Renato Fellin

Executive Function Correlates with Walking Speed in Older Persons: The InCHIANTI Study

Objectives: To study the association between performance on psychological tests of executive function and performance on lower extremity tasks with different attentional demands in a large sample of nondemented, older adults.

Effect of Native and Oxidized Low-Density Lipoprotein on Endothelial Nitric Oxide and Superoxide Production Key Role of l-Arginine Availability

BACKGROUND Native and oxidized LDLs (n-LDL and ox-LDL) are involved in the atherogenic process and affect endothelium-dependent vascular tone through their interaction with nitric oxide (NO). METHODS AND RESULTS In this study we evaluated directly, by using a porphyrinic microsensor, the effect of increasing lipoprotein concentrations on endothelial NO and superoxide (O(2)(-)) production. We investigated where lipoproteins may affect the L-arginine-NO pathway by pretreating cells with L-arginine, L-N-arginine methyl ester (L-NAME), and superoxide dismutase. Bovine aortic endothelial cells were exposed for 1 hour to increasing concentrations of n-LDL (from 0 to 240 mg cholesterol/dL) and ox-LDL (from 0 to 140 mg cholesterol/dL). A stimulated (calcium ionophore) NO concentration decreased to 29% of the control at n-LDL concentration of 80 mg cholesterol/dL and to 15% of the control at 20 mg cholesterol/dL of ox-LDL. L-Arginine partially neutralized the inhibitory effect of n-LDL and ox-LDL on the NO generation. Superoxide dismutase pretreatment did not modify NO production, whereas L-NAME blunted NO generation at all LDL concentrations. O(2)(-) production was increased at low n-LDL and very low ox-LDL concentrations; this was reversed by L-arginine. CONCLUSIONS These findings confirm the inhibitory role of n-LDL and ox-LDL on NO generation and suggest that lipoproteins may induce a decreased uptake of L-arginine. The local depletion of the L-arginine substrate may derange the NO synthase, leading to overproduction of O(2)(-) from oxygen, the other substrate of NO synthase.

Predictive Value of the Short Physical Performance Battery Following Hospitalization in Older Patients

BACKGROUND Hospitalization represents a stressful and potentially hazardous event for older persons. We evaluated the value of the Short Physical Performance Battery (SPPB) in predicting rates of functional decline, rehospitalization, and death in older acutely ill patients in the year after discharge from the hospital. METHODS Prospective cohort study of 87 patients aged 65 years and older who were able to walk and with a Mini-Mental State Examination score ≥ 18 and admitted to the hospital with a clinical diagnosis of congestive heart failure, pneumonia, chronic obstructive pulmonary disease, or minor stroke. Patients were evaluated with the SPPB at hospital admission, were reevaluated the day of hospital discharge, and 1 month later. Subsequently, they were followed every 3 months by telephone interviews to ascertain functional decline, new hospitalizations, and vital status. RESULTS After adjustment for potential confounders, including self-report activity of daily living and comorbidity, the SPPB score at discharge was inversely correlated with the rate of decline in activity of daily living performance over the follow-up (p < .05). In a multivariable discrete-time survival analysis, patients with poor SPPB scores at hospital discharge (0-4) had a greater risk of rehospitalization or death (odds ratio: 5.38, 95% confidence interval: 1.82-15.9) compared with those with better SPPB scores (8-12). Patients with early decline in SPPB score after discharge also had steeper increase in activity of daily living difficulty and higher risk of rehospitalization or death over the next year. CONCLUSIONS In older acutely ill patients who have been hospitalized, the SPPB provides important prognostic information. Lower extremity performance-based functional assessment might identify older patients at high risk of poor outcomes after hospital discharge.

Activation of Microglia by Amyloid β Requires P2X7 Receptor Expression

Extracellular ATP is a mediator of intercellular communication and a danger signal. Release of this and other nucleotides modulates microglia responses via P2Y and P2X receptors, among which the P2X7 subtype stands out for its proinflammatory activity and for up-regulation in a transgenic model of Alzheimer disease and in brains from Alzheimer disease patients. Here we show that amyloid β (Aβ) triggered increases in intracellular Ca2+ ([Ca2+]i), ATP release, IL-1β secretion, and plasma membrane permeabilization in microglia from wild-type but not from P2X7-deleted mice. Likewise, intra-hippocampal injection of Aβ caused a large accumulation of IL-1β in wild-type but not in P2X7−/− mice. These observations suggest that Aβ activates a purinergic autocrine/paracrine stimulatory loop of which the P2X7 receptor is an obligate component. Identification of the P2X7 receptor as a non-dispensable factor of Aβ-mediated microglia stimulation may open new avenues for the treatment of Alzheimer disease.

Relationship of Alcohol Intake With Inflammatory Markers and Plasminogen Activator Inhibitior-1 in Well-Functioning Older Adults The Health, Aging, and Body Composition Study

Background—Increased levels of acute-phase reactants predict the onset of poor health outcomes. A U-shaped association has been reported between alcohol intake and health outcomes, which suggests that alcohol intake may modify levels of acute-phase reactants. We investigated the relationship between weekly alcohol intake and interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-&agr; (TNF-&agr;), and plasminogen activator inhibitor-1 (PAI-1). Methods and Results—Data are from year 1 of the Health, Aging, and Body Composition study, a biracial cohort of 3075 well-functioning men and women aged 70 to 79 years, living in Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2574 persons (51.2% women; 40.1% black) with complete data. After adjustment for age, race, smoking status, history of diabetes, history of cardiovascular disease, physical activity, high-density lipoprotein cholesterol, antiinflammatory medications, statins, and total fat mass, alcohol intake showed a J-shaped relationship with mean IL-6 (P for quadratic term <0.001) and CRP (P =0.014) levels. The association was consistent in both men and women. Compared with subjects who consumed 1 to 7 drinks per week, those who never drank had an increased likelihood of having high levels of both IL-6 and CRP, as did those who drank 8 or more drinks per week. We found no relationship between alcohol intake and levels of TNF-&agr; and PAI-1 (P =0.137 and 0.08, respectively). Conclusions—In well-functioning older persons, light alcohol consumption is associated with lower levels of IL-6 and CRP. These results might suggest an additional biological explanation to the epidemiological link between moderate alcohol consumption and cardiovascular events.

Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: A clinical and molecular genetic analysis

BACKGROUND Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. METHODS We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. FINDINGS Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G-->A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. INTERPRETATION The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.

Role of Anti-Oxidants in Atherosclerosis: Epidemiological and Clinical Update

Low density lipoprotein (LDL) oxidative modification in the vascular wall seems to be a key factor in atherosclerosis development. Oxidised LDLs might recruit monocytes and favour their transformation into foam cells through a receptor-mediated intake (scavenger pathway). Moreover oxidised LDLs show cytotoxic potential which is probably responsible for endothelial cell damage and macrophage degeneration in the atherosclerotic human plaque. Following the oxidation hypothesis of atherosclerosis the role of natural antioxidants, i.e. Vitamin C, Vitamin E and carotenoids, has been investigated in a large number of epidemiological, clinical and experimental studies. Animal studies indicate that dietary antioxidants may reduce atherosclerosis progression, and observational data in humans suggest that antioxidant vitamin ingestion is associated with reduced cardiovascular disease, but the results of randomised controlled trials are mainly disappointing. It has been suggested that natural antioxidants may be effective only in selected subgroups of patients with high levels of oxidative stress or depletion of natural antioxidant defence systems. The favourable effects shown by some studies relating antioxidant dietary intake and cardiovascular disease, may have been exerted by other chemicals present in foods. Flavonoids are the ideal candidates, since they are plentiful in foods containing antioxidant vitamins (i.e. fruits and vegetables) and are potent antioxidants. Tea and wine, rich in flavonoids, seem to have beneficial effects on multiple mechanisms involved in atherosclerosis. Future studies should probably select patients in a context of high-oxidative stress / low-antioxidant defence, to verify if antioxidants may really prove useful as therapeutic anti-atherosclerotic agents.

Copper/zinc ratio and systemic oxidant load: effect of aging and aging-related degenerative diseases

There is evidence that copper and zinc have pro-oxidant and antioxidant properties, respectively, so that their imbalance may be expected to condition oxidative stress status. Oxidative stress is relevant in aging and in age-related degenerative diseases. In this study, blood content of copper, zinc, and ceruloplasmin as well as of lipid peroxides were investigated in 81 healthy and 62 disabled octo-nonagenarians affected by chronic degenerative diseases, and in 81 healthy adults. Serum copper/zinc ratio and ceruloplasmin were significantly higher in the elderly than in the healthy adults. Moreover, all these parameters were significantly higher in the disabled than in the healthy elderly. Notably, the increased copper/zinc ratio found in healthy elderly was due to high copper values, whereas in the disabled, both high copper and low serum zinc concentrations were present. The copper/zinc ratio was significantly and positively related to systemic oxidative stress status in all groups. The higher the serum copper/zinc ratio the higher the lipid peroxides plasma content. We conclude that there is a strict relationship between copper/zinc ratio and systemic oxidant burden. Moreover, advanced age and, particularly, advanced age-related chronic degenerative diseases are associated with a significant increase in the copper/zinc ratio and systemic oxidative stress.

Characterization of a New Form of Inherited Hypercholesterolemia Familial Recessive Hypercholesterolemia

We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.

Diabetes, Cardiovascular Risk Factors and Idiopathic Sudden Sensorineural Hearing Loss: A Case-Control Study

Aims/Hypothesis: Idiopathic sudden sensorineural hearing loss (ISSNHL) represents an acute inner ear disorder with an overall incidence of 5–20/100000 individuals per year in western countries. No clear causes for this disease have been found so far, but cochlear ischemia has been hypothesized as one of the etiopathological mechanisms. The aim of our study was to assess the role of diabetes and traditional cardiovascular risk factors in the pathogenesis of ISSNHL. Materials/Methods: Case-control study of 141 patients (75 males/66 females) matched for age and gender. Cases were affected by ISSNHL, defined as a sudden hearing loss ≧30 dB, within 3 frequencies, developing over 72 h. The control group was composed of 271 sex- and age-matched subjects (142 males/129 females) who agreed to participate in this observational study and provided blood samples for laboratory investigations. Cardiovascular risk factors examined were: diabetes mellitus, smoking history, hypercholesterolemia, hypertriglyceridemia and hypertension. Results: On the univariate analysis, diabetes prevalence was higher in the ISSNHL group (15.6%) compared to controls (8.5%) (p = 0.03). Also hypercholesterolemia was significantly more frequent in the ISSNHL group compared to the control population. There were no statistically significant differences between the 2 populations concerning other cardiovascular risk factors. The risk of ISSNHL tended to increase as the number of cardiovascular risk factors increased (p for linear trend = 0.018). Conclusions: Our findings suggest that diabetes mellitus, hypercholesterolemia and a high burden of cardiovascular risk factors are associated with the risk of ISSNHL.