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Roberta Lamanna,
Alessandro Corti,
Mariacarla Iorio,
Francesca Nocchi,
Patrizia Urciuoli,
Simone Lapi,
Fabrizio Scatena,
Maria Franzini,
Renato Vanacore,
Evelina Lorenzini,
Vanna Fierabracci, Aldo Paolicchi
Blood transfusion = Trasfusione del sangue 02/2013; · 2.10 Impact Factor
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ABSTRACT: BACKGROUND: We assessed GGT fractions correlates and their reference values in the Offspring Cohort of the Framingham Heart Study. METHODS: Correlates of GGT fractions were assessed by multivariable regression analysis in 3203 individuals [47% men, mean age (SD): 59 (10) yrs.]. GGT fractions reference values were established by empirical quantile analysis in a reference group of 432 healthy subjects [45% men, 57 (10) years]. RESULTS: Fractional GGT levels were higher in men than in women (P<0.0001). In both sexes, fractions were associated with: triglycerides were associated with b-GGT, alcohol consumption with m-, s- and f-GGT. C-reactive protein with m- and s-GGT, while plasminogen activator inhibitor-1 with b- and f-GGT. Body mass index, blood pressure, glucose and triglycerides correlated with b- and f-GGT. In comparison with the reference group [b-GGT/s-GGT median (Q1-Q3): 0.51 (0.35-0.79) U/L], subjects affected by cardiovascular disease or diabetes showed no change of b/s ratio [0.52 (0.34-0.79) U/L, 0.57 (0.40-0.83) U/L, respectively]. The b/s ratio was higher in presence of metabolic syndrome [0.61 (0.42-0.87) U/L, P<0.0001], while lower in heavy alcohol consumers [0.41 (0.28-0.64) U/L, P<0.0001]. CONCLUSIONS: Metabolic and cardiovascular risk markers are important correlates of GGT fractions, in particular of b-GGT.
Clinica chimica acta; international journal of clinical chemistry 12/2012; · 2.54 Impact Factor
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Toxicology in Vitro 09/2012; · 2.78 Impact Factor
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ABSTRACT: BACKGROUND: Four fractions of gamma-glutamyltransferase (GGT) with different molecular weight (b-, m-, s-, and f-GGT) are present in human plasma. Differential GGT fraction pattern is found in non-alcoholic liver disease (NAFLD) and chronic viral hepatitis, characterized by normal or decreased b-GGT/s-GGT (b/s) ratio, respectively. METHODS: Chromatographic fractional GGT analysis was performed on plasma obtained from 51 subjects: 27 alcoholics (mean (SD), age 45 (9) years; 23 males; 14 positive for viral infection), 24 abstinents from at least 1 month (43 (12) years; 20 males; 6 positive for viral infection). Twenty-seven blood donors matched for age and gender (44 (9) years; 23 males) were selected as controls. RESULTS: All fractions were significantly increased in alcoholics (P<0.001), s-GGT showing the largest increase, while only m-GGT and s-GGT were elevated in abstainers (P<0.01), in comparison with controls. The b/s ratio was significantly lower in both alcoholics and abstainers than in controls (median (25th-75th perc.): 0.10 (0.07-0.15), 0.16 (0.10-0.24), 0.35 (0.29-0.53), respectively, P<0.001). Viral infection did not significantly changes absolute values of individual GGT fractions in alcoholics, but the b/s ratio was significantly lower in virus positive than in virus negative subjects (0.08 (0.05-0.12), 0.14 (0.09-0.20), respectively, P<0.01). CONCLUSIONS: The fraction pattern analysis might increase the specificity of GGT as biomarker of alcohol abuse, especially concerning the differential diagnosis between alcoholism and NAFLD, a common cause of elevated GGT level in the general population.
Drug and alcohol dependence 06/2012; · 3.60 Impact Factor
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Inflammatory Bowel Diseases 01/2012; · 4.86 Impact Factor
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ABSTRACT: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gamma-glutamyltransferase (GGT), an enzyme induced by oxidative stress and involved in the catabolism of GSH and its derivatives, is increased in the airways of CF patients with inflammation, but the possible implications of its increase have not yet been investigated in detail.
The present study was aimed to evaluate the origin and the biochemical characteristics of the GGT detectable in CF sputum. We found GGT activity both in neutrophils and in the fluid, the latter significantly correlating with myeloperoxidase expression. In neutrophils, GGT was associated with intracellular granules. In the fluid, gel-filtration chromatography showed the presence of two distinct GGT fractions, the first corresponding to the human plasma b-GGT fraction, the other to the free enzyme. The same fractions were also observed in the supernatant of ionomycin and fMLP-activated neutrophils. Western blot analysis confirmed the presence of a single band of GGT immunoreactive peptide in the CF sputum samples and in isolated neutrophils.
In conclusion, our data indicate that neutrophils are able to transport and release GGT, thus increasing GGT activity in CF sputum. The prompt release of GGT may have consequences on all GGT substrates, including major inflammatory mediators such as S-nitrosoglutathione and leukotrienes, and could participate in early modulation of inflammatory response.
PLoS ONE 01/2012; 7(4):e34772. · 4.09 Impact Factor
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Vanna Fierabracci,
Maria Franzini,
Angelo Baggiani,
Irene Fornaciari,
Silvia Burchielli,
Patrizia Urciuoli,
Roberta Lamanna,
Simone Lapi,
Francesca Nocchi,
Maria Carla Iorio,
Michele Emdin,
Alfonso Pompella, Aldo Paolicchi
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ABSTRACT: Plasma samples from human cord blood, and fetuses, newborns, and adults of different mammalians species were analyzed by gel-filtration chromatography, to ascertain whether gamma-glutamyltransferase (GGT) fractions reflect liver maturation. Human cord blood plasma showed higher b-, m-, and s-GGT fraction as compared to adult women. In rat and mouse fetuses and in newborns, b-GGT was the most abundant fraction. As in adult humans, in adult rats, mice, rabbits, sheep, and mini pigs, f-GGT was the most abundant fraction. GGT fractions are a common feature of all mammalian species tested. Their pattern changes seem to reflect liver postnatal maturation, function.
Biomarkers 12/2011; 17(1):43-7. · 2.21 Impact Factor
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Maria Franzini,
Irene Fornaciari,
Vanna Fierabracci,
Hassan Aziz Elawadi,
Valeria Bolognesi,
Simona Maltinti,
Angelo Ricchiuti,
Nicola De Bortoli,
Santino Marchi,
Alfonso Pompella,
Claudio Passino,
Michele Emdin, Aldo Paolicchi
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ABSTRACT: Serum gamma-glutamyltransferase (GGT) activity is a sensitive but non-specific marker of non-alcoholic fatty liver disease (NAFLD). Recently, four GGT fractions (big-, medium-, small-, free-GGT) were described in humans.
We aimed to investigate whether a specific GGT fraction pattern is associated with NAFLD.
Gamma-glutamyltransferase fractions were determined in patients with NAFLD (n = 90), and compared with those in control subjects (n = 70), and chronic hepatitis C (CHC, n = 45) age and gender matched.
Total GGT was elevated in NAFLD as compared to controls (median, 25°-75° percentile: 39.4, 20.0-82.0 U/L vs. 18.4, 13.2-24.9 U/L respectively, P < 0.001). All fractions were higher in NAFLD than in controls (P < 0.001). The b-GGT showed the highest diagnostic accuracy for NAFLD diagnosis [area under ROC curve (ROC-AUC): 0.85; cut-off 2.6 U/L, sensitivity 74%, specificity 81%]. Also subjects with CHC showed increased GGT (41.5, 21.9-84.5 U/L, P < 0.001 vs. controls, P = n.s. vs. NAFLD), as well as m-, s-, and f-GGT, while b-GGT did not show any significant increase (P = n.s. vs. HS, P < 0.001 vs. NAFLD). In subjects with CHC, s-GGT showed the best diagnostic value (ROC-AUC: 0.853; cut-off 14.1 U/L, sensitivity 73%, specificity 90%). Serum GGT did not show any value in the differential diagnosis between NAFLD and CHC (ROC-AUC 0.507, P = n.s.), while b-GGT/s-GGT ratio showed the highest diagnostic accuracy for distinguishing NAFLD and CHC (ROC-AUC: 0.93; cut-off value 0.16, sensitivity 82%, specificity 90%).
b-GGT increases in NAFLD, but not in CHC. GGT fraction analysis might help in improving the sensitivity and specificity of the diagnosis of NAFLD and other liver dysfunctions.
Liver international: official journal of the International Association for the Study of the Liver 11/2011; 32(4):629-34. · 3.82 Impact Factor
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Alessandro Antonelli,
Silvia Martina Ferrari,
Silvia Frascerra,
Fabio Galetta,
Ferdinando Franzoni,
Alda Corrado,
Mario Miccoli,
Salvatore Benvenga, Aldo Paolicchi,
Ele Ferrannini,
Poupak Fallahi
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ABSTRACT: Chemokine (CXC motif) ligand (CXCL)9 (CXCL9) has been shown to be involved in autoimmune thyroid disorders, however no data are present about CXCL9 circulating levels in chronic autoimmune thyroiditis (AT) vs controls. Serum CXCL9 (and for comparison CXCL10) has been measured in patients with AT vs normal control and nontoxic multinodular goiter, and this parameter has been related to the clinical phenotype. For this study we selected 189 consecutive patients with newly diagnosed AT, 63 euthyroid controls, 30 patients with nontoxic multinodular goiter. The three groups were similar in gender distribution and age; 26% of AT patients had subclinical hypothyroidism. Serum CXCL9 was significantly higher in AT (148±110 pg/mL) than in controls (71±34 pg/mL) or patients with multinodular goiter (87±35 pg/mL) (p<0.0001). Among AT patients, CXCL9 levels were significantly higher in patients older than 50 years, those with a hypoechoic ultrasonographic pattern or with hypothyroidism. Also CXCL10 was confirmed to be associated with AT, overall in presence of hypothyroidism. In a multiple linear regression model of CXCL9 (ln[pg/mL]) vs age, thyroid volume, TSH, AbTg, AbTPO, hypoechoic pattern, the presence of hypervascularity, and CXCL10 (ln[pg/mL]), only TSH and CXCL10 (ln[pg/mL]) were significantly related to serum CXCL9 levels. We show that circulating CXCL9 is increased in patients with aggressive thyroiditis and hypothyroidism. A strong relation between circulating CXCL9 and CXCL10 has been first shown, underlining the importance of a T helper 1 immune attack in the initiation of AT.
Cytokine 05/2011; 55(2):288-93. · 3.02 Impact Factor
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ABSTRACT: Degenerative aortic valve disease is characterized by some of the histological features of atherosclerotic lesions. Gamma-glutamyltransferase (GGT) has been recently implicated in pathogenesis of atherosclerosis, as well as in modulation of cells involved in calcium metabolism. We aimed to evaluate the possible implication of this enzyme activity in aortic valve disease.
GGT immunohistochemistry was performed on valve leaflets of 64 patients with aortic valve stenosis undergoing valve replacement. Fractional GGT activity in plasma and tissue was analysed in a subgroup of cases by molecular exclusion chromatography.
A close association was found between tissue extracellular GGT staining and lipid deposits (p<0.0001). GGT was expressed by CD68-positive cells around neovessels, as well as by MMP-9- and TRAP-positive multinucleated cells in the vicinity of bone metaplasia areas. Total plasma GGT levels were associated with low HDL-c (p=0.028) and high triglycerides (p=0.017). Total GGT activity in tissue was negatively correlated with the extent of valves calcification (p=0.03). Both serum and tissue GGT levels were negatively associated with severity of valve stenosis, as judged by peak transvalvular pressure gradients (p<0.0003 and p<0.002, respectively).
Accumulation of GGT activity inside the lipid component of valves leaflets suggests a common mechanism of lesion shaping underlying both atherosclerosis and degenerative aortic valve disease. Moreover, the finding of GGT expression in cells with an osteoclast-like phenotype, and its negative correlation with both valves calcification and degree of valvular stenosis lend additional support to the recently envisaged involvement of GGT in the homeostasis of calcified tissues.
Atherosclerosis 12/2010; 213(2):385-91. · 3.79 Impact Factor
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Barbara Baragatti,
Enrica Ciofini,
Francesca Scebba,
Debora Angeloni,
Daria Sodini,
Stefano Luin,
Gian Michele Ratto,
Virginia Ottaviano,
Eleonora Pagni, Aldo Paolicchi,
Simona Nencioni,
Flavio Coceani
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ABSTRACT: The fetal ductus arteriosus (DA) contracts to oxygen, and this feature, maturing through gestation, is considered important for its closure at birth. We have previously obtained evidence of the involvement of cytochrome P-450, possibly of the 3A subfamily (CYP3A), in oxygen sensing and have also identified endothelin (ET)-1 as the attendant effector for the contraction. Here, we examined comparatively wild-type (WT) and CYP3A-null (Cyp3a(-/-)) mice for direct validation of this concept. We found that the CYP3A subfamily is represented only by CYP3A13 in the WT DA. CYP3A13 was also detected in the DA by immunofluorescence microscopy, being primarily colocalized with the endoplasmic reticulum in both endothelial and muscle cells. However, a distinct signal was also evident in the plasma membrane. Isolated DAs from term WT animals developed a sustained contraction to oxygen with transient contractions superimposed. Conversely, no tonic response occurred in Cyp3a(-/-) DAs, whereas the phasic response persisted unabated. Oxygen did not contract the preterm WT DA but caused a full-fledged contraction after retinoic acid (RA) treatment. RA also promoted an oxygen contraction in the Cyp3a(-/-) DA. However, responses of RA-treated WT and Cyp3a(-/-) mice differed in that only the former abated with ET-1 suppression. This implies the existence of an alternative target for RA responsible for the oxygen-induced contraction in the absence of CYP3A13. In vivo, the DA was constricted in WT and Cyp3a(-/-) newborns, although with a tendency to be less narrowed in the mutant. We conclude that oxygen acts primarily through the complex CYP3A13 (sensor)/ET-1 (effector) and, in an accessory way, directly onto ET-1. However, even in the absence of CYP3A13, the DA may close postnatally thanks to the contribution of ET-1 and the likely involvement of compensating mechanism(s) identifiable with an alternative oxygen-sensing system and/or the withdrawal of relaxing influence(s) operating prenatally.
AJP Heart and Circulatory Physiology 12/2010; 300(3):H892-901. · 3.71 Impact Factor
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Maria Franzini,
Irene Fornaciari,
Gabriele Siciliano,
Leda Volpi,
Giulia Ricci,
Santino Marchi,
Giuseppina Gagliardi,
Angelo Baggiani,
Francesca Torracca,
Vanna Fierabracci,
Mario Miccoli,
Alfonso Pompella,
Michele Emdin, Aldo Paolicchi
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ABSTRACT: Elevation of serum gamma-glutamyltransferase (GGT), in absence of a clinically significant liver damage, is often found in Myotonic Dystrophy type-1 (DM1). In this study we investigated if a specific GGT fraction pattern is present in DM1.
We compared total and fractional GGT values (b-, m-, s-, f-GGT) among patients with DM1 or liver disease (LD) and healthy subjects (HS).
The increase of GGT in DM1 and LD, vs HS, was mainly due to s-GGT (median: 32.7; 66.7; and 7.9 U/L, respectively), and b-GGT (8.5; 18.9; and 2.1 U/L). The subset of DM1 patients matched with HS with corresponding serum GGT showed higher b-GGT (6.0 vs 4.2 U/L).
DM1 patients with normal total GGT values showed an alteration of the production and release in the blood of GGT fractions. Since increased s-GGT is also found in LD, a sub-clinical liver damage likely occurs in DM1 subjects apparently free of liver disease.
Clinical biochemistry 10/2010; 43(15):1246-8. · 2.02 Impact Factor
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ABSTRACT: In this work we compared the results of the GSNO determination in human plasma by two independent methods. The first method is based on the pre-column derivatization of GSNO thiolic part by p-hydroxymercury benzoate (PHMB) and followed by the determination of GS-PHMB product by reversed phase chromatography coupled to chemical vapour generation atomic fluorescence spectrometry (RPC-CVGAFS). The second method is based on RPC separation of GSNO from interfering compounds and the post-column, on-line enzymatic hydrolysis of GSNO by commercial gamma-glutamyl transferase (GGT) and fluorescence detection. Endogenous GSNO was determined only in plasma from blood sampled by syringe (not by Vacutainers) and ranged between 157 and 257nM on the basis of RPC-CVGAFS method, and between 90 and 225nM by RPC-FD method. There was a good correlation between the two methods (slope=1.06+/-0.09, R(2)=0.9543). RPC-CVGAFS method based on PHMB derivatization determined a GSNO concentration 60+/-20nM in excess with respect to RPC-FD method. Sampling issues connected with common blood sampling procedures like venipuncture and sampling in syringe or Vacutainers still introduce in GSNO analysis unknown factors, which require further investigations.
Talanta 06/2010; 81(4-5):1295-9. · 3.79 Impact Factor
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ABSTRACT: Gamma-glutamyltransferase (GGT) is a key enzyme involved in glutathione metabolism and whose expression is often significantly increased in human malignancies. In the past years, several studies focused on the possible role of GGT in tumor progression, invasion and drug resistance. The involvement of a pro-oxidant activity of GGT, besides its early recognized contributions to cellular antioxidant defenses, has been repeatedly documented. GGT-derived pro-oxidants can modulate important redox-sensitive processes and functions of the cell, with particular reference to its proliferative/apoptotic balance, which has obvious and important implications in tumor progression and drug resistance. In addition, the specificity of the enzymatic reaction carried out by GGT suggests that suitable pro-drugs could be selectively metabolized (activated) by GGT expressed in tumor tissue. This paper is a review of the recent investigation in the field, focusing on the potential role of GGT as a diagnostic/prognostic marker, as well as a target for anticancer treatments.
Anticancer research 04/2010; 30(4):1169-81. · 1.73 Impact Factor
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ABSTRACT: Until now, the following are not known: (1) the mechanisms underlying the induction of chemokine (C-X-C motif) ligand 10 (CXCL10) secretion by cytokines in thyrocytes; (2) if pioglitazone is able, like rosiglitazone, to inhibit the interferon (IFN)-γ-induced chemokine expression in Graves disease (GD) or ophthalmopathy (GO); and (3) the mechanisms underlying the inhibition by thiazolidinediones of the cytokines-induced CXCL10 release in thyrocytes. The aims of this study were (1) to study the mechanisms underlying the induction of CXCL10 secretion by cytokines in GD thyrocytes; (2) to test the effect of pioglitazone on IFNγ-inducible CXCL10 secretion in primary thyrocytes, orbital fibroblasts, and preadipocytes from GD and GO patients; and (3) to evaluate the mechanism of action of thiazolidinediones on nuclear factor (NF)-κB activation. The results of the study (1) demonstrate that IFNγ + TNFα enhanced the DNA binding activity of NF-κB in GD thyrocytes, in association with the release of CXCL10; (2) show that pioglitazone exerts a dose-dependent inhibition on IFNγ + TNFα-induced CXCL10 secretion in thyrocytes, orbital fibroblasts, and preadipocytes, similar to the effect observed with rosiglitazone; and (3) demonstrate that thiazolidinediones (pioglitazone and rosiglitazone) act by reducing the IFNγ + TNFα activation of NF-κB in Graves thyrocytes. To the best of our knowledge, this is the first study showing that cytokines are able to activate NF-κB in Graves thyrocytes and a parallel inhibitory effect of pioglitazone both on CXCL10 chemokine secretion and NF-κB activation. Future studies will be needed to verify if new targeted peroxisome proliferator-activated receptor-γ activators may be able to exert the anti-inflammatory effects without the risk of expanding retrobulbar fat mass.
Metabolism: clinical and experimental 03/2010; 60(2):277-83. · 2.59 Impact Factor
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Maria Franzini, Aldo Paolicchi,
Irene Fornaciari,
Virginia Ottaviano,
Vanna Fierabracci,
Maristella Maltinti,
Andrea Ripoli,
Luc Zyw,
Fabrizio Scatena,
Claudio Passino,
Alfonso Pompella,
Michele Emdin
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ABSTRACT: Serum gamma-glutamyltransferase activity (GGT), even when within its normal reference range, catalyzes low density lipoprotein oxidation in vitro and predicts cardiovascular events. Of the four GGT fractions (b-GGT, m-GGT, s-GGT, and f-GGT) recently identified in blood, only b-GGT is found within atherosclerotic plaques. Our goal was to identify the determinants of the GGT fractions (b-, m-, s-, and f-GGT) and their association with established cardiovascular risk factors in healthy subjects.
Multiple linear regression analysis was applied to estimate the association of fractional GGT with gender, age, body mass index, arterial pressure (AP), plasma glucose, alanine aminotransferase (ALT), high and low density lipoproteins (LDL-C) cholesterol (HDL-C), triglycerides (TG) and C-reactive protein (CRP) in 200 healthy subjects.
All GGT fractions were associated with ALT; b-GGT with AP, TG, and CRP; m-GGT with LDL-C, TG and CRP; s-GGT with TG and CRP, and f-GGT only with LDL-C, whereas gender was associated with s-GGT and f-GGT only.
In healthy individuals, cardiovascular risk factors are associated with high molecular weight GGT fractions, namely with b-GGT, the only form present within the plaque. This finding adds to the present knowledge concerning the relevance of GGT, within its reference range, for atherosclerosis-related events.
Clinical Chemistry and Laboratory Medicine 02/2010; 48(5):713-7. · 2.15 Impact Factor
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Patrizia Urciuoli,
Simona Passeri,
Francesca Ceccarelli,
Barbara Luchetti, Aldo Paolicchi,
Simone Lapi,
Francesca Nocchi,
Roberta Lamanna,
Mariacarla Iorio,
Renato Vanacore,
Alessandro Mazzoni,
Fabrizio Scatena
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ABSTRACT: . The fact that only a small percentage of cord blood units (CBU) stored are actually used for transplantation contributes to raising the already high costs of their processing and cryopreservation. The identification of predictors allowing the early identification of suitable CBU would allow a reduction of costs for the collection, storage and characterisation of CBU with insufficient volume or cell numbers. In our bank we have adopted a cut-off value for using CBU of 8 x 10(8) nucleated cells and a volume >or= 60 mL.
In 365 banked CBU, we evaluated the correlation between neonatal/gestational parameters and laboratory data used to assess their quality.
Biparietal diameter (BPD) and abdominal circumference were significantly and positively correlated with CBU volume (r(2)=0.12, p=0.0011 and r(2)=0.092, p=0.0063, respectively). Receiver operating characteristic (ROC) analysis showed that both parameters can be used to identify CBU with insufficient volume (BPD: area under the curve 0.69, 95% CI=0.57-0.82, p=0.004; abdominal circumference: area under the curve 0.67, 95% CI=0.54-0.79, p<0.01). BPD and head circumference, but not abdominal circumference or femoral length, were positively correlated with white blood cell (WBC) count (r(2)=0.215, p=0.031, and r(2)=0.299, p=0.015, respectively). Abdominal circumference, but not BPD, head circumference or femoral length, was statistically significantly correlated with the number of CD34(+) cells in the CBU. Weight at birth and placental weight were positively correlated with WBC count, blood volume, CD34(+) cell count, total colony-forming units and burst-forming units.
. Pre-birth assessment of BPD might allow the selection of donors who would yield CBU of sufficient volume and WBC count and avoid the costs of collecting, transferring, storing and analysing CBU with a high probability of resulting unsuitable for transplantation.
Blood transfusion = Trasfusione del sangue 01/2010; 8(1):36-43. · 2.10 Impact Factor
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ABSTRACT: Serum gamma-glutamyltransferase (GGT) is thought to derive from the liver, but its values predict morbidity and mortality for several diseases, such as cardiac infarction, stroke, diabetes, renal failure and cancer. We assessed total GGT and its fractions in the culture supernatants of human cell lines (melanoma, prostate cancer, bronchial epithelium) by gel filtration chromatography. We also compared the GGT elution profile in plasma and the corresponding very-low-density lipoprotein (VLDL) fraction. All the cell lines tested released soluble GGT whose activity increased in parallel with the cell growth. Released GGT presented a molecular weight of 2000 kDa, identical to the b-GGT fraction of human plasma and corresponding to that of VLDL. But ultracentrifugation studies showed that b-GGT had a higher density than VLDL. The b-GGT present in human plasma can be produced by tissues other than the liver, thus explaining the increase of serum GGT observed in diseases of other organs.
Biomarkers 11/2009; 14(7):486-92. · 2.21 Impact Factor
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Barbara Baragatti,
Michal Laniado Schwartzman,
Debora Angeloni,
Francesca Scebba,
Enrica Ciofini,
Daria Sodini,
Virginia Ottaviano,
Simona Nencioni, Aldo Paolicchi,
Joan P Graves,
Darryl C Zeldin,
Katherine Gotlinger,
Stefano Luin,
Flavio Coceani
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ABSTRACT: We have previously shown (Ref. 2) that endothelium-derived hyperpolarizing factor (EDHF) becomes functional in the fetal ductus arteriosus on removal of nitric oxide and carbon monoxide. From this, it was proposed that EDHF originates from a cytochrome P-450 (CYP450)-catalyzed reaction being inhibited by the two agents. Here, we have examined in the mouse ductus whether EDHF can be identified as an arachidonic acid product of a CYP450 epoxygenase and allied pathways. We did not detect transcripts of the mouse CYP2C subfamily in vessel, while CYP2J subfamily transcripts were expressed with CYP2J6 and CYP2J9. These CYP2J hemoproteins were also detected in the ductus by immunofluorescence microscopy, being colocalized with the endoplasmic reticulum in both endothelial and muscle cells. Distinct CYP450 transcripts were also detected and were responsible for omega-hydroxylation (CYP4A31) and 12R-hydroxylation (CYP4B1). Mass spectrometric analysis showed formation of epoxyeicosatrienoic acids (EETs) in the intact ductus, with 11,12- and 14,15-EETs being more prominent than 5,6- and 8,9-EETs. However, their yield did not increase with nitric oxide/carbon monoxide suppression, nor did it abate with endothelium removal. No evidence was obtained for formation of 12R-hydroxyeicosatrienoic acid and omega-hydroxylation products. 2S-hydroxyeicosatetraenoic acid was instead detected, and, contrary to data implicating this compound as an alternative EDHF, its suppression with baicalein did not modify the EDHF-mediated relaxation to bradykinin. We conclude that none of the more common CYP450-linked arachidonic acid metabolites appears to qualify as EDHF in mouse ductus. We speculate that some novel eicosanoid or a totally unrelated compound requiring CYP450 for its synthesis accounts for EDHF in this vessel.
AJP Heart and Circulatory Physiology 10/2009; 297(6):H2161-8. · 3.71 Impact Factor
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ABSTRACT: Serum gamma-glutamyltransferase activity (GGT) has been documented as an independent cardiovascular risk factor. However, to-date its value has not been compared with C-reactive protein (CRP) and other indexes in a multimarker prognostic strategy in patients with coronary artery disease.
We prospectively evaluated 474 subjects with angiographically documented CAD. GGT and traditional humoral and clinical parameters were measured at hospital admission. A multivariate model was used to predict all-cause and cardiac mortality.
GGT showed an independent prognostic value after adjustment for possible confounders, including alcohol consumption, and beyond established risk factors, such as extent of coronary atherosclerotic disease, left ventricular ejection fraction, age, serum glucose, cholesterol subfractions, and C-reactive protein (CRP). At a 3-year follow-up, cardiac mortality was 9% in patients with serum GGT activity >25 U/L vs. 3.5% in those with serum GGT<25 U/L (p=0.028). The association of three independent biomarkers (higher GGT, CRP, fasting glucose) identified a subgroup of 45 patients with the highest risk of cardiac death at 3 years (26.6%, vs. no event or 2.7% in the subsets of 87 and 198 patients with, respectively, no/one risk factor above cut-off value, p<0.0001).
GGT is confirmed as independent risk factor in patients with established coronary artery disease. GGT, CRP, fasting glucose show an additive prognostic value, whereas low values of these biomarkers identify a subset of patients with the lowest risk of cardiac death.
International journal of cardiology 07/2009; 136(1):80-5. · 7.08 Impact Factor
