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Gabriele Siciliano

Publications and source records attributed to Gabriele Siciliano.

At least 19 recordsLinked to original sources
PubMed2006

Absence of angiogenic genes modification in Italian ALS patients.

To investigate the role of vascular endothelial growth factor (VEGF) and angiogenin (ANG) as genetic determinants in the susceptibility to sporadic ALS in Italian patients. VEGF genotype and haplotype analysis revealed no association between any variants and the risk of ALS. Regarding ANG gene, no mutation was detected and the rs11701 polymorphism, previously described as associated with ALS, was not differently distributed between patients and controls. Overall, our data argue against the hypothesis of both genes as risk factors for motoneuron neurodegeneration, at least in an Italian population.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia.

Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514_1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.

Adenosine Triphosphatases↗
PubMed2006

Antimyoclonic effect of levetiracetam in MERRF syndrome.

The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF.

Activities of Daily Living↗
PubMed2006

Genes and the environment in neurodegeneration.

Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.) and discuss possible links of gene-environment interplay including, where implicated, mitochondrial genes.

Alzheimer Disease↗
PubMed2006

Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity.

The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.

Adolescent↗
PubMed2006

Mitochondrial dysfunction, oxidative stress and neurodegeneration.

Mitochondria play a critical role in several metabolic processes and apoptotic pathways, regulating life cycle from the cradle to the grave. Despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. Moreover, a growing body of evidence seems to indicate that oxidative stress, which is increased in damaged mitochondria, is an earlier event associated with neurodegeneration. Here we examine the current evidences in this field, which indicate a key role of mitochondria and oxidative stress in contributing to the neurodegenerative processes.

Alzheimer Disease↗
PubMed2006

Mitochondrial dysfunction and Alzheimer's disease: new developments.

There is substantial evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with Alzheimer's disease (AD). However, the precise role of mitochondria in the neurodegenerative cascade leading to AD is still unclear, leaving the answer to the question "what's first: the chicken or the egg?" pending. Here we focus our attention on the progress made in this field in the past few years, which indicates a key role of this fossil organelle and of its specific DNA in contributing to the disease.

Alzheimer Disease↗
PubMed2005

Modulation of hydrogen peroxide-induced DNA damage, MAPKs activation and cell death in PC12 by ergothioneine.

BACKGROUND & AIMS: Ergothioneine (EGT) is a natural occurring compound, synthesized by soil bacteria in fungal substrates, exhibiting antioxidant functions in many cell models. The aim of this study was to assess the effect of EGT in the prevention of H2O2-dependent cell death and oxidative damage on a model of neural cell derived from rat pheocromocytoma, the PC12. METHODS: The ability of EGT was tested by the 3 (4,5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay and Comet assay. H2O2 insult was challenged with increasing concentration of antioxidant using two different incubation periods: 1 and 23 h of EGT pre-treatment followed by 23 and 1 h of H2O2, respectively, for both the MTT and the Comet assay data. CONCLUSION: The pre-treatment for 23 h with EGT, 250 microM and 1mM, followed by 1h of H2O2 incubation at the concentration of 250 and 500 microM, resulted in increased cell viability (P < 0.001) compared to the H2O2 cell batch. This correlated with a decrease in DNA damage as visualized by the Comet assay. Moreover, protein analysis reveals that in the presence of 250 microM of H2O2, EGT acted as a p38-MAPK and Akt specific inhibitor. EGT may play a protective role in rescuing cells from stress-induced apoptosis, likely by activating an intracellular antioxidant pathway involving p38 MAPK genes cascade.

Animals↗
PubMed2005

Subclinical cardiac involvement in patients with facioscapulohumeral muscular dystrophy.

Myocardial involvement is a common finding in certain myopathies, while it has not been extensively investigated in facioscapulohumeral muscular dystrophy (FSHD1A). Aim of this study was to assess in FSHD1A patients the electrical and functional properties of the myocardium. Twenty-four patients with FSHD1A (mean age 41.2+/-14.5 years) and 24 matched healthy subjects were studied. Standard- and signal-averaged electrocardiography were recorded to determine QT dispersion and the presence of ventricular late potentials (VLPs). Standard echocardiography with systo-diastolic variations of integrated backscatter signal (CV-IBS) were performed to assess functional properties of the myocardium. Compared with control subjects, patients with FSHD1A had significantly lower CV-IBS and higher QT dispersion. Nine patients had positive VLPs. QT and QTc dispersion were inversely related to CV-IBS at both septum and posterior wall levels. Moreover, septal CV-IBS was inversely related to the Kpnl-BinI4q fragment size. These results suggest a subclinical cardiac involvement in FSHD1A patients, which can represent a substrate for ventricular arrhythmias and heart failure.

Adult↗
PubMed2005

SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study.

Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait. In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified. The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.

Adolescent↗
PubMed2005

Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I.

BACKGROUND: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in alpha-dystroglycan glycosylation. OBJECTIVES: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations. DESIGN: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes. RESULTS: Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C>A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed. CONCLUSIONS: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.

Adolescent↗
PubMed2005

Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy.

PURPOSE: To prospectively evaluate several diffusion-tensor magnetic resonance (MR) imaging indexes (mean diffusivity [MD], fractional anisotropy [FA], and eigenvalues) of corticospinal tract impairment in patients with progressive muscular atrophy (PMA) and patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: This study had institutional review board approval, and written informed consent was obtained from all subjects. Eight male patients with PMA (mean age, 63 years +/- 13 [standard deviation]), eighteen patients with ALS (14 men and four women; mean age, 64 years +/- 7), and twelve control subjects (four men and eight women; mean age, 65 years +/- 6) underwent diffusion-tensor MR imaging at which 25 spin-echo echo-planar imaging diffusion-weighted images (b = 1000 sec/mm2) were acquired along noncollinear directions. MD and FA were measured along the corticospinal tracts in each patient and subject. Changes in diffusion along and orthogonal to fiber bundles in patients were evaluated by using diffusion-tensor eigenvalues. Differences in diffusion-tensor imaging indexes between patients with PMA and those with ALS, as compared with these indexes in control subjects, were evaluated with Mann-Whitney testing. Correlations between diffusion-tensor imaging indexes and clinical variables were estimated with Pearson and Spearman rank correlation testing. RESULTS: As compared with MD (697.1 x 10(-6) mm2/sec +/- 28.1) and FA (0.585 +/- 0.032) in control subjects, MD was typically significantly increased (734.7 x 10(-6) mm2/sec +/- 41.2, P = .035) and FA significantly decreased (0.534 +/- 0.053, P = .037) along the corticospinal tracts in patients with ALS, while these parameters showed no significant change in patients with PMA (MD, 707.0 x 10(-6) mm2/sec +/- 44.2; FA, 0.559 +/- 0.028). Estimation of diffusion-tensor eigenvalues revealed normal diffusion along fiber tracts in all patients, while diffusion was increased orthogonal to fiber tracts only in patients with typical ALS. In patients with ALS, MD correlated with disease duration while FA correlated with disease severity. CONCLUSION: Diffusion-tensor MR imaging reveals corticospinal tract impairment in ALS but not in PMA.

Aged↗
PubMed2005

Advanced oxidation protein products in serum of patients with myotonic disease type I: association with serum gamma-glutamyltransferase and disease severity.

Steinert's disease (myotonic dystrophy type 1; MD) is caused by a CTG trinucleotide expansion on 19q13.3. Although the pathogenic mechanism underlying multisystem involvement in MD is still unclear, a role of oxidative stress in this disease has been suggested. We investigated 39 MD patients to assess the plasma concentration of advanced oxidation protein products (AOPPs) and gamma-glutamyltransferase (GGT) and related them to clinical severity scores. Plasma AOPP levels (p=0.021), total serum GGT activity (p=0.0005) and GGT activity associated with low-density lipoprotein (p=0.0021) were significantly higher in patients than in controls. There was significant correlation between serum GGT levels and AOPPs (r=0.5831; p=0.0022). A statistically significant increase in serum GGT with age was found in MD patients (p=0.0193). Receiver operating characteristic curve analysis showed that higher AOPP levels were significantly associated with extra-muscular signs of the disease, i.e., cataracts and heart involvement (area under the curve+/-SE=0.908+/-0.083), but not with muscular involvement. The concomitant increment in GGT and AOPPs indicates a possible role of oxidative stress in the pathogenesis of MD type 1, while the association of increased AOPP levels with extra-muscular signs of the disease suggests that individual susceptibility to oxidative stress can modulate the extra-muscular phenotype of the disease.

Adolescent↗
PubMed2005

Cx26 gene mutations in idiopathic progressive hearing loss.

OBJECTIVE: The present study evaluated the frequency and type of mutations throughout the entire GJB2 region in a population of 39 patients affected with sporadic progressive "idiopathic" hearing loss. MATERIAL: A large series of patients suffering from progressive hearing loss underwent a systematic screening program to identify the etiology of the hearing loss. Of these patients, 39 presented with sporadic idiopathic progressive hearing loss and were included in this study. METHOD: We performed molecular analysis of GJB2 in each patient sequencing the genomic deoxyribonucleic acid (DNA) in both directions for detection of GJB2 mutations. Furthermore, in all patients bearing a Cx26 mutation, a search was also conducted for mutations or deletions of GJB6 (Cx30 gene) and for the A1555G mutation of the mitochondrial DNA. A control group was also considered to evaluate the frequency of Cx26 mutations in the normal population. RESULTS: A Cx26 gene mutation was detected in nine cases. One subject was found to bear a homozygous genotype for the 35delG mutation, another subject was compound heterozygous for 35delG and E47X, and the remaining patients showed heterozygous genotypes (35delG, L90P, R127H, M34T, V153I, V37I). No mutation or delection of the Cx30 gene was observed in these nine patients, and none of them presented with the A1555G mutation in the mitochondrial DNA. In the control group (40 individuals), a Cx26 mutation was detected in two cases (5%). CONCLUSIONS: About 23% of our patients (nine subjects) presented with mutations in GJB2, and 18% (seven subjects) were heterozygous. However, most of the described mutations are recessive, so a monogenic model of inheritance cannot explain the deafness phenotype. On the basis of these findings, we can speculate that the heterozygote Cx26 genotype could be a cause of progressive hearing loss, probably in association with mutations in other alleles. Thus, we recommend carefully following all hearing-impaired subjects with GJB2 mutations, even if they present with only mild hearing loss, because the hearing deficit could worsen. Furthermore, molecular analysis of the Cx26 gene should also be performed in adult patients affected with idiopathic progressive hearing loss.

Adult↗
PubMed2004

Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis?

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.

Adult↗
PubMed2004

Lactate production and catecholamine profile during aerobic exercise in normotensive OSAS patients.

BACKGROUND AND PURPOSE: The aim of the study was to evaluate the catecholaminergic activity and lactate concentration during exercise in normotensive patients with obstructive sleep apnoea syndrome (OSAS). PATIENTS AND METHODS: Thirteen normotensive patients affected by OSAS (mean age+/-standard error (SE), 52.6+/-2.8 yrs; mean apnoea-hypopnea index, 35.7+/-20.3) were enrolled in the study. Night-polysomnography and multiple sleep latency test in the sleep laboratory were performed for every patient. Patients also underwent an incremental workload exercise on a cycloergometer. We evaluated plasma epinephrine and norepinephrine levels in aerobic exercise conditions, relating them to lactate levels. RESULTS: Analysis of the venous lactate curve showed that exercise lactate levels were significantly higher (peak normalised levels, 782 vs. 270%; P<0.001 ), and an earlier lactate threshold was detected, in the patients compared to normal controls. While plasma catecholamine levels were abnormally high in almost all patients at rest, exercise values were not significantly different from controls. Lactate/norepinephrine and lactate/epinephrine area ratios were significantly higher in OSAS subjects than in controls (2.25 vs. 1.21 and 2.37 vs. 1.03, respectively). CONCLUSIONS: The results indicate that abnormal production of lactate during exercise occurs in OSAS, possibly due to some muscular metabolic modification. While catecholaminergic activity is abnormally increased at rest, this activity does not seem to play a significant role in lactate concentration during exercise in these patients.

Blood Pressure↗
PubMed2004

Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosispatients.

Calcineurin (CaN) is a Ser/Thr protein phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion that calcineurin is oxidatively inhibited by mutant Cu, Zn superoxide dismutase (SOD1) typical of familial ALS patients in vitro and in transgenic mice. We report that calcineurin activity is markedly inhibited in lymphocytes from 37 sporadic, eight familial ALS patients and an asymptomatic subject carrying an SOD1 mutation as compared to 28 healthy controls. Two other healthy subjects, heterozygous for the D90A mutation from a recessive pedigree, have normal calcineurin activity. Immunoreactive CaN protein, age, sex and riluzole treatment are not related to calcineurin activity in samples from patients. However, we have observed a marked increase in total protein oxidation in extracts from ALS lymphocytes, as compared to extracts from control subjects. These data confirm that modification of calcineurin activity and possibly of calcineurin-mediated pathways of signal transduction (including modulation of apoptotic neuronal death) may contribute to the pathogenesis of ALS.

Adult↗