Biomedical subjects

G Squadrito

Publications and source records attributed to G Squadrito.

At least 37 records · Page 2Linked to original sources

PubMed1999

Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease.

BACKGROUND: Hepatitis B virus (HBV) infections in patients who lack detectable hepatitis B surface antigen (HBsAg) are called occult infections. Although such infections have been identified in patients with chronic hepatitis C liver disease, their prevalence and clinical significance are not known. METHODS: With the polymerase chain reaction, we searched for HBV DNA in liver and serum samples from 200 HBsAg-negative patients with hepatitis C virus (HCV)-related liver disease (147 with chronic hepatitis, 48 with cirrhosis, and 5 with minimal histologic changes). One hundred of the patients had detectable antibodies to the HBV core antigen (anti-HBc); 100 were negative for all HBV markers. Eighty-three were treated with interferon alfa. We also studied 50 patients with liver disease who were negative both for HBsAg and for HCV markers. In six patients found to have occult HBV infection, we evaluated possible genomic rearrangements through cloning or direct sequencing procedures. RESULTS: Sixty-six of the 200 patients with chronic hepatitis C liver disease (33 percent) had HBV sequences, as did 7 of the 50 patients with liver disease unrelated to hepatitis C (14 percent, P=0.01). Among the 66 patients, 46 were anti-HBc-positive and 20 were negative for all HBV markers (P<0.001). Twenty-two of these 66 patients (33 percent) had cirrhosis, as compared with 26 of the 134 patients with hepatitis C infection but no HBV sequences (19 percent, P=0.04). HBV sequences were detected in 26 of the 55 patients in whom interferon therapy was ineffective and 7 of the 28 patients in whom interferon therapy was effective (P=0.06). None of the sequenced HBV genomes had changes known to interfere with viral activity and gene expression. CONCLUSIONS: Occult hepatitis B infection occurs frequently in patients with chronic hepatitis C liver disease and may have clinical significance.

Adult↗

PubMed1999

The lazaroid, U-74389G, inhibits inducible nitric oxide synthase activity, reverses vascular failure and protects against endotoxin shock.

The aim of our study was to investigate the effect of the 21-aminosteroid U-74389G [21- < 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl-pregna-1,4,9,(11) triene-3,20-dione(z)-2-butenedionate] on the l-arginine-nitric oxide (NO) pathway in a rat model of endotoxin shock. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella Enteritidis lipopolysaccharide (LPS). Rats were treated with U-74389G (7.5, 15 and 30 mg/kg i.v.) or vehicle (1 ml/kg i.v.) 5 min after endotoxin challenge. Lipopolysaccharide administration reduced survival rate (0%, 72 h after endotoxin administration) decreased mean arterial blood pressure, enhanced plasma concentration of bilirubin and alanine aminotransferase and increased plasma nitrite concentrations. Lipopolysaccharide injection also increased the activity of inducible NO synthase in the liver and in the aorta. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (1 nM-10 microM). In addition lipopolysaccharide (50 microg/ml for 4 h) in vitro stimulation significantly increased nitrite production in peritoneal macrophages harvested from normal rats. Treatment with U-74389G (15 and 30 mg/kg i.v., 5 min after endotoxin challenge) significantly protected against lipopolysaccharide-induced lethality (90% survival rate 24 h and 80% 72 h after lipopolysaccharide injection, respectively, following the highest dose of the drug), reduced hypotension, ameliorated liver function, decreased plasma nitrite levels, restored the hyporeactivity of aortic rings to their control values and inhibited the activity of inducible NO synthase in the liver and in the aorta. Finally, U-74389G in vitro (12.5, 25 and 50 microM) significantly inhibited nitrite production in endotoxin stimulated peritoneal macrophages. The data suggest that U-74389G may exert beneficial effects in an experimental model of septic shock by inhibiting the activity of the inducible NO synthase.

Alanine Transaminase↗

PubMed1999

Cyclosporin-A reduces leukocyte accumulation and protects against myocardial ischaemia reperfusion injury in rats.

The present study was designed to evaluate the effect of cyclosporin A in a rat model of myocardial ischaemia reperfusion injury (MI/R). Anaesthetized rats were subjected to total occlusion (20 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum tumor necrosis factor (TNF-alpha), cardiac mRNA for TNF-alpha, cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining and myocardial contractility (left ventricle dP/dtmax) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and myeloperoxidase activity (a marker of leukocyte accumulation) both in the area-at-risk and in the necrotic area, reduced myocardial contractility and induced a marked increase in the serum levels of the TNF-alpha. Furthermore increased cardiac mRNA for TNF-alpha was measurable within 10 to 20 min of left main coronary artery occlusion in the area-at-risk and increased levels were generally sustained for 0.5 h. Finally, myocardial ischaemia-reperfusion injury increased ICAM-1 staining in the myocardium. Administration of cyclosporin A (0.25, 0.5 and 1 mg/kg as an i.v. infusion 5 min after coronary artery occlusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, reduced serum levels of TNF-alpha and the cardiac cytokine mRNA levels, and blunted ICAM-1 immunostaining in the injured myocardium. The data suggest that cyclosporin A suppresses leukocyte accumulation and protects against myocardial ischaemia-reperfusion injury.

Animals↗

PubMed1999

Effect of sulfatide on acute lung injury during endotoxemia in rats.

Experimental studies have shown that intrapulmonary leukocyte sequestration and activation is implicated in the pathogenesis of acute lung injury during endotoxemia. Selectins are involved in the adhesion of leukocyte to the endothelium. Sulfatide is recognized by P selectin and blocks this adhesion molecule. We studied the effects of sulfatide on endotoxin-induced lung damage in rats. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0%, 72 h after endotoxin challenge) decreased mean arterial blood pressure (MAP), produced leukopenia (Controls = 11,234+/-231 cells/mL, LPS = 4,567+/-123 cells/mL) and increased lung myeloperoxidase activity (MPO; a marker of leukocyte accumulation) in the lung (Controls = 0.35+/-0.1 U/g/tissue; LPS = 10+/-1.2 U/g/tissue). Furthermore LPS administration markedly impaired the concentration-response curves for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings. There was also an increased staining for P-selectin in the pulmonary arteries. Sulfatide treatment (10 mg/kg, 30 min. after LPS challenge), significantly protected against LPS-induced lethality (90% survival rate and 70% survival rate 24 h and 72 h after LPS injection), reduced LPS induced hypotension, reverted leukopenia (8,895+/-234 cells/ml) and lowered lung MPO activity (1.7+/-0.9 U/g/tissue). Furthermore sulfatide restored to control values the LPS-induced impairment in arterial pulmonary vasorelaxation and reduced P-selectin immunostaining. Our data indicate that sulfatide attenuates LPS-induced lung injury and protects against endotoxin shock.

Acute Disease↗

PubMed1999

Long-term response to interferon alpha is unrelated to "interferon sensitivity determining region" variability in patients with chronic hepatitis C virus-1b infection.

BACKGROUND/AIMS: Contradictory data have been reported about the predictive value of the variability in interferon sensitivity determining region (ISDR) of hepatitis C virus (HCV) genotype-1b on response to interferon-alpha (IFN-alpha) therapy. The aim of this study was to examine this issue in a series of patients with long-term response to IFN treatment. METHODS: We retrospectively analyzed 24 patients with chronic HCV genotype-1b infection treated with IFN-alpha (total dose median 677, range 216-1350 MU) selected in 6 Italian Liver Units. These patients were defined as true long-term responders (LTR) since they showed persisting biochemical and virological responses to IFN treatment (mean follow-up 38 months). HCV genomes from pretreatment serum samples were amplified and directly sequenced. The ISDR amino-acid sequences obtained were aligned and compared with the published sequence of HCV-J. RESULTS: Amino-acid substitutions were found in 23 of the 24 patients, and 22 of them showed an H to R amino-acid change at codon 2218. Fourteen patients showed only one mutation (at codon 2218), two had 2, five had 3, one had 4 and one had 5 mutations. When we compared the ISDR sequences from the 24 LTR with those of non-responders (NR), we found no significant correlation between the number of mutations and the response to therapy. CONCLUSIONS: Our results demonstrate that the persisting efficacy of IFN treatment in patients with chronic HCV is not related to the number of ISDR amino acid substitutions of the infecting viruses. Further studies are needed to verify whether other NS5A sequences outside the ISDR might be involved in the mechanisms of IFN resistance.

Adult↗

PubMed1999

Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock.

1. We investigated the effects of recombinant human erythropoietin (rh-EPO) in splanchnic artery occlusion (SAO) shock. Sham operated animals were used as controls. Survival rate, mean arterial blood pressure (MAP), serum Tumor Necrosis Factor (TNF-alpha), plasma nitrite/nitrate concentrations, red blood cell (RBC) count, blood haemoglobin (Hb), the responsiveness of aortic rings to phenylephrine (PE, 1 nM-10 microM) and the activity of inducible nitric oxide synthase (iNOS) were studied. 2. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrations, increased plasma nitrite/nitrate levels (60+/-9.5 microM; sham shocked rats= 2+/-0.4 microM), decreased MAP, unchanged RBC count and blood Hb and enhanced iNOS activity in the aorta. Moreover aortic rings from shocked rats showed a marked hyporeactivity to PE. 3. Rh-EPO (25, 50 and 100 U 100 g(-1), 5 min following the onset of reperfusion) increased survival rate (70% at 4 h of reperfusion with the highest dose), reduced plasma nitrite/nitrate concentrations (10.3+/-3.3 microM), increased MAP, did not change RBC count and blood Hb, and inhibited iNOS activity in thoracic aortae. Furthermore rh-EPO, either in vivo or in vitro (10 U for 1 h in the organ bath), restored to control values the hyporeactivity to PE. Finally rh-EPO inhibited the activity of iNOS in peritoneal macrophages activated with endotoxin. 4. Our data suggest that rh-EPO protects against SAO shock by inhibiting iNOS activity.

Animals↗

PubMed1999

Tacrolimus suppresses tumour necrosis factor-alpha and protects against splanchnic artery occlusion shock.

1. Tumour necrosis factor (TNF-alpha) is a pleiotropic cytokine which is deeply involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. Tacrolimus, formerly known as FK506, is a macrolide antibiotic, that blocks the transcription of several proinflammatory cytokines including TNF-alpha. 2. Male anaesthetized rats were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrations (415+/-12 U ml(-1)), decreased mean arterial blood pressure (MAP), leukopenia and increased ileal leukocyte accumulation studied by means of myeloperoxidase activity (MPO=7.5+/-0.3 U g(-1) tissue). Moreover aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM), reduced responsiveness to acetylcholine (ACh, 10 nM - 10 microM) and increased staining for intercellular adhesion molecule-1 (ICAM-1). Furthermore increased mRNA for TNF-alpha was observed in peritoneal macrophages of SAO shocked rats. 3. Tacrolimus (100 microg kg(-1), 5 min after splanchnic arteries occlusion) increased survival rate (SAO + Tacrolimus = 100% at 4 h of reperfusion), reverted the marked hypotension, reduced serum TNF-alpha (15+/-3 U ml(-1)), ameliorated leukopenia, reduced ileal MPO (0.9+/-0.01 U g(-1) tissue), restored to control values the hyporeactivity to PE. improved the reduced responsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in the aorta. Finally tacrolimus suppressed cytokine mRNA levels in peritoneal macrophages. 4. The data suggest that tacrolimus may represent a new therapeutic approach in circulatory shock.

Animals↗

PubMed1999

Adrenocorticotropin reverses vascular dysfunction and protects against splanchnic artery occlusion shock.

1. Tumour necrosis factor (TNF-alpha) is involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. On the other hand, inhibition of TNF-alpha is an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock. We therefore investigated the effects of the melanocortin peptide ACTH-(1 - 24) (adrenocorticotropin fragment 1 - 24) on the vascular failure induced by SAO shock. 2. SAO-shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham-shocked rats survived for more than 4 h), enhanced serum TNF-alpha concentrations (755+/-81 U ml-1), decreased mean arterial blood pressure, leukopenia, and increased ileal leukocyte accumulation, as revealed by means of myeloperoxidase activity (MPO=9.4+/-1 U g-1 tissue). Moreover, aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM) (Emax and ED50 in shocked rats=7.16 mN mg-1 tissue and 120 nM, respectively; Emax and ED50 in sham-shocked rats=16.31 mN mg-1 tissue and 100 nM, respectively), reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) (Emax and ED50 in shocked rats=30% relaxation and 520 nM, respectively; Emax and ED50 in sham-shocked rats=82% relaxation and 510 nM, respectively) and increased staining for intercellular adhesion molecule-1 (ICAM-1). 3. ACTH-(1 - 24) [160 microg kg-1 intravenously (i.v.), 5 min after SAO] increased survival rate [SAO+ACTH-(1 - 24)=80% at 4 h of reperfusion], reversed hypotension, reduced serum TNF-alpha (55+/-13 U ml-1), ameliorated leukopenia, reduced ileal MPO (1.2+/-0.2 U g-1 tissue), restored the reactivity to PE, improved the responsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in the aorta. 4. Adrenalectomy only in part - but not significantly - reduced the ACTH-induced shock reversal, the survival rate of SAO+ACTH-(1 - 24) adrenalectomized rats being 60% at 4 h of reperfusion; and methylprednisolone (80 mg-1 i.v., 5 min after SAO) had a non-significant effect (10% survival) at 4 h of reperfusion. 5. The present data show that melanocortins are effective also in SAO shock, their effect being, at least in part, mediated by reduced production of TNF-alpha. Furthermore, they demonstrate, for the first time, that this inhibition is responsible for the adrenocorticotropin-induced reversal of vascular failure and leukocyte accumulation.

Adrenocorticotropic Hormone↗

PubMed1999

Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury.

1. Soybean phytoestrogens have no oestrogen agonist effects on the reproductive system and therefore it is reasonable to explore the potential of these naturally occurring plant oestrogens in the cardiovascular pathology. We therefore investigated the effects of genistein in a rat model of myocardial ischaemia-reperfusion injury. 2. Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham operated rats were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum and macrophage Tumour Necrosis Factor-alpha (TNF-alpha), cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining, cardiac mRNA for ICAM-1 evaluated by the means of reverse transcriptase polymerase chain reaction (RT - PCR), ventricular arrhythmias and myocardial contractility (left ventricle dP/dt(max)) were evaluated. 3. Myocardial ischaemia and reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and MPO activity both in the area-at-risk and in the necrotic area, reduced myocardial contractility, caused ventricular arrhythmias and induced a marked increase in serum and macrophage TNF-alpha. Furthermore myocardial ischaemia-reperfusion injury increased ICAM-1 expression in the myocardium. 4. Administration of genistein (1 mg kg(-1), i.v., 5 min after coronary artery occlusion) lowered myocardial necrosis and MPO activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, decreased the occurrence of ventricular arrhythmias, reduced serum and macrophages levels of TNF-alpha and blunted ICAM-1 expression in the injured myocardium. Finally genistein added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia-reperfusion injury significantly reduced TNF-alpha production. 5. Our data suggest that genistein limits the inflammatory response and protects against myocardial ischaemia-reperfusion injury.

Animals↗

PubMed1999

Epidemiological and virological analysis of couples infected with hepatitis C virus.

BACKGROUND: If transmission of hepatitis C virus (HCV) infection through parenteral exposure is well documented, sexual transmission of HCV is still debated. AIMS: To perform extensive epidemiological and virological analysis in 24 couples in which each spouse was anti-HCV positive in order to delineate more precisely potential sexual transmission of HCV. PATIENTS: Twenty four couples in which each partner was anti-HCV positive. These 48 spouses were recruited in a liver unit by regular screening of spouses of index patients. METHODS: All 48 spouses completed an epidemiological questionnaire on risk factors for HCV. Qualitative detection of serum HCV RNA and determination of HCV type by genotyping and serotyping were performed. Sequence analysis of HCV strains by phylogenetic analysis was carried out in seven couples with concordant genotypes. RESULTS: The mean (SD) partnership duration was 12 (10) years. Serum HCV RNA was detected in both partners in 18 of the couples (75%) and in only one partner in six of the couples (25%). HCV typing showed concordant genotypes in 12 couples (50%), discordant genotypes in seven (29%), and in the other five couples (21%) only one spouse could be genotyped. Of the 48 spouses, 33 had a major risk factor for HCV transmission such as transfusion (n = 6) and intravenous drug use (n = 27). Eleven of the 12 couples infected with the same HCV genotype had at least one parenteral risk factor for viral transmission in both spouses. Whatever the genotype concordance, in most couples (75%), both spouses showed parenteral risk factors for viral transmission. Sequence analysis of HCV strains was possible in seven of 12 couples with identical genotype and showed different and identical isolates in four and three couples respectively. CONCLUSION: The study emphasises the risk of overestimating the importance of a very low sexual HCV transmission risk as against other, mainly parenteral, risk factors.

Adult↗

PubMed1998

Sulfatide reduces leucocyte accumulation and reverts vascular failure in splanchnic artery occlusion shock.

Selectin-mediated leucocyte accumulation is implicated in the pathogenesis of splanchnic artery occlusion. Sulfatide is recognized by P-selectin and blocks this adhesion molecule. We investigated the effects of sulfatide in rats subjected to splanchnic artery occlusion shock. Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed severe shock resulting in death within 85-90 min after the release of occlusion. Sham operated animals were used as controls. Splanchnic artery occlusion shocked rats had marked hypotension, enhanced levels of tumor necrosis factor-alpha (TNF-alpha) in serum and macrophages, leucopenia and increased ileal leucocyte accumulation, studied by the means of myeloperoxidase activity. Furthermore, aortae from shocked rats showed marked hyporeactivity to phenylephrine (1 nM-10 microM), reduced responsiveness to acetylcholine (10 nM-10 microM) and an increased staining for P-selectin in the vasculature. In vivo administration of sulfatide (10 mg/kg, i.v., 5 min after occlusion of the splanchnic arteries) increased survival rate (90%, 4 h after splanchnic artery occlusion shock), enhanced mean arterial blood pressure, reduced serum TNF-alpha (37 +/- 11 U/ml vs. 398 +/- 18 U/ml), ameliorated leucopenia and reduced ileal myeloproxidase activity (1.2 +/- 0.4 U/g tissue vs. 8.2 +/- 0.8 U/g tissue). Aortae from splanchnic artery occlusion shocked rats treated with sulfatide exhibited a greater contractile response to phenylephrine and improved responsiveness to acetylcholine. Moreover sulfatide-treated rats showed a reduced staining for P-selectin in the aorta and in the superior mesenteric artery. Finally, passive immunization with specific monoclonal antibodies raised against P-selectin significantly protected from the lethality induced by splanchnic artery occlusion shock. Our results suggest that sulfatide protects against splanchnic artery occlusion shock.

Acetylcholine↗

PubMed1998

Increased levels of the soluble adhesion molecule E-selectin in patients with chronic myeloproliferative disorders and thromboembolic complications.

Patients with chronic myeloproliferative disorders (CMD) show a high frequency of thrombosis. For this reason we evaluated endothelial cell markers, soluble adhesion molecule E-selectin (sELAM), and thrombomodulin (TM) in 25 patients with CMD. Among them nine presented thromboses in their past history. Data were compared with those obtained in a group of healthy subjects and a group of patients with secondary thrombocytosis. The mean plasma concentrations of sELAM were elevated in patients with CMD, as compared with healthy subjects (81.27 +/- 42.8 ng/ml vs. 41.75 +/- 13; P < 0.02). Similarly, the mean plasma concentrations of sTM were increased in CMD patients in comparison with the control group (102.0 +/- 73 ng/ml vs. 16.7 +/- 9.6; P < 0.01). More markedly elevated sELAM levels were observed in CMD patients with thrombosis than in patients without thrombosis (113.16 +/- 29.5 ng/ml vs. 55.11 +/- 19.1 ng/ml; P < 0.001), while no significant difference was found between CMD patients without thrombosis and secondary thrombocytosis (50.72 +/- 10.8 ng/ml). Plasma thrombomodulin values in CMD patients with thrombosis (131 +/- 93.8 ng/ml) were higher than those without thrombosis (65.77 +/- 43.9 ng/ml; P < 0.02). sTM values were also significantly increased in patients with secondary thrombocytosis (P < 0.01). It is speculated that the plasma, sELAM levels may reflect endothelium activation and that it is possibly useful in predicting the thrombotic risk in myeloproliferative disorders.

Adult↗

PubMed1998

Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury.

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3+/-10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8+/-15.8 nmol/g tissuev 9.53+/-2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73+/-1.86 DeltaABS/mlv 1.61+/-0.45 DeltaABS/ml); endogenous antioxidant wasting [cardiac VE=23.5+/-10.2 nmol/g tissuev 61.4+/-13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15+/-1.23 micromol/g proteinv 7.34+/-0.92 micromol/g protein and cardiac superoxide dismutase (SOD)=8.9+/-4.1 U/mg proteinv 17. 5+/-4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4+/-5.8 mmHgv 85.3+/-6.2 mmHg); heart rate (HR) (275+/-35 beats/minv 368+/-34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050+/-187 mmHg/sv 2520+/-194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23+/-2.1 U/g tissuev 0.92+/-0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3+/-14.8%P<0. 005, following the highest dose), reduced lipid peroxidation (MAL=43. 5+/-14.7 nmol/g tissueP<0.001 and CD=4.01+/-2.21 DeltaABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8+/-14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2+/-2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92+/-1.33 micromol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1+/-5.3 mmHgP<0.05, HR=317+/-27 beats/minP<0.05, LV dP/dtmax=1427+/-143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1+/-1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.

Alkenes↗

PubMed1998

Translocation (5;10)(q13;q26) in acute monoblastic leukemia.

We report a case of acute monoblastic leukemia [French-American-British (FAB) M5a] observed in a 38-year-old man and associated at diagnosis with a t(5;10)(q13;q26) found in cells from a bone marrow culture. The patient survived only 2 months after diagnosis. t(5;10) as a solitary chromosome abnormality has not been previously reported in M5a, and, in the case that we describe, it appears to be correlated with a poor prognosis.

Adult↗

PubMed1998

Hepatitis C virus (HCV) hypervariable region 1 complexity does not correlate with severity of liver disease, HCV type, viral load or duration of infection.

BACKGROUND/AIMS: Several studies have suggested that infection with a highly heterogeneous population of hepatitis C virus correlates with a low response rate to interferon. It is still debated, however, whether or not this heterogeneity might be associated with liver disease severity. The aim of this study was to analyse hepatitis C virus genome complexity in patients with various stages of liver disease. METHODS: We used polymerase chain reaction-single strand conformation polymorphism (SSCP) analysis to estimate the degree of complexity of the hypervariable region (HVR1) in 95 anti-HCV and serum HCV-RNA positive patients. They were divided into two groups according to Knodell's histological activity index (HAI) grading: 22 with HAI <4 and 73 with HAI> or =4, including 19 with cirrhosis. RESULTS: The number of visible SSCP bands ranged from 1 to 7. There was no significant difference in the number of SSCP bands between patients with HAI <4 and patients with HAI> or =4 (median number of bands was 4 in both groups). The number of SSCP bands was not correlated to the biochemical activity, the genotype, the HCV-RNA titre or the duration of hepatitis C virus infection. CONCLUSIONS: The HCV-HVR1 complexity profile alone does not correlate with the severity of liver disease, whatever the biological and virological profile of the viral infection.

Female↗

PubMed1998

Inhibition of tumour necrosis factor and reversal of endotoxin-induced shock by U-83836E, a 'second generation' lazaroid in rats.

1. Antioxidants can exert protective effects in endotoxic shock by either a reduction of the oxidant damage or attenuation of Tumour Necrosis Factor (TNF-alpha) production. 2. Lazaroids are a family of compounds that inhibit lipid peroxidation. Besides, they can also reduce TNF-alpha. U-83836E is a new lazaroid lacking the glucocorticoid ring. 3. Aim of our study was to investigate the effect of U-83836E on TNF-alpha production either in vivo or in vitro. Endotoxic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg(-1) of S. enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0% survival, 72 h after endotoxin administration), decreased mean arterial blood pressure, increased serum and macrophage TNF-alpha and enhanced plasma malonylaldehyde (MAL) levels. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE 1 nM-10 microM). 4. Treatment with U-83836E (7.5, 15 and 30 mg kg(-1), i.v.) 5 min after endotoxin challenge significantly protected against LPS induced lethality (90% survival rate and 80% survival rate 24 h and 72 h after LPS injection respectively, following the highest dose of the drug), reduced hypotension, blunted plasma MAL, decreased serum and macrophage TNF-alpha and restored the hyporeactivity of aortic rings to control values. In vitro LPS stimulation (50 microg ml(-1) for 4 h) significantly increased cytokine production in macrophages (Mphi) harvested from untreated normal rats. Pretreatment with pertussis toxin (PT; 0.1, 1 and 10 ng ml(-1) 4 h before LPS) significantly increased TNF-alpha production. PT effects on these LPS responses were correlated with a PT mediated ADP ribosylation of a 41 kDa protein. U-83836E (50 microM) reduced, in a dose dependent manner, LPS induced TNF-alpha production and inhibited the PT effects on cytokine production and on ADP ribosylation of the protein. 5. Our data suggest that lazaroids may affect the early events associated with LPS receptor mediated activation of a G protein in LPS induced TNF-alpha production. These molecular events may explain, at least in part, the in vivo inhibition of cytokine production and reversal of endotoxic shock.

Animals↗

PubMed1998

Protective effects of the new lazaroid "U-83836E" in splanchnic artery occlusion (SAO) shock.

We studied the effects of the new antioxidant drug U-83836E during splanchnic artery occlusion (SAO) shock in the rat. Serum tumor necrosis factor (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure (MAP), survival rate and the responsiveness to acetylcholine of aortic rings were investigated. SAO shock produced a marked increase in serum TNF-alpha (241.4 +/- 18.2 U/ml vs Not Detectable in basal), reduced MAP (51.4 +/- 4 mmHg vs 85.1 +/- 5 mmHg), survival time (80 +/- 10 min vs > 240 min), WBC count (2.8 +/- 0.4 x 10(3)/mm3 cells vs 11.7 +/- 0.9 x 10(3)/mm3 cells) and blunted the responsiveness to ACh of aortic rings (60 +/- 3% tension vs 23 +/- 4% tension). The analogue of vitamin E, U-84836E, administered at onset of reperfusion, lowered serum TNF-alpha (38.4 +/- 6.5 U/ml; p < 0.001), improved MAP (67.5 +/- 3.8 mmHg; p < 0.001), WBC count (8.9 +/- 0.6 x 10(3)/mm3; p < 0.001), and survival time (235 +/- 15 min; p < 0.001), and restored the responsiveness to ACh of aortic rings (32 +/- 3.7% tension; p < 0.001). These preliminary data suggest that this new compound could be a promising drug in shock therapy.

Acetylcholine↗

PubMed1997

17Beta-oestradiol reduces cardiac leukocyte accumulation in myocardial ischaemia reperfusion injury in rat.

We investigated whether oestrogens modulate the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Anaesthetized rats were subjected to total occlusion (1 h) of the left main coronary artery followed by 1 h reperfusion. Sham myocardial ischaemia-reperfusion rats (Sham) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity, serum creatinine phosphokinase activity, serum and macrophages tumour necrosis factor (TNF-alpha) and the myocardial staining of intercellular adhesion molecule-1 (ICAM-1) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum creatinine phosphokinase activity (348 +/- 38 U/ml) and cardiac myeloperoxidase activity, a marker of polymorphonuclear leukocyte accumulation, both in the area at risk and in the necrotic area (MPO 9 +/- 1.1 mU/g tissue and 8.2 +/- 1 mU/g tissue, respectively), and induced a marked increase in the macrophage (156 +/- 14 U/ml at the end of reperfusion) and serum (344 +/- 12 U/ml, at the end of reperfusion) levels of TNF-alpha. Finally, myocardial ischaemia-reperfusion injury increased ICAM-1 staining in the myocardium. Administration of 17beta-oestradiol (5, 10 and 20 microg/kg, i.m. 5 min after induction of myocardial ischaemia-reperfusion injury), lowered myocardial necrosis and myeloperoxidase activity in the area at risk and in the necrotic area, reduced serum and macrophages TNF-alpha (20 +/- 3 U/ml and 9 +/- 3 U/ml, respectively) and decreased serum creatinine phosphokinase activity (67 +/- 3 U/ml). Oestrogen treatment also blunted the increased staining of ICAM-1 in the injured myocardium. Finally, 17beta-oestradiol added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia-reperfusion injury, significantly reduced TNF-alpha production. Our results suggest that 17beta-oestradiol, by inhibiting TNF-alpha production, limits the deleterious ICAM-1-mediated binding of leukocytes to injured myocardium and protects against myocardial ischaemia-reperfusion injury.

Animals↗