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Marcello Di Nisio

Publications and source records attributed to Marcello Di Nisio.

18 recordsLinked to original sources
PubMed2006

Impact of adjustment for quality on results of metaanalyses of diagnostic accuracy.

BACKGROUND: We examined whether and to what extent different strategies of defining and incorporating quality of included studies affect the results of metaanalyses of diagnostic accuracy. METHODS: We evaluated the methodological quality of 487 diagnostic-accuracy studies in 30 systematic reviews with the QUADAS (Quality Assessment of Diagnostic-Accuracy Studies) checklist. We applied 3 strategies that varied both in the definition of quality and in the statistical approach to incorporate the quality-assessment results into metaanalyses. We compared magnitudes of diagnostic odds ratios, widths of their confidence intervals, and changes in a hypothetical clinical decision between strategies. RESULTS: Following 2 definitions of quality, we concluded that only 70 or 72 of 487 studies were of "high quality". This small number was partly due to poor reporting of quality items. None of the strategies for accounting for differences in quality led systematically to accuracy estimates that were less optimistic than ignoring quality in metaanalyses. Limiting the review to high-quality studies considerably reduced the number of studies in all reviews, with wider confidence intervals as a result. In 18 reviews, the quality adjustment would have resulted in a different decision about the usefulness of the test. CONCLUSIONS: Although reporting the results of quality assessment of individual studies is necessary in systematic reviews, reader wariness is warranted regarding claims that differences in methodological quality have been accounted for. Obstacles for adjusting for quality in metaanalyses are poor reporting of design features and patient characteristics and the relatively low number of studies in most diagnostic reviews.

Diagnostic Techniques and Procedures↗
PubMed2006

The haematocrit and platelet target in polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low-dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8.85%) major thrombosis and 226 (13.8%) total thrombosis were encountered during 4393 person-years follow-up (median 2.8 years). In time-dependent multivariable analysis, a haematocrit in the evaluable range of 40-55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow-up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

Aged↗
PubMed2006

Evidence of bias and variation in diagnostic accuracy studies.

BACKGROUND: Studies with methodologic shortcomings can overestimate the accuracy of a medical test. We sought to determine and compare the direction and magnitude of the effects of a number of potential sources of bias and variation in studies on estimates of diagnostic accuracy. METHODS: We identified meta-analyses of the diagnostic accuracy of tests through an electronic search of the databases MEDLINE, EMBASE, DARE and MEDION (1999-2002). We included meta-analyses with at least 10 primary studies without preselection based on design features. Pairs of reviewers independently extracted study characteristics and original data from the primary studies. We used a multivariable meta-epidemiologic regression model to investigate the direction and strength of the association between 15 study features on estimates of diagnostic accuracy. RESULTS: We selected 31 meta-analyses with 487 primary studies of test evaluations. Only 1 study had no design deficiencies. The quality of reporting was poor in most of the studies. We found significantly higher estimates of diagnostic accuracy in studies with nonconsecutive inclusion of patients (relative diagnostic odds ratio [RDOR] 1.5, 95% confidence interval [CI] 1.0-2.1) and retrospective data collection (RDOR 1.6, 95% CI 1.1-2.2). The estimates were highest in studies that had severe cases and healthy controls (RDOR 4.9, 95% CI 0.6-37.3). Studies that selected patients based on whether they had been referred for the index test, rather than on clinical symptoms, produced significantly lower estimates of diagnostic accuracy (RDOR 0.5, 95% CI 0.3-0.9). The variance between meta-analyses of the effect of design features was large to moderate for type of design (cohort v. case-control), the use of composite reference standards and the use of differential verification; the variance was close to zero for the other design features. INTERPRETATION: Shortcomings in study design can affect estimates of diagnostic accuracy, but the magnitude of the effect may vary from one situation to another. Design features and clinical characteristics of patient groups should be carefully considered by researchers when designing new studies and by readers when appraising the results of such studies. Unfortunately, incomplete reporting hampers the evaluation of potential sources of bias in diagnostic accuracy studies.

Clinical Trials as Topic↗
PubMed2005

Plasma cytokine and P-selectin levels in advanced malignancy: prognostic value and impact of low-molecular weight heparin administration.

BACKGROUND: The survival benefit described in patients with cancer treated with low molecular weight heparin (LMWH) may result from a LMWH-mediated effect on the immune system or on the cross-talk between platelets and tumor cells. METHODS: Plasma levels of interleukin (IL)-10, IL-6, interferon (IFN)-gamma, and P-selectin were measured in patients with advanced stage malignancy who were randomized to receive standard cancer care with or without the addition of LMWH. RESULTS: Patients with IL-6 levels above the median had a median survival of 6.5 months versus 8.8 months for those with values below this cutoff (P = 0.02). IL-10 levels were found to be similarly correlated with survival such that IL-10 concentrations above the detection limit of the assay were associated with a doubled risk of dying in comparison to undetectable IL-10 (P = 0.02). No significant association was found between survival and circulating levels of IFN-gamma. For P-selectin, patients with values below the fourth quartile had a median survival of 8.8 months versus 6.5 months for patients with levels above the fourth quartile (P = 0.02). In multivariate analysis, IL-10 remained an independent unfavorable prognostic factor (hazard ratio, 2.13; 95% confidence interval, 1.08-4.20). In patients treated with LMWH, the plasma levels of IL-6, IL-10, IFN-gamma, and P-selectin demonstrated similar correlations with survival. However, none of the markers was associated with the beneficial survival effects observed with the administration of LMWH. CONCLUSIONS: IL-10, IL-6, and P-selectin levels predicted a poor outcome in patients with advanced stage malignancy. The prolongation in survival observed with LMWH in patients with cancer apparently cannot be explained by a LMWH effect on these circulating markers.

Adult↗
PubMed2005

Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated heparin: a new potential chemosensitizer for cancer therapy.

Anticoagulant treatment with heparins is frequently used to prevent venous thromboembolism in cancer patients. In the present study, we investigated the ability of unfractionated heparin (UFH) to inhibit P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) on human breast cancer cell line (MDA-MB231) and its doxo-resistant subline. Results were a compared to the classic reversing agent, Verapamil (Ver), used, as reference at 50 microM concentration. We analysed the Pgp function by calcein acetoxymethylester (calcein-AM) uptake, a fluorescent marker substrate, before and after in vitro exposure to UFH at clinically achievable dose of 20 U/ml. The mean percentage of calcein-AM retained into cancer cells after 3 and 12 h were 32 +/- 10.9 and 45 +/- 12.3, respectively, for UFH pretreated cells and 25.3 +/- 8.7 and 29.4 +/- 10.4, respectively, for Ver pretreated cells when compared to control cells, receiving only medium. Pgp activity was studied by measuring intracellular drug accumulation in doxo-resistant subline, treated (2 h) with either UFH or Ver, prior exposure (2 h) at different doxo concentrations (2, 4 and 8 microM). The mean percentage of remaining intracellular doxo were 55.4 +/- 4.5 , 51.4 +/- 3.9 and 50 +/- 1.8 percent, respectively for UFH treated cells, and 44.1 +/- 5.8, 39.3 +/- 4.4 and 19.4 +/- 8.6%, respectively, for Ver treated cells as compared with control cells, receiving only doxo. These results were consistent with the increase of sensitivity to doxo of the same doxo-resistant subline resulting in a 2.2, 2.6 and 2.2-fold increase, respectively, for UFH-doxo combination and 2.2, 2.5 and 2.0-fold respectively, for Ver-doxo combination respect to cells receiving doxo alone, as assessed by MTT test. In conclusion, these findings demonstrate the potentiating effect in vitro of UFH on doxo accumulation and cytotoxicity in the MDA-231 cell line and its doxo-resistant subline and suggest that UFH could to be used, as an potential chemosensitizer, in clinical chemotherapy for increasing in vivo, the efficacy of the anticancer treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review.

BACKGROUND AND OBJECTIVES: The aim of this systematic review was to summarize the evidence from randomized controlled trials (RCT) concerning the efficacy and safety of medical or surgical treatments of superficial vein thrombosis (SVT) for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE). DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE and the Cochrane (CENTRAL) database to identify all randomized trials that evaluated the effect of surgical or medical treatment in the prevention of venous thromboembolism (VTE) in patients with SVT of the legs. RESULTS: Five studies were included. Pooling of the data was not possible due to the heterogeneity among the studies. Moreover, three studies had major methodological drawbacks limiting the clinical applicability of the results. One of the remaining (pilot) studies showed a non-significant trend in favor of high- compared to low-dose unfractionated heparin for the prevention of VTE. The last remaining study showed a non-significant trend in favor of short-term treatment with low-molecular-weight heparin (LMWH) or a non-steroidal anti-inflammatory drug (NSAID) as compared to placebo shortly after treatment with respect to VTE, but the apparent benefit disappeared after three months of follow-up. Active treatment of SVT reduced the incidences of SVT extension or recurrence. INTERPRETATION AND CONCLUSIONS: Treatment with a therapeutic or prophylactic dose of LMWH or a NSAID reduces the incidence of SVT extension or recurrence, but not VTE. More RCT are needed before any evidence-based recommendations on the treatment of SVT for the prevention of VTE can be given. With the present lack of solid evidence we would suggest treating patients with at least intermediate doses of LMWH.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques.

BACKGROUND AND PURPOSE: Transforming growth factor-beta (TGF-beta) is a growth factor/cytokine involved in vascular remodeling and atherogenesis. Recent studies in apolipoprotein E-deficient mice have demonstrated a pivotal role of TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques. Furthermore, inhibition of TGF-beta signaling has been shown to accelerate plaque formation and its progression toward an unstable phenotype in mice. However, if this mechanism is operative also in humans is still unknown. The aim of this study was to characterize the expression of TGF-beta1 in human carotid plaque and to correlate it with the extent of inflammatory infiltration and collagen content with the clinical signs of plaque instability. METHODS: Plaques were obtained from patients undergoing carotid endoarterectomy and divided into symptomatic and asymptomatic according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for TGF-beta1 expression by Immunocytochemistry, Western, and Northern blotting analysis. Immunocytochemistry was used to identify CD68+ macrophages, CD3 T lymphocytes, HLA-DR+ cells, and alpha-smooth muscle cells. Procollagen and interstitial collagen content were analyzed by immunohistochemistry and Sirius Red staining, respectively. RESULTS: Plaque TGF-beta1 mRNA was increased up to 3-fold in asymptomatic as compared with symptomatic plaques. Plaques from asymptomatic group had fewer (P<0.0001) macrophages and T lymphocytes compared with symptomatic plaques. TGF-beta1 gene was transcriptionally active as demonstrated by increased (P<0.0001) TGF-beta1 protein expression in asymptomatic plaques. Immunohistochemistry showed that TGF-beta was mainly expressed in plaque shoulder and was associated with a comparable increase (P<0.0001) in plaque procollagen and collagen content. CONCLUSIONS: In conclusion, this study demonstrates the higher expression of TGF-beta1 in human asymptomatic lesions and provides evidence that TGF-beta1 may play an important role in the process of plaque stabilization.

Aged↗
PubMed2004

Soluble thrombomodulin and vascular adhesion molecule-1 are associated to leptin plasma levels in obese women.

Recent studies have suggested that leptin, a plasma protein secreted by adipocytes, may play a role in artherothrombosis. In this study, we tested the hypothesis that leptin contributes to in vivo endothelial dysfunction in obese subjects. A cross-sectional comparison of plasma leptin, soluble thrombomodulin (sTM) and soluble vascular adhesion molecule-1 (VCAM-1) was carried out in 35 obese women (age 48+/-13) selected with a body mass index (BMI) > or =30kg/m(2) and 25 normal weight women (age 50+/-11, BMI < 25). An additional study was conducted to determine the short-term effects of weight loss induced by caloric restriction. Plasma levels of leptin, sTM and sVCAM-1 were measured before and after weight loss. Obese women had higher levels of leptin (35+/-22 versus 22+/-19, P<0.01), sTM (4.8+/-1.8 versus 1.9+/-1.5, P<0.001) and sVCAM-1 (726+/-109 versus 583+/-50, P<0.001) than non-obese women. sTM and sVCAM-1 concentrations had a positive correlation with BMI (sTM, r=0.70, P<0.001; sVCAM-1, r=0.60, P<0.001), waist circumference (sTM, r=0.66, P<0.001; sVCAM-1, r=0.37, P<0.01) and leptin levels (sTM, r=0.53, P<0.001; sVCAM-1, r=0.42, P<0.005). At multiple regression analysis leptin predicted sTM and sVCAM-1 independently of obesity measures and other covariates. Twenty-nine obese patients who completed the program of weight reduction showed a significant decrease in leptin, sTM, and sVCAM-1 levels. The magnitude of decrease of sTM and sVCAM-1 was related to the magnitude of reduction in leptin levels. Therefore, our results show that obesity is associated with enhanced levels of atherosclerosis markers. These abnormalities are related to abdominal obesity possibly mediated by leptin levels, and are reversible with weight loss.

Arteriosclerosis↗
PubMed2004

Circulating leptin is associated with oxidized LDL in postmenopausal women.

Recently, leptin has been suggested as a possible cause of atherosclerotic disease. In the present study, we have investigated in postmenopausal women (n = 60; age: 52 +/- 13) the relationship between circulating levels of leptin, oxidized LDL (Ox-LDL) and other biochemical and anthropometric variables of atherosclerotic risk. In addition, we have evaluated soluble thrombomodulin (sTM) as a marker of endothelial damage. An additional study was conducted in a subgroup of obese subjects to determine the short-term effects of weight loss on selected variables. Ox-LDL showed a positive correlation with leptin circulating levels (r = 0.65, P < 0.0001). A significant association was also found between Ox-LDL and body mass index (r = 0.69, P < 0.0001), waist-to-hip ratio (r = 0.50, P < 0.0001), insulin levels (r = 0.65, P < 0.0001), HOMA index (r = 0.55, p < 0.0001) and sTM (r = 0.74, P < 0.0001) levels. After multivariate regression analysis leptin was still related to Ox-LDL levels (P = 0.007). In obese women who completed the program of weight reduction, leptin changes persisted as a significant predictor of plasma changes in Ox-LDL levels. These findings suggested a novel link between leptin and Ox-LDL, possibly involved in atherosclerotic disease.

Arteriosclerosis↗
PubMed2004

Antithrombotic therapy and cancer.

PURPOSE OF THE REVIEW: To assess the current evidence from recent clinical trials investigating antithrombotic agents for the prophylaxis and treatment of venous thromboembolism in cancer patients and for the effects of these agents on cancer progression. RECENT FINDINGS: A growing body of evidence supports the preventive use of antithrombotic strategies in subgroups of cancer patients. Moreover, in the long-term management of deep venous thrombosis in cancer patients, low-molecular-weight heparin seems to represent a valid alternative to vitamin K antagonists. Finally, several studies have claimed a direct anticancer activity and a positive impact on prognosis of some antithrombotic agents, eg, aspirin and low-molecular-weight heparin. SUMMARY: Although recent evidence suggests low-molecular-weight heparin as a possible option in the management and prevention of venous thromboembolism in cancer patients, more evidence from large randomized, prospective, controlled trials is needed to determine the exact the magnitude of the risk-benefit ratio associated with its use. The promising results on the effects of antithrombotic agents in the prognosis of cancer patients deserve further evaluation to estimate the potential and the feasibility of this approach.

Anticoagulants↗
PubMed2003

Identification of three genetic risk factors for venous thrombosis using a multiplex allele-specific PCR assay: comparison of conventional and new alternative methods for the preparation of DNA from clinical samples.

The demand for thrombophilia testing at the molecular level is increasing and with it the need for a simple and rapid and cost-saving procedure for the preparation of genomic DNA from whole blood samples. The aim of this paper is to compare the efficiency of two conventional commercial procedures (Genomic, Eurobio-Labtek, and Nucleospin, Macherey-Nagel) and two our alternative approaches (microwave irradiation and resin-binding method) for extraction DNA and their suitability and convenience for multiple sample preparation for simultaneous identification of the factor V Leiden, prothrombin 20210 and methylene tetrahydrofolate reductase (MTHFR) 677 variants by multiplex allele specific amplification (ASA-PCR). We have found that chemical-based kit (Genomic) produced higher DNA recovery (mean recovery 40 +/- 4.2 microg/ml; A260/A280 ratio 1,81 +/- 0.05) within 40 min., while the mini spin colum kit (Nucleospin Quickpure) obtained lower yield but the best DNA quality (mean recovery 25.7 +/- 2.3 microg/ml; A (260)/ A (280) ratio = 1,83 +/- 0.06) with fewer processing time (25 min). Costs of each extraction varied from 3.28 Euro for Genomic to 3.6 Euro for Nucleospin. Microwave radiation and resin-based method (GeneFizz) were single step/single tube procedures, that provided template DNA suitable for ASA-PCR assay, without any purification steps. The costs varied from 0.12 Euro for microwave to 1,23 Euro for resin based procedure. In conclusion, our alternative procedures were much faster (<15 min per extraction) and convenient (5.00-7.00 Euro per test) but equally sensitive compared to conventional DNA extraction methods. Moreover, these procedures are easily adaptable to the routine processing of high number of clinical samples and coupled with ASA-PCR assay result particularly suitable for a large scale screening for the diagnosis and prevention of the thrombotic risk.

DNA↗
PubMed2002

Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin.

OBJECTIVES: We sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta(1) (TGF-beta(1)) circulating levels and its production in the monocytes of hypercholesterolemic patients. BACKGROUND: Transforming growth factor-beta(1) is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients. METHODS: We evaluated, in a cross-over study design, plasma TGF-beta(1) levels and ex vivo TGF-beta(1) production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta(1) messenger ribonucleic acid (mRNA) expression and TGF-beta(1) in vitro production. RESULTS: Lipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta(1) plasma levels (from 1.7 +/- 0.5 ng/ml to 3.1 +/- 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 +/- 0.8 ng/ml to 3.9 +/- 1.0 ng/ml, p < 0.001). The increase in TGF-beta(1) levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta(1) production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 microM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin. CONCLUSIONS: 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta(1) plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta(1) expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested.

Anticholesteremic Agents↗
PubMed2002

Association of factor VII levels with inflammatory parameters in hypercholesterolemic patients.

Inflammatory markers have been demonstrated to be associated with increased risk of cardiovascular events. In this setting, C-reactive protein (CRP) was shown to add predictive value to cholesterol levels. We investigated hypercholesterolemic patients and related their inflammatory variables and their coagulation state focusing on factor VII, a coagulation protein which plays an established role in thrombogenesis. We examined the relationship between factor VII clotting activity (FVIIc), FVII antigen (FVIIAg) and activated FVII (FVIIa) levels against CRP, interleukin-6 soluble receptor (IL-6sR), P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta(1) (TGF-beta(1)), in fifty-eight hypercholesterolemic subjects. Patients were subjected to 6-8 weeks of lipid lowering treatment with diet or diet plus pravastatin (40 mg/day). Univariate analysis showed that FVII levels were positively associated with CRP (FVIIAg: r=0.56, P<0.0001; FVIIc: r=0.57, P<0.0001; FVIIa: r=0.39, P<0.001) and IL-6sR (FVIIAg: r=0.59, P<0.0001; FVIIc: r=0.52, P<0.0001; FVIIa: r=0.47; P<0.001). CRP was still correlated, at the baseline, with FVIIAg and FVIIc levels after multiple stepwise regression analysis (FVIIAg: P<0.0001; FVIIc: P<0.0001, respectively) and with FVIIAg at the end of lipid lowering treatment (P<0.0001). Our data indicate that the FVII level is independently associated with inflammatory variables and suggest their pathophysiological link in hypercholesterolemic patients.

Adult↗
PubMed2002

Transforming growth factor-beta1 levels in hypertensive patients: association with body mass index and leptin.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has been demonstrated to be overexpressed in hypertension. Leptin, an adipocyte product, has been shown to play a role in obesity-related hypertension and in vitro studies demonstrated a biologic interaction between leptin and TGF-beta1. Thus, we evaluate a possible in vivo association between TGF-beta1, body mass index (BMI), and leptin circulating levels in hypertensive subjects. METHODS: Blood samples for fasting leptin and TGF-beta1, were evaluated in 29 overweight, 46 obese, and 29 nonobese hypertensive patients before and after a 12-week calorie-restricted diet. Monocyte cultures were used for in vitro experiments. RESULTS: Transforming growth factor-beta1 was significantly elevated in hypertensive obese patients (n = 46) as compared with TGF-beta1 levels of hypertensive patients with normal BMI (n = 29) (8. 9 +/- 3 ng/mL v 4.4 +/- 2; P < .001). The circulating levels of TGF-beta1 were associated with BMI and leptin levels in an univariate analysis (r = 0.59, P < .0001; r = 0.62, P < .0001, respectively) and these associations were still present after stepwise multivariate analysis. Weight loss of 10% produced a parallel decrease in TGF-beta1 (from 8.9 +/- 3 ng/mL to 5.3 +/- 2.8 ng/mL; P < .01) and leptin levels (from 30 +/- 24 ng/mL to 17 +/- 14; P < .05). In vitro experiments showed that leptin is able to induce a dose-dependent increase in TGF-beta1 production and mRNA expression in human monocyte cultures. CONCLUSIONS: Our data indicate that TGF-beta1 levels are positively associated with BMI and leptin levels in hypertensive patients and suggest that adipose tissue may be an important determinant of TGF-beta1 levels possibly by a leptin-dependent pathway.

Adult↗