Biomedical subjects

E Filippi

Publications and source records attributed to E Filippi.

7 recordsLinked to original sources

PubMed2006

The G972R variant of the insulin receptor substrate-1 gene impairs insulin signaling and cell differentiation in 3T3L1 adipocytes; treatment with a PPARgamma agonist restores normal cell signaling and differentiation.

The insulin receptor substrate-1 (IRS-1) plays a central role in insulin sensitivity, and association studies have shown that the IRS-1 G972R variant is a risk factor for insulin resistance. However, how this mutation may lead to impaired insulin sensitivity is still to be determined. Our study aimed to evaluate, after transfection of the IRS-1 G972R variant in 3T3L1 adipocytes, the effect of this mutation on insulin signaling and on cell differentiation. The 3T3L1 cells were transfected with pcDNA3 expression vector containing either the human wild-type IRS-1 or the G972R variant. After induction of differentiation, the 3T3L1 transfected with wild-type IRS-1 differentiated in 6-8 days, while the cells transfected with G972R variant did not differentiate. To determine whether the defect in IRS-1 was responsible for this, we analyzed the expression of several genes involved in the insulin signaling pathway. Results showed that PPARgamma expression was significantly reduced in cells transfected with the mutated IRS-1, together with a significant decrease in binding of phosphatidylinositol-3 kinase (PI 3-kinase) to IRS-1 G972R and in PI 3-kinase activity. In addition, we observed that the interaction between the insulin receptor (IR) and the IRS-1 G972R protein was increased and that the autophosphorylation of the IR was significantly inhibited in 3T3L1-G972R cells compared with 3T3L1-WT. Treatment of the 3T3L1-G972R cells with pioglitazone (PIO), a PPARgamma agonist, restored differentiation with higher level of PPARgamma expression and restoration of PI 3-kinase binding to IRS-1 G972R and PI 3-kinase activity. IR autophosphorylation was also increased. Withdrawal of PIO in fully differentiated 3T3L1-G972R cells determined the reappearance of the insulin signaling defect. Finally, we observed higher levels of IRS-2 expression, suggesting that IRS-2 may play a more important role in adipocyte insulin signaling. In conclusion, IRS-1 G972R variant impairs insulin signaling, and treatment with PPARgamma agonist restores the normal phenotype of 3T3L1 cells.

3T3 Cells↗

PubMed2004

The G972R variant of the insulin receptor substrate-1 (IRS-1) gene is associated with insulin resistance in "uncomplicated" obese subjects evaluated by hyperinsulinemic-euglycemic clamp.

Several association studies have indicated the insulin receptor substrate-1 (IRS-1) gene G972R variant as a genetic risk factor for insulin resistance, particularly in presence of obesity. A few studies have also suggested a possible effect of the G972R variant on insulin secretion. The aim of this study was to evaluate the role of the IRS-1 gene G972R variant in 61 subjects with "uncomplicated" obesity [i.e. without diabetes, hypertension, dyslipidemia, coronary artery disease (CAD)], studied by hyperinsulinemic-euglycemic clamp. The presence of the G972R variant, detected in real-time with LightCycler hybridisation probes, was related to the indexes of insulin sensitivity. Furthermore, the possible role of this variant on insulin secretion was studied by means of insulin release indexes derived from oral tolerance test (OGTT). Twenty-four point five percent (24.5%) (no.=15) of the obese subjects proved to be carriers of the G972R variant. M index (p<0.05), non-oxidative glucose (p<0.01), insulin clearance (p<0.03) and insulin sensitivity index (ISI) (p<0.005) were all significantly reduced in G972R carriers compared to non-carriers, indicating a significant reduction in insulin sensitivity in carriers of the variant. A logistic regression analysis confirmed the independent association between the G972R variant and reduced insulin sensitivity (p<0.03). The interaction between obesity and the G972R variant was also independently associated with a reduced insulin sensitivity (p<0.005), suggesting that obesity and G972R variant were more than additive in predicting insulin resistance. The analysis of insulin release indexes did not show any significant differences. Our results demonstrate the association of the G972R variant of the IRS-1 gene with reduced insulin sensitivity in obese subjects, and indicate a possible interaction between the IRS-1 variant and obesity in worsening of insulin sensitivity.

Adult↗

PubMed1996

Lazaroid U-74389F attenuates phorbol ester-induced lung injury in rabbits.

We examined the effect of the antioxidant lazaroid U-74389F on acute lung injury induced in rabbits by phorbol myristate acetate (PMA). Thirty minutes after receiving either U-74389F (15 mg.kg-1 i.v.) or U-74389F vehicle, rabbits (n = 60) were given PMA (60 micrograms.kg-1 i.v.). PMA vehicle injected rabbits (n = 20) served as controls. Over a 5 h period after PMA or PMA vehicle injection, we measured arterial pH, arterial oxygen tension (Pa,O2), arterial carbon dioxide tension (Pa,CO2), and the plasma concentration of the neutrophil chemoattractant interleukin-8 (IL-8). At postmortem, lungs were inspected for macroscopic injury and examined histologically. Malondialdehyde levels were assayed in lung tissue as an index of lipid peroxidation. In bronchoalveolar lavage (BAL), total and differential cell counts, protein and IL-8 concentrations were measured. Compared to normal controls, rabbits challenged with PMA alone developed arterial acidosis, hypercapnia and hypoxaemia, accompanied by significant rise in plasma IL-8 concentration. U-74389F pretreated animals did not develop significant arterial blood gas abnormalities and had significantly lower IL-8 concentration in plasma. U-74389F did not prevent PMA-induced lipid peroxidation. However, macroscopic signs of lung injury and the degree of alveolar haemorrhage and protein extravasation were significantly less severe in pretreated rabbits than in those given PMA alone. In addition, U-74389F significantly reduced IL-8 concentration and neutrophil number in BAL. By histological assessment, 80% of lung neutrophils were localized in alveolar spaces of animals receiving PMA alone. Conversely, in U-74389F pretreated animals, 75% of neutrophils were distributed within extra-alveolar blood vessels and alveolar septa. We conclude that lazaroid U-74389F attenuates lung injury in rabbits given PMA by preventing neutrophil migration into pulmonary alveoli. This effect may, in part, be related to downregulation of IL-8 production.

Animals↗

PubMed1995

Radiologic evaluation of emphysema in patients with chronic obstructive pulmonary disease. Chest radiography versus high resolution computed tomography.

To objectively reappraise the role of the chest radiograph (CXR) in the clinical assessment of emphysema, we compared a standardized reading of CXR with both a visual scoring and a quantitative analysis of high resolution computed tomography (HRCT) of the chest in 46 consecutive patients with chronic obstructive pulmonary disease (COPD) and fixed expiratory airflow limitation. CXR were scored for signs of overinflation and pulmonary vascular deficiency by three independent observers. HRCT scans were independently scored for extent of emphysema and for both severity and extent of emphysema. In 28 of 46 patients, inspiratory and expiratory HRCT scans were analyzed quantitatively by measuring the mean CT number in Hounsfield Units (HU) and the percentage of lung area with CT numbers < -900 HU. Quantitative CT data were compared with reference values obtained in seven normal nonsmokers. The CXR score of emphysema showed a highly significant interobserver reproducibility and correlated linearly (p < 0.001) with HRCT visual scores and quantitative data from both inspiratory and expiratory CT scan. CXR score correlated with functional indices of airflow obstruction, overinflation, and impaired lung diffusing capacity in a way comparable to that obtained by using qualitative and quantitative CT data. Patients with no signs of emphysema on CXR had mean expiratory CT numbers within normal range and a fraction of lung area with CT numbers < -900 HU on expiratory scan not exceeding 15% of total cross-sectional area. The latter value was consistently greater than 15% in patients with CXR score > 0.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1986

Chronic myocarditis leading to a right ventricular cardiomyopathy. Case report.

A case of dilated cardiomyopathy arose after a spontaneous abortion at the second month of pregnancy is reported. Whereas clinical, hemodynamic and gross features pointed to a diagnosis of right ventricular cardiomyopathy, histologic findings of inflammatory infiltration, myocyte degeneration and interstitial fibrosis of the atrial and ventricular walls allowed to a correct diagnosis of chronic myocarditis.

Abortion, Spontaneous↗

PubMedDate not supplied

[Spheroidal deposits of amyloid in prolactin-secreting pituitary adenomas].

Nine peculiar cases of pituitary adenomas were pointed out by a retrospective investigation at the Ospedale di Legnano (from 1978 to 1984) and at the Ospedale di Circolo di Varese (from 1973 to 1986). These tumours are chromophobe adenomas with diffuse structure. Histologically they show typical, large, spheroid and concentric amyloid deposits, in addition to common, amorphous--often perivascular--ones. They were investigated by histochemical methods (Crystal-Violet, Congo-Red) and by immunohistochemical ones as well (anti-PRL and anti-GH), showing that these deposits are amyloid and are in close relation with PRL production. In particular, by immunohistochemical methods we found out that the cells of the tumours displaying spheroidal bodies do contain prolactin, not GH. The amyloid deposits are also immunohistochemically positive to anti-PRL serum, not to anti-GH serum. Finally, by considering the information present in literature, we have discussed the possible pathogenic mechanisms leading to amyloid deposits in pituitary adenomas.

Adenoma, Chromophobe↗

PubMedDate not supplied

[Quantification of pulmonary emphysema with computerized tomography. Comparison with various methods].

Computed Tomography (CT) has been proved to be the most accurate imaging modality to diagnose emphysema in vivo. Our study was aimed at comparing different CT methods for pulmonary emphysema quantification in patients with severe chronic obstructive pulmonary disease (COPD). Forty-six consecutive inpatients affected with COPD underwent high resolution CT (HRCT). Three scans were acquired at 3 preselected anatomic levels at both full inspiration and expiration. Three different observers were asked to subjectively evaluate, under blind conditions, the extent alone and both the severity and the extent of emphysema on the 6 scans. HRCT findings were also analyzed quantitatively by measuring the mean CT number in Hounsfield Units (HU) and the % of lung area with CT numbers < -900 HU (pixel index). Quantitative CT data were compared with reference values obtained in 7 normal nonsmokers. The CT visual score of emphysema exhibited medium-high interobserver reproducibility with correlation coefficients ranging from 0.80 to 0.96 and a good correlation with pulmonary function tests, particularly relative to the assessment of the extent of emphysema alone as expressed by one observer. CT quantification demonstrated an excellent correlation with functional indices of expiratory airflow, lung volumes and diffusion coefficients (p < 0.001). The expiratory measurements were better than the inspiratory ones while the analysis of both CT number and pixel index gave comparable results. Only the CT expiratory quantitative data allowed to differentiate the patients affected with COPD from the controls. In conclusion, the severity of emphysema as expressed by CT correctly reflects the functional impairment of patients with severe COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗