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Metabolic syndrome (MetS) is an important predictor of mortality in older adulthood, but it is not reliably related to measures of body composition such as body mass index in older adults, as opposed to those in earlier life stages. Previous research suggests that skeletal muscle mass is related to cardiovascular risk in older adulthood, but it is difficult to measure muscle mass accurately and independently of body fat. This study aimed to examine the relationship between body composition and cardiovascular risk factors among women in older adulthood. A cross-sectional observational clinical study was conducted at a single medical clinic in Tokyo, Japan. Participants included 90 healthy Japanese women aged 65 years and older. MetS risk factors were assessed. Appendicular skeletal muscle mass (ASM) was assessed using dual-emission X-ray absorptiometry. Visceral fat area (VFA) was measured using computed tomography. VFA positively correlated with ASM and MetS, whereas ASM and MetS did not correlate with each other. Using VFA and ASM data in a MetS multiple linear regression model, the association between VFA and MetS remained positive, whereas a significant negative relationship emerged between ASM and MetS. Lower muscle mass was independently associated with higher cardiovascular risk after controlling for VFA. Clinical interventions to reduce muscle loss in older adulthood may be beneficial for reducing the risk of MetS and improving cardiovascular health. [ABSTRACT FROM AUTHOR]

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

Introduction: Metabolic syndrome causes insulin resistance and is associated with risk factor clustering, thereby increasing the risk of atherosclerosis. Recently, endothelial nitric oxide synthase deficient (eNOS-/-) mice have been reported to show metabolic disorders. Interestingly, eNOS has also been reported to be expressed in non-endothelial cells including adipocytes, but the functions of eNOS in adipocytes remain unclear. Methods and Results: The eNOS expression was induced with adipocyte differentiation and inhibition of eNOS/NO enhanced lipolysis in vitro and in vivo. Furthermore, the administration of a high fat diet (HFD) was able to induce non-alcoholic steatohepatitis (NASH) in eNOS-/- mice but not in wild type mice. A PPARγ antagonist increased eNOS expression in adipocytes and suppressed HFD-induced fatty liver changes. Conclusions: eNOS-/- mice induce NASH development, and these findings provide new insights into the therapeutic approach for fatty liver disease and related disorders. [ABSTRACT FROM AUTHOR]

Objective This study aimed to explore the relationships among physicians’ confidence in conducting medical interviews, their attitudes toward the patient–physician relationship, and undergraduate training in communication skills among resident physicians in Japan. Methods Participants were 63 first-year resident physicians at a university hospital in Tokyo. The Physician Confidence in the Medical Interview scale (PCMI) was constructed based on the framework of the Calgary–Cambridge Guide. Additionally, participants’ attitudes toward the patient–physician relationship (Patient–Practitioner Orientation Scale; PPOS), undergraduate experience of communication skills training, and demographic characteristics were assessed through a self-reported questionnaire. Results The internal consistency of the PCMI and PPOS scales were adequate. As expected from the undergraduate curriculum for medical interviews in Japan, residents had relatively higher confidence in their communication skills with respect to gathering information and building the relationship, whereas less confident about sharing information and planning treatment. The PCMI was associated with a more patient-centered attitude as measured by the PPOS. Conclusion These scales could be useful tools to measure physicians’ confidence and attitudes in communicating with patients and to explore their changes through medical education. Practice implications Residency programs should consider including systematic training and assessment in communication skills related to sharing information and planning treatment. [ABSTRACT FROM AUTHOR]

Background: In recent years, the growing global urbanization and urban population have resulted in the emergence of various health problems unique to urban areas. Therefore, training general practitioners and family physicians who can tackle the complex health problems of urban areas and improve the health of urban people is one of the most important issues of our time. However, findings on competencies for urban general practitioners (GP) and family physicians (FP) were limited. This study aimed to identify their comprehensive and content-validated list of competencies. Methods: We used the modified Delphi method to develop a content-validated competency list. First, we analyzed and synthesized the competencies extracted from the literature review using qualitative thematic analysis methods to create an initial competency list of 34 items. We then assembled 39 expert panelists in four groups of study participants: physicians, nurses, patients, and medical education specialists. The expert panelists were asked to indicate their level of agreement with the lists and provide revised comments on the description of each competency via a web-based questionnaire. Their responses were analyzed quantitatively and qualitatively by the research team and used to revise the list. These processes were repeated, and the survey was completed when it was determined that consensus had been reached. Results: Three rounds of Delphi were conducted. 39 responded in the first round, 38 in the second round, and 36 in the third round. The initial list of competencies was revised and consolidated from 34 to 14 items in the first round, bringing the total to 20 items along with six new items proposed by the panelists. In the second round, it was revised and consolidated into a list of 18 items. In the third round, all 18 items were considered to have been agreed upon by the panelists, so the survey was closed. Conclusion: We identified a comprehensive 18-item list of competencies for urban GP/FP in a content-validated manner. Several are newly discovered competencies in this study. The findings of this study will be useful for the future training of urban GP/FP and for solving urban health problems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Tumor necrosis factor (TNF-α) 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-α-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-α-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-α stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-α-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-α 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-α in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Objective: Pulsatile forces regulate vascular remodeling and trigger vascular diseases such as saphenous vein graft disease. The saphenous vein is exposed to high pressure and pulsatility only after implantation. Statins have been proved to reduce the incidence of vein graft failure. Thus, we investigated the molecular mechanisms of pulsatile stretch-induced saphenous vein smooth muscle cell (SMC) proliferation and potential beneficial effects of statins. Methods and results: Human saphenous vein SMCs were subjected to cyclic stretch (60 cycles/min) in Flex I plates. Cerivastatin and simvastatin significantly prevented stretch-induced increase in SMC proliferation. Stretch induced the membrane accumulation of Rho A and Rho kinase inhibitors (Y-27632 and hydroxyfasudil) and dominant negative Rho A mutant significantly prevented stretch-induced SMC proliferation. In addition, stretch increased the levels of both p44/42 mitogen-activated protein (MAP) kinase and Akt phosphorylation. MAP kinase kinase (MEK)1/2 inhibitor U0126, phosphatidylinositol (PI) 3-kinase inhibitors (wortmaninn and LY294002), and dominant negative Akt mutant significantly prevented stretch-induced SMC proliferation. Cerivastatin significantly prevented stretch-induced membrane accumulation of Rho A. On the other hand, stretch-induced phosphorylation of p44/42 MAP kinase and Akt was not prevented by cerivastatin. Mevalonate restored the preventive effect of cerivasatain on stretch-induced Rho A membrane accumulation. Stretch induced hyperphosphorylation of retinoblastoma protein (pRb), which was prevented by cerivastatin and the Rho kinase inhibitors. Conclusion: Statins prevent stretch-induced saphenous vein SMC proliferation via inhibition of the Rho/Rho-kinase pathway. This may explain the beneficial effects of this class of drug, especially for patients after coronary artery bypass grafting. [Copyright &y& Elsevier]

Activation of the coagulation pathway and the inhibition of the fibrinolytic pathway play a pivotal role in the pathogenesis of thrombotic vascular disease such as acute coronary syndromes. Statins have been proved to be effective in patients with acute coronary syndromes in terms of reduction of cardiovascular events. It is assumed that the direct effects on vascular cells, which are independent of lipid-lowering, particularly the alterations in coagulation and fibrinolytic pathways, may contribute to these benefits. Indeed, in endothelial cells and vascular smooth muscle cells as well as in monocytes/macrophages, stains reduce tissue factor and plasminogen activator-1 expression and activity and increase tissue plasminogen activator expression and activity. These effects are mainly mediated by the inhibition of the Rho pathway, whereas the activation of Akt by statins plays a role in the suppression of tissue factor expression. These effects on coagulation and fibrinolytic pathways may be particularly important in patients with acute coronary syndromes. [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor on a case of a transient heart failure that occurred in an elderly woman after a fall.

Physicians' empathy and ambiguity tolerance have recently become a focus of medical education. However, the association between the two concepts remains unclear. This study examined the association between empathy and ambiguity tolerance in the clinical context among medical trainees. We conducted a multicenter cross-sectional study in 12 institutions: 2 universities for medical students and 10 hospitals for residents. We assessed ambiguity tolerance using the Japanese version of the Tolerance of Ambiguity in Medical Students and Doctors scale. The outcome variable was empathy, measured using the Japanese translation of the Jefferson Scales of Empathy (JSE). Data from 100 medical students and 135 residents were analyzed. After adjustment for possible confounders, the factor scores of 'tolerance for things that are not black or white in medicine' showed a dose-dependent association with the JSE. There was no clear trend in the association between the total scores or other factor scores and empathy. This nationwide multicenter study showed that the factor scores of 'tolerance for things that are not black or white in medicine' were associated with empathy among medical trainees. Our findings may be helpful for developing interventions in the field of medical education to nurture empathy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in which the authors discuss their study conducted to examine the association of admission due to gastrointestinal hemorrhage with the use of antithrombotic drugs or aspirin among older patients.

The concept of social accountability in medical schools is globally accepted, but data regarding Japanese medical schools are lacking and unclear. This study aimed to elucidate the perception of social accountability of medical schools in Japan and compare this to global frameworks. A document on Japanese medical accreditation standards (Basic Medical Education: Japanese Specifications WFME Global Standards for Quality Improvement) was used for this study. We included 45 medical schools in a qualitative content analysis done via inductive category formation. The documents were also assessed using the social obligation scale. Three main categories and 15 categories were identified. The three main categories were as follows: Issues in society, Quality assurance of medical school, and Improvement of individual quality. Most categories were common to those in global frameworks, but some were characteristic of the Japanese context. The distribution of schools on the social obligation scale in six elements varied mainly 'from responsibility to responsiveness' or equal unless the elements were promoted by national policy. The social accountability of Japanese medical schools is mostly common with the global frameworks. Our findings will help the social accountability of medical schools to become better understood and developed beyond contextual borders. [ABSTRACT FROM AUTHOR]

Introduction: An understanding of social determinants of health (SDH) and patients' social circumstances is recommended to deliver contextualised care. However, the processes of patient care related to SDH in clinical settings have not been described in detail. Observable practice activities (OPAs) are a collection of learning objectives and activities that must be observed in daily practice and can be used to describe the precise processes for professionals to follow in specific situations (process OPA.) Methods: We used a modified Delphi technique to generate expert consensus about the process OPA for patient care related to SDH in primary care settings. To reflect the opinions of various stakeholders, the expert panel comprised clinical professionals (physicians, nurses, public health nurses, social workers, pharmacists and medical clerks), residents, medical students, researchers (medical education, health care, sociology of marginalised people), support members for marginalised people and patients. The Delphi rounds were conducted online. In Round 1, a list of potentially important steps in the processes of care was distributed to panellists. The list was modified, and one new step was added. In Round 2, all steps were acknowledged with few modifications. Results: Of 63 experts recruited, 61 participated, and all participants completed the Delphi rounds. A total of 14 observable steps were identified, which were divided into four components: communication, practice, maintenance and advocacy. The importance of ongoing patient–physician relationships and collaboration with professionals and stakeholders was emphasised for the whole process of care. Discussion: This study presents the consensus of a variety of experts on the process OPA for patient care related to SDHs. Further research is warranted to investigate how this Communication–Practice–Maintenance–Advocacy framework could affect medical education, quality of patient care, and patient outcomes. This study illustrates a means of improving curricula by showing the Communication‐Practice‐Maintenance‐Advocacy (CPMA) framework to be useful for incorporating social determinants of health into healthcare to enhance education. [ABSTRACT FROM AUTHOR]

Abstract: Our previous study has demonstrated that testosterone rapidly activates endothelial nitric oxide synthase (eNOS), enhancing nitric oxide (NO) release from endothelial cells (ECs) via the phosphatidylinositol 3-kinase/Akt (PI3-kinase/Akt) pathway. The upstream regulators of this pathway are unknown. In this study, we further investigated the non-genomic action of testosterone in human aortic ECs. Acute (30min) activation of eNOS caused by testosterone was unaffected by pretreatment with a transcriptional inhibitor, actinomycin D. Non-permeable testosterone-BSA rapidly induced Akt and eNOS phosphorylation. In contrast, luciferase reporter assay showed that the transcriptional activity of the androgen-responsive element (ARE) was increased by testosterone, but not by testosterone-BSA at 2h after stimulation. Immunostaining displayed co-localization of androgen receptor (AR) with caveolin-1. Fractional analysis showed that AR was expressed in caveolae-enriched membrane fractions. Immunoprecipitation assays revealed the association of AR with caveolin-1 and c-Src, suggesting complex formation among them. Testosterone rapidly increased the phosphorylation of c-Src on Tyr416, which was inhibited by an AR antagonist and by siRNA for AR. PP2, a specific-inhibitor of Src kinase, abolished the testosterone-induced phosphorylation of Akt and eNOS. Our data indicate that testosterone induces rapid assembly of a membrane signaling complex among AR, caveolin-1 and c-Src, which then facilitates activation of the c-Src/ PI3-kinase/Akt cascade, resulting in activation of eNOS. [Copyright &y& Elsevier]

Abstract: 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 β-galactosidase (SA-β-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 μmol/L)-treated HUVEC was SA-β-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-β-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. [Copyright &y& Elsevier]

Tests the hypothesis that acute intake of red wine may exert a positive effect on flow-mediated vasodilatation in men. Improvement in endothelium-dependent vasodilatation after acute intake of red wine or red wine without alcohol in men; Constituents of red wine that help improve endothelial function.

Background: The medical practice of general practitioners/family physicians in urban areas differs from that in rural areas, accounting for the difference in specific competencies. However, variations in competencies in community healthcare required for general practitioners/family physicians in urban areas compared with those in rural areas have not yet been fully clarified. Thus, this study aimed to elucidate the competencies required for general practitioners/family physicians, especially in those characteristic to urban areas, and compare them with those in non-urban/rural areas. Methods: A qualitative study with individual interviews and qualitative data analysis was conducted. Participants were selected by purposive sampling, and 10 general practitioners/family physicians with clinical experience of ≥7 y after graduation and ≥ 1 y in both urban and non-urban (rural) areas in Japan were recruited. Additionally, semi-structured individual interviews in a private room around the workplace of the interviewee between September 2014 and September 2016 were conducted. For data collection, interview transcripts were analyzed according to the "Steps for Coding and Theorization" method, a sequential and thematic qualitative data analysis technique and data analysis since March 2018. Results: We interviewed 10 general practitioners/family physicians of Japan and extracted 10 themes as competencies characteristic to general practitioners/family physicians in urban areas. In addition to the known competencies on urban underserved care, we newly clarified the competencies of the ability to integrate divided care and ability to coordinate and collaborate with various medical care and welfare professionals in urban areas. Conclusion: This study was one of the few studies describing the characteristic competencies of urban general practitioners. In summary, a competency necessary for general practitioners in urban areas is to understand the urban context and provide contextual care suitable for urban areas. In the modern age, where urban population concentration is progressing and the interest in urban health is rising, our study will give certain suggestions for primary care education and practice necessary for urban areas. [ABSTRACT FROM AUTHOR]

Background: Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear. Methods: Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy. Results: Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice. Conclusion: Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim To investigate the relationship between physical function, mortality and autonomic nervous activity measured by heart rate variability of elderly in long-term care. Methods Cross-sectional and longitudinal studies were carried out at hospitals and health service facilities for the elderly in Nagano prefecture, Japan, from July 2007 to March 2011. A total of 105 long-term care older adults and 17 control older adults with independent physical function were included. The Functional Independence Measure ( FIM) and Barthel Index were determined as indices of physical function. Twenty-four-hour Holter monitoring was carried out. From RR intervals in electrocardiograms, heart rate and standard deviations of all NN intervals in all 5-min segments of the entire recording, power spectral density, low frequency, high frequency and low frequency/high frequency ( LF/ HF) were calculated. Results FIM score and Barthel Index were 46 ± 26 and 30 ± 31, respectively, in long-term care elderly. FIM and Barthel index were significantly correlated with heart rate and the standard deviations of all NN intervals after adjustment for age, sex, cardiovascular risk factors and FIM. Furthermore, LF/ HF was significantly decreased in long-term care elderly compared with control elderly after adjustment for covariates. In addition, decrease in LF/ HF was an independent risk factor for mortality. Conclusion Low LF/ HF activity was observed in long-term care elderly and was related to an increase of overall mortality. Geriatr Gerontol Int 2014; 14: 159-166. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Physicians are uncertain about what medical services should be provided to older and/or disabled patients. Better understanding of health outcome prioritization among health care providers and recipients may help the process of decision- and policy-making. For this purpose, surveys were conducted on priorities of health care outcomes for the elderly. Design: Survey research. Setting: Four groups of health care providers and four groups of health care recipients. Participants: A total of 2512 health care providers and 4277 recipients. Measurements: Questionnaires were sent to more than 8000 health care providers and more than 9000 health care recipients: geriatricians, physicians who commonly see older patients or work in long term care facilities, staff members and participants in adult day care, patients in outpatient geriatric clinics, family members of patients with dementia, and community-dwelling older adults. The questionnaire asked the subjects to rank 12 measures of health care outcomes. Results: The mean response rate was 49%. All health care provider groups considered “improvement of quality of life” the most important. In contrast, in health care recipient groups, “effective treatment of illness,” “improvement of physical function,” and “reduction of carer burden” were given high priority, whereas “improvement of quality of life” was perceived as less important. All the groups, including health care providers and recipients, ranked “reduction of mortality” the least important, followed by “avoiding institutional care.” Stratification analysis showed that the results did not differ by sex, nursing care level, or the existence of relatives who required nursing care, whereas age slightly influenced the order of high-ranked measures. Conclusion: Priorities of health care services and their differences between providers and recipients should be taken into account in the health care of older patients and the design of health care policies and research. [Copyright &y& Elsevier]

Abstract: Hyperphosphatemia has emerged as a cardiovascular risk factor that stimulates calcification in vessels. We explored molecules that were induced by inorganic phosphate (Pi) at an early stage in vascular smooth muscle cells (VSMC). In the present study, we examined the role of thrombomodulin (TM) in Pi-induced VSMC calcification based on the results of DNA microarray analysis. Both mRNA and protein expression of TM were markedly augmented in Pi-induced calcification. Conversely, knockdown of TM by siRNA significantly inhibited calcification, in addition to Pi-induced apoptosis which plays critical roles in VSMC calcification. We further found that TM suppressed both of mRNA and protein expression of growth arrest-specific gene 6 (Gas6), a key molecule regulating apoptosis. Recombinant extracellular epidermal growth factor (EGF)-repeat domain of TM exaggerated calcification and this effect was abrogated by a neutralizing antibody for EGF receptor, suggesting that the cleaved and secreted form of TM may activate EGF receptor. We also found that downregulation of Gas6 by TM/EGF receptor axis was mediated by ERK in VSMC calcification. In the aorta of adenine-fed rat, a typical medial calcification model with hyperphosphatemia, we found that TM expression was increased. Furthermore, in human calcified aorta, increased TM expression was also observed. These results indicate that TM is a novel molecule that promotes apoptosis and vascular calcification by regulation of Gas6, presumably via EGF receptor/ERK axis. [Copyright &y& Elsevier]

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. Geriatr Gerontol Int 2012; 12: 425-430. [ABSTRACT FROM AUTHOR]

Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescenceaccelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD+-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging. [ABSTRACT FROM AUTHOR]

Abstract: This report describes a case of tako-tsubo-like left ventricular dysfunction in a patient with chronically occluded left anterior descending artery. A 74-year-od female, experiencing severe pain due to osteoarthritis, presented with chest pain lasting for 6 h. Electrocardiography revealed ST-segment elevation in the anterior and lateral walls. Left ventriculography in the acute phase displayed an akinetic apex and hyperkinetic basal region. Emergent coronary angiography revealed total occlusion of the left anterior descending artery. Although direct coronary angioplasty to the totally occluded left anterior descending artery was unsuccessful, the left ventricular function returned to normal within three weeks after admission. Thallium scintigraphy showed no significant abnormality, and cardiac enzyme elevation showed only a slight increase. In this case, tako-tsubo-like left ventricular dysfunction was considered to occur in the presence of chronically occluded left anterior descending artery. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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)-β via a redox-dependent mechanism involving glutathione (GSH)/glutaredoxin (GRX)1. Here we demonstrate that the redox regulation of PDGFR-β is involved in the effect of DHEA on VSMC. DHEA suppressed the PDGF-BB-dependent phosphorylation of PDGFR-β. 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-β-phosphorylation by DHEA. A promoter analysis of GRX1 and γ-glutamylcysteine synthetase (γ-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 PPARα plays a role in the induction of GRX1 and γ-GCS expression by DHEA. In conclusion, the redox regulation of PDGFR-β is involved in the suppressive effect of DHEA on VSMC proliferation through the up-regulation of GSH/GRX system. [Copyright &y& Elsevier]

Abstract: Objective: 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. Methods: 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. Results: 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 (P <0.01 by log-rank test). Cox proportional hazards models showed that the subjects with the lowest tertile of plasma testosterone (<14.2nmol/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. Conclusions: 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. [Copyright &y& Elsevier]

Abstract: Objectives: Arterial calcification makes the management of hemodynamics more difficult. Some reports have previously shown that simple assessment of aortic calcification using plain radiography is associated with cardiovascular (CV) events; however, these studies simply assessed whether aortic calcification was present or absent only, without considering its extent. Here, we evaluated validity of grading aortic arch calcification (AAC) to predict new CV events. Methods and results: We retrospectively reviewed chest X-rays in 239 asymptomatic out-patients who underwent measurement of endothelial function at the 1994–2000 without past history of CV events. The extent of AAC was divided into four grades (0–3). Among these subjects, the follow-up of CV events in 209 patients was completed. At baseline, AAC grade was positively related to age, pulse pressure, diabetes and renal dysfunction. Impairment of endothelial function, as determined by flow-mediated dilation (FMD), was also correlated to increasing AAC grade. Fifty-seven CV events in total occurred during a mean follow-up period of 69±45 months. With multivariate adjustment, Kaplan–Meier analysis showed that the incidence was significantly higher in patients with higher AAC grade (grades 2 and 3) than in those with grade 0 or 1 (p <0.01, log-rank test). Two kinds of multivariate Cox-proportional hazards analyses showed the predictive values of AAC grade were significant (hazard ratio, 2.49; p =0.01, 2.56; p <0.01, respectively), and the predictive power was superior to that of renal dysfunction or FMD. In addition, the prediction was valuable even in patients without CKD. Conclusions: AAC detectable on chest X-ray is a strong independent predictor of CV events beyond traditional risk factors including endothelial dysfunction. Risk stratification by assessment of AAC may provide important information for management of atherosclerotic disease. [Copyright &y& Elsevier]

Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men. However, little is known about the mechanism underlying the cardioprotective effects of androgens. Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor (AR)-dependent transactivation of growth arrest-specific gene 6 (Gas6), a key regulator of inorganic phosphate (P,)induced calcification of vascular smooth muscle cells (VSMC). Testosterone and nonaromatizable androgen dihydrotestosterone inhibited Pi-induced calcification of human aortic VSMC in a concentration-dependent manner. Androgen inhibited Pi-induced VSMC apoptosis, an essential process for VSMC calcification. The effects on VSMC calcification were mediated by restoration of Pi-induced down-regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation. These effects of androgen were blocked by an AR antagonist, flutamide, but not by an estrogen receptor antagonist, ICI 182,780. We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region. Dihydrotestosterone stimulated Gas6 promoter activity, and this effect was abrogated by flutamide and by AR siRNA. Sitespecific mutation revealed that the proximal ARE was essential for androgen-dependent transactivation of Gas6. Furthermore, chromatin immunoprecipitation assays demonstrated ligand-dependent binding of the AR to the proximal ARE of Gas6. These results indicate that AR signaling directly regulates Gas6 transcription, which leads to inhibition of vascular calcification, and provides a mechanistic insight into the cardioprotective action of androgens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mechanical forces and the activation of the renin-angiotensin system (RAS) may alter the NO/O2•- balance, imparing endothelial nitric oxide (NO) availability. This study investigates the link between RAS and NO/O2•- balance in human aortic endothelial cells (HAEC) exposed to pulsatile stretch with and without ACE inhibitor quinaprilat or angiotensin II type 1 (AT1) receptor antagonist losartan. Pulsatile stretch increased Ang II levels and O2•- production, reducing NO release. RAS blockade with quinaprilat or losartan restored the balance between NO and O2•-. These results provide a molecular basis for understanding the vascular protective effects of ACE inhibition and AT1 receptor antagonism. [ABSTRACT FROM AUTHOR]

• The bleeding risk of oral anticoagulant use in very old patients remains controversial. • The outcomes of prescribing oral anticoagulants were observed in a hospital-based study. • Patients with disability had a higher incidence of stroke even though they took oral anticoagulants. • Disability level could be a surrogate marker for optimizing oral anticoagulant treatment. Background: Atrial fibrillation (AF) in patients aged ≥75 is one of the major risk factors for stroke, and prescription of oral anticoagulants (OACs) should be considered in these patients. We investigated the use of OAC' for patients certificated for long-term care (LTC) insurance, who have a high risk of bleeding among older patients. Methods and Results: From 1169 consecutive inpatients aged 75 or older who were admitted to the geriatric ward of The University of Tokyo Hospital between 2012 and 2017, we identified 175 patients (men 48%, mean age 85.5 years) who had AF during admission. The patients' background, prescription of OACs on discharge, and the level of LTC insurance were checked. Patients were followed up for 1 to 5 years. Major bleeding, stroke, and all-cause mortality were investigated as outcomes. Among patients with AF, 63.4% were taking OACs. In multivariate analysis, older age, low BMI and no history of stroke were significant factors for not prescribing OACs. Care level patients with OACs had a higher incidence of stroke than others. There was no difference, irrespective of OAC prescription and disability level, in incidence of major bleeding. Care level patients without OACs had higher mortality than others. Conclusions: These results suggest that older care level patients with AF may benefit less from OACs. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells. Methods and results: Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01mmol/L H2O2. 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 H2O2-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±0.01mm2, P <0.001) and descending aorta (5.09±0.86 to 1.75±0.41mm2, P <0.05), 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. Conclusions: These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy. [Copyright &y& Elsevier]

Abstract: Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins'' effect to prevent vascular calcification. [Copyright &y& Elsevier]

Aging is an independent risk factor for the development of cardiovascular disease. Vascular aging is mainly characterized by endothelial dysfunction, which, in turn, is primarily attributable to increased superoxide (O2⋅−) formation with age. To date, the source of this age-associated increased O2⋅− production remains obscure. We investigated whether like in hyperglycemia or hypertension protein kinase C (PKC)-mediated activation of the NAD(P)H oxidase system is involved. Here we show that both PKC translocation, necessary for its activation, and expression of the cytosolic subunits of the NAD(P)H oxidase, p47phox and p67phox, remain unchanged with age. Therefore, we suggest that oxidative stress-associated vascular aging mechanistically differs from endothelial dysfunction seen in the context of other cardiovascular risk factors, for which the PKC/NAD(P)H oxidase pathway has been shown responsible. [Copyright &y& Elsevier]

A letter to the editor is presented which is concerned with the pulmonary features of being underweight in older men.

A letter to the editor is presented which is concerned with a case study of a patient with large B-cell lymphoma who had symptoms which resembled progressive dementia.

A letter to the editor is presented wherein the authors discuss a study which was conducted to study adverse drug reactions (ADR) in elderly patients taking six or more drugs by using the inpatient database of a geriatric department.

A letter to the editor is presented which is concerned with research which investigated the factors associated with prolonged hospital stays in a geriatric ward in a university hospital in Japan.

A letter to the editor is presented which is concerned with sleep apnea in patients with metabolic syndrome.