance, urinary problems and parkinsonism. Conclusion: WML were associated with various symptoms of functional decline in older persons. Evaluating WML in relation to functional decline would be important for preventing disability in elderly people.

Adiponectin exhibits diverse protective effects against atherogenesis and antagonizes many effects of TNFalpha. Here, we investigated the effect of adiponectin and TNFalpha on vascular calcification, a critical event in the development and progression of vascular disease. In human aortic smooth muscle cells (HASMC), TNFalpha augmented inorganic phosphate (Pi)-induced calcification, whereas adiponectin significantly suppressed it and abolished the stimulatory effect of TNFalpha in a concentration-dependent manner. Similarly, adiponectin ameliorated the accelerating effect of TNFalpha on Pi-induced apoptosis, the essential process of HASMC calcification. Furthermore, these effects of TNFalpha and adiponectin were associated with AMP-activated protein kinase (AMPK)-dependent growth arrest-specific gene 6 (Gas6) expression and Akt signaling. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced phosphorylation of AMPK and significantly inhibited Pi-induced calcification in HASMC. Conversely, pharmacological inhibition of AMPK by compound C blocked both AMPK activation and the inhibitory effect of adiponectin on calcification, providing evidence that AMPK plays a regulatory role in vascular calcification. Reporter assay revealed that adiponectin restored Gas6 promoter activity decreased by TNFalpha, and the effect of adiponectin was abrogated by compound C. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFalpha on vascular calcification by restoration of the AMPK-dependent Gas6-mediated survival pathway.

Vascular calcification is clinically important in the development of cardiovascular disease. It has been suggested that apoptosis is one of the processes regulating calcification in vascular smooth muscle cells (VSMC). In this review, we discuss the role of apoptosis in inorganic phosphate (Pi)- induced calcification, focusing on regulation of the survival pathway mediated by growth arrest- specific gene 6 (Gas6). Further, we mention the beneficial effect of statins mediated by inhibition of apoptosis which is accompanied by restoration of the Gas6-mediated survival pathway. These findings indicate that Gas6 is a novel target of statins' effects to prevent vascular calcification.

Dehydroepiandrosterone (DHEA) modulates sensitivity to radiation-induced injury in human neuroglioma cells (H4) through effects on Akt signalling by glutathione (GSH)-dependent redox regulation. Previous treatment of H4 cells with DHEA for 18 h reduced the gamma-ray-induced phosphorylation of Akt, activated p21(waf1) synthesis and up-regulated phosphorylation of Rb independent of p53. These reactions were followed by a decrease in cell number and an increase in apoptosis and G(2)/M checkpoint arrest. The suppression of phosphorylation of Akt by DHEA was due to regulation of the dephosphorylation by protein phosphatase 2A (PP2A). DHEA up-regulated the expression of gamma-glutamylcysteine synthetase, a rate-limiting enzyme of glutathione (GSH) synthesis, and the levels of GSH to maintain PP2A activity. The results suggested that DHEA increases the sensitivity of cells to gamma-ray irradiation by inducing apoptosis and cell cycle arrest through GSH-dependent regulation of the reduced form of PP2A to down-regulate the Akt signalling pathway., Free Radical Research, 42(11-12), pp.957-965; 2008

We report an 82-year old man prescribed paroxetine who had hyponatremia and in whom the syndrome of inappropriate secretion of antidiuretic hormone was diagnosed. He had taken sulpiride for depressed mental status. However, he showed parkinsonism, which was an adverse effect from the treatment of sulpiride. Therefore sulpiride was changed to selective serotonin reuptake inhibitor, paroxetine 10mg daily. His depressed mental status deteriorated after paroxetine treatment started. His depression had not lessened after 12 days, and the dosage was increased to 20mg daily. On the 15th day after starting paroxetine, routine laboratory tests showed that his serum sodium level was 126 mEq/l. We recognized that his confusion and loss of appetite were symptoms of hyponatremia, rather than of worsening depression. Laboratory data revealed hyponatremia, low serum osmolarity (242 mOsm/kg) with a relatively high level of serum antidiuretic hormone, and concentrated urine (439 mOsm/kg). We diagnosed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), associated with paroxetine. The dosage of paroxetine was reduced gradually and the serum sodium level returned to normal on day 2 after medication ceased completely. Paroxetine produces fewer adverse effects than other types of antidepressants. However, its use can be associated with inappropriate secretion of antidiuretic hormone in the body and may lead to SIADH, which is characterized by hyponatremia, a potentially fatal condition that is typically asymptomatic until it becomes severe. SIADH is more likely in some populations, including the elderly. Serum sodium levels should be monitored closely, especially in elderly patients.

Yeast Sir2 plays critical roles in gene silencing, stress resistance and longevity. Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53. To investigate a role of Sirt1 in endothelial dysfunction and premature senescence, we examined the effects of Sirt1 inhibition in human umbilical vein endothelial cells (HUVEC). Sirt1 inhibition by sirtinol, which is a 2-hydroxy-1-napthaldehyde derivative, or siRNA for Sirt1-induced premature senescence-like phenotype, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 mumol/L)-treated HUVEC was SA-beta-gal-positive, whereas only 17% of vehicle-treated cells were positive. Sirt1 inhibition by sirtinol or Sirt1 siRNA increased PAI-1 expression and decreased both protein expression and activity of eNOS. Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered. Impaired epidermal growth factor-induced activation of mitogen-activated protein kinases was associated with Sirt1 inhibition-induced senescence-like growth arrest. Conversely, overexpression of Sirt1 prevented hydrogen peroxide-induced SA-beta-gal activity, morphological changes and deranged expression of PAI-1 and eNOS. These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression. Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS.

Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells.Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H(2)O(2). Edaravone treatment (10mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H(2)O(2)-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18+/-0.01 to 0.09+/-0.01 mm(2), P0.001) and descending aorta (5.09+/-0.86 to 1.75+/-0.41 mm(2), P0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment.These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.

Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells.

An 81-year-old woman was admitted due to exacerbation of chronic back pain from a vertebral osteoporosis fracture. The lumbar MRI examination revealed compression fracture of Th12 and L1 bones. Initial treatment with roxoprofen, calcitonin, bupurenorfin, and morphine did not achieve pain reduction in the patient. Because her geriatric depression scale score was low, we next tried to treat the pain using an antidepressant. Although the pain was improved by amitriptyline, the side effects of dry mouth and urinary incontinence were occurred. Milnacipran, a serotonin and norepinephrine reuptake inhibitor (SNRI), was then tried for the treatment of the chronic pain instead of amitriptyline, but the pain was increased. Then, she was given amitriptyline again for treatment of the chronic back pain instead of SNRI. The second-time amitriptyline treatment was effective to reduce the pain, with minimal side-effects. Because chronic pain due to osteoporosis is often difficult to treat in elderly patients, the classic antidepressant, amitriptyline, may help pain control by narcotics and anti-inflammatory agents in some elderly patients.

We report a 94-year-old woman, who underwent percutaneous endoscopic Jejunostomy (PEJ) tube feeding for enteral nutrition, developed the intussusception of the small intestine. She suffered from nontuberculous mycobacterium (NTM), and her lung inflammation deteriorated due to aspiration pneumonia and malnutrition. Because of old age, dysphagia, esophageal hiatus hernia, gastro-esophageal reflux and her bedridden condition due to severe osteoporosis, oral nutritional supplementation is nearly impossible. To reduce the aspiration risk, we chose PEJ instead of percutaneous endoscopic gastrostomy (PEG) as the route of tube feeding. Six months after the placement of a PEJ tube, aspiration pneumonia was diagnosed and she was readmitted to our hospital. During hospitalization, she had sudden diarrhea, vomiting, and lower abdominal pain. Abdominal CT scan and radiographs using contrast medium showed small intestinal intussusception related to the PEJ tube. We observed the clinical course without performing surgery, pulling it back towards the stomach and placing an ileus tube, because the small intestine was not completely obstructed. Two months later, although she suffered from aspiration pneumonia once more, she remained in a stable condition without further intervention so that she could move to aother hospital. Recently PEJ has been expected to prevent aspiration pneumonia, but we believe that it can be a risk factor for intussusception. Although the PEJ can be a good parenteral nutrition route for frail elderly with dysphagia, we need to consider possible complications including intussusception.

To promote advance directives, it is crucial to understand how many older persons have wishes related to end-of-life care. Additionally, it is important to understand how cognitive function or mood affect these wishes.For the interview-based survey, 99 inpatients aged 75 years or older were enrolled after excluding patients with a Mini-Mental State Examination score of 20 or less. For the questionnaire-based survey, 99 outpatients aged 75 years or older without dementia were enrolled. Both surveys comprised the same items on older patients' wishes related to artificial nutrition and hydration (ANH) during end-of-life care.Of the total enrolled patients, 76.8% participated in the interviews. Of these, 50.0% were against ANH during their end-of-life care, including the patients who were definitely against ANH (26.3%). In contrast, just 5.3% wished to receive ANH. In the questionnaire survey, 65.6% of the respondents were against ANH, and 4.9% wished to receive ANH. Aging and Mini-Mental State Examination scores of less than 24 were significantly associated with a higher tendency to decline from participating in the interview. However, the distribution of the interview answers was not associated with age, Mini-Mental State Examination or Geriatric Depression Scale scores. Of the interviewed patients, 84.2% agreed to their responses being preserved in their medical records.Although the majority of the elderly patients were against ANH during end-of-life care, many patients did not have definite wishes in Japan. The percentage of those who were against ANH was not associated with cognitive function or depressive state. Geriatr Gerontol Int 2016; 16: 1204-1210.

Both life expectancy and healthy life expectancy in Japan have been increasing and are among the highest in the world, but the gap between them has also been widening. To examine the recent trends in old age disability, chronic medical conditions and mortality in Japan, we retrospectively analyzed three nationally representative datasets: Comprehensive Survey of Living Conditions (2001–2013), Patient Survey (1996–2011) and Vital Statistics (1995–2010). We obtained the sex- and age-stratified trends in disability rate, treatment rates of nine selected chronic medical conditions (cerebrovascular diseases, joint disorders, fractures, osteoporosis, ischemic heart disease, diabetes mellitus, hypertension, pneumonia and malignant neoplasms), total mortality rate and mortality rates from specific causes (cerebrovascular diseases, heart diseases, pneumonia and malignant neoplasms) in both sexes in four age strata (65–69, 70–74, 75–79, 80–84 years). Disability rates declined significantly in both sexes. Treatment rates of all selected medical conditions also decreased significantly, except for fractures in women and pneumonia. Both total mortality rate and cause-specific mortality rates decreased in both sexes. We concluded that the recent decline in disability rates, treatment rates of chronic medical conditions and mortality rates points toward overall improvement in health conditions in adults over the age of 65 years in Japan. Nonetheless, considering the increase in the number of older adults, the absolute number of older adults with disability or chronic medical conditions will continue to increase and challenge medical and long-term care systems.

Vascular calcification is a risk factor for cerebral and cardiovascular events and has a high prevalence among elderly. To finding ways of prevent or cure vascular calcification may leads to not only a healthy longevity but also medical expenditure reduction. However, the molecular mechanism underlying this pathogenic process is still obscure. To clarify the mechanism of vascular calcification, the development of animal models that exhibit extensive and robust vascular calcification is an important issue for research in vascular biology.

BACKGROUND: Some patients with obstructive sleep apnea syndrome remove the CPAP device during sleep, although they start CPAP at bedtime. We hypothesized that body position changes and oxygen desaturations may be associated with patient removal of the CPAP device. METHODS: We consecutively enrolled 36 poor CPAP adherers and 25 good CPAP adherers. Body positions and oxygen desaturations were evaluated when these subjects used CPAP during sleep for 2 nights, permitting the removal of the CPAP device during the recording. RESULTS: Twelve poor CPAP adherers exhibited subject removal of the CPAP device within 4 h from the start of body position recording. The frequency of body position changes was significantly higher within 15 min before the CPAP removal than during other periods when CPAP was used. At the same time, oxygen desaturations were significantly more frequent within 15 min before CPAP removal than during other periods when CPAP was used. In addition, the majority (66.7%) of the CPAP removal events were followed by a change from a supine position to a non-supine position within 5 min. The number of body position changes during the first 4-h recording was significantly higher in the poor CPAP adherers who had removed their CPAP device compared with the poor CPAP adherers who had not removed their device. However, the number of body position changes or oxygen desaturation index under CPAP during the first 4-h recording was not significantly different between the poor CPAP adherers and good CPAP adherers. CONCLUSIONS: Our findings are the first to indicate associations among CPAP removal, body position changes, and oxygen desaturations during sleep in poor CPAP adherers. However, our findings also indicated that most good CPAP adherers make frequent body position changes without removal of CPAP device, suggesting that patients can adapt to the discomfort of CPAP therapy at the time of body position changes.

Background Preventing falls and bone fractures in hospital care is an important issue in geriatric medicine. Use of hypnotics is a potential risk factor for falls and bone fractures in older patients. However, data are lacking on the association between use of hypnotics and the occurrence of bone fracture. Methods We used a national inpatient database including 1,057 hospitals in Japan and included dementia patients aged 50 years or older who were hospitalized during a period of 12 months between April 2012 and March 2013. The primary outcome was the occurrence of bone fracture during hospitalization. Use of hypnotics was compared between patients with and without bone fracture in this matched case-control study. Results Of 140,494 patients, 830 patients suffered from in-hospital fracture. A 1:4 matching with age, sex and hospital created 817 cases with fracture and 3,158 matched patients without fracture. With adjustment for the Charlson comorbidity index, emergent admission, activities of daily living, and scores for level walking, a higher occurrence of fractures were seen with short-acting benzodiazepine hypnotics (odds ratio, 1.43; 95% confidence interval, 1.19–1.73; P

Background: Multiple consultations in older patients may increase the chance of overlapping prescriptions or inappropriate drug prescribing. Methods: We carried out a survey investigating the status of multiple consultations and the polypharmacy of patients attending geriatric outpatient units of five university hospitals. Results: The patients who received multiple consultations did not have a different number of diagnosed disorders and drugs prescribed by geriatricians compared with the patients who received a single consultation. Conclusions: No significant difference in diagnostic and prescribing profiles between the patients with referrals and those without, together with the relatively smaller incidence of inappropriate prescriptions by referrals to non-geriatric specialists, suggest that multiple consultations per se may not necessarily increase the risk for adverse drug events in clinical settings.

An 81-year-old woman with Graves’ disease and osteoporosis was referred to the hospital because of anorexia over one month and impaired consciousness. She also presented with low-grade fever and emaciation. Laboratory tests revealed marked hypercalcemia (corrected serum calcium level of 12.4 mg/dL), which was initially suspected to result from vitamin D toxicity, because she had been taking vitamin D3 (alphacalcidol of 0.5 µg/day) for the treatment of osteoporosis. However, discontinuation of vitamin D3 and fluid infusion did not ameliorate hypercalcemia one week later. After excluding hyperparathyroidism and malignancy-related hypercalcemia, hypercalcemia was considered to be attributable to the exacerbation of hyperthyroidism (free T4 of 6.69 ng/dL, free T3 of 13.27 pg/mL and thyroid stimulating hormone (TSH)

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K–dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 μmol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway.