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Biomedical subjects

M Cattaneo

Publications and source records attributed to M Cattaneo.

At least 37 records · Page 2Linked to original sources
PubMed2001

Hyperhomocysteinemia and thrombosis.

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12, and B6) as cofactors or cosubstrates. In 1969, McCully first reported the presence of severe atherosclerotic lesions in patients with severe hyperhomocysteinemia and hypothesized the existence of a pathogenic link between hyperhomocysteinemia and atherogenesis. Several case-control and cross-sectional studies were consistent with the initial hypothesis of McCully, showing that moderate hyperhomocysteinemia is also associated with heightened risk of occlusive arterial disease. Less consistent results have been reported by prospective cohort studies of subjects who were healthy at the time of their enrollment, whereas prospective cohort studies of patients with overt coronary artery disease or other conditions at risk consistently confirmed the association between moderate hyperhomocysteinemia and cardiovascular morbidity and mortality. More recently, an association between moderate hyperhomocysteinemia and heightened risk of venous thromboembolism has been documented, suggesting that hyperhomocysteinemia might be involved not only in atherogenesis, but also in thrombogenesis. The mechanisms by which hyperhomocysteinemia might contribute to atherogenesis and thrombogenesis are incompletely understood. The mainstay of treatment of hyperhomocysteinemia is folic acid, alone or in combination with vitamin B12 and vitamin B6. Although it is quite clear that vitamins effectively reduce the plasma levels of total homocysteine (tHcy), we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blind trials of the effects of vitamins on the thrombotic risk will help in defining whether the relationship between hyperhomocysteinemia and thrombosis is causal, and will potentially have a dramatic effect in the prevention of thromboembolic events.

Animals↗
PubMed2001

Allelic polymorphisms in the transcriptional regulatory region of human SEL1L.

In this work, we explored the existence of genetic variants within the SEL1L transcriptional regulatory region by direct sequencing of the basal promoter. SEL1L is the human ortholog of the Caenorhabditis elegans gene sel-1, a negative regulator of LIN-12/NOTCH receptor proteins. To understand the relation in SEL1L transcription pattern observed in different epithelial cells, we analysed its promoter activity. We found it to be considerably higher only in pancreatic cells. We then looked for the presence of genetic variability within this region by sequencing the minimal promoter of 63 individuals (126 alleles); two new and associated polymorphic variants were found only in few lung carcinoma bearing patients. The functional effects of this polymorphism was analysed by transient transfection assay which resulted in a significant increase in the transcriptional activity of the gene.

Alleles↗
PubMed2001

Risk management of HBsAg or anti-HCV positive healthcare workers in hospital.

Recommendations are made for controlling the transmission of the hepatitis B and hepatitis C viruses from healthcare workers to patients. These recommendations were based both on the literature and on experts' opinions, obtained during a Consensus Conference. The quality of the published information and of the experts' opinions was classified into 6 levels, based on the source of the information. The recommendations can be summarised as follows: all healthcare workers must undergo hepatitis B virus vaccination and adopt the standard measures for infection control in hospitals; healthcare workers who directly perform invasive procedures must undergo serological testing and the evaluation of markers of viral infection. Those found to be positive for: 1) HBsAg and HBeAg, 2) HBsAg and hepatitis B virus DNA, or 3) anti-hepatitis C virus and hepatitis C virus RNA must abstain from directly performing invasive procedures; no other limitations in their activities are necessary. Infected healthcare workers are urged to inform their patients of their infectious status, although this is left to the discretion of the healthcare worker; whose privacy is guaranteed by law. If exposure to hepatitis B virus occurs, the healthcare worker must undergo prophylaxis with specific immunoglobulins, in addition to vaccination.

Algorithms↗
PubMed2001

Effects of surgical stress and nitrous oxide anaesthesia on peri-operative plasma levels of total homocysteine. A randomised, controlled study in general surgery.

Previous studies of patients have shown that anaesthesia with nitrous oxide (N2O) increases the plasma levels of total homocysteine. In a randomised, controlled trial we measured the plasma total homocysteine levels in patients undergoing general surgery before and after anaesthesia with and without N2O. Plasma total homocysteine levels were measured before anaesthesia and 1, 3-5 and 24 h after incision in 24 patients randomly allocated to anaesthesia with N2O (n = 12) and without N2O (n = 12). Total homocysteine levels significantly decreased from 10.4 +/- 2.7 to 8.2 +/- 2.9 micromol x l(-1) in the non-N2O group 24 h after incision (p < 0.02), while they tended to increase slightly in the N2O group from 10.5 +/- 4.5 to 10.9 +/- 4.3 micromol x l(-1) (p > 0.05). Our randomised controlled study indicates that total homocysteine decreases after general surgery in patients in whom anaesthesia is maintained without N2O, but not in patients in whom anaesthesia is maintained with N2O.

Adolescent↗
PubMed2001

Cloning and functional analysis of SEL1L promoter region, a pancreas-specific gene.

We examined the promoter activity of SEL1L, the human ortholog of the C. elegans gene sel-1, a negative regulator of LIN-12/NOTCH receptor proteins. To understand the relation in SEL1L transcription pattern observed in different epithelial cells, we determined the transcription start site and sequenced the 5' flanking region. Sequence analysis revealed the presence of consensus promoter elements--GC boxes and a CAAT box--but the absence of a TATA motif. Potential binding sites for transcription factors that are involved in tissue-specific gene expression were identified, including: activator protein-2 (AP-2), hepatocyte nuclear factor-3 (HNF3 beta), homeobox Nkx2-5 and GATA-1. Transcription activity of the TATA-less SEL1L promoter was analyzed by transient transfection using luciferase reporter gene constructs. A core basal promoter of 302 bp was sufficient for constitutive promoter activity in all the cell types studied. This genomic fragment contains a CAAT and several GC boxes. The activity of the SEL1L promoter was considerably higher in mouse pancreatic beta cells (beta TC3) than in several human pancreatic neoplastic cell lines; an even greater reduction of its activity was observed in cells of nonpancreatic origin. These results suggest that SEL1L promoter may be a useful tool in gene therapy applications for pancreatic pathologies.

Animals↗
PubMed2001

Mechanisms of platelet aggregation.

Platelet aggregation is initiated by receptor activation coupled to intracellular signaling leading to activation of integrin alphaIIbbeta3. Recent advances in the study of platelet receptors for collagen, von Willebrand factor, thrombin, and adenosine diphosphate are providing new insights into the mechanisms of platelet aggregation.

Animals↗
PubMed2001

Multicenter study of homocysteine measurement--performance characteristics of different methods, influence of standards on interlaboratory agreement of results.

After the demonstration that moderate hyperhomocysteinemia is associated with thrombosis, many hematological labs are becoming interested in total homocysteine (tHcy) measurement. This prompted us to organize a collaborative study to investigate the performance of methods used in this setting and to assess the between-lab comparability of results. Two pairs of pooled plasma (A1-A2 and B1-B2) were prepared at the coordinating Center. tHcy levels were normal in A1-A2 and moderately high in B1-B2. Within each pair tHcy levels were similar but not identical. Aliquots were taken from each pool to prepare sets of 100 samples (coded from 1 to 100). Each set consisted of 25 replicates for each pool. Samples were frozen and shipped in dry ice to 16 labs with a common frozen aqueous standard. Labs were asked to measure (in blind) tHcy with their methods and standards. Results were sent to the coordinating Center both as raw readings and as tHcy levels. The following methods were used: High Pressure Liquid Chromatography (HPLC) in 12 labs (home-made in 10 and commercial in 2); Enzyme Immuno Assays (EIA) in 2; Fluorescence Polarization Immunoassay (FPIA) in 2 and Capillary Electrophoresis (CE) in one. Results for paired pools (A1-A2 and B1-B2) were analyzed by the Student t test to assess for the ability to discriminate between similar but not identical tHcy levels. Results for each pool were used to assess within-lab reproducibility and between-lab comparability. Within-lab reproducibility expressed as median CV ranged from 12.6 to 13.9% (home-made HPLC); from 9.2 to 11.4% (commercial HPLC); from 21.8 to 24.2% (EIA); from 2.7 to 3.3% (FPIA) and from 11.2 to 22.0% (CE). All labs, except one using CE and 2 using home-made HPLC, were able to discriminate between similar tHcy levels in the normal range (pools A1-A2). Ten labs (4 using home-made HPLC, 2 commercial HPLC, 2 FPIA, one EIA and one CE) were able to discriminate between similar moderately high tHcy levels (pools B1-B2). Between-lab comparability expressed as CV was 14.0% 13.9%, 15.6% and 14.5% for pools A1, A2, B1, and B2. These values were considerably lower (CV values < 5.2%) when a common plasma standard was used for calculation of tHcy levels, while the use of a common aqueous standard failed to achieve the necessary harmonization. In conclusion, performance characteristics of the FPIA method compare favorably with the well-established HPLC methods. It is simpler and more suitable to be used by general hematological labs. Between-lab comparability of results is still a problem. The establishment of an international plasma standard would be of help to harmonize tHcy measurement across laboratories.

Chromatography, High Pressure Liquid↗
PubMed2001

Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.

Factor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.

3' Untranslated Regions↗
PubMed2000

SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers.

We have cloned the human full-length cDNA SEL1L, which is highly similar to the C. elegans sel-1 gene, an important negative regulator of the "notch" pathway which acts as a key regulator of the cellular proliferation and specification processes in both vertebrates and invertebrates. The SEL1L gene maps to 14q24.3-31 and here we report its fine localization by HAPPY mapping, which determines its molecular distance to microsatellite markers isolated in the region. We have found two new polymorphic (CA)n microsatellites located in the gene, and have identified the exon-intron boundaries. The gene is composed of 21 exons spanning 70 kb of genomic DNA. Human SEL1L protein exhibits a high degree of similarity compared to the mouse and nematode homologs.

Amino Acid Sequence↗
PubMed2000

Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly.

Alterations of coagulation and fibrinolytic systems might contribute to the increased cardiovascular and cerebrovascular mortality observed in patients with both chronic growth hormone (GH) excess (acromegaly) and deficiency (GHD). However, contrasting results have been so far reported. To assess the importance of GH in modulating haemostatic system, several haemostatic variables in patients with GHD and acromegaly were measured. Twenty-four adult patients with GHD (8 childhood- and 16 adult-onset; age: 41+/-12 years, insulin like growth factor-I, IGF-I: 6.7+/-4 nmol/L), 10 non-diabetic acromegalic patients (age: 39+/-15 years; IGF-I: 109+/-37 nmol/L) and 64 healthy volunteers age- and sex-matched with cases were studied. The plasma levels of tissue-type plasminogen activator antigen (t-PA), prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were measured by ELISA. Plasminogen activator inhibitor type I (PAI-1) was measured by an immunoactivity assay and fibrinogen by von Clauss method. GH levels were measured by IFMA and IGF-I by RIA. GHD patients had higher PAI-1 (12.7+/-16.7 vs 4.8+/-5.3 U/ml, p<0.01), fibrinogen (363+/-104 vs 291+/-71 mg/dL, p< 0.05) and TAT levels (6.8+/-9 vs 3.6+/-2.8 ng/ml, p<0.05) than controls. Taking the 95th pecentile of the normal distribution in the control group as the cut-off point for normal plasma levels of the haemostatic variables, high PAI levels were found in 25% of patients with GHD (P<0.01), while high fibrinogen and TAT levels were observed in 21% (P<0.05). The alterations were mostly present in patients with adult-onset GHD, with the exception of hyperfibrinogenaemia which was equally present in adult- and childhood-onset patients. Acromegalic patients had higher mean fibrinogen levels than controls (398+/-111 vs 291+/-71 mg/dL, p< 0.05), 40% having hyperfibrinogenaemia (P<0.01, vs controls). They also had t-PA levels lower than controls and GHD. No correlations between hormonal and haemostatic variables were found. Body mass index and waist to hip ratio correlated positively with PAI-1 levels in GHD patients only. In conclusion, this study shows that several abnormalities of coagulation variables (increased PAI-1. fibrinogen and TAT levels) are present in patients with GHD, while only hyperfibrinogenaemia is found in patients with acromegaly. These changes do not appear to be directly related to IGF-I levels or to the degree of GH deficiency/excess. However, these abnormalities may be an additional trigger for the development of coronary heart disease and thromboembolic complications mostly in patients with GHD.

Acromegaly↗
PubMed2000

Melanoma antigen genes 1 and 2 are differentially expressed in human gastric and cardial carcinomas.

BACKGROUND: MAGE genes encode for tumor-rejection antigens and are expressed in tumors of different histologic types but not in normal tissues, with the exception of testis and placenta. The aim of this study was to evaluate the frequency of MAGE-1 and -2 expression in gastric and in cardial carcinomas; these conditions have been described as two distinct diseases, having different etiologies, epidemiologic patterns, and gene mutations. METHODS: Two groups of patients were studied: patients with distal gastric carcinoma and patients with carcinoma of the cardia. A group of patients with intestinal metaplasia in the gastric mucosa and controls were also included. All of them underwent upper GI endoscopy. Paired biopsy specimens were taken for routine histology and for RNA extraction, to study the expression of MAGE-1 and -2 genes. RESULTS: None of the intestinal metaplastic samples or controls expressed MAGE-1 and -2 at detectable levels. Whereas 40% of the gastric cancer patients expressed either MAGE-1 or -2, 26.6% transcribed both. In the cardial cancer group, 20% of the cases expressed at least one MAGE, and only 6.6% expressed both genes. These results might reinforce the concept that cancer of the cardia is a distinct neoplastic disease with regard to esophageal and gastric (distal) carcinomas. CONCLUSIONS: Here we show that MAGE gene expression occurs in advanced stages of gastric and cardial cancer and therefore appears to be a late event. This might point to a reconsideration of their potential role in cancer immunotherapy.

Adult↗
PubMed2000

Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2CYC receptors.

Two unrelated patients with a congenital bleeding diathesis associated with a severe defect of the platelet ADP receptor coupled to adenylate cyclase (P2(CYC)) have been described so far. In one of them, platelet secretion was shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granule stores, thromboxane A(2) production, and ADP-induced primary wave of aggregation) have a moderate defect of P2(CYC). Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for normal platelet secretion, and PSD patients may be heterozygotes for the congenital severe defect of P2(CYC). In this study, we describe 2 new related patients with a severe defect of P2(CYC) and the son of one of them, who is to be considered an obligate heterozygote for the defect. The 2 patients with the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack of inhibition of adenylate cyclase by ADP, and a deficiency of platelet-binding sites for [(33)P]2 MeS-ADP (240 and 225 sites per platelet; normal range, 530 to 1102). The son of one of them had a mildly prolonged bleeding time and abnormalities of platelet aggregation and secretion similar to those found in patients with PSD. In addition, his platelets showed a moderate defect of binding sites for [(33)P]2 MeS-ADP (430 sites per platelet) and of adenylate cyclase inhibition by ADP. This study of a family with the platelet disorder characterized by a defect of the platelet P2(CYC) receptor supports our hypothesis that the full complement of the platelet ADP receptors is essential for normal platelet secretion and that some patients with the common, ill-defined diagnosis of PSD are actually heterozygous for the defect.

Adenosine Diphosphate↗
PubMed2000

Hyperhomocysteinaemia and atherothrombosis.

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine that is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. In 1969, McCully first reported the presence of severe atherosclerotic lesions in patients with severe hyperhomocysteinaemia and hypothesized the existence of a pathogenic link between hyperhomocysteinaemia and atherogenesis. Several case-control and cross-sectional studies confirmed the initial hypothesis of McCully, showing that also moderate hyperhomocysteinaemia is associated with a heightened risk of occlusive arterial disease. Less consistent results have been reported by prospective cohort studies of subjects who were healthy at the time of their enrollment, whereas prospective cohort studies of patients with overt coronary artery disease or other risk conditions consistently confirmed the association between moderate hyperhomocysteinaemia and the risk of cardiovascular morbidity and mortality. More recently, an association between moderate hyperhomocysteinaemia and heightened risk of venous thromboembolism has been documented, suggesting that hyperhomocysteinaemia might be involved not only in atherogenesis, but also in thrombogenesis. The mechanisms by which hyperhomocysteinaemia might contribute to atherogenesis and thrombogenesis are incompletely understood. The mainstay of treatment of hyperhomocysteinaemia is folic acid, alone or in combination with vitamins B12 and B6. Although it is quite clear that vitamins effectively reduce the plasma levels of total Hcy, we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blinded trials on the effects of vitamins on thrombotic risk will help in defining whether the relationship between hyperhomocysteinaemia and thrombosis is causal, and will potentially have a dramatic impact on the prevention of thromboembolic events.

Causality↗