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Biomedical subjects

G Mauco

Publications and source records attributed to G Mauco.

At least 19 recordsLinked to original sources
PubMed2006

Protective role of selectin ligand inhibition in a large animal model of kidney ischemia-reperfusion injury.

Experiments in rodents have demonstrated an important role for selectins in kidney ischemia-reperfusion injury (IRI). However, the relevance of this in larger mammals, as well as the impact on long-term structure and function is unknown. We tested the hypothesis that small molecule selectin ligand inhibition attenuates IRI, cellular inflammation, and long-term effects on renal interstitial fibrosis. We used a porcine model of kidney IRI and used Texas Biotechnology Corporation (TBC)-1269, a selectin ligand inhibitor. Renal function, tissue inflammation, and tubulointerstitial fibrosis development were evaluated up to 16 weeks. Both warm and cold ischemia models were studied for relevance to native and transplant kidney injury. Pigs treated with TBC-1269 during 45 min of warm ischemia (WI) showed significantly increased glomerular filtration rate compared to control animals. In pigs with severe IRI (WI for 60 min), TBC-1269 treatment during IRI significantly increased renal recovery. Cellular inflammation was strongly reduced, particularly influx of CD4 cells. Quantitative measurement of fibrosis by picrosirius red staining showed strong reduction in TBC-1269-treated groups. TBC-1269 also reduced cold IRI, inflammation, and fibrosis in kidneys preserved for 24 h at 4 degrees C and autotransplanted. The selectin ligand inhibitor TBC-1269 provides a novel and effective approach to attenuate IRI in both warm and cold ischemia in large mammals, in both short and long terms. Selectin ligand inhibition is an attractive strategy for evaluation in human kidney IRI.

Animals↗
PubMed2006

Protective effect of PEG 35,000 Da on renal cells: paradoxical activation of JNK signaling pathway during cold storage.

Polyethylene glycol (PEG), a high-molecular weight colloid, is added to preservation solutions in order to decrease cold- and ischemia-induced injuries of the grafted organ. We evaluated on LLC-PK1, a porcine proximal tubular epithelial cell line (1) the efficiency of several commercial preservation solutions (University of Wisconsin, Euro-Collins, Celsior, SCOT, IGL-1), and (2) whether adding PEG (400-35,000 Da) in a simple extracellular-type buffer modified cell integrity and mitogen-activated protein kinase (MAPK) signaling pathways. SCOT was the most efficient commercial solution. Moreover, only PEG 35,000 Da totally preserved cell viability, induced a decrease on reactive oxygen species production and a decrease on p38-MAPK activation. Furthermore PEG 35,000 Da stimulated c-Jun N-terminal kinase (JNK). However, the inhibition of JNK pathway, with the specific SP600125 inhibitor, in the presence of PEG 35,000 Da did not affect cell survival. We also confirmed on whole pig kidney the protective effect of PEG 35,000 Da on cold-induced tubular injuries. This study confirms PEG antioxidative properties, but we demonstrate that its effect on JNK signaling pathway had also a paradoxical effect on cell death. This sheds a new light on PEG effects during cell preservation, independently from the classical immuno-camouflaging hypothesis.

Adenosine Triphosphate↗
PubMed2005

Determination of HbA1c concentrations in patients with acute myocardial infarction: comparison of the DCA 2000 device with the HPLC method.

BACKGROUND: Recent studies suggest that HbA1c is an important predictor of the glycometabolic state of patients admitted for acute myocardial infarction (AMI). OBJECTIVE: We aimed at comparing the results of HbA1c concentrations obtained by 2 different methods in patients with AMI. RESEARCH DESIGN AND METHODS: In a first study, HbA1c was measured in all patients consecutively hospitalized for AMI, during a 6 month period using the HPLC method and the DCA 2000 device in the biochemistry laboratory. In a second study, HbA1c measured by the DCA 2000 device in the intensive care unit was compared with HbA1c determined by HPLC in the biochemistry laboratory in a similar sample of patients. In patients without personal history of diabetes, those patients with HbA1c > 6.5% (HPLC method), were classified as possible diabetes. RESULTS: A total of 146 patients were included (119 males, 27 females; mean age: 63 +/- 15 years). Twenty-seven of the patients had a personal history of diabetes. HbA1c determined by 2 techniques were highly correlated (r = 0.939, P < 0.0001). The mean of the differences (Bland and Altman analysis) was 0.4 +/- 0.3%. Compared with the HPLC method, the sensitivity of DCA 2000 device for the detection of possible diabetes was 81.8 +/- 11.6 and the specificity was 99.1 +/- 0.9%. The diagnostic accuracy of DCA method was 97.5 +/- 1.4%. In the second study, the HbA1c concentrations of 21 additional subjects, determined in an intensive care unit, were not different from the first 21 patients of the first study. CONCLUSIONS: HbA1c can be effectively determined using the DCA 2000 device. This method is reliable and easy to be implemented in an intensive care unit.

Autoanalysis↗
PubMed2005

[Value of systematic biological markers of inflammation for the prognosis at 12 months of patients undergoing programmed coronary angioplasty].

Value of systematic dosage of biological markers of inflammation for the prognosis at 12 months of patients undergoing programmed coronary angioplasty Systematic dosage of proteins of inflammation has been suggested for assessing the prognosis of athero-thrombotic diseases. The authors undertook a study of plasma C-reactive protein (CRP) and interleukin 6 (IL-6) for evaluating the prognosis of patients undergoing programmed coronary angioplasty. A prospective monocentric study of 117 patients (65 +/- 8 years) was divided into a control group of 28 patients undergoing coronary angiography (Group 1) and 89 patients undergoing programmed coronary angioplasty (Group 2). Serum IL-6 and CRP levels were measured before arterial puncture and at H12 and H24 after coronary catheterisation. The follow-up period was 12 months. The angioplasty did not significantly increase CRP and IL-6 concentrations compared with coronary angiography. Twenty patients (Group 2) (22%) suffered a cardiovascular event in the 12 months' follow-up. These patients had significantly higher CRP levels at H0, H12 and H24 after coronary angioplasty than those who had uncomplicated outcomes. This was not observed for IL-6 concentrations because of the wide dispersion of the results obtained. Increased CRP concentrations between H0 and H24 was also a good predictive factor independently of high basal CRP levels potentially due to other causes than atheroma. Coronary angioplasty is associated with increased CRP at H0, H12 and H24. These values are correlated with the risk of future events at 6 and 12 months. This information is easily obtained and should help management of these patients.

Aged↗
PubMed2004

Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes.

OBJECTIVES: It is controversial that serum lipIds affect the development and progression of microvascular complications in patients with type 1 diabetes. METHODS: We prospectively followed 297 patients with type 1 diabetes without end-stage renal disease for 7 Years (range: 2-10). Serum lipIds were measured at baseline (total and HDL-cholesterol, triglycerIdes and calculated LDL-cholesterol, Lipoprotein (a)). The primary end-point was the occurrence of a renal event and the secondary end-point was the occurrence of a retinal event, defined as the progression to a higher stage of diabetic nephropathy or retinopathy, respectively. RESULTS: Serum triglycerIde (TG) levels were higher in patients who progressed in nephropathy than in those who dId not [median 1.21 (range 0.41-2.96) vs 0.91 (0.31-11.07) mmol/l; p=0.0037] and in those who developed retinal events than in those who dId not [1.05 (0.46-8.27) vs 0.87 mmol/l (0.31-11.07); p=0.0302], both in the whole cohort and in patients with normoalbuminuria at baseline. After adjustment for systolic blood pressure (SBP), diabetes duration, gender, stage of complications at baseline and glycohemoglobin (HbA1c), the relative risk for progression was 2.01 (95% CI: 1.07-3.77) for nephropathy and 2.30 (95% CI: 1.03-5.12) for retinopathy for patients having serum TG in the highest tertile, compared to the others. This result persisted when only patients with normoalbuminuria were consIdered. CONCLUSION: High triglycerIde levels are an independent predictive factor of both renal and retinal complications in patients with type 1 diabetes.

Adult↗
PubMed2004

Prognostic value of admission plasma glucose and HbA in acute myocardial infarction.

OBJECTIVE: Stress hyperglycaemia increases the risk of mortality after acute myocardial infarction in diabetic and in non-diabetic patients. We aimed to determine the contribution of admission plasma glucose and HbA(1c) on post-acute myocardial infarction prognosis. PATIENTS AND METHODS: Admission plasma glucose and HbA(1c) were simultaneously measured in all patients consecutively hospitalized for acute myocardial infarction. Patient survival was measured on 5 and 28 days after admission. Patients were defined as having 'previously diagnosed diabetes' (personal history of diabetes defined using ADA 1997 criteria), 'no diabetes', those without previously diagnosed diabetes and HbA(1c) below 6.5%, or 'possible diabetes', i.e. those without previously diagnosed diabetes and HbA(1c) above 6.5%. RESULTS: Of the 146 patients included, four had died by day 5 and 14 by day 28. Admission plasma glucose was higher in patients who had died by day 28 (11.7 +/- 5.8 vs. 8.0 +/- 3.3 mmol/l, P = 0.002), whereas HbA(1c) was not (6.4 +/- 1.9 vs. 6.1 +/- 0.8%, NS). Admission plasma glucose was significantly higher in those who had died by day 28 after adjustment on HbA(1c). A multivariate analysis, including sex, age and heart failure prior to acute myocardial infarction, showed that admission plasma glucose concentration was an independent predictor of survival after acute myocardial infarction. Twenty-seven of the patients had previously diagnosed diabetes and 119 had no history of diabetes. Eleven were found to have possible diabetes. Admission plasma glucose was significantly higher in previously diagnosed diabetes (11.1 +/- 5.6) than in the other groups: 7.7 +/- 2.9 in non-diabetes, 8.2 +/- 2.1 in possible diabetes (P < 0.0001). The relationship between HbA(1c)-adjusted admission plasma glucose and mortality after acute myocardial infarction was also found in the non-diabetes group. CONCLUSIONS: Admission plasma glucose, even after adjustment on HbA(1c), is a prognostic factor associated with mortality after acute myocardial infarction. Acute rather than the chronic pre-existing glycometabolic state accounts for the prognosis after acute myocardial infarction.

Acute Disease↗
PubMed2002

Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease.

BACKGROUND: Acetylsalicylic acid, or aspirin, is widely used in secondary prevention of coronary artery diseases, but the inhibition of platelet aggregation is not uniform in all individuals. OBJECTIVE: To investigate the prevalence of aspirin resistance at rest and during exercise in coronary artery disease patients. MATERIALS AND METHODS: Fifty patients with stable coronary artery disease were prospectively studied. All patients received aspirin (75-300 mg/day for >1 month) and no other antiplatelet therapy. Aspirin resistance was studied, at rest and immediately after a stress test, using the standardized platelet function analyzer (PFA-100(R), Dade-Behring). Aspirin resistance was defined as a normal collagen/epinephrine closure time (<186 s). RESULTS: Ten patients (20%) were aspirin-resistant at rest. Out of the 40 patients who were aspirin-sensitive at rest, 9 (22%) were aspirin-resistant immediately after the exercise stress test. There were no differences in aspirin sensitivity regarding gender, age, diabetes, hypertension, dyslipidemia, platelet count, medical treatment or number of the coronary arteries involved. CONCLUSIONS: Aspirin resistance is detected, at rest, in 20% of our patients with stable coronary artery disease. Aspirin treatment does not seem to protect against exercise-induced platelet activation in 22% of such patients, despite aspirin sensitivity at rest.

Aged↗
PubMed2002

Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.

BACKGROUND: Platelet activation plays an important role in arterial thrombosis and the widespread use of aspirin has reduced major events by 25% in the secondary prevention of cardiovascular diseases. However, it appears that aspirin antiplatelet effect is not uniform and 8-45% of the population are, in vitro, aspirin resistant, and it is well recognized that platelets can be activated by pathways that are not blocked by aspirin, such as adenosine diphosphate (ADP). OBJECTIVES: To investigate whether aspirin-resistant patients have a modified sensitivity to ADP-induced platelet activation MATERIALS AND METHODS: Seventy-two patients were enrolled. Platelet function was measured by the PFA-100(R) analyser; platelet GP IIb-IIIa activation by ADP 10 micro M was assessed by flow cytometry using PAC-1 MoAb. RESULTS: Using a collagen/epinephrine coated cartridge on the PFA-100(R), the prevalence of aspirin resistance was 29.2% (n=21). For aspirin-resistant patients, the collagen/ADP coated cartridge showed a closure time significantly shorter (p=0.004) compared to the sensitive and control groups. Platelets from aspirin-resistant patients bound PAC-1 significantly more (p=0.03) than the aspirin-sensitive patients and controls when activated with 10 micro M ADP. CONCLUSIONS: Platelets from aspirin-resistant patients appear to be more sensitive and activable by ADP. This hypersensitivity could provide a possible explanation for the so-called aspirin resistance, and this could justify therapeutic improvement with alternative antiplatelet agents.

Adenosine Diphosphate↗
PubMed2001

Plasmalogen degradation by oxidative stress: production and disappearance of specific fatty aldehydes and fatty alpha-hydroxyaldehydes.

Plasmalogens are often considered as antioxidant molecules that protect cells from oxidative stress. Their vinyl ether bond could indeed be among the first targets for newly formed radicals. However, the long chain aldehydes released from plasmalogens were seldom studied and possible injurious or harmless effects were poorly examined. Thus, the sensitivity of the vinyl ether bond of plasmalogens was investigated in a cerebral cortex homogenate under UV irradiation- or Fe2+/ascorbate-induced peroxidation. Kinetics of aldehyde production was followed by gas chromatography/mass spectrometry. This confirmed that plasmalogens were highly sensitive to oxidative stress (70% cleavage after 90 min UV irradiation and 30% after 30 min of Fe2+/ascorbate). The aldehydes corresponding to sn-1 position 16:0, 18:0, or 18:1 were poorly detected. Conversely, oxidation of plasmalogens yielded preferentially 15:0, 17:0, and 17:1 aldehydes under UV and the alpha-hydroxyaldehydes 16:0-OH and 18:0-OH following a Fe2+/ascorbate oxidation. Kinetics showed that free aldehydes and above all free alpha-hydroxyaldehydes disappeared from the medium as soon as produced. Consequently, the behavior of these released aldehydes in the tissues has to be investigated in order to ascertain the protective effect of plasmalogens against oxidation.

Aldehydes↗
PubMed2000

The platelet cytoskeleton regulates the aggregation-dependent synthesis of phosphatidylinositol 3,4-bisphosphate induced by thrombin.

Pretreatment of intact platelets with cytochalasin D prevented actin polymerization and cytoskeleton reorganization induced by thrombin, but did not affect platelet aggregation. Under these conditions, synthesis of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) stimulated by thrombin was strongly inhibited, while production of phosphatidic acid was unaffected. The inhibitory effect of cytochalasin D was not observed when platelet aggregation was prevented by the RGDS peptide. We also found that cytochalasin D did not affect PtdIns(3,4)P2 synthesis induced by concanavalin A (ConA), which is known to occur through an aggregation-independent mechanism. Moreover, thrombin, but not ConA, induced the translocation of phosphatidylinositol 3-kinase to the cytoskeleton. This process was equally inhibited by both the RGDS peptide and cytochalasin D. These results demonstrate that the cytoskeleton represents a functional link between thrombin-induced aggregation and synthesis of PtdIns(3,4)P2.

Blood Platelets↗
PubMed2000

Modifications of bone and connective tissue after orthostatic bedrest.

Eight male volunteers were submitted to a 6-week anti-orthostatic bedrest trial followed by a 1-month reambulation period. We prospectively monitored whole-body composition by dual-energy X-ray absorptiometry, bone and connective tissue metabolism by biochemical markers and calcium regulating hormones by 1-84 parathyroid hormone and 1,25-dihydroxyvitamin D(3). Bone mineral density (BMD) did not vary significantly; however, a trend toward an increase in head BMD and a decrease in trunk, lumbar vertebrae and lower limb BMD was observed. A decrease in the lower limb lean content occurred by day 27 and was maximum by day 42 after the beginning of bedrest; it normalized by day 30 after bedrest. The serum levels of both osteocalcin and C-terminal crosslinked telopeptide of type I collagen increased as a consequence of bedrest. A slight increase in the serum levels of the N-terminal propeptide of type III collagen, a marker of connective tissue metabolism, was observed during the bedrest period. Except for the C-terminal extension propeptide of type I collagen, all markers decreased to baseline pre-immobilization levels during the 1-month recovery phase. Serum PTH and 1,25-dihydroxyvitamin D(3) levels were low during the bedrest period and rose during the reambulation phase. These results seem to reflect early changes in bone and connective tissue metabolism as a result of bedrest unloading, but their order of magnitude remains moderate, thus emphasizing the necessity to perform longer-duration trials.

Absorptiometry, Photon↗
PubMed2000

Head-down tilt bed rest and immune responses.

Head-down tilt bed rest (HDT) is used as a model for studying the physiological changes occurring in weightlessness during spaceflight. In the present study, eight volunteers were subjected to a strict HDT of -6 degrees for 42 days. Blood samples were obtained 37 and 13 days before, at days 13, 34, and 41 during, and 12, 33, and 47 days after HDT. FACScan analysis was used to determine cell subpopulations. Plasma was used to quantify various circulating hormone levels. Whole blood and reconstituted blood were stimulated with various activators such as phytohaemagglutinin-P (PHA), PHA combined with phorbol-12-myristate 13-acetate (PMA), anti-CD2, anti-CD3, and lipopolysaccharide. Supernatants were collected and analysed for the interleukins IL-1beta, IL-2, IL-6, and IL-10, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). The total number of T lymphocytes and monocytes did not change significantly, whereas the number of polymorphonuclear cells increased during HDT. The percentage of CD2+ and CD3+ cells was increased at day 35 of HDT. The percentage and total number of natural killer cells (CD2+/CD3-/CD56+) was increased 12 days before and 14 days after HDT. TNF-alpha secretion did not change significantly during HDT. IL-2, IL-10 and IFN-gamma were increased at day 34 of HDT. IL-1beta levels were increased before and during HDT compared to post-HDT measurements. No significant changes were observed in plasma immunoglobulin, complement factors and other factors of the inflammatory system. Prolactin levels increased slightly but significantly at day 35 of HDT, thyreotropin and growth hormone levels remained virtually unchanged. Cortisol decreased slightly but significantly over the entire duration of the study. The changes observed during HDT do not indicate that the immune system is blunted, and these changes do not seem to correlate with the duration of HDT. Taken together these results show that a HDT does not reproduce the changes in immune responses observed after spaceflight.

Bed Rest↗
PubMed1999

Phosphatidylinositol 3-kinase translocates onto liver endoplasmic reticulum and may account for the inhibition of glucose-6-phosphatase during refeeding.

By using a rapid procedure of isolation of microsomes, we have shown that the liver glucose-6-phosphatase activity was lowered by about 30% (p < 0.001) after refeeding for 360 min rats previously unfed for 48 h, whereas the amount of glucose-6-phosphatase protein was not lowered during the same time. The amount of the regulatory subunit (p85) and the catalytic activity of phosphatidylinositol 3-kinase (PI3K) were higher by a factor of 2.6 and 2.4, respectively (p < 0.01), in microsomes from refed as compared with fasted rats. This resulted from a translocation process because the total amount of p85 was the same in the whole liver homogenates from fasted and refed rats. The amount of insulin receptor substrate 1 (IRS1) was also higher by a factor of 2.6 in microsomes from refed rats (p < 0. 01). Microsome-bound IRS1 was only detected in p85 immunoprecipitates. These results strongly suggest that an insulin-triggered mechanism of translocation of PI3K onto microsomes occurs in the liver of rats during refeeding. This process, via the lipid products of PI3K, which are potent inhibitors of glucose-6-phosphatase (Mithieux, G., Danièle, N., Payrastre, B., and Zitoun, C. (1998) J. Biol. Chem. 273, 17-19), may account for the inhibition of the enzyme and participate to the inhibition of hepatic glucose production occurring in this situation.

Adipocytes↗
PubMed1998

Lipid products of phosphoinositide 3-kinase interact with Rac1 GTPase and stimulate GDP dissociation.

A number of reports suggest that under different conditions leading to cytoskeleton reorganization the GTPase Rac1 and possibly RhoA are downstream targets of phosphoinositide 3-kinase (PI 3-kinase). In order to gain more insight into this particular signaling pathway, we have addressed the question of a possible direct interaction of PI 3-kinase products with the Rho family GTPases RhoA, Rac1, and Cdc42. Using recombinant proteins, we found that Rac1 and, to a lesser extent, RhoA but not Cdc42 were capable to selectively bind to phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in a mixture of crude brain phosphoinositides. Nucleotide-depleted Rac1 was the most efficient, but the GDP- and GTP-bound forms retained significant PtdIns(3,4,5)P3 binding activity. This protein-lipid association involved electrostatic as well as hydrophobic interactions, since both phosphate groups located at specific positions of the inositol ring and fatty-acyl chains were absolutely required. Based on the sequence of Rac1, two potential binding sites were identified, one at the C terminus and one in the extra alpha-helical domain. Deletion of these two domains resulted in a complete loss of binding to PI 3-kinase products. Finally, PtdIns(3, 4,5)P3 strongly stimulated GDP dissociation from Rac1 in a dose-dependent manner. In agreement, data obtained in intact cells suggest that PtdIns(3,4,5)P3 might target Rac1 to peculiar membrane domains, allowing formation of specific clusters containing not only small GTPases but other partners bearing pleckstrin homology domains such as specific exchange factors required for Rac1 and RhoA activation.

Androstadienes↗
PubMed1998

Phosphatidylinositol 3,4,5-trisphosphate-dependent stimulation of phospholipase C-gamma2 is an early key event in FcgammaRIIA-mediated activation of human platelets.

Platelets express a single class of Fcgamma receptor (FcgammaRIIA), which is involved in heparin-associated thrombocytopenia and possibly in inflammation. FcgammaRIIA cross-linking induces platelet secretion and aggregation, together with a number of cellular events such as tyrosine phosphorylation, activation of phospholipase C-gamma2 (PLC-gamma2), and calcium signaling. Here, we show that in response to FcgammaRIIA cross-linking, phosphatidylinositol (3,4, 5)-trisphosphate (PtdIns(3,4,5)P3) is rapidly produced, whereas phosphatidylinositol (3,4)-bisphosphate accumulates more slowly, demonstrating a marked activation of phosphoinositide 3-kinase (PI 3-kinase). Inhibition of PI 3-kinase by wortmannin or LY294002 abolished platelet secretion and aggregation, as well as phospholipase C (PLC) activation, indicating a role of this lipid kinase in the early phase of platelet activation. Inhibition of PLCgamma2 was not related to its tyrosine phosphorylation state, since wortmannin actually suppressed its dephosphorylation, which requires platelet aggregation and integrin alphaIIb/beta3 engagement. In contrast, the stable association of PLCgamma2 to the membrane/cytoskeleton interface observed at early stage of platelet activation was fully abolished upon inhibition of PI 3-kinase. In addition, PLCgamma2 was able to preferentially interact in vitro with PtdIns(3,4,5)P3. Finally, exogenous PtdIns(3,4,5)P3 restored PLC activation in permeabilized platelets treated with wortmannin. We propose that PI 3-kinase and its product PtdIns(3,4,5)P3 play a key role in the activation and adequate location of PLCgamma2 induced by FcgammaRIIA cross-linking.

Androstadienes↗
PubMed1998

Stimulation of phosphoinositide kinases by thrombin is restricted to the plasma membrane in platelets.

This study was based on the hypothesis that lipid kinases in the different subcellular fractions would be differently affected by thrombin-treatment of platelets prior to subcellular fractionation. When using our previously reported method for subcellular fractionation on Percoll self-generated gradients, marker enzymes were detected as previously described. Stimulation of intact platelets with thrombin induced increased activities of PtdIns 4-kinase, PtdIns(4)P 5-kinase and PtdIns(4,5)P(2) 3-kinase in the plasma membrane fraction. PtdIns 4-kinase was also detected in internal membranes but was not modified by thrombin. We conclude that the production of phosphoinositides phosphorylated on the D3 and D5 positions of the inositol ring is restricted to the plasma membrane and that only the enzymes that are present in, or relocated to, the plasma membrane when platelets are activated are stimulated by thrombin.

Journal Article↗