An Approach to Prevent Frailty in Community Dwelling Older Adults: a pilot study performed in Campania region in the framework of the PERSSILAA project.

We developed and tested an innovative physical training method in older adults that embeds the gym program into everyday life in the most conservative way possible. Physical training was included in the activities of local parishes where older women from Southern Italy spend most of their free time and was delivered by trained physical therapists with the support of an ICT tool known as CoCo. 113 older women (aged 72.0 [69.0-75.0] years) noncompliant to conventional exercise programs participated to the study. 57 of them underwent the final anthropometric assessment and 50 the final physical tests. In study completers handgrip strength and physical performance evaluated with the chair-stand, the two minutes step and the chair-sit and -reach tests significantly improved. Quality of life as evaluated with the EuroQol-5dimension (EQ-5D) questionnaire improved as well. In conclusion, a training program designed to minimally impact on life habits of older people is effective in improving fitness in patients noncompliant to other to physical exercise programs.

Innovative Approaches to Active and Healthy Ageing: Campania Experience to Improve the Adoption of Innovative Good Practices.

The demographic projections on the European population predict that people aged over 60 will increase by about two million/year in the next decades. Since 2012, the Campania Reference Site of the European Innovation Partnership on Active and Healthy Ageing supports the innovation of the Regional Health System, to face up demographic changes and sustainability. Campania Reference Site provides the opportunity to connect loco-regional stakeholders in social and health care services (universities, healthcare providers, social services, local communities and municipalities), with international organizations, in order to adopt and scale up innovative solutions and approaches. This paper describes the building process of Campania Reference Site and the main results achieved, that have been allowing it to become a hub for open innovation in the field of active and healthy aging at regional, national and international level.

The European Innovation Partnership on Active and Healthy Ageing Synergies: Protocol for a Prospective Observational Study to Measure the Impact of a Community-Based Program on Prevention and Mitigation of Frailty (ICP - PMF) in Community-Dwelling Older Adults.

Aim of this paper is to describe the protocol of the study "Impact of a Community-based Program on Prevention and Mitigation of Frailty in community-dwelling older adults" developed in the framework of the European Innovation Partnership on Active and Healthy Ageing. This proposal has been developed by the Partnership Action groups on frailty, fall prevention and polypharmacy in older. The proposal wants to assess the impact of community-based programs aimed to counteract three main outcomes related to frailty: hospitalization, institutionalization and death. Bringing together researchers from seven European countries, the proposal aims to achieve the critical mass and the geographical extension enough to provide information useful to all older European citizens. An observational study will be carried out to calculate the incidence of the different outcomes in relation to the various interventions that will be assessed; results will be compared with data coming from already established national, regional and local dataset using the observed/expected approach. The sample will be made up by at least 2000 citizens for each outcome. All the citizens will be assessed at the baseline with two multidimensional questionnaires: the RISC questionnaire and the Short Functional Geriatric Evaluation questionnaire. The outcomes will be assessed every six-twelve months.

Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases.

Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na(+)/K(+) regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF) the defective CF transmembrane conductance regulator protein may be responsible for the impaired transport of glutathione (GSH), the first line defense of the lung against oxidative stress. The aim of this single-blind, randomized, placebo-controlled trial was to evaluate the effect of inhaled GSH in patients with CF. METHODS: 54 adult and 51 pediatric patients were randomized to receive inhaled GSH or placebo twice daily for 12 months. RESULTS: Twelve month treatment with inhaled GSH did not achieve our predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients. CONCLUSIONS: Inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01450267; URL: www.clinicaltrialsgov.

Moderate alcohol consumption predicts long-term mortality in elderly subjects with chronic heart failure.

OBJECTIVE: Moderate alcohol consumption is related to a reduction of mortality. However, this phenomenon is not well established in the elderly, especially in the presence of chronic heart failure (CHF). The aim of the study was to verify the effect of moderate alcohol consumption on 12-year mortality in elderly community-dwelling with and without CHF. SETTINGS: community-dwelling from 5 regions of Italy. PARTICIPANTS: A cohort of 1332 subjects aged 65 and older. MEASUREMENT: Mortality after 12-year follow-up in elderly subjects (≥65 years old) with and without CHF was studied. Moderate alcohol consumption was considered ≤250 ml/day (drinkers). RESULTS: In the absence of CHF (n=947), mortality was 42.2% in drinkers vs. 53.7% in non-drinker elderly subjects (p=0.021). In contrast, in the presence of CHF (n=117), mortality was 86.5% in drinkers vs. 69.7% in non-drinker elderly subjects (p=0.004). Accordingly, Cox regression analysis shows that a moderate alcohol consumption is protective of mortality in the absence (HR=0.79; CI 95% 0.66-0.95; p<0.01) but it is predictive of mortality in the presence of CHF (HR=1.29; CI 95% 1.05-1.97; p<0.05). CONCLUSIONS: Our data demonstrates that moderate alcohol consumption is associated with an increased long-term mortality risk in the elderly in the presence of CHF.

PUFA for human health: diet or supplementation?

Large doses of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are used to treat several diseases including hypertriglyceridemia in humans. Modest levels of EPA and DHA may be obtained from food, particularly from fatty fish. This review presents the literature examining the differences between omega-3 fatty acid dietary supplementation and prescribed omega-3-acid ethyl esters (P-OM3). Reports published between 1995 and 2007 containing sources, recommended intake, and differences in the various formulations of omega-3 fatty acids were sought in PubMed and the Food and Drug Administration (FDA) Websites. However, lack of head-to-head clinical trials using both P-OM3 and dietary-supplement omega-3 fatty acids is the greatest limitation of this review. Although many kinds of omega-3 fatty acid dietary supplements are available, the efficacy, quality, and safety of these products are questionable because they are beyond any pharmaceutical control. Thus, P-OM3 is the only FDA approved omega-3 fatty acid product which is available in the United States as an adjunct to diet to improve human health.

Frailty predicts long-term mortality in elderly subjects with chronic heart failure.

BACKGROUND: The elderly are characterized by a high prevalence of chronic heart failure (CHF) and frailty, which is a complex interaction of physical, psychological and social impairment. This study aimed to examine the predictive role of frailty on long-term mortality in elderly subjects with CHF. MATERIALS AND METHODS: The study assessed long-term mortality after 12-year follow up in 120 subjects with CHF and 1139 subjects without CHF, selected in 1992, from a random sample of the elderly population in the Campania region of Italy. Frailty was assessed according to a 'Frailty Staging System'. RESULTS: Subjects with CHF were prevalently female (60%) and older than 75 years (mean 75.9 +/- 6.7); subjects without CHF were prevalently female (56.4%) and younger than 75 years (mean 74.0 +/- 6.3). In subjects with and without CHF stratified into classes of frailty there was a statistically significant increase in age, comorbidity, disability and low social support, and a decrease in MMSE score. Moreover, death progressively increased more with frailty in subjects (70.0% to 94.4%, P < 0.03) than in those without (43.8.% to 88.3%, P < 0.0001) CHF. The Kaplan-Meier analysis shows that at 9 years the probability of survival progressively decreased as frailty increased (45.5% to 0%) in subjects with CHF and from 62.8% to 25.9% in subjects without CHF. The Cox regression analysis indicated that frailty is predictive of mortality in the multivariate model adjusted for several variables including sex and age in subjects with and without CHF. Moreover, the analysis showed that frailty is more predictive of mortality in elderly subjects with CHF when it was analyzed either as continuous (1.48 vs. 1.36) or as a dummy (3 vs. 1 = 1.62 vs. 1.24) variable. CONCLUSIONS: Thus mortality among elderly subjects with or without CHF increases with frailty. Moreover, frailty is more predictive of long-term mortality in elderly subjects with than in those without CHF. Hence, frailty represents a new independent variable for predicting long-term mortality in elderly subjects with CHF.

Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.

Neurotoxicity induced by Cefepime in a very old hemodialysis patient.

Neurotoxicity is an unusual complication of cephalosporin therapy. Only few cases of neurotoxicity induced by Cefepime have been described and probably the frequency of Cefepime-induced status epilepticus is underestimated. We report a case of an 82 year-old male, ESRD patient on chronic hemodialysis program affected by pneumonia, who received a treatment with intravenous Cefepime (1 g/day) and developed a seizure 4 days after the starting antibiotic therapy. Cefepime-induced neurotoxicity was suspected and its administration was immediately discontinued. In order to increase Cefepime clearance a hemodialysis session was urgently started and an improvement of his conscious level was observed. On the following day, after a second hemodialysis session his clinical condition and the status of neurotoxicity were completely recovered. The patient was discharged from the hospital in stable clinical condition one week later. At variance with the cases previously reported, the daily dose of Cefepime administrated to our patient was 50% lower and respected drug prescription dosage. Thus, we speculate on the hypothesis that advanced age of our patient and metabolic encephalopathy induced by chronic uremia made him more sensitive to the neurotoxicity induced by the drug. In conclusion, our case suggests that, in very old patients on long-term hemodialysis, it should be considered, to avoid neurotoxicity, to monitor the clinical neurological status, to use Cefepime at lower dosage than that allowed in patients with severe renal impairment (1 g/day) and, when possible, to evaluate Cefepime plasma levels. However, in these patients, other agents of the same class should be considered such as Cefotaxime and Ceftriaxone which are characterized by both an hepatic and renal excretion. In alternative to cephalosporins, antibiotics with the same action spectrum in the absence of neurological toxicity (i.e. Meropenem) should be recommended.

Verbal memory impairment in congestive heart failure.

Cognitive dysfunction, mainly memory impairment, characterizes congestive heart failure (CHF). Aim of this study was to verify whether: (1) CHF has differential effects on primary and secondary memory; (2) memory dysfunction can be diagnosed by a screening instrument. In a multicenter study we enrolled 369 patients with stable CHF who underwent a structured assessment of verbal memory mechanisms and selected cognitive functions. Performance on some verbal memory indexes (Recency, Rey's immediate and delayed recall, Learning efficiency) progressively decreased from II to IV New York Heart Association (NYHA) class. Rate of forgetting was uniformly high across NYHA classes II-IV. Verbal memory indexes were highly correlated with most nonverbal scores. The Mini Mental State Examination (MMSE) had poor sensitivity and specificity versus primary or secondary verbal memory dysfunction. Therefore, a deficit of both primary and secondary memory is relatively common in CHF but cannot be accurately recognized by a screening neuropsychological test.

Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. METHODS: To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4+/-0.8 months [mean+/-SD], 58 children aged 7.9+/-3.8 years, 42 adults aged 42.5+/-5.1 years, and 40 elderly subjects aged 71.8+/-3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. RESULTS: Atherosclerosis was 6- to 19-fold greater (P<0.01) in extracranial arteries than in intracranial arteries, and it increased linearly with age. Intracranial arteries showed significantly greater antioxidant enzyme activities than did extracranial arteries. However, the antioxidant protection of intracranial arteries decreased significantly in older age, coinciding with a marked acceleration of atherogenesis. An increase in matrix metalloproteinase-9 protein expression and in gelatinolytic activity consistent with the degree of intracranial atherosclerosis was also observed. CONCLUSIONS: These results suggest that a greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherogenesis and that with increasing age intracranial arteries respond with accelerated atherogenesis when their antioxidant protection decreases relatively more than that of extracranial arteries.

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

OBJECTIVES: The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). BACKGROUND: Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. METHODS: We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). RESULTS: In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05). CONCLUSIONS: Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1.

BACKGROUND: Although individuals with diabetes mellitus frequently have dyslipidaemias and high blood pressure, much of the increased risk for coronary heart disease is not explained by these and other classical risk factors. Thus, other less widely recognized risk factors, including increased susceptibility of low-density lipoprotein (LDL) to oxidation, might enhance vascular dysfunction and atherogenesis in diabetes. AIMS: We compared both the rate and extent of LDL oxidation ex vivo between 78 poorly controlled individuals with type 1 diabetes and 78 age- and sex-matched non-diabetic controls. We then initiated intensive insulin therapy for 3 months to determine the impact of improved glucose control on LDL composition and oxidation. RESULTS: Diabetic and non-diabetic individuals did not have significantly different body weights, dietary intake, blood pressure, renal function or plasma lipid levels. LDL composition was also similar in both groups. In contrast, vitamin E content in LDL was significantly lower in diabetic patients. Measures of LDL lipid oxidation, including conjugated diene, lipid peroxide and thiobarbituric acid reactive substances formation, as well as measures of LDL protein modification, were significantly greater in diabetic patients. Levels of hyperglycaemia correlated strongly with each measure of LDL lipid oxidation (r ranges from 0.60-0.81, P<0.05 for each correlation). After improved glucose control (average reduction in % Hb(Alc)of 5.5 units) all measures of LDL oxidation improved dramatically and approached values for non-diabetics. Absolute values of LDL oxidation increased among all categories of age in both diabetic and control individuals, and this relationship persisted even after adjustment for differences in glucose concentrations. CONCLUSIONS: We demonstrate that hyperglycaemia has a potent but reversible effect on LDL oxidation and that age may independently enhance LDL susceptibility to oxidation. These pathophysiological effects may play an important role in determining vascular complications and atherogenesis in poorly controlled type 1 diabetic patients.

Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells.

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.

Exercise training restores ischemic preconditioning in the aging heart.

OBJECTIVES: To investigate the effects of ischemic preconditioning in hearts from adult and both sedentary and trained senescent rats. BACKGROUND: Ischemic preconditioning does not prevent postischemic dysfunction in the aging heart, probably because of reduction of cardiac norepinephrine release. Exercise training can reverse the age-related decrease of norepinephrine production. METHODS: We investigated the effects on mechanical parameters of ischemic preconditioning against 20 min of global ischemia followed by 40 min of reperfusion in isolated perfused hearts from adult (six months) and sedentary or trained (six weeks of graduated swim training) senescent (24 months) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. RESULTS: Final recovery of percent-developed pressure was significantly improved after preconditioning in adult hearts (91.6+/-9.6%) versus unconditioned controls (54.2+/-5.1%, p<0.01). The effect of preconditioning on developed pressure recovery was absent in sedentary but present in trained senescent hearts (39.6+/-4.1% vs. 64.3+/-7.1%, p<0.05). Norepinephrine release significantly increased after preconditioning in adult and in trained but not in sedentary senescent hearts. The depletion of myocardial norepinephrine stores by reserpine abolished preconditioning effects in adult and trained senescent hearts. CONCLUSIONS: In adult and trained but not in sedentary senescent hearts, preconditioning reduces postischemic dysfunction and is associated with an increase in norepinephrine release. Preconditioning was blocked by reserpine in both adult and trained senescent hearts. Thus, exercise training may restore preconditioning in the senescent heart through an increase of norepinephrine release.