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BC: Articoli scritti da F. Zarrilli

Suicidio tra umanesimo e scienza
Suicide between humanism and science
<p>Suicide is among the first 10 causes of death in industrialized countries,&nbsp;even if its incidence is declining. Familiarity frequently occurs in suicide and a myriad of polymorphisms in candidate&nbsp;genes has been studied as risk factors. Among these, genes encoding enzymes, transporters or receptors of the&nbsp;serotoninergic and dopaminergic systems have been widely studied with conflicting results. Also the metabolism of&nbsp;cholesterol (and serum cholesterol concentrations) seems to have a role in the pathogenesis of suicide. In the last&nbsp;years, our group contributed to study brain derived neurotrophic factor (BDNF) and its TrkB receptor genes in the&nbsp;DNA from Wernicke area from a large cohort of suicide subjects and controls. In particular, we excluded that the<br />expression of BDNF and its receptor may be modulated by gene mutations. However, the levels of BDNF gene<br />expression were significantly lower in the brain tissue from suicide subjects. We demonstrated that the altered BDNF&nbsp;expression was due to the enhanced methylation of BDNF promoter. These studies first revealed the association&nbsp;between epigenetics and suicide suggesting a novel model of interaction between environment and genes in the&nbsp;pathogenesis of suicide.</p>
Biochimica Clinica ; 38(2) 121-128
Opinioni - Opinions
 
Emofilia, come si concluderà la storia?
Hemophilia, how will end the story?
<p>Hemophilia A (HA) and B (HB) are the most frequent inherited bleeding&nbsp;disorders caused by defects in the F8C and F9 genes that encode coagulation factor VIII and factor IX, respectively.&nbsp;Both HA and HB are X-linked recessive diseases and have an incidence of 1:5000 and 1:30,000 males, respectively.&nbsp;The diagnosis is based on normal prothrombin time, altered activated partial thromboplastin time and reduced activity<br />of factor VIII or factor IX in plasma. Furthermore, laboratory contributes to identify the inhibitor (an immunoglobulin&nbsp;against the factor that some hemophilic patients develop during therapy) and to reveal acquired hemophilia. Carrier&nbsp;females of HA and HB are tipically asymptomatic and can be identified only by molecular analysis; their evaluation is&nbsp;important, as one third of cases of hemophilia is due to novel mutations and in these cases the mother (and&nbsp;consanguineous females) of the proband have no risk to be carrier. Both diseases are due to a myriad of different&nbsp;mutations (mostly private), so that the molecular diagnosis is based on scanning techniques or gene sequencing.&nbsp;Given the number of hemophilic patients that experience severe perinatal complications, high-risk couples usually&nbsp;require prenatal diagnosis. We revise here our experience on 50 prenatal diagnoses of hemophilia. The clinical&nbsp;heterogeneity of hemophilic patients prompted many groups to study prothrombotic gene variants in these subjects&nbsp;to investigate whether such variants modify the clinical expression of disease. Finally, therapy (using recombinant&nbsp;factors) and, in a near future, gene therapy will change the natural history of hemophilic patients.</p>
Biochimica Clinica ; 37(6) 454-460
Rassegne - Reviews
 
Identificazione e caratterizzazione di mutazioni in regioni regolatorie del gene malattia della fibrosi cistica
Identification and characterization of mutations in regulatory regions of cystic fibrosis disease gene
<p>Mutation&nbsp;epidemiology is crucial for cystic fibrosis (CF) diagnosis and counselling. ~6%-7% of alleles from CF patients do not bear&nbsp;mutations in the coding regions of the Cystic Fibrosis Transmembrane Regulator (CFTR) disease gene. In these&nbsp;patients, mutations may be present in non-coding, regulatory regions of the gene as i) intronic regions (particularly in&nbsp;high conserved sequences), ii) the promoter region or iii) the area at the 3&rsquo; of the gene, which is the target of microRNA&nbsp;regulation. We studied these regions by gene sequencing in a group of CF patients with one or both unidentified&nbsp;mutations after the analysis of CFTR coding regions, and in a group of CF patients with a different clinical expression of&nbsp;disease to evaluate if mutations in such regions may have a role in modulating CF clinical expression. Our analysis&nbsp;revealed: i) a dozen of mutations (most novel) in the large promoter area of 6000 bp at the 5&rsquo; of the gene; expression&nbsp;studies in four cell lines demonstrated that a half of such mutations may have a pathogenic effect; ii) a series of mutations&nbsp;in 52 conserved sequence tags (CSTs), i.e. intronic regions with a high homology between humans and mouse;&nbsp;expression studies revealed the pathogenic effect of one of these mutations; iii) finally, three mutations in the 1500 bp&nbsp;region at the 3&rsquo; of the gene; one of this has a pathogenic role, enhancing the interaction of CFTR with two inhibitory&nbsp;microRNAs. To the best of our knowledge, this is the first example of such pathogenic mechanism in a monogenic&nbsp;disorder. On the contrary, no mutations were identified in patients with different clinical expression in any of the three<br />non-coding regions. To conclude, the sequencing of non coding regions may improve the detection rate of molecular&nbsp;analysis in CF, but functional studies are required to define the pathogenic effect of novel mutations.</p>
Biochimica Clinica ; 37(6) 465-469
Contributi scientifici - Scientific papers
 
Polimorfismo I/D del gene per l’enzima di conversione dell’angiotensina (ACE): gene della longevità o fattore di rischio nella patologia ipertensiva?
Polymorphism of the angiotensin converting enzyme gene: longevity gene or risk factor in hypertensive disease?
<p>In recent decades, the increase in life expectancy stimulated the study of aging processes and the search for&nbsp;candidate genes involved in longevity. The angiotensin converting enzyme (ACE), present in all endothelial cells, plays&nbsp;an essential role in maintaining the homeostasis of blood flow by regulating the production of the vasoconstrictor&nbsp;angiotensin II and inactivating the bradykinin. Some studies reported a possible association between the polymorphism&nbsp;I/D of ACE gene and either hypertension and longevity. The present study was aimed to confirm these data. We studied&nbsp;two large cohorts of nonagenarians and centenarians. One was from Sardinia (200 subjects, 88 males, mean age: 96&nbsp;years) and their data were compared to a group of 222 subjects (106 males, mean age: 44 years) from the general&nbsp;population of the same geographic area. The latter group of longeve subjects (161 subjects, 71 males, mean age: 97&nbsp;years) was from Southern Italy. Furthermore, we studied 146 hypertensive patients (98 males, mean age: 51 years) and&nbsp;172 normotensive subjects (86 males, mean age: 33 years) from Southern Italy. The ACE I/D polymorphism was typed&nbsp;by polymerase chain reaction; the amplified 490 bp (allele I) and 190 bp (allele D) were visualized on 2% agarose gel.&nbsp;Hypertensive subjects had a significantly different distribution of ACE genotypes as compared to normotensive ones&nbsp;(P=0.001) and a higher frequency of the D/D genotype. Long-lived subjects from Sardinia showed a significantly different&nbsp;distribution of ACE genotypes as compared to subjects from the general population of the same geographic area (P&nbsp;&lt;0.001), to long-lived subjects from Southern Italy (P &lt;0.001), to hypertensive patients (P=0.011) and to normotensive&nbsp;subjects from Southern Italy (P &lt;0.001). Surprisingly, they had the highest frequency of the D/D genotype among the&nbsp;compared groups. Our study indicates that: i) centenarians of different ethnic origin have a different genetic background,&nbsp;ii) there is a possible association between longevity and allelic variants of ACE, even if only in specific ethnic groups (i.e.,&nbsp;Sardinian) and iii) ACE polymorphisms are a predisposing factor to hypertension.</p>
Biochimica Clinica ; 37(6) 461-464
Contributi scientifici - Scientific papers