Peroxisome Proliferator-activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model.

We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor γ (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARγ-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c+ infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-ß and the TGF-ß pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-ß production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.

17ß-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle.

Menopause results in a progressive decline in 17ß-estradiol (E2) levels, increased adiposity, decreased insulin sensitivity, and a higher risk for type 2 diabetes. Estrogen therapies can help reverse these effects, but the mechanism(s) by which E2 modulates susceptibility to metabolic disease is not well understood. In young C57BL/6N mice, short-term ovariectomy decreased-whereas E2 therapy restored-mitochondrial respiratory function, cellular redox state (GSH/GSSG), and insulin sensitivity in skeletal muscle. E2 was detected by liquid chromatography-mass spectrometry in mitochondrial membranes and varied according to whole-body E2 status independently of ERα. Loss of E2 increased mitochondrial membrane microviscosity and H2O2 emitting potential, whereas E2 administration in vivo and in vitro restored membrane E2 content, microviscosity, complex I and I + III activities, H2O2 emitting potential, and submaximal OXPHOS responsiveness. These findings demonstrate that E2 directly modulates membrane biophysical properties and bioenergetic function in mitochondria, offering a direct mechanism by which E2 status broadly influences energy homeostasis.

Cardiovascular mortality in men with erectile dysfunction: increased risk but not inevitable.

INTRODUCTION: It is unclear whether men with erectile dysfunction (ED) ultimately die of cardiovascular (CV) causes. AIM: This study examined the causes of death in men with ED and their risk of CV death. METHODS: Based on statutory death registrations and hospital morbidity data, the risk of CV death in men with ED in a linked-data study was assessed against the CV mortality risk in a reference male population. MAIN OUTCOME MEASURES: Deaths from CV causes as proportions of all deaths. Age-specific rate, mortality rate ratio (MRR), standardized mortality rate ratio (SMRR), and adjusted hazard ratio (HR). RESULTS: CV mortality was 4.0%. Compared with the reference population, the risk of CV death was higher in men with ED (SMRR 2.2; 95% confidence interval [CI] 1.6, 3.0). Risk of CV mortality was higher in men with CV disease prior to ED (adjusted HR 1.7; 95% CI 1.1, 2.6) or with history of hospital admissions for CV events (adjusted HR 2.2; 95% CI 1.3, 3.8), compared with those without the respective history. MRR was significantly increased in the 40-69 years age group (MRR 4.1; 95% CI 3.2, 5.2). The median time interval between manifestation of ED and CV death was 10.0 years. A greater proportion of deaths from oncological than from CV causes (25.0% vs. 10.8%) occurred within the first 5 years of the manifestation of ED. CONCLUSIONS: Although the risk of CV mortality is greater in men with ED, almost as many men die of oncological as of CV causes, with a higher proportion of oncological deaths occurring sooner subsequent to the first manifestation of ED.

Erectile dysfunction as a predictor for subsequent atherosclerotic cardiovascular events: findings from a linked-data study.

INTRODUCTION: In spite of the mounting interest in the nexus between erectile dysfunction (ED) and cardiovascular (CV) diseases, there is little published information on the role of ED as a predictor for subsequent CV events. AIM: This study aimed to investigate the role of ED as a predictor for atherosclerotic CV events subsequent to the manifestation of ED. Method. The investigation involved the retrospective study of data on a cohort of men with ED linked to hospital morbidity data and death registrations. By using the linked data, the incidence rates of atherosclerotic CV events subsequent to the manifestation of ED were estimated in men with ED and no atherosclerotic CV disease reported prior to the manifestation of ED. The risk of subsequent atherosclerotic CV events in men with ED was assessed by comparing these incidence rates with those in the general male population. MAIN OUTCOME MEASURE: Standardized incidence rate ratio (SIRR), comparing the incidence of atherosclerotic CV events subsequent to the manifestation of ED in a cohort of 1,660 men with ED to the incidence in the general male population. RESULTS: On the basis of hospital admissions and death registrations, men with ED had a statistically significantly higher incidence of atherosclerotic CV events (SIRR 2.2; 95% confidence interval 1.9, 2.4). There were significantly increased incidence rate ratios in all age groups younger than 70 years, with a statistically highly significant downward trend with increase of age (P < 0.0001) across these age groups. Younger age at first manifestation of ED, cigarette smoking, presence of comorbidities and socioeconomic disadvantage were all associated with higher hazard ratios for subsequent atherosclerotic CV events. CONCLUSIONS: The findings show that ED is not only significantly associated with but is also strongly predictive of subsequent atherosclerotic CV events. This is even more striking when ED presents at a younger age.

Sex life after 65: how does erectile dysfunction affect ageing and elderly men?

INTRODUCTION: We report the findings pertinent to the ageing and elderly participants of a population-based study of erectile dysfunction (ED). METHOD: We examined the sociodemographic characteristics, self-reported morbidities and responses to the 5-item International Index of Erectile Function (IIEF-5) of participants aged > or = 65 years and > or = 80 years. RESULTS: Most (73%) participants were married or had partners. Among the participants aged > or = 65 years, the prevalence of ED (IIEF-5 scores <22) was 67% and of severe ED (IIEF-5 scores <8) 48%. About 32% were sexually active, and 11% had regular sexual intercourse. Cardiovascular disease (CVD) was reported in 37% and diabetes mellitus (DM) in 13%, with odds of ED at 3.91 and 4.68, respectively. Among those aged > or = 80 years, the prevalence of ED was 68% and of severe ED 57%. About 12% were sexually active, and 3% had regular sexual intercourse. CVD was reported in 44% and DM in 11%, with corresponding odds of ED at 2.55 and 2.90. CONCLUSIONS: Most ageing and elderly men are in a relationship and many are sexually active. ED is prevalent and severe. Morbidities are common and significantly associated with ED, impairing the sex lives of affected men.

Alcohol consumption and male erectile dysfunction: an unfounded reputation for risk?

INTRODUCTION: Alcohol consumption is a contentious social topic and is often assumed to have deleterious effects on sexual performance. There is a lack of consensus on whether alcohol consumption may in fact be beneficial to erectile function. AIM: We examined the data from a population-based cross-sectional study of men's health to assess the association between usual alcohol consumption and erectile dysfunction (ED). METHOD: Reply-paid questionnaires were posted to a randomly selected age-stratified male population sample obtained from the Western Australian (WA) Electoral Roll. MAIN OUTCOME MEASURES: The survey questionnaire included sociodemographic details, self-reported clinical information, and drinking habits. The 5-item International Index of Erectile Function (IIEF-5) was used to assess erectile function. RESULTS: Most (87%) participants were current alcohol drinkers, with binge drinking, as defined by the Australian National Health and Medical Research Council (NHMRC), reported by 20% of drinkers. Compared with never-drinkers, the age-adjusted odds of ED were lower among current, weekend, and binge drinkers and higher among ex-drinkers. Among current drinkers, the odds were lowest for consumption within the NHMRC guidelines of between 1 and 20 standard drinks a week. On further adjustment for cardiovascular disease (CVD) or for cigarette smoking, age-adjusted odds of ED were reduced by 25-30% among alcohol drinkers. CONCLUSIONS: Our findings suggest a modest negative association between alcohol consumption and ED and confounding of the association by CVD and cigarette smoking. The Western Australia Men's Health Study certainly provides no justification for advising men with ED whose drinking habits are consistent with NHMRC guidelines that they should cease or reduce their consumption of alcohol.

Is the relationship between cigarette smoking and male erectile dysfunction independent of cardiovascular disease? Findings from a population-based cross-sectional study.

INTRODUCTION: Cigarette smoking has been implicated in the pathophysiology of cardiovascular disease (CVD) and as a risk factor for erectile dysfunction (ED). However, various aspects of the associations between cigarette smoking, ED, and CVD need further elucidation. AIM: We explored the relationship between cigarette smoking, ED, and CVD using data from a population-based cross-sectional study of 1,580 participants. METHODS: Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the Western Australia Electoral Roll. MAIN OUTCOME MEASURES: In addition to items covering sociodemographic and self-reported clinical information and smoking habits, the 5-item International Index of Erectile Function was used to assess erectile function. RESULTS: Compared with never smokers, the odds of ED, adjusted for age, square of age, and CVD, were significantly higher among current smokers (odds ratio [OR] = 1.40; 95% confidence interval [CI] 1.02, 1.92) and ever smokers (OR = 1.57; 95% CI 1.02, 2.42). Similarly, the adjusted odds of severe ED were significantly higher among former smokers. Albeit not statistically significant, the age-adjusted odds of ED among current smokers increased with the number of cigarettes smoked. Among former smokers, the age-adjusted odds of ED were significantly higher 6-10 years following cessation of smoking than < or = 5 or > 10 years. Compared with never smokers without CVD, the age-adjusted odds of ED among former smokers and ever smokers without CVD were about 1.6. Regardless of smoking, these odds were significantly higher among participants with CVD. CONCLUSIONS: Compared with never smokers, former smokers and ever smokers have significantly higher odds of ED. The relationship between smoking and ED is independent of that between smoking and CVD, and not because of confounding by CVD. Patterns of ED in former smokers suggest that there may be a latent interval between active smoking and symptomatic ED, involving a process initially triggered by smoking.

Male erectile dysfunction and cardiovascular disease: is there an intimate nexus?

INTRODUCTION: Various studies report increased risk of erectile dysfunction (ED) in men with cardiovascular (CV) disease and postulate an intimate nexus between the two conditions. AIM: To examine the association of ED with CV risk factors and disease in a population-based cross-sectional observational study conducted in Western Australia (WA). Method. Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the WA Electoral Roll. MAIN OUTCOME MEASURES: In addition to items covering sociodemographic and self-reported clinical information, the 5-item International Index of Erectile Function (IIEF-5) was used. RESULTS: Of the 1,580 participants, the ages of 1,514 were known and ranged from 20 to 99 years (mean 57.9, median 59.1, standard deviation 18.5). CV risk factors and disease were more prevalent with increasing age and among participants with ED and severe ED. The age-adjusted odds of ED were significantly higher among participants with hypertension (odds ratio [OR] 1.47; 95% confidence intervals [CI] 1.05, 2.07), ischemic heart disease (OR 1.80; 95% CI 1.10, 2.94), and stroke (OR 3.30; 95% CI 1.22, 8.88), and with these conditions and peripheral arterial disease grouped together as CV disease (OR 1.85; 95% CI 1.34, 2.56). Many participants with hyperlipidemia were receiving treatment, and the age-adjusted odds for ED were not significantly higher. The age-adjusted odds of ED among participants with diabetes mellitus were 2.76 (95% CI 1.52, 5.00), and were 3.21 (95% CI 1.03, 10.05) when hypertension and hyperlipidemia were also present. CONCLUSIONS: The findings support the postulated intimate nexus between ED and CV disease. The adverse effects of age and CV risk factors and disease on erectile function compound each other. The socioeconomic, epidemiologic, and clinical implications are immense.

Male erectile dysfunction: its prevalence in Western australia and associated sociodemographic factors.

INTRODUCTION: This is a report of a population-based cross-sectional observational study in Western Australia (WA) on male erectile dysfunction (ED). AIM: To assess the prevalence of ED in WA and to examine its associated sociodemographic factors. METHOD: Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the WA Electoral Roll. MAIN OUTCOME MEASURES: In addition to items covering sociodemographic and clinical information, the Australian Standard Classification of Occupations (ASCO), the Socioeconomic Index for Area (SEIFA), and the 5-item International Index of Erectile Function (IIEF-5) were used. RESULTS: One thousand seven hundred seventy (41.9%) of 4,228 questionnaires were returned. One thousand five hundred eighty (89.3%) were completed questionnaires from men aged 20.1 to 99.6 years (mean 57.9, median 59.1, standard deviation 18.5). The prevalences of any ED and of severe ED among adult males in WA, adjusted for age distribution, were 25.1 and 8.5%, respectively. Standardized to World Health Organization (WHO) World Standard Population, the corresponding prevalences were 23.4 and 7.4%. Prevalence, as well as severity, of ED increased with age. Thirty-eight percent of the participants who were married or had partners experienced ED (severe ED 19.1%). The prevalence of ED was not significantly different between "white-collar" and "blue-collar" workers. Despite the great majority of the affected participants having experienced ED for >1 year, only 14.1% reported having ever received any treatment for ED. CONCLUSIONS: The study has provided population-based epidemiological data on ED in Western Australian men covering a wide range of ages. The finding that ED is age related, highly prevalent, and grossly underdiagnosed and undertreated is pertinent to global population aging and a rapidly aging Australian population. To facilitate comparisons across populations with different age distributions, all future population-based studies on ED should be standardized to WHO World Standard Population.

The erectile-endothelial dysfunction nexus: new opportunities for cardiovascular risk prevention.

Erectile and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors and are longitudinal predictors of cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction is intimately linked through increased expression and activation of endothelial nitric oxide synthase, and the subsequent physiological actions of nitric oxide. Endothelial production of nitric oxide by endothelial nitric oxide synthase in the corpus cavernosum is involved in the maintenance of penile erection. Erectile dysfunction can be detected clinically using systematic questioning and could potentially be employed as an independent predictor of cardiovascular risk to target treatment of cardiovascular risk factors. Both erectile and endothelial dysfunction respond to lifestyle modifications, particularly in individuals with the metabolic syndrome. Drugs that improve endothelial dysfunction can also improve erectile dysfunction, but responses are not always concordant. Phosphodiesterase type 5 inhibitors, however, are powerful agents that commonly improve erectile and endothelial dysfunction, with potential cardiac applications. The recent Princeton consensus requires more extensive implementation and evaluation in clinical practice. The judicious diagnosis of erectile dysfunction, nevertheless, provides a unique opportunity for the prevention of cardiovascular disease.