Biomedical subjects

Vilma Mantovani

Publications and source records attributed to Vilma Mantovani.

10 recordsLinked to original sources

PubMed2006

Plasma total homocysteine and cardiovascular risk in patients submitted to liver transplantation.

Patients submitted to orthotopic liver transplantation (OLT) show an increased rate of cardiovascular events. OLT subjects have high homocysteine (Hcy) levels, but no data are available on the association of Hcy with cardiovascular events. In a cross-sectional analysis, 230 subjects were studied at least 6 months after OLT (159 on cyclosporine, 71 on tacrolimus). Routine laboratory data and total Hcy were recorded, as well as the history of diabetes, hypertension, dyslipidemia, and overweight. Cardiovascular events occurring in a follow-up of 2-36 months were registered. OLT subjects had higher-than-normal Hcy (median 16.7 micromol/L, range 6.1-171.8) without difference between the 2 immunosuppressive agents. The prevalence of Hcy >15 micromol/L was also similar, and significantly correlated with creatinine levels. A total of 28 arterial events occurred in 25 patients during follow-up (11 in coronary arteries, 10 in peripheral arteries, and 7 in splanchnic arteries). Deep vein thromboses occurred in 2 patients, and splanchnic vein thromboses in 4 patients. Cardiovascular events were frequently associated to high Hcy and hypertension. Cox regression analysis showed that high Hcy was significantly associated with arterial events. The risk of any arterial event, coronary artery or peripheral artery event increased by nearly 10% for any increase in Hcy of 5 micromol/L. In conclusion, high Hcy may be involved in the pathogenesis of cardiovascular events in OLT patients. The usefulness of Hcy-lowering therapy remains to be verified.

Adult↗

PubMed2005

Genetic distinctions between autoimmune hepatitis in Italy and North America.

AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P = 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P = 0.01) and in controls (16% vs 34%, P = 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P = 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.

Adolescent↗

PubMed2005

Mutations of the CFTR gene in idiopathic pancreatic hyperenzymemia.

OBJECTIVES: Idiopathic pancreatic hyperenzymemia is a new syndrome that is characterized by a chronic increase of serum pancreatic enzymes in the absence of pancreatic disease. The aim of this study was to assess whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may have a role in the etiology of this hyperenzymemia. METHODS: Seventy subjects with idiopathic pancreatic hyperenzymemia, 44 men and 26 women (mean age, 48 years; range, 8-74 years), were studied. Thirteen of these 70 subjects had the familial form of the syndrome. The mutation analysis of the CFTR gene was carried out using diagnostic commercial kits for the simultaneous detection of 29 mutations and Tn polymorphism. RESULTS: Among the 70 subjects studied, 7 (10.0%) had CFTR gene mutations. None of these 7 subjects had the familial form of pancreatic hyperenzymemia. These mutations were DeltaF 508 in 1 subject, 2789 + 5 G > A in another subject, and T5 allele in the remaining 5. All these mutations were heterozygous, with the exception of 1 T5 allele that was homozygous in 1 subject. CONCLUSIONS: The frequencies of the mutations of the CFTR gene found in these subjects are similar to the carrier frequencies in the general Italian population. This finding does not support a role for CFTR gene mutations in the etiology of idiopathic pancreatic hyperenzymemia.

Adolescent↗

PubMed2003

Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer.

The first-degree relatives of patients affected by colorectal cancer, who do not belong to familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families, have a doubled risk of developing tumors of the large intestine. We have previously demonstrated that subjects with a single first-degree relative (SFDR) with colon cancer have a doubled risk for developing colorectal adenomas, and in these cases, polyps recur more frequently. The mechanism underlying this predisposition has not been clarified. In this study, we evaluated the frequency of microsatellite instability (MSI) using the five markers suggested by the National Cancer Institute workshop, target gene mutations, hMLH1 and hMSH2 expression, and hMLH1 promoter hypermethylation in the adenomas of patients with and without a SFDR affected by colon cancer. Seventy polyps were obtained from 70 patients: 27 with a single FDR with colon cancer and 43 without such a history. Of the 70 polyps, 12 were MSI-H (17.1%), 20 were MSI-L (28.6%), and 30 were microsatellite stable (42.9%). Of the 27 patients with positive family history, 8 polyps (29.6%) were MSI-H compared with those with negative history in which 4 polyps (9.3%) were MSI-H (P < 0.02). Of the 12 MSI-H polyps, all of the polyps obtained from patients with positive family history had loss of hMLH1 immunostaining versus one with negative family history (P < 0.02). Of the MSI-H polyps, 2 had a somatic frameshift mutation of the MBD4 gene, 1 of MSH6, 1 of BAX, and 2 of transforming growth factor betaRII. Furthermore, 6 of 8 polyps from patients with positive family history with MSI-H and loss of MLH1 had hypermethylation of the MLH1promoter versus none of the MSI-H with negative family history (P < 0.02). All 6 polyps of the 27 from SFDR positive subjects, with hMLH1 promoter hypermethylation loss of hMLH1 and MSI, were located in the right colon (P < 0.02). Hypermethylation of the promoter of hMLH1, consequent loss of hMLH1 expression, and MSI are at the basis of approximately 25% of adenomatous polyps developed in subjects with a SFDR affected by colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by early onset non-insulin-dependent diabetes mellitus, autosomal dominant inheritance, and primary defect in the function of the beta cells of the pancreas. Mutations in the glucokinase (GCK) gene account for 8%-56% of MODY, with the highest prevalences being found in the southern Europe. While screening for GCK mutations in 28 MODY families of Italian origin, we identified 17 different mutations (corresponding to 61% prevalence), including eight previously undescribed ones. The novel sequence variants included five missense mutations (p.Lys161Asn c.483G>C in exon 4, p.Phe171Leu c.511T>C in exon 5 and p.Thr228Ala c.682A>G, p.Thr228Arg c.683C>G, p.Gly258Cys c.772G>T in exon 7), one nonsense mutation (p.Ser383Ter c.1148C>A in exon 9), the splice site variant c.1253+1G>T in intron 9, and the deletion of 12 nucleotides in exon 10 (p.Ser433_Ile436del c.1298_1309del12). Our study indicates that mutations in the GCK/MODY2 gene are a very common cause of MODY in the Italian population and broadens our knowledge of the naturally occurring GCK mutation repertoire.

Adolescent↗

PubMed2003

Mutations of the CFTR gene in pancreatic disease.

INTRODUCTION: An association has been found between CFTR gene mutations and chronic pancreatitis; however, there is a lack of information about the frequency of CFTR gene mutations in acute pancreatitis and in pancreatic cancer. AIM: To prospectively evaluate the prevalence of CFTR gene mutations in acute pancreatitis, chronic pancreatitis, and pancreatic cancer. METHODOLOGY: Ninety-eight consecutive patients were studied and divided into 3 groups: 34 patients with acute pancreatitis, 46 patients with chronic pancreatitis, and 18 patients with pancreatic cancer. The mutation analysis of the CFTR gene was carried out using diagnostic commercial kits for the simultaneous detection of 29 mutations and Tn polymorphism. RESULTS: Among the 98 patients studied, 12 (12.2%) had CFTR gene mutations: 2 of the 34 patients (5.9%) with acute pancreatitis, 9 of the 46 (19.6%) with chronic pancreatitis, and 1 of the 18 (5.6%) with pancreatic cancer. All the mutations were found in heterozygosis (2 DeltaF508, 1 W1282X, and 9 T5 allele). CONCLUSION: Our prospective study adds further information about the frequency of CFTR mutations in patients with a single episode of acute pancreatitis. Furthermore, our results suggest an association of CFTR gene mutations with chronic alcoholic pancreatitis and emphasize the need for a multicenter study, possibly multinational, to conclusively establish the role of CFTR mutations as a genetic susceptibility factor for this disease.

Acute Disease↗

PubMed2002

Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?

We investigated whether molecular defects in the CYP21 gene were detectable in two common sex chromosome aberrations, the Turner and the Klinefelter syndromes. We found abnormal 17-hydroxyprogesterone levels after adrenal stimulation in 26/60 (43.3%) patients affected by these chromosome aberrations, as compared with only 11/68 (16.2%) normal controls (P=0.0014, odds ratio 4.0). Screening of the CYP21 gene identified a single Val281Leu missense mutation in exon 7 in 9/63 (14.3%) of the patients, all nine of whom were heterozygote carriers; the mutation frequency was significantly higher than in the general population (P=0.007, odds ratio=3.5). The hormonal and molecular data indicate that these common sex chromosome aberrations are associated with a remarkably high frequency of steroidogenic defects. It may be hypothesised that reduced levels of steroid 21-hydroxylase could confer a survival advantage, leading to a successful pregnancy.

17-alpha-Hydroxyprogesterone↗

PubMedDate not supplied

Frequency of the HFE gene mutations in five Italian populations.

Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), appear to be associated with milder forms of hereditary hemochromatosis. There is a high prevalence of the C282Y mutation in northern European populations, whereas in those of the Mediterranean basin the prevalence seems low and almost absent in Far East countries. This mutation seems usually to occur on the ancestral haplotype 7.1. Accordingly, a Celtic origin of this mutation has been suggested. The aim of this study was to determine the frequency of HFE gene mutations in five geographic regions in Italy. Samples were tested for C282Y, H63D, and S65C mutations of the HFE gene according to methods of each laboratory and the results were standardized with the exchange of typed samples between the different laboratories. In addition, C282Y-positive DNA samples were typed for D6S105 allele 8 and HLA-A3 by ARMS-PCR. We have found that the allele frequency of the C282Y mutation decreases from northeast Italy (Friuli, 6%) to northwest Italy (Piedmont, 4.8%) and to central Italy (Emilia-Romagna, 1.7%). However, this mutation is lacking in the two regions of the Mediterranean basin's center (Sicily and Sardinia). Accordingly, a significant difference in the frequency of the mutation was observed between these Italian regions (P = 0.07 x 10(-3)). In contrast, no difference was observed in allele frequency of H63D in the five Italian regions. Finally, as regards the S65C mutation a very low frequency was observed in Friuli, Emilia-Romagna, and Sardinia, whereas in Sicily and Piedmont we have not found this mutation. In conclusion, these data are consistent with the hypothesis that the C282Y mutation occurred in Caucasian populations of Celtic origin, whereas the H63D mutation is more ancient as demonstrated by the ubiquitous distribution.

Amino Acid Substitution↗

PubMedDate not supplied

Association between HFE mutations and acute myocardial infarction: a study in patients from Northern and Southern Italy.

There is interest in the role of iron in age-related diseases such as atherosclerosis. Tissue iron deposition could be harmful, because Fe(2+) can react with H(2)O(2) to form OH(-) radicals and Fe(2+) can react with O(2) to form reactive oxygen species. Free radicals react with cell membranes and cell organelles and could lead to the development of atherosclerosis by initiating lipid peroxidation. Hereditary hemochromatosis provides an opportunity for studying the effects of iron on cardiovascular disease. Some studies have shown that individuals who carried HFE mutations may be at greater risk of developing coronary heart disease than those without the mutations. In contrast, a large number of studies have reported no association between HFE mutations and coronary heart disease. These studies have possible confounding factors, such as the homogeneity of the population in term of geographical origin among others. We studied the relation between HFE mutations and acute myocardial infarction in two case-control studies involving two sets of subjects representing different age groups from different geographic regions in Italy. The first one was composed of 172 older patients (139 males and 33 females; mean age 67) and 207 healthy controls (91 males and 116 females; mean age 46) from Emilia-Romagna. The second one was composed of younger 77 patients (75 males and 2 females; mean age 41) and 172 healthy controls (75 males and 97 females, mean age: 38) from Sicily. All patients were genotyped for ApoE alleles, since the ApoE- epsilon 4 allele is considered a risk factor for cardiovascular diseases and can interfere with other genetic and environmental factors by modifying susceptibility to this disease. DNA typing for C282Y and H63D HFE alleles was performed also. There were no significant differences in frequencies of the different HFE alleles between acute myocardial infarction patients and controls in cohorts of both old and young patients. Also taking into account the presence or absence of the ApoE- epsilon 4 allele, no significant differences in H63D allele frequencies were observed. Thus, our study, performed in two samples of genetically homogeneous patients and controls, does not support the suggestion that HFE mutations may be associated with acute myocardial infarction in susceptible individuals.

Adult↗

PubMedDate not supplied

Fast CYP2E1 genotyping using automated fluorescent detection.

BACKGROUND: Among polymorphic genes coding for xenobiotic-metabolizing enzymes, the ethanol-inducible CYP2E1 gene (1667 bp) is known to play a major role in the metabolism ofseveral chemicals. OBJECTIVES: In order to apply large-scale genotyping, we explored the use of a Single Nucleotide Primer Extension (SNuPE) assay coupled with automated fluorescent detection to assess the presence of low-frequency CYP2E1*5B (c2) allele. METHODS: a classic PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) method specific for polymorphic5'-flanking region of CYP2E1 gene was tested in conjunction with a newly developed accelerated SNuPE assay. RESULTS: compared to the classic PCR-RFLP method, the accelerated SNuPE assay proved to be both sensitive and specific for fast CYP2E1 genotyping. CONCLUSIONS: automated fluorescent methods as SNuPE assay are usefulfor public health perspectives, allowing rapid genotyping of metabolic genes in large population studies in clinical or epidemiological settings.

Alleles↗