Search PubMed⌕ Search

Biomedical subjects

G De Sandre

Publications and source records attributed to G De Sandre.

At least 19 recordsLinked to original sources
PubMed1999

Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha?

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.

Adipose Tissue↗
PubMed1998

Chronic parvovirus B19 infection induces the production of anti-virus antibodies with autoantigen binding properties.

Human parvovirus B19 infection in adults shows some clinical features similar to those found in autoimmune connective tissue diseases. To better clarify the relationship between viral infection and autoimmunity, we have evaluated the ability of anti-parvovirus antibodies to specifically recognize autoantigens in ten patients with chronic symmetric arthritis resembling rheumatoid arthritis or with recurrent episodes of arthritis and cutaneous manifestations and persistence of specific IgM antibodies against B19 parvovirus. We synthetized a 24-amino acid immunodominant peptide corresponding to a part of the virus protein 1 and virus protein 2 overlapping region. The peptide has been used to test patients' sera at different time points with an enzyme-linked immunosorbent assay (ELISA) and to purify anti-virus antibodies by affinity chromatography on a peptide-Sepharose column. Eluted immunoglobulins recognized the B19 peptide in both direct and competitive ELISA. Affinity-purified anti-parvovirus antibodies were then tested on a panel of autoantigens including human keratin, collagen type II, thyreoglobulin, single-strand (ss)DNA, cardiolipin and ribonucleoprotein antigen Sm. Eluted antibodies specifically recognized keratin, collagen type II, ssDNA and cardiolipin. Autoantibody activity was not detected in the immunoglobulin fraction after complete removal of anti-peptide antibodies and in antibodies eluted from normal donors. Epstein-Barr virus-transformed cell clones obtained from two subjects produced antibodies which simultaneously recognize the viral peptide and several autoantigens. To further confirm the role of the virus in inducing an autoantibody response, eight BALB/c mice were immunized with the viral peptide coupled to a carrier protein. Autoantibody activity against keratin, collagen II, cardiolipin and ssDNA was detected in six of the eight mice which developed a strong anti-virus response. Together, these data indicate that B19 parvovirus may be linked to the induction of an autoimmune response.

Adolescent↗
PubMed1997

Serum laminin and type III procollagen in chronic hepatitis C. Diagnostic value in the assessment of disease activity and fibrosis.

Laminin P1 (pepsin-resistant fragment of laminin) and aminoterminal peptide of type III procollagen are measurable in serum and are now considered useful serum markers of fibrogenesis and inflammation in chronic liver diseases. However, very few studies thus far have focused on assessing the diagnostic value of these markers in detecting fibrosis and necro-inflammatory activity in chronically diseased liver. The aim of the present study was therefore to investigate the correlations of laminin and type III procollagen with liver histology and to compare their diagnostic value in detecting the degree of liver fibrosis and necro-inflammatory activity in a homogeneous group of 99 patients suffering from chronic hepatitis C, and lacking other factors which can directly affect the serum levels of the two markers. Both these serum markers were measured by radioimmunoassay, employing commercially available kits. The three main aspects of liver pathology, i.e. portal-periportal activity, lobular activity and fibrosis, were histologically evaluated and semiquantitatively expressed by numerical scores. The results of this study show that laminin and type III procollagen were both positively correlated with the histological scores for portal-periportal activity and with those for fibrosis, whereas no significant correlation was observed between each of the two serum markers and the histological scores for lobular activity. The sensitivity and specificity of laminin and type III procollagen in detecting histological aspects of fibrosis and disease activity in liver, computed at various cut-off levels, showed overlapping trends for the two markers; however, the diagnostic value was in general rather low, whatever the cut-off considered. We therefore conclude that the 'static' measurement of both serum laminin and type III procollagen is of limited value for individual diagnosis of liver damage.

Adolescent↗
PubMed1996

Serum laminin P1 in chronic viral hepatitis: correlations with liver histological activity and diagnostic value.

Laminin is a major basement membrane-associated, non-collagenous glycoprotein of the extracellular matrix and is deposited in the space of Disse during sinusoidal capillarisation. Laminin P1, a pepsin-resistant fragment originating from the central portion of the cross-shaped laminin molecule, is detectable in serum and has been related to liver fibrosis and portal hypertension. In this study we investigated the behaviour of serum laminin P1, measured by radioimmunoassay, in a homogeneous group of 95 patients suffering from chronic viral hepatitis, types C or B, in order to determine the relationships between serum laminin P1 and each of the main histological aspects of the disease process (i.e. portal-periportal activity, lobular activity and fibrosis), which were assigned numerical scores. Moreover, we computed, at several cut-off levels, the sensitivity, specificity and positive and negative predictive values of laminin P1 in detecting both necroinflammatory activity and fibrosis in the liver. The results show that serum laminin P1 levels parallel the severity of liver disease, the highest laminin concentrations being observed in cirrhotic patients. They suggest also that serum laminin P1 should be considered a marker of the liver disease process as a whole, rather than a marker exclusively linked to fibrosis. Nevertheless, the usefulness of serum laminin P1 measurement, as investigated in this study, seems too limited to be recommended for routine clinical practice.

Adolescent↗
PubMed1996

Hereditary hemochromatosis: generation of a transcription map within a refined and extended map of the HLA class I region.

Hereditary hemochromatosis, a common severe inherited disease, maps to the short arm of chromosome 6 close to the HLA-A locus. Recently, linkage data on Italian and French populations confirmed this location, while a similar analysis on Australian and British populations located the gene closer to D6S105, a marker residing telomeric of HLA-A. To increase our knowledge on the region of highest linkage disequilibrium in our population and possibly to identify the disease gene, a 1.2-Mb detailed physical and transcription map was generated, spanning the HLA class I region. Thirty-eight unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of fetal brain, adult brain, liver, placenta, and the CaCo2 cell line, were characterized. All cDNA fragments were positioned in a refined and extended map of the human major histocompatibility complex spanning from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes have been detected and integrated in the map. Thirteen cDNA fragments show no similarity with known sequences and could be candidates for the disease. Their characterization and assessment for involvement in hemochromatosis are still under investigation. Seven new polymorphisms, some tightly linked to the disease, were also identified and localized.

Animals↗
PubMed1996

Identification of three novel mutations in the PIG-A gene in paroxysmal nocturnal haemoglobinuria (PNH) patients.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by the absence of glycosyl phosphatidylinositol (GPI)-anchored surface proteins resulting from a defect in one step of GPI-anchor biosynthesis. Recent analysis has shown that mutations at the PIG-A (phosphatidylinositoglycan-class A) gene are responsible for GPI-anchor deficiency in all PNH patients. In the current study, we describe three new mutations of the PIG-A gene in Italian patients with PNH. The analysis has been performed by RNA/single-strand conformation polymorphism using genomic DNA purified from nucleated peripheral blood cells. An abnormal pattern of migration of polymerase chain reaction amplified fragments containing exons 2 and 5 was observed. Sequencing analysis led to the identification of three mutations: a transversion C-to-A creating a stop codon (Y98X), an A insertion at position 460 (460insA), and a C deletion (1114delC). All the mutations cause a premature termination of the translation of the PIG-A protein.

Base Sequence↗
PubMed1996

Plasma factor VII and its relation to adipose tissue fatty acids and other atherogenic risk factors in healthy men.

In this study the authors examined the relationships of plasma factor VII (F-VII) to adipose tissue fatty acid composition, as an objective index of the habitual dietary fat intake, as well as to a number of other atherogenic risk factors in 60 healthy male volunteers (aged 38 years). Significant positive correlations were found between plasma F-VII [measured as antigen (F-VIIAg) and coagulant activity, using bovine thromboplastin (F-VIIbt)] and body mass index (BMI), waist-thigh girth ratio (WTR), cigarette smoking and plasma triglyceride concentration. After adjustment for BMI, only plasma triglycerides remained positively correlated with F-VII (r = 0 center dot 27, P = 0 center dot 03, and r = 0 center dot 29, P < 0 center dot 01, for F-VIIbt and F-VIIAg respectively). A significant positive relation was found between F-VII and the total proportion of fatty acid as monounsaturated fatty acid (r = 0 center dot 26, P < 0 center dot 05, for F-VIIAg), whereas inverse relations were found between F-VII, the total proportion of fatty acid as polyunsaturated fatty acid (r = -0 center dot 26 and r = -0 center dot 25, P < 0 center dot 05, for F-VIIbt and F-VIIAg respectively), polyunsaturated-saturated fat ratio (r = -0 center dot 25, P < 0 center dot 05, for F-VIIbt) and, more significantly, between F-VII and adipose-tissue alpha-linolenic acid (r = -0 center dot 29, P < 0 center dot 01, for F-VIIbt and r = -0 center dot 49, P < 0 center dot 001, for F-VIIAg). All these correlations remained significant after matching for BMI. In a multiple linear regression analysis, only adipose tissue alpha-linolenic acid was a negative and independent predictor of F-VIIAg (P = 0 center dot 004) and, at borderline significance, of F-VIIbt (P = 0 center dot 061) when allowance was made for BMI, WTR, smoking and plasma triglycerides. In conclusion, this study shows significant relations between F-VII and adipose tissue fatty acid composition in healthy male individuals; it supports the possibility that adipose tissue poly-unsaturated fatty acids, derived from dietary intake, play a role in the relation between F-VII and coronary heart disease (CHD), thus suggesting that high dietary polyunsaturated fatty acid intake (especially alpha-linolenic acid) may reduce the risk for CHD by an improvement of a number of risk factors, including a lowering of plasma F-VII (both activity and antigen).

Adipose Tissue↗
PubMed1996

The white blood cell count: its relationship to plasma insulin and other cardiovascular risk factors in healthy male individuals.

OBJECTIVES: To evaluate the relationships of total and differential white blood cell (WBC) count to the components of the so-called insulin resistance syndrome. SUBJECTS AND DESIGN: The study population consisted of a random sample of 90 38-year-old healthy men with normal glucose tolerance. INTERVENTIONS: A 75 g oral glucose tolerance test was performed in all participants. MAIN OUTCOME MEASURES: Total and differential WBC count, lipids, blood pressure, plasma glucose, C-peptide and insulin (at fasting and 2 h after glucose load). RESULTS: Total WBC count correlated consistently with plasma 2-h glucose (r = 0.38; P < 0.001), fasting and 2-h postload insulin (r = 0.26 and r = 0.33; P < 0.01-0.001, respectively) and C-peptide (r = 0.28 and r = 0.32; P < 0.01-0.001) concentrations. Smokers had significantly higher total leukocytes (P < 0.01), neutrophils and lymphocytes than nonsmokers. Furthermore, total WBC count correlated positively with body mass index, blood pressure, plasma triglycerides, fibrinogen, and negatively with HDL cholesterol concentration. As differential WBC count, most variables correlated essentially to neutrophils and/or lymphocytes, whereas plasma insulin and C-peptide concentrations correlated essentially to lymphocytes and monocytes, but not to neutrophils. In a multiple linear regression analysis, only 2-h plasma glucose (P < 0.01) and fibrinogen (P < 0.05) were positive predictors of total WBC count after adjusting for all potentially confounding variables. CONCLUSIONS: The results indicate that increased, albeit normal, WBC count associates with the cluster of metabolic and haemodynamic disorders typical of the insulin resistance syndrome, and suggest that increased WBC count may be yet another component of this syndrome.

Adult↗
PubMed1996

Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men.

The associations between abdominal visceral fat and the plasma hemostatic system were examined in 38-year-old healthy men (n=52) with a wide range of fatness and fat distribution. Plasma hemostatic factors and metabolic parameters, including glucose tolerance, were measured, and body fatness and adipose tissue distribution were assessed by using computed tomography. The men with more visceral fat (ie, higher than the median value [n=26]) had a less favorable metabolic profile than the men with less visceral fat (n=26). They also had significantly (P<.05) higher plasma fibrinogen, factor VIII clotting activity, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor-1 (PAI-1) activity (19.2+/-2.4 versus 8.5+/-1.6 AU/mL, P<.001) and lower basal tissue-type plasminogen activator activity. After adjustment for plasma insulin, the men with larger abdominal visceral fat area still had significantly higher plasma PAI-1 activity, but no difference was found in any of the other hemostatic factors. In multiple linear regression analysis, abdominal visceral fat area was a positive predictor of plasma PAI-1 activity, but it failed to show any significant association with other hemostatic factors after controlling for plasma insulin. These results suggest the presence of relationships between abdominal visceral fat and several plasma hemostatic factors that are largely mediated by concomitant alterations in plasma insulin concentration. In addition, our results suggest that abdominal accumulation of visceral fat is an independent predictor of plasma PAI-1 activity.

Adipose Tissue↗
PubMed1996

Moderate alcohol consumption and its relation to visceral fat and plasma androgens in healthy women.

OBJECTIVE: To study the inter-relationships between daily alcohol intake, fat distribution and plasma androgens in order to verify whether daily alcohol intake correlates with abdominal body fat and, if so, to what extent such a relation is mediated by plasma androgens. SUBJECTS: A random sample of 87 clinically healthy women (aged 38 y) with a light-moderate alcohol consumption and without clinical evidence suggestive of any endocrine disorder. MEASUREMENTS: Anthropometric and computed tomography (CT scans made at the level of L4-L5 in a subgroup of 18 women) measurements of body fatness and adipose tissue distribution, main behavioural factors, including daily alcohol intake and plasma androgens (i.e. total and free testosterone levels). RESULTS: After adjustment for BMI, cigarette smoking and physical activity, significant differences were found in waist circumference and waist-hip ratio as well as in plasma androgens with increasing daily alcohol intake. Waist-thigh ratio tended to parallel waist-hip ratio, but did not achieve statistical significance. In simple linear regression analysis, abdominal visceral fat area, derived from CT, correlated positively with both plasma free testosterone and alcohol intake. While the above reported difference in body fat distribution totally disappeared after controlling also for free testosterone level, the differences in plasma androgens with increasing alcohol intake remained essentially unchanged when allowance was made also for waist-hip ratio. In multiple linear regression analysis, daily alcohol intake appeared to be positively and independently correlated to both plasma total and free testosterone levels. Neither BMI nor waist-hip ratio nor fasting insulin made any significant contribution to the prediction of plasma androgens after daily alcohol intake had been taken into account. CONCLUSIONS: The results of this study show that moderate alcohol consumption correlates with abdominal distribution of body fat, likely due to enlarged visceral fat area, and increased plasma androgenicity (i.e. higher total and free testosterone levels) in adult healthy women. These data also suggest that the relation between alcohol intake and fat distribution may be, at least in part, mediated by plasma androgens.

Adipose Tissue↗
PubMed1996

Long-term variations of serum laminin and procollagen III peptide in chronic HCV hepatitis after alpha-interferon therapy.

Twenty-three out of 40 patients affected by chronic HCV hepatitis responded (i.e. aminotransferases returned to normal) after 6-month treatment with 6 MU tiw of recombinant alpha-interferon 2a (IFN); in 11 (Group 1), the remission was maintained for a mean observation time of 33.15 months (range 20-50) after withdrawal of therapy; 12 (Group 2) relapsing after IFN withdrawal, were treated again obtaining in 10 a second response. Seventeen did not respond (Group 3). Serum markers of connective tissue metabolism (laminin and aminoterminal peptide of type III procollagen -NPIIIP-) were assayed in all patients before treatment and every 6th month, to evaluate long-term effects of IFN therapy. In non-responders, NPIIIP after treatment was not different from baseline, while laminin significantly increased at 6 and 12 months; in responders, NPIIIP decreased significantly after therapy, maintaining values lower than baseline on long-term observation. Laminin decreased significantly six months after the end of therapy and remained lower than baseline in all sustained responders. In this group, the drop in laminin was progressive, whereas in Group 2, laminin showed only a slight decrease on long-term control. Our data show that these serum markers persistently decrease in sustained responders to IFN, while in relapsed cases, prolonged therapy is needed to obtain minor effects on laminin; on the contrary, in non-responders, NPIIIP remains unchanged and laminin significantly increases, suggesting a persistence of active fibrogenesis.

Antiviral Agents↗
PubMed1996

Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men--role of the metabolic syndrome.

The relationship between liver steatosis, evaluated by ultrasonography, and various plasma haemostatic factors was examined in 64 apparently healthy males, aged 38 years. Plasma levels of factor VII clotting activity (F-VIIc), plasminogen activator inhibitor-1 (PAI-1) activity and antigen, tissue-type plasminogen activator (t-PA) activity significantly differed in men with liver steatosis (n = 31) as compared with those without steatosis (n = 33). No significant differences were found in t-PA antigen and F-VII antigen. The men with liver steatosis also had significantly higher body mass index (BMI), plasma triglyceride and 2 h post-load insulin concentrations. While the differences in plasma haemostatic factors were substantially unchanged after adjustment for BMI, they totally disappeared when further allowance was made for plasma triglyceride and 2 h insulin concentrations. In conclusion, these results indicate that liver steatosis correlates specifically with increased PAI-1, F-VIIc and decreased t-PA levels, and suggest that such a relation is largely mediated by concomitant alterations in plasma triglyceride and insulin concentrations.

Adult↗
PubMed1996

Ultrasonographic intra-abdominal depth and its relation to haemostatic factors in healthy males.

OBJECTIVE: To examine the relationship of intra-abdominal fat to plasma haemostatic factors. SUBJECTS: 60 healthy, predominantly nonobese, male volunteers aged 38 years. MEASUREMENTS: Anthropometry, sonographic intra-abdominal depth (IAD), as an indicator of intra-abdominal fat, plasma lipids, plasma insulin (at fasting and after glucose load), various plasma haemostatic factors. RESULTS: Sonographic IAD correlated positively with plasma fibrinogen (r = 0.33; P < 0.01), PAI-1 activity (r = 0.52; P < 0.0001) and antigen (r = 0.32; P < 0.05), and negatively with t-PA activity, at baseline and after stasis (r = -0.28 and r = 0.31; P < 0.05). Factor VII levels did not correlate significantly with sonographic IAD. Haemostatic variables were also closely associated with BMI, plasma triglyceride and insulin concentrations. Most correlations of haemostatic factors with IAD disappeared after adjustment for either BMI or insulin or triglycerides, except PAI-1 levels which maintained a significant association even after simultaneous adjustment for all potential confounders. CONCLUSIONS: These results, obtained by sonography, confirm our previous findings of significant associations of haemostatic variables with visceral fat accumulation by using computed tomography, and highlight the role of the intra-abdominal fat as an independent predictor of PAI-1 activity.

Abdomen↗