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We report an elderly case with nontuberculous mycobacteria (NTM). Four years after left lung upper lobectomy due to lung cancer by the video-assisted thoracic surgery (VATS), an 81 year-old patient complained of general fatigue and appetite loss. Although he did not exhibit fever or respiratory tract symptoms, a Chest X ray film revealed unilateral massive pleural effusion in the left lung. NTM (Runyon classification type II) was grown in the sputum culture. Neither mycobacterium tuberculosis DNA nor M. avium-intracellulare complex DNA was detected by polymerase chain reaction. The pleural effusion adenosine deaminase (ADA) activity was 127.6U/l. NTM was considered as the most probable diagnosis. After admission his condition and appetite improved. Chest computed tomography (CT) scan showed reduction of left pleural effusion, but another pulmonary nodule lesions were sustained. Although the abnormal findings on chest CT did not totally resolve, we did not prescribe antituberculosis drugs, based on the comprehensive assessment of his NTM disease state. The pathogenesis and diagnosis of HTM in elderly cases was discussed.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

Blood pressure variability is one of the characteristic features of hypertension in the elderly. However, its clinical significance remains to be determined. We therefore examined the impact of blood pressure variability on the development of cardiovascular events in elderly hypertensive patients. A total of 106 consecutive hypertensive patients aged more than 60 years old (mean age, 73.9 +/- 8.1 years old; male, 54%), all of whom underwent 24-h ambulatory blood pressure monitoring, were followed up (median, 34 months; range, 3-60 months). During the follow-up period, 39 cardiovascular events were observed, including 14 cases of cerebral infarction and 7 cases of acute myocardial infarction. The coefficient of variation (CV) of 24-h systolic blood pressure (SBP) values was used as an index of blood pressure variability. The patients showed a mean CV value of 10.6%, and were divided into two groups according to this mean value as a cut-off point: a high CV group (n = 46) and a low CV group (n = 60). Although baseline clinical characteristics were similar in the two groups, Kaplan-Meier plots for event-free survival revealed that the rate of cardiovascular events was significantly higher in high CV group than in low CV group (p < 0.05). Cox's proportional hazards analysis showed that increased blood pressure variability (a high CV value of 24-h SBP) was an independent predictive variable for cardiovascular events. The CV value of daytime SBP and the SD value of both 24-h SBP and daytime SBP also had positive correlations with the onset of cardiovascular events. These results suggest that increased blood pressure variability may be an independent risk factor for cardiovascular events in elderly hypertensive patients.

Several bedside portable swallowing tests have been advocated for screening for dysphagia. However, the clinical usefulness and limitation of these tests have not been examined in elderly patients with dementia. We performed the repetitive saliva swallowing test (RSST) and the simple swallowing provocation test (SSPT) in 37 elderly inpatients (81.8 +/- 1.2 years old). Simultaneously, cognitive and verbal communication ability were assessed by the Hasegawa Dementia Scale revised version (HDSR) and the Mini-Communication Test (MCT). RSST was completed only in 22 patients (59%), whereas SSPT was successfully completed in all cases. Scores of HDSR and MCT were significantly lower in patients who were unable to cooperate with RSST compared to successful examinees (HDSR: 7 +/- 1 vs 15 +/- 3, p < 0.0; MCT: 47 +/- 8 vs 81 +/- 5, p < 0.01). Dysphagia was detected in 14 patients (64%) by RSST and 5 (14%) by SSPT. Patients with dysphagia showed significantly lower cognitive function (p < 0.05) and verbal communication ability (p < 0.05). In conclusion, RSST is more sensitive to detect dysphagia in elderly patients; however, compliance with RSST is strongly influenced by the patient's cognitive function and verbal communication ability. Comprehensive geriatric assessment will help to choose an alternative test for dysphagia such as SSPT which is more specific test for aspiration pneumonia.

To develop a portable risk index for falls.Risk factors were chosen from previously established factors then we added several environmental factors to the risk index; previous falls in the last 12 month, trippig or stumbling, inability to ascend or descend stairs without help, decreased walking speed, inability to cross a road within the green signal interval, inability to walk 1km without a break, inability to stand on one leg for 5 seconds (eyes open), using a cane, inability to wring out a towel, dizziness or faintness, stooped or rounded back, knee joint pain, visual disturbance, hearing disturbance, cognitive decline, fear of falling, receiving 5 or more prescribed drugs, sensation of darkness at home, obstacles inside, barrier on the carpet or floor, using steps daily at home, steep slopes around home.The questionnaire sheet was completed by 2,439 community-dwelling elderly subjects (76.3 +/- 7.4 years old). The frequency of each items of fall risk index was compared between fallers (history of fall within one year) and non-fallers. Multiple regression analysis was performed to identify independent risk factors for previous falls.Except barrier, step use and steep slope around home, all items in the fall risk index were more frequent in fallers. Multivariate analysis revealed that tripping or stumbling, inability to cross a road within the green signal interval, dizziness or faintness, obstacles inside, inability to wring out a towel, cane use and knee joint pain were independent risk factors for previous falls. These 7 selected items were further analyzed as predictors. The maximum sum of sensitivity and specificity was reached at the cut-off point of 2/3 (sensitivity 0.65, specificity 0.72) by receiver operating curve.Portable fall risk index is useful for clinical settings to identify high-risk subjects.

The current regimens of hormone replacement therapy for postmenopausal women, estrogen combined with progestogen, have failed to show beneficial effects for the prevention of atherosclerotic disease. Although the relatively higher dose of estrogen contained in those regimens exerted adverse effects, there are few data examining a lower dose of estrogen in an atherosclerosis model. Therefore, we investigated experimentally whether lower doses of estrogen could inhibit neointimal formation after balloon injury of the rat carotid artery. Ten-week-old Wistar rats were subjected to ovariectomy or sham-operation (n=7). Four days after ovariectomy, rats were implanted with an osmotic mini-pump containing 17-beta estradiol (0.2, 1, 2, 10 and 20 microg/kg/day; n=6, 4, 8, 6 and 5, respectively) or placebo (n=10). After 3 days of hormone therapy, balloon injury was performed in the left common carotid artery. Neointimal formation was histologically evaluated 2 weeks after injury. Cross-sectional intimal area and the ratio of intimal area to medial area were dose-dependently reduced by estrogen replacement compared with those in ovariectomized rats without estrogen replacement. The effects of estrogen replacement were identical to those of an angiotensin II type 1 receptor blocker, candesartan. Interestingly, the effect was significant even in rats receiving lower doses of estrogen, in which plasma estradiol concentrations were not increased and the hyperplastic response of the uterus was minimal. These results suggest the efficacy of low-dose estrogen therapy for the protection of atherosclerosis.

Background: The objectives of this study were to determine whether medications, particularly inappropriate prescribing, would be reduced after admission to long-term care facilities, and whether adverse drug withdrawal events (ADWEs) would occur in relation to discontinuation of medications. Methods: The study consists of a retrospective survey using medical chart review in five health service facilities for the elderly in Japan. All the patients who were admitted to the facilities between January 2001 and December 2002 (N = 627) were participants in the study. Medications taken on admission, at 1 month and 3 months after admission, and events (significant worsening of the disease status, accidents, new symptoms and signs, and other acute events) during a 3-month period were recorded. Inappropriate prescribing was determined using Beers’ criteria with some modification. ADWEs were determined using the Naranjo causality algorithm. Results: On admission, the patients were taking 3.5 ± 2.5 (mean ± SD) drugs. One month later, the number of prescribed drugs was decreased by 17% (P

Background: It has been widely accepted that control of serum cholesterol levels is effective for prevention of cardiovascular events. Recent data have suggested that this is also the case in the elderly. Methods: A research group (chaired by T. Kita) was organized as part of the Comprehensive Research on Aging and Health conducted by the Japanese Ministry for Health, Labour, and Welfare in 1999–2002 to determine the best strategy for control of cholesterol levels in elderly Japanese with hypercholesterolemia. In order to do this a review of the literature was conducted. Conclusion: The research group concluded: (i) Japanese patients aged 65–74 years with hypercholesterolemia should be treated by following the Guideline for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases by the Japan Atherosclerosis Society (2002), as cholesterol-lowering therapy would bring a similar, or even larger, preventive effect to the elderly, whose absolute risk of cardiovascular events is higher than that in the younger population; (ii) target cholesterol levels in elderly Japanese aged ≥ 75 years with hypercholesterolemia should be determined individually according to their physical activities. It is noted that the elderly are more susceptible to drug-related adverse effects than the younger since renal and liver functions, required for metabolizing drugs, in the elderly are relatively weaker.

Flow-mediated dilation (FMD) of the brachial artery, carotid intima-media thickness (IMT) and pulse wave velocity (PWV) have been shown to be good surrogate markers of clinical atherosclerosis. We determined the interrelation between these measurements, and examined whether their combination would be of clinical significance. One hundred and thirty-five consecutive subjects (79 women/56 men) were enrolled, including 110 patients with risk factors for atherosclerosis, and 33 patients with atherosclerotic disease such as coronary heart disease, stroke or arteriosclerosis obliterans. IMT and plaque formation of the carotid artery and FMD of the brachial artery were assessed using ultrasonography. Brachial-ankle PWV (baPWV) was measured using an automated device (form ABI/PWV, Colin). Age, FMD, IMT and PWV were significantly correlated with each other. Multivariate analysis revealed an independent correlation between the parameters except for FMD, and all four parameters were independently correlated with each other in subjects

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

The effect of 17 beta-estradiol (E2) on the proliferation of cardiac fibroblasts (CFs) remains controversial. This study investigated which subtype of estrogen receptor (ER), ER alpha or ER beta, mediated the effect of E2 on CF growth by the gain of function analysis using an adenovirus vector. One hundred nanomoles per liter of E2 attenuated DNA synthesis by up to 10%, and transactivated the estrogen-responsive element determined by luciferase assay in rat neonatal CFs. We constructed replication-deficient adenoviruses bearing the coding region of human ER alpha, ER beta, or the dominant-negative form of ER beta (designated AxCAER alpha, AxCAER beta, and AxCADNER beta, respectively). When CFs were infected with AxCAER alpha or AxCAER beta at multiplicity of infection of 20 or higher, DNA synthesis was decreased by 50% in response to E2 and the effect was abolished by co-infection with AxCADNER beta. Similarly, transcriptional activity of ER in CFs infected with AxCAER alpha or AxCAER beta was markedly enhanced and co-infection with AxCADNER beta abolished the effects. These results suggest that E2 inhibits CF growth and that both ER subtypes mediate the effect comparably and redundantly.

It has been demonstrated that 17beta-estradiol (E2) has an inhibitory effect on the proliferation of vascular smooth muscle cells (VSMCs) through an estrogen receptor (ER)-dependent pathway. Both ER subtypes, classical ER (ERalpha) and the newly identified ER subtype (ERbeta), are expressed in VSMCs. However, it remains unknown which receptor plays the critical role in the inhibitory effect on VSMC proliferation.We constructed replication-deficient adenoviruses bearing the coding region of human ERalpha, ERbeta, and the dominant-negative form of ERbeta (designated AxCAERalpha, AxCAERbeta, and AxCADNERbeta, respectively). Prior to infection with the adenoviruses, 100 nmol/l E2 attenuated DNA synthesis by up to 14% and transactivated the estrogen-induced expression of the desired mRNA in rat VSMCs. This was accompanied by increased transcriptional activity of estrogen responsive element in response to E2, and the increase was comparable between AxCAERalpha and AxCAERbeta. When VSMCs were infected with AxCAERbeta at a multiplicity of infection of 5 or higher, DNA synthesis as well as cell number decreased by 50% in response to E2, and the effect was abolished by co-infection with AxCADNERbeta. In contrast, when VSMCs were infected with AxCAERalpha, the reduction in DNA synthesis was minimal.Our results indicate that ERbeta is more potent than ERalpha in the inhibitory effect on VSMC proliferation.

Background: It is known that the process of arteriosclerosis is affected by sex and estrogen. The present study was thus undertaken to examine the effects of these factors on arterial calcification, a form of arteriosclerosis, using a rat model of vitamin D toxicity. Methods and results: Vehicle or 5 µg/kg per day 1α(OH)D3 was given to male and female 30-week-old Fisher rats for 2 weeks. Arterial calcification, evaluated by calcium content in the aorta, was 70% more marked in male rats compared to that in female rats, whereas calcium content in the aorta was similar in vehicle-treated male and female rats. Next, the effects of ovariectomy and estrogen replacement (estradiol dipropionate 20 µg/kg per week) were examined in female rats given 5 µg/kg per day 1α(OH)D3 for 2 weeks. Calcium content in the aorta was significantly higher in ovariectomized rats than in sham-operated rats and in ovariectomized and estrogen-replaced rats. No difference between the groups was seen when vehicle was given to the animals. Conclusions: These results suggest that sex and estrogen can modify the process of arterial calcification. The mechanisms remain to be determined, although the effects were independent of serum calcium level.

Objectives and background : Nocturnal apnea and hypoxia are implicated in the pathogenesis of pulmonary and systemic hypertension in obstructive sleep apnea syndrome (OSAS). We have hypothesized that vasodilating factors including nitric oxide (NO) are affected by nocturnal apnea and hypoxia in patients with OSAS. Method : We examined the serum level of NO production in 24 patients with OSAS (mean age 54.2±7.9 years) and 24 age-matched control subjects (53.4±8.1 years) and tested the effects of oxygen administration on the production of NO in the patients. Results : The serum level of nitrite/nitrates (NO x ), which are stable metabolites of NO, was lower in patients with OSAS than in control subjects. Administration of 1–2 l/min of oxygen during night increased the patients' NO x level from 35.6±7.3 to 57.8±11.6 μM. Compressed air administration did not affect the NO x level in the patients. Conclusion : These results indicate that systemic NO production is impaired in OSAS patients, possibly due to nocturnal hypoxia.

To evaluate verbal communication ability in the elderly, we developed a new portable "mini-communication test (MCT)" with 13 sub-scales, which was constructively validated based on 45 items from other reported scales. Clinical reliability and validity were tested in 354 inpatients in a long-term care hospital (81.9 +/- 8.3 years old) and 124 inpatients (80.39 +/- 8.1 years old) and 34 outpatients (76.5 +/- 7.0 years old) in Kyorin University Hospital. All patients were evaluated in approximately 7 minutes each. The test-retest correlation coefficient was 0.99. Inter-rater coefficient of variation was 0.107. The Cronbach alpha value of the test was 0.93. MCT positively correlated with the Barthel Index (r = 0.65, p < 0.01). Hasegawa Dementia Scale Revised version (r = 0.93, p < 0.001) and Vitality Index (r = 0.66, p < 0.01). MCT could be a new tool to assess communication ability in elderly patients with or without dementia.

Objective— Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). Methods and Results— Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45±0.14 versus 1.31±0.41, respectively; P N ω -nitro- l -arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0±3.9% versus 15.8±2.8%, respectively; P Conclusions— Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.

OBJECTIVE: Estrogen has been implicated in feeding behavior and adiposity. This study was undertaken to elucidate the mechanism underlying the anti-obesity and anorectic action of estrogen and the role of estrogen receptor (ER) in the central nervous system. METHODS AND RESULTS: Ovariectomy in 8-week-old female Wistar rats induced hyperphagia along with an increase in body weight and abdominal fat accumulation compared to control sham-operated rats. These changes were fully reversed by subcutaneous replacement of estradiol and were abrogated by pair-feeding. Then, the effects of intracerebroventricular infusion of estradiol, alone or in combination with antisense oligodeoxynucleotides (ODN), for ER in ovariectomized rats were examined. The estradiol group showed 10–20% lower daily food intake, and after the 2-week infusion period a 14% reduction in body weight with a similar reduction in abdominal fat compared to the vehicle group. The inhibitory effect of estradiol on food intake and body weight was blocked by co-administration of ER-s antisense ODN, whereas ER-α antisense ODN did not show any influence. CONCLUSION: These results indicate that ER-s in the central nervous system is involved in the anorectic action of estrogen.

Background: The aim of the present paper was to establish a new objective scale to measure vitality related to activities of daily living in elderly patients with dementia. Methods: Cross-sectional and longitudinal observational studies were carried out on patients and residents in long-term care facilities. Reliability of the scale was examined by determining test–retest reliability, interrater reliability and internal consistency. Validity of the scale was evaluated with respect to criterion validity and predictive validity. Clinical usefulness of the scale was tested by measuring the time taken to perform scoring and evaluating the changes in the score before and after behavioral therapy for functional urinary incontinence. Results: The test–retest correlation coefficient was 0.98. Mean kappa coefficient of Vitality Index was 0.63. Interrater coefficient of variation was 0.14. Cronbach α of the Index was 0.88. Vitality Index was negatively correlated with Geriatric Depression Scale (GDS) (P < 0.01). A low score was an independent risk factor for survival. Behavioral therapy for functional urinary incontinence increased Activities of Daily Living (ADL) (P < 0.05) and Vitality Index (P < 0.05). Conclusion: Vitality Index could be a new tool to assess patients with dementia.

Accumulating evidence suggests that estrogen exerts cardioprotective effects and protects against neointima formation in response to vascular injury in vivo, whereas angiotensin (Ang) II stimulation via the Ang II type 1 (AT 1 ) receptor exaggerates vascular injury. We postulate that estrogen treatment antagonizes the AT 1 receptor-mediated growth-promoting effects in vascular smooth muscle cells (VSMCs). The present in vitro study was designed to explore this possibility and to establish the cellular mechanism whereby estrogen attenuates the growth of VSMCs. Primary cultures of VSMCs derived from male adult Sprague-Dawley rats express exclusively AT 1 receptors. Treatment with Ang II enhanced proliferation of VSMC and c- fos expression, whereas 17β-estradiol (E2) attenuated these vasotrophic effects of Ang II. We also demonstrated that E2 attenuated AT 1 receptor-mediated extracellular signal-regulated kinase activation and that this effect of E2 was restored by pretreatment with vanadate or okadaic acid. Moreover, we demonstrated that E2 enhanced SHP-1 activity, rapidly reaching a peak after 3 minutes of E2 stimulation, whereas E2 transactivated mitogen-activated protein kinase phosphatase-1 expression, showing a peak after 60 minutes of E2 treatment. SHP-1 activation was not influenced by actinomycin D treatment, whereas E2-mediated mitogen-activated protein kinase phosphatase-1 expression was attenuated. Taken together, our results suggest a novel mechanism of vasoprotection by which estrogen antagonizes the effect of the AT 1 receptor via the activation and induction of phosphatases through nongenomic as well as genomic signaling.

Aim: Study on the pathways between social disengagement and sarcopenia or its diagnostic physical functions remains inadequate. This study aims to examine the relationship between social engagement and physical functions with a particular focus on two components of social engagement – social participation and social relations – and their differential pathways to physical performance.

Purpose：Preventing embolic cerebral infarction is important since it decreases activity of daily living and quality of life in old people. However, appropriate use of anticoagulants is difficult in frail old people because of increasing risk of bleeding events. Thus the present study examined the predictive factor for practical management of anticoagulants in older patients.

Inadequate nutrition intake is considered as an important factor for developing frailty which lead to poor health outcomes in elderly. Recently whole diet approach and food diversity studies were conducted instead of focusing on a single nutrient since food and meals contain interacting elements. However, it is still unknown what kind of food consumption pattern is influential to frailty. Thus, the purpose of this study is to assess the relationship between food groups consumption and frailty in community-dwelling elderly. We used baseline data from a cohort study in Kashiwa city, Chiba prefecture, Japan. The participants were randomly selected from elderly aged 65 years old and over who were non-eligible for long-term care. We assessed frequency of each food group consumption by self-administered questionnaire. Food was divided into 10 groups: meat, fish, eggs, dairy products, soy beans, vegetables, fruits, seaweed, potatoes and fried foods. Frailty was defined using Kihon checklist (a Japanese Frailty Index). Binary logistic regression analysis was run to examine the association between food groups and frailty. Among 2,003 participants (mean age was 73.0 ± 5.6), 186 (9.3%) participants were classified as frail group. In logistic regression model, low consumption of meat (OR 1.46, 95%CI 1.05–2.04), fish (OR 1.46, 95%CI 1.06–2.01) and soy beans (OR 1.52, 95%CI 1.05–2.22) were positively associated with frailty. Frail elderly tended to eat less meat, fish and soybean which are among protein foods group, suggesting that increasing frequency of regular protein foods group intake might be essential in prevention of frailty progression.

Contains fulltext : 136938.pdf (Publisher’s version ) (Open Access) BACKGROUND: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

On April 29, 2015, Son and colleagues published an article entitled “Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma” in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor β (TGFβ)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential “two-hit” model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6Chi macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)-signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.

Aim Vascular calcification is a critical problem in patients with chronic kidney disease (CKD). In this study, we examined the effects of a HMG Co-A reductase inhibitor (statin) and an angiotensin Ⅱ type 1 receptor blocker (ARB) on renal failure-induced vascular calcification. Method and result Severe renal failure was induced in rats by feeding a 0.75% adenine diet for six weeks. These rats had hyperphosphatemia, hypertension and hypercholesterolemia. A histological assessment showed extensive linear calcification in the aortic media and a significant increase in the aortic content of calcium and phosphorus. Oral administration of pravastatin (a statin; 1-10 mg/kg/day) or olmesartan (an ARB; 1-10 mg/kg/day) dose-dependently inhibited the aortic calcification in parallel with their renoprotective, lipid-lowering and blood pressure-lowering effects. Of note, the lowest dose of pravastatin inhibited aortic calcification with no influence on the renal function, BP and cholesterol, suggesting that it has direct vasoprotective properties. Intriguingly, the combined administration of pravastatin and olmesartan at the lowest doses synergistically ameliorated the aortic calcification, and the protective effect was at least partly attributable to the inhibition of RF-induced apoptosis in the aortic wall. An in vitro model of inorganic phosphate (Pi)-induced vascular smooth muscle cell calcification mimicked these effects of pravastatin and olmesartan, and the beneficial effect of the combination was attributable to the inhibitory effects on Pi-induced apoptosis via the restoration of the Gas6/Axl-mediated anti-apoptotic pathway. Conclusion A statin and an ARB exerted potent protective effects against vascular calcification due to CKD, probably through their pleiotropic effects. In addition, combination therapy with pravastatin and olmesartan may provide a new therapeutic strategy for the prevention of vascular calcification.

Endogenous estrogen is considered to be protective against cognitive dysfunction. However, clinical trials examining the efficacy of hormone replacement therapy (HRT) in postmenopausal women showed rather deteriorating effects of HRT on cognitive function and dementia, resulting in the recommendation of no use of HRT for the prevention of dementia. By contrast, recent advances in androgen research have suggested the effects of androgen on cognitive function in older men with mild cognitive impairment, pending the mechanistic clarification and clinical trials. Also, the protective role of androgen in cognitive and physical function in older women has been highlighted. Recent topics on the relationship between sex hormones and cognitive function were overviewed in this paper.

Background —The renin-angiotensin system is thought to be critical for the development of cardiac hypertrophy, whereas the role of the angiotensin II type 2 (AT 2 ) receptor in the process is not defined. Using the AT 2 receptor–null ( Agtr2 −) mouse, we tested the hypothesis that the AT 2 receptor could exert an antigrowth effect in cardiac hypertrophy. Methods and Results —Cardiac hypertrophy was induced by suprarenal abdominal aortic banding in 10- to 12-week-old Agtr2 − and wild-type ( Agtr2 +) mice for 6 or 12 weeks. Carotid arterial pressure was not different between the strains, although aortic banding increased arterial pressure by ≈40 mm Hg. Aortic banding increased the heart-weight/body-weight ratio and the cross-sectional area of cardiomyocytes by 15%, resulting in comparable cardiomyocyte hypertrophy in the 2 strains. In contrast, coronary arterial thickening and perivascular fibrosis, determined by the media/lumen-area ratio and the collagen/vessel-area ratio, respectively, were 50% greater in Agtr2 − than in Agtr2 + mice after banding, whereas these parameters were similar in sham-operated mice. Radioligand binding studies using the whole heart and immunohistochemistry showed that AT 2 receptor expression was limited and localized in the coronary artery and perivascular region. Conclusions —These results suggest that the AT 2 receptor mediates an inhibitory effect on coronary arterial remodeling, such as medial hypertrophy and perivascular fibrosis in response to pressure overload, and an activation of the renin-angiotensin system.

We investigated the expression of parathyroid hormone-related protein (PTHrP) in atherosclerotic lesions and the role of PTHrP in the development of arterial neointima formation. Immunohistochemical staining of PTHrP in the neointima of rat aorta produced by balloon injury and of rat femoral artery produced by non-obstructive polyethylene cuff placement, and in the atherosclerotic lesion of human coronary artery was performed using anti-human PTHrP-(1-34) antibody. Anti-muscle actin antibody, HHF-35, and anti-macrophage antibody, HAM-56, were used to identify smooth muscle cells and macrophages, respectively. Immunoreactivity of PTHrP was detected in the thickened intima of rat and human lesions where the predominant cell types were smooth muscle cells or macrophages dependently on the lesion type. In the next series of experiments, we examined the effect of PTHrP on the development of cuff-induced intimal thickening of rat femoral artery. Either PTHrP-(1-34) or PTHrP-(7-34), a PTH/PTHrP receptor antagonist, suspended in pluronic F-127 gel was locally applied around the rat femoral artery. Intimal thickening induced by cuff placement was evaluated 2 weeks later. PTHrP-(1-34) dose-dependently inhibited intimal thickening determined as intima/media ratio and % stenosis whereas PTHrP-(7-34) dose-dependently enhanced that. These results suggest that PTHrP, which is expressed in atherosclerotic lesions, inhibits the development of neointimal formation.

Akishita, Masahiro, Masatsugu Horiuchi, Hiroyuki Yamada, Lunan Zhang, Gotaro Shirakami, Kouichi Tamura, Yasuyoshi Ouchi, and Victor J. Dzau. Inflammation influences vascular remodeling through AT2receptor expression and signaling. Physiol. Genomics 2: 13–20, 2000.—The AT2receptor, which exerts growth inhibitory effects in cell culture, is present scantily in the adult vasculature but is reexpressed after vascular injury. To examine the in vivo role of this receptor in vascular diseases, we developed a mouse model of vascular remodeling and compared the responses in wild-type ( Agtr2+) and AT2receptor knockout ( Agtr2−) mice. Polyethylene cuff placement on the femoral artery led to the vascular expression of cytokines, the transcriptional factor interferon regulatory factor-1 (IRF-1), and both the AT1and AT2receptors. Although the expressions of IRF-1 and AT1receptor were induced to comparable levels in both the Agtr2+and Agtr2−mice, the neointimal lesion size and the smooth muscle cell proliferation were twice greater in the Agtr2−than in the Agtr2+mouse. Correlated with this difference, AT2receptor expression was induced predominantly in the smooth muscle cells of Agtr2+mouse. These results demonstrate that the AT2receptor plays an important role in nonocclusive inflammatory injury by mediating the effects of inflammation on vascular smooth muscle growth inhibition.

Abstract —Endothelial dysfunction has been reported to be the initial step in atherosclerosis. A noninvasive technique that uses ultrasound to measure the intima-media thickness of the carotid artery has been applied to evaluate localized atherosclerosis. This study was undertaken to elucidate whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery. Thirty-four men with atherosclerosis (mean±SE age 61±2 years) and 33 age-matched men without clinical atherosclerosis were examined. The intima-media thickness and plaque formation of the common carotid artery were assessed by B-mode ultrasonography. We also noninvasively measured brachial artery diameter by the same ultrasound machine when the subjects were at rest, during reactive hyperemia, which causes endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The atherosclerosis group had a significantly greater intima-media thickness of the common carotid artery than did the control group (1.02±0.04 versus 0.91±0.03 mm, P P

This study examines the role of sphingolipids in mediating the apoptosis of PC12W cells induced by the angiotensin II type 2 (AT2) receptor. PC12W cells express abundant AT2 receptor but not angiotensin II type 1 receptor and undergo apoptosis when stimulated by angiotensin II. AT2receptor-induced ceramide accumulation preceded the onset of caspase 3 activation and DNA fragmentation. AT2 receptor-induced ceramide accumulation did not result from the degradation of complex sphingolipids (SL) such as sphingomyelin or glycosphingolipids, as no changes in neutral or acidic sphingomyelinase activities, sphingomyelin level, nor in cellular glycolipid composition were observed. AT2 receptor activated serine palmitoyltransferase with a maximum time of 24 h after angiotensin II stimulation. The AT2 receptor-induced accumulation of ceramide was blocked by inhibitors of the de novo pathway of SL synthesis, β-chloro-l-alanine and fumonisin B1. Inhibition of the de novo biosynthesis of SLs by fumonisin B1 and β-chloro-l-alanine completely abrogated the AT2 receptor-mediated apoptosis. Pertussis toxin and orthovanadate blocked AT2 receptor-mediated ceramide production. Taken together our data demonstrate that in PC12W cells the stimulation of AT2 receptor induces the activation of de novo pathway, and a metabolite of this pathway, possibly ceramide, mediates AT2 receptor-induced apoptosis.

Abstract —Angiotensin II (Ang II) plays an important role in regulating cardiovascular hemodynamics and structure. Multiple lines of evidence have suggested the existence of Ang II receptor subtypes, and at least 2 distinct receptor subtypes have been defined on the basis of their differential pharmacological and biochemical properties and designated as type 1 (AT 1 ) and type 2 (AT 2 ) receptors. To date, most of the known effects of Ang II in adult tissues are attributable to the AT 1 receptor. Recent cloning of the AT 2 receptor contributes to reveal its physiological functions, but many functions of the AT 2 receptor are still an enigma. AT 1 and AT 2 receptors belong to the 7-transmembrane, G protein–coupled receptor family. However, accumulating evidence demonstrates that the function and signaling mechanisms of these receptor subtypes are quite different, and these receptors may exert opposite effects in terms of cell growth and blood pressure regulation. We will review the role of the AT 2 receptor in the cardiovascular system and the molecular and cellular mechanisms of AT 2 receptor action.

Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day 15-20), during which the blood vessels undergo remodeling. To examine directly the influence of AT2 receptor expression in the developmental biology of VSMC, we studied cultures of VSMC from fetal and postnatal wild-type (Agtr2(+)) and AT2 receptor null (Agtr2(-)) mice. Consistent with in vivo data, AT2 receptor binding in cultured Agtr2(+) VSMC increased by age, peaking at embryonic day 20, and decreased dramatically after birth. Angiotensin II-induced growth in Agtr2(+) VSMC (embryonic day 20) was increased by the AT2 receptor blocker PD123319, indicating that the AT2 receptors are functional and exert an antigrowth effect in Agtr2(+) VSMC. Growth of VSMC in response to serum decreased age dependently and was higher in Agtr2(-) than in Agtr2(+), inversely correlating with AT2 receptor expression. However, serum-induced growth in Agtr2(+) and Agtr2(-) VSMC and the exaggerated Agtr2(-) VSMC growth was maintained even in the presence of PD123319 or losartan, an AT1 receptor blocker. Moreover, Agtr2(-) VSMC showed greater growth responses to platelet-derived growth factor and basic fibroblast growth factor, indicating that Agtr2(-) cells exhibit a generalized exaggerated growth phenotype. We studied the mechanism responsible for this phenotype and observed that extracellular signal-regulated kinase (ERK) activity was higher in Agtr2(-) VSMC at baseline and also in response to serum. ERK kinase inhibitor PD98059 inhibited both growth and ERK phosphorylation dose-dependently, while the regression lines between growth and ERK phosphorylation were identical in Agtr2(+) and Agtr2(-) VSMC, suggesting that increased ERK activity in Agtr2(-) VSMC is pivotal in the growth enhancement. Furthermore, the difference in ERK phosphorylation between Agtr2(+) and Agtr2(-) was abolished by vanadate but not by okadaic acid, implicating tyrosine phosphatase in the difference in ERK activity. These results suggest that the AT2 receptor expression during the fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of ERK cascade.

加齢とともに薬物有害作用出現頻度が上昇するが, これは多剤投与と密接な関係があり, 投与薬剤が増加するにつれ Medication Error も増える. 緊急入院症例の1/3は Medication Error による過量投与である. 高齢者の薬物有害作用は重篤な例が増加し, 発現臓器も多岐にわたり, 薬剤起因性老年症候群と呼ぶことも可能である. 多剤投与の原因は加齢により病名数が増加し, 症状所見が増加することによる. 高齢者の薬物有害作用を減少させるためには, 患者の総合的機能評価を行い, 患者からみた薬の優先順位を考え (Patient-Oriented Medication), 非薬物療法を常に念頭におく. こうした観点を踏まえた高齢者の薬物療法の教育体制の整備が重要である.

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.