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In recent decades, the increase in life expectancy stimulated the study of aging processes and the search for candidate genes involved in longevity. The angiotensin converting enzyme (ACE), present in all endothelial cells, plays an essential role in maintaining the homeostasis of blood flow by regulating the production of the vasoconstrictor angiotensin II and inactivating the bradykinin. Some studies reported a possible association between the polymorphism I/D of ACE gene and either hypertension and longevity. The present study was aimed to confirm these data. We studied two large cohorts of nonagenarians and centenarians. One was from Sardinia (200 subjects, 88 males, mean age: 96 years) and their data were compared to a group of 222 subjects (106 males, mean age: 44 years) from the general population of the same geographic area. The latter group of longeve subjects (161 subjects, 71 males, mean age: 97 years) was from Southern Italy. Furthermore, we studied 146 hypertensive patients (98 males, mean age: 51 years) and 172 normotensive subjects (86 males, mean age: 33 years) from Southern Italy. The ACE I/D polymorphism was typed by polymerase chain reaction; the amplified 490 bp (allele I) and 190 bp (allele D) were visualized on 2% agarose gel. Hypertensive subjects had a significantly different distribution of ACE genotypes as compared to normotensive ones (P=0.001) and a higher frequency of the D/D genotype. Long-lived subjects from Sardinia showed a significantly different distribution of ACE genotypes as compared to subjects from the general population of the same geographic area (P

Background: Numerous recent evidence suggests that homocysteine (HC), a putative risk factor for stroke and coronary artery disease [1,2], could play a role in the physiopathology of several neurodegenerative disorders, such as Alzheimer’s Parkinson’s diseases and amyotrophic lateral sclerosis (ALS) [3,4,5]. HC, an aminoacid involved in the methionine metabolism, acts as a neurotoxin through several mechanisms, including free radicals and cytosolic accumulation, mitochondrial dysfunctions, activation of apoptotic pathways, and excitotoxic aminoacid-mediated damage [5]. A recent report showed that plasma HC levels were significantly elevated in ALS, and in particular in those patients with a faster progression of the disease, suggesting that this endogenous molecule might represent a marker of neurodegeneration in this devastating motor neuron disorder [5]. Objectives: Aim of the study was to assay the CSF and plasma levels of HC in ALS patients and controls, and to evaluate the relationship between HC levels and clinical variables of the disease. Methods: Cerebrospinal fluid from sixty-nine (♂45, ♀24) and plasma from sixty-five ALS patients (♂42, ♀23) were taken and stored at -80° C until use. Controls (CSF = 55; plasma = 67) were patients admitted to our hospital for neurological disorders with no known relationship to HC changes. CSF and plasma from ALS patients and controls were obtained as a necessary step of the diagnostic workup. HC levels in CSF and plasma were assayed using a high performance liquid chromatograph (HPLC) and a fluorimetric detector. Results: The median level of total HC in the CSF of ALS patients was 0.46 microM, significantly higher than that of the controls (0.24 microM, +91.6%, P < 0.001). A similar trend was observed when HC was assayed in plasma (ALS, 12.4 microM vs. controls, 7.26 lM, +70.8%, P < 0.001). The CSF and plasma HC levels showed no relationship with the disease progression, age at onset, and the site of onset. Conclusions: CSF and plasma homocysteine levels were significantly increased in patients with ALS compared with controls. This enhancement seems to be independent of the vitamin levels. Our data suggest that homocysteine might represent a biochemical marker in ALS, and it might be related to the pathophysiology of the disease. References 1. Pezzini A, Del Zotto E, Padovani A. Homocysteine and cerebral ischemia: pathogenic and therapeutical implications. Curr Med Chem 2007; 14: 249–263. 2. Humphrey LL, Fu R, Rogers K, et al. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc 2008; 83: 1203–1212. 3. Tchantchou F, Shea TB. Folate deprivation, the methionine cycle, and Alzheimer_s disease. Vitam Horm 2008; 79:83–97. 4. Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004; 63: 886–891. 5. Zoccolella S, Simone IL, Lamberti P, et al. Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis. Neurology 2008; 70: 222–225.

Apolipoprotein E is a major determinant in lipoprotein metabolism and cardiovascular disease, it has emerged as an important molecule in several biological processes including Alzheimer's disease and cognitive function. ApoE is a polymorphic protein (ε2, ε3, ε4) with three proteic isoforms, ApoE2, ApoE3, ApoE4 (1). The aim of the study was to verify the frequencies of allelic variants a population of healthy elderly people. ApoE polymorphisms were determined by Real Time-PCR. The genotype frequencies of ApoE in our group of 71 centenarians (mean age 100.9 ±1.3) were: ε2/ε3 (12.67%); ε3/ε4 (5.63%). In the control group, consisting of 97 individuals (mean age 92.98 ±2.53), the genotype frequencies were: ε2/ε3 (7.21%); ε3/ε4 (15.46%). Differences between genotype frequencies in centenarians and control group were statistically significant (P

Antonietta Caruso, Chiara Bellia, Alessia Pivetti, Luisa Agnello, Federica Bazza, Concetta Scazzone, Giulia Bivona, Bruna Lo Sasso, Marcello CiaccioDepartment of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, ItalyBackground: The aim of this study was to investigate the effect of two genetic polymorphisms in the coding regions (exon 3 and exon 4) of the EPHX1 gene, ie, 337T>C and 416A>G, respectively, on the metabolism of carbamazepine (CBZ) 10,11-epoxide (the active metabolite of CBZ) by evaluating the variation in serum CBZ 10,11-epoxide levels 4 hours after administration of the drug. Moreover, we reported the genotype frequencies of the CYP3A4*22 (rs 35599367, C>T) variant and its influence on the metabolism of CBZ.Methods: The analysis was performed in 50 patients receiving CBZ as monotherapy. DNA was extracted from leukocytes using a commercially available kit. Serum CBZ 10,11-epoxide levels were measured by high-performance liquid chromatography. Allelic discrimination was performed using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the difference in mean values for CBZ 10,11-epoxide levels according to genotype was performed using the Student's t-test with Statistical Package for the Social Sciences version 13 software.Results: Fourteen percent of the study group were CC, 42% were CT, and 44% were TT for the EPHX1 337T>C variant. No GG homozygote was identified for the EPHX1 416A.G variant; 64% were AA and 36% were AG. When we compared serum CBZ 10,11-epoxide levels 4 hours after drug administration, we found no statistically significant difference between the 337 CC, CT, and TT genotypes. Similarly, no difference in serum CBZ 10,11-epoxide levels was found between 416A>G AA and AG. Genotype frequencies for the CYP3A4*22 (rs 35599367 C>T) allelic variant were 94% for CC and 6% for CT, with no statistically significant difference in serum CBZ 10,11-epoxide levels between these genotypes 4 hours after administration of the drug (2.6±1.3 µg/µL and 2.5±1.2 µg/µL, respectively).Conclusion: Although there is some evidence of involvement of these polymorphisms in enzyme activity in vitro, we found no interference with CBZ metabolism in vivo.Keywords: EPHX1 gene, CBZ 10,11-epoxide, CYP3A4*22, drug metabolism

In recent decades, the increase in life expectancy stimulated the study of aging processes and the search for candidate genes involved in longevity. The angiotensin converting enzyme (ACE), present in all endothelial cells, plays an essential role in maintaining the homeostasis of blood flow by regulating the production of the vasoconstrictor angiotensin II and inactivating the bradykinin. Some studies reported a possible association between the polymorphism I/D of ACE gene and either hypertension and longevity. The present study was aimed to confirm these data. We studied two large cohorts of nonagenarians and centenarians. One was from Sardinia (200 subjects, 88 males, mean age: 96 years) and their data were compared to a group of 222 subjects (106 males, mean age: 44 years) from the general population of the same geographic area. The latter group of longeve subjects (161 subjects, 71 males, mean age: 97 years) was from Southern Italy. Furthermore, we studied 146 hypertensive patients (98 males, mean age: 51 years) and 172 normotensive subjects (86 males, mean age: 33 years) from Southern Italy. The ACE I/D polymorphism was typed by polymerase chain reaction; the amplified 490 bp (allele I) and 190 bp (allele D) were visualized on 2% agarose gel. Hypertensive subjects had a significantly different distribution of ACE genotypes as compared to normotensive ones (P=0.001) and a higher frequency of the D/D genotype. Long-lived subjects from Sardinia showed a significantly different distribution of ACE genotypes as compared to subjects from the general population of the same geographic area (P