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Biomedical subjects

A Ferrante

Publications and source records attributed to A Ferrante.

At least 73 records · Page 4Linked to original sources
PubMed1996

Adhesion and TNF priming in neutrophil-mediated cartilage damage.

Neutrophils predominate in the acute stages of rheumatoid arthritis and are implicated in the cartilage damage which is characteristic of this disease. In vitro neutrophils can be primed for increased ability to damage host tissues by a number of cytokines including tumor necrosis factor-alpha (TNF). The role of adherence in this process was investigated. Opsonization of cartilage with aggregated IgG (HAGG) and complement promoted neutrophil damage to cartilage. Adherence was increased by HAGG and TNF. Separation of neutrophils from cartilage markedly reduced the neutrophil-mediated injury and abolished the priming effect of TNF. Inactivation of complement or antibodies against CD11a or CD11b reduced neutrophil-mediated cartilage damage and markedly reduced TNF-priming of this damage and yet did not alter adherence of control or TNF-primed cells. These results suggest that neutrophil damage to cartilage is promoted by agents that favor adherence. The failure to block adhesion of neutrophils by complement inactivation or antibodies to CD11a or CD11b suggests that neutrophil adherence to cartilage occurs simultaneously through several different receptors. The massive reduction of TNF enhancement of neutrophil damage to cartilage by preventing adhesion suggests that adherence is required for this action of TNF.

Animals↗
PubMed1996

Detection of anti-myeloperoxidase antibodies in the serum of patients with type 1 diabetes mellitus.

Anti-myeloperoxidase (anti-MPO) antibodies were detected in 34 of 88 (38%) patients with type 1 diabetes mellitus but in only 3 of 55 (5.7%) healthy subjects and in 4 of 20 patients with autoimmune disease. Specificity of anti-MPO antibodies was assessed by MPO inhibition studies. No relationship was found between the occurrence of anti-MPO and anti-thyroperoxidase antibodies. Levels of soluble intercellular adhesion molecule 1 (ICAM-1) were found to be higher in anti-MPO antibody-positive (n = 28, 508 +/- 126 ng/ml) than in anti-MPO antibody-negative (n = 58, 438 +/- 140 ng/ml: P < 0.05) patients. A state of chronic neutrophil activation has been described in diabetes mellitus. As anti-MPO antibodies can stimulate neutrophils to damage endothelial cells in systemic vasculitis, this suggests that a similar mechanism may be operative in the development of diabetic angiopathy.

Adolescent↗
PubMed1996

Tumor necrosis factor priming of peripheral blood neutrophils from rheumatoid arthritis patients.

Recently it was shown that tumor necrosis factor-alpha (TNF) receptors on neutrophils may be down-regulated after stimulation with proinflammatory mediators. Since in rheumatoid arthritis neutrophils are likely to encounter these mediators in the circulation, we tested the hypothesis that rheumatoid arthritis neutrophil TNF receptors are down-regulated. Peripheral blood neutrophils from patients with rheumatoid arthritis and healthy subjects were compared with respect to their TNF binding activity and ability to be primed by TNF. There were no differences between rheumatoid arthritis and control neutrophils in receptor-mediated TNF binding, superoxide release in response to agonist, and TNF priming of this respiratory burst or in the ability to degrade cartilage in vitro and TNF priming for increased cartilage damage. It is evident that rheumatoid arthritis blood neutrophils retain the ability to bind TNF and can be primed by TNF for increased oxygen radical production and augmented cartilage damage. These findings further implicate the role of neutrophils in the pathogenesis of arthritis.

Aged↗
PubMed1996

The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group.

BACKGROUND: Adrenal cortical carcinoma is an uncommon tumor with a poor prognosis. The low incidence of this tumor makes it difficult to achieve reliable data on clinical manifestations, natural history, and the impact of therapies. The purpose of this study was to evaluate such aspects in a large series. METHODS: A retrospective series of 129 cases (55 men and 74 women, mean age of 49 years) was collected from 18 surgical institutions. At the time of diagnosis 45.7% of patients had endocrine symptoms. One hundred twenty-four patients underwent surgery, which was considered curative in 91 cases and palliative in 33. Sixty-three patients had local disease, 48 had regional disease, and 43 had distant metastases. RESULTS: This study confirmed a higher incidence in the 40- to 50-year-old population with a female prevalence; hormonal hyperincretion was more common in women, but it was not caused by advanced disease. The overall 5-year survival rate was 35%. Tumor stage and curative resection affected prognosis significantly. The influence of gender, side, age, and hormonal function has not been confirmed. Adjuvant therapies were ineffective in prolonging survival. Reoperated patients experienced better survival (mean, 41.5 months) than nonreoperated cases (mean, 15.6 months). CONCLUSIONS: The poor prognosis of adrenal cortical carcinoma may be improved by early diagnosis and complete resection. Radical surgery is the sole effective therapy, particularly in early stages. Surgical treatment of recurrence seems to improve survival and should be attempted systematically. Adjuvant therapies obtained contrasting results, and their role should be evaluated in prospective multicentric trials.

Actuarial Analysis↗
PubMed1996

GM-CSF-induced priming of human neutrophils for enhanced phagocytosis and killing of asexual blood stages of Plasmodium falciparum: synergistic effects of GM-CSF and TNF.

Granulocyte macrophage-colony stimulation factor (GM-CSF), which is a haematopoietic cytokine generated by activated T lymphocytes and macrophages during infection, was investigated for its effects on human neutrophil-mediated killing of asexual blood forms of Plasmodium falciparum. Pretreatment of neutrophils with human recombinant-GM-CSF markedly increased the parasite killing (measured by a radiometric assay), in the presence of normal serum (containing complement), immune serum (IS), purified IgG (from IS) or heat inactivated IS. GM-CSF pretreatment also enhanced phagocytosis of the parasite by neutrophils and the expression of CR3, Fc gamma RII and Fc gamma RIII receptors. Treatment of neutrophils with a combination of GM-CSF and TNF resulted in a synergistic increase in phagocytosis and killing of the parasite. The findings suggest that GM-CSF is likely to form part of the cytokine network responsible for regulating the antiparasitic activity of the neutrophil in malaria.

Animals↗
PubMed1996

Dope busts in the West: minor cannabis offences in the Western Australian criminal justice system.

Proponents of cannabis law reform argue that many people who are convicted for minor cannabis offences have no prior criminal conviction and are otherwise law-abiding citizens. This study of criminal justice system data in a strict prohibition jurisdiction (Western Australia) found that over 10% of all charges and 85% of all drug charges were for cannabis. Approximately 90% of these were for minor offences. Over 40% of those charged with cannabis possession/use as their most serious offence had never been arrested for any prior offence. Almost half of those first arrested for cannabis possession/use had not been arrested up to 10 years later. Younger first-time arrested cannabis users were more likely to be re-arrested than older offenders. Almost all adult cannabis offenders who went to court were convicted and fined. Nearly 95% of those imprisoned for possession/use of cannabis were gaoled for fine default. The findings accord with earlier research showing that the vast majority of these offenders are, in all respects apart from their cannabis use, a non-criminal section of the community.

Journal Article↗
PubMed1996

Tumor necrosis factor primes neutrophils to kill Staphylococcus aureus by an oxygen-dependent mechanism and Plasmodium falciparum by an oxygen-independent mechanism.

The cytokine tumor necrosis factor (TNF) plays the important role of priming neutrophils for increased antimicrobial activity. We now demonstrate that human neutrophils which lack the ability to generate oxygen radicals, from patients with chronic granulomatous disease, show TNF-induced enhancement of killing of intraerythrocytic stages of Plasmodium falciparum but not of Staphylococcus aureus.

Animals↗
PubMed1996

Cord blood neutrophil responses to polyunsaturated fatty acids: effects on degranulation and oxidative respiratory burst.

Lipid mediators such as arachidonic acid (AA) generated during inflammation play an important role in stimulating phagocytic cell responses. Since cord blood neutrophils show reduced responses to agonists such as the bacterial tripeptide f-Met-Leu-Phe (fMLP), it would be of interest to know whether cord blood neutrophils show normal or reduced responses to AA and other fatty acids. The data showed that the polyunsaturated n-6 fatty acid (PUFA) AA stimulated cord blood neutrophils to produce a respiratory response (measured by chemiluminescence) and degranulation. Other PUFAs, eicosapentanoic acid and docosahexaenoic acid, elicited similar responses in cord blood neutrophils. Specific granule release and chemiluminescence response in cord blood neutrophils were evident at 0.1-0.5 microgram/ml of PUFA, concentrations normally found in vivo during inflammation or following diets enriched with n-3 fatty acids. Neutrophil responses to PUFA were significantly better than those to either fMLP or phorbol myristate acetate. Cord blood neutrophils primed with PUFA showed enhanced responses to fMLP. These results suggest that cord blood neutrophils respond to a similar degree to adult neutrophils to the AA which is generated during the inflammatory response and to the n-3 fatty acids eicosapentaenoic acid/docosahexaenoic acid, both of which may be used in diet manipulation of neurological function and immunological reactions.

Adult↗
PubMed1996

Effect of tumor necrosis factor-alpha on the metabolism of arachidonic acid in human neutrophils.

Although tumor necrosis factor-alpha (TNF-alpha) has been shown to induce marked changes in the physiology/pathophysiology of cells, little is known about the effects of this cytokine on cellular lipid metabolism. In this study we examined the effects of TNF-alpha on the metabolism of eicosatetraenoic acid (arachidonic acid, (20:4(n-6)) in human neutrophils. Pretreatment of neutrophils with TNF-alpha caused a rapid increase in the incorporation of [1-14C]20:4(n-6) substrate into cellular phosphatidylinositol and phosphatidic acid and a slower rise in the incorporation into phosphatidylcholine and phosphatidylethanolamine. Radioactivity was exclusively associated with the sn-2 position of each molecule. The labeling pattern of other phospholipids, neutral lipids, and eicosanoids was unchanged. TNF-alpha had no effect on the distribution of radioactivity in 1-acyl, 1-alkyl, and 1-alk-1-enyl subclasses of phosphatidylcholine, phosphatidylethanolamine, and triglyceride. Chain elongation, beta-oxidation and desaturation of [1-14C]20:4(n-6) were not modulated by the cytokine. TNF-alpha stimulated the release of [3H]20:4(n-6) from prelabeled neutrophils and also induced the production of endogenous unesterified 20:4(n-6). Concomitantly, treatment with the cytokine caused a decrease in the mass of cellular phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine and an increase in the levels of corresponding lysophospholipids, but had no significant effect on sphingomyelin, phosphatidic acid, diglyceride, and other lipids. TNF-alpha did not evoke neutrophils prelabeled with [3H]lyso platelet activating factor to produce [3H]phosphatidylethanol, [3H]phosphatidic acid, or [3H]diglyceride in the presence of ethanol, indicating that phospholipases D and C were not activated. Treatment of the leukocytes with the cytokine had no effect on the activity of neutral and acidic sphingomyelinase. These data collectively provide evidence that TNF-alpha specifically induces the turnover of neutrophil phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine, which are enriched with 20:4(n-6) by the activation of phospholipase A2.

Arachidonic Acid↗
PubMed1995

Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function.

Plasminogen activator inhibitor type 2 (PAI-2) is a serine proteinase inhibitor or serpin that is a major product of macrophages in response to endotoxin and inflammatory cytokines. We have explored the role of PAI-2 in apoptotic cell death initiated by tumor necrosis factor alpha (TNF). HeLa cells stably transfected with PAI-2 cDNA were protected from TNF-induced apoptosis, whereas cells transfected with antisense PAI-2 cDNA, a control gene, or the plasmid vector alone remained susceptible. The level of PAI-2 expressed by different HeLa cell clones was inversely correlated with their sensitivity to TNF. Loss of TNF sensitivity was not a result of loss of TNF receptor binding. In contrast, PAI-2 expression did not confer protection against apoptosis induced by ultraviolet or ionizing radiation. The serine proteinase urokinase-type plasminogen activator was not demonstrated to be the target of PAI-2 action. The P1-Arg amino acid residue of PAI-2 was determined to be required for protection, because cells expressing PAI-2 with an Ala in this position were not protected from TNF-mediated cell death. The results suggest that intracellular PAI-2 might be an important factor in regulating cell death in TNF-mediated inflammatory processes through inhibition of a proteinase involved in TNF-induced apoptosis.

Amino Acid Sequence↗
PubMed1995

Polyenoic very-long-chain fatty acids mobilize intracellular calcium from a thapsigargin-insensitive pool in human neutrophils. The relationship between Ca2+ mobilization and superoxide production induced by long- and very-long-chain fatty acids.

Fatty acids with more than 22 carbon atoms (very-long-chain fatty acids; VLCFAs) are normal cellular components that have been implicated in the pathophysiology of a number of peroxisomal disorders. To date, however, essentially nothing is known regarding their biological activities. Ca2+ mobilization is an important intracellular signalling system for a variety of agonists and cell types. Given that several polyunsaturated long-chain fatty acids mobilize intracellular Ca2+ and that we have postulated that the VLCFAs may be involved in signal transduction, we examined whether the tetraenoic VLCFA induced Ca2+ mobilization in human neutrophils. We report that fatty acid-induced intracellular Ca2+ mobilization declined for fatty acid species of more than 20 carbon atoms, but increased again as the carbon chain length approached 30. This Ca2+ mobilization occurred independently of inositol 1,4,5-triphosphate production and protein kinase C translocation and involved both the release of Ca2+ from the intracellular stores and changes to the influx or efflux of the ion. We further observed that triacontatetraenoic acid [30:4(n-6)] mobilized Ca2+ from a thapsigargin-insensitive intracellular pool distinct from the thapsigargin-sensitive pools affected by arachidonic acid [20:4(n - 6)] or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). 20:4 (n - 6) induced strong superoxide production (chemiluminescence) which was inhibited by thapsigargin pretreatment. In contrast, fatty acid-induced superoxide production progressively declined as the carbon chain length increased beyond 20-22 carbon atoms. Further studies suggested that the thapsigargin-insensitive Ca2+ mobilization elicited by 30:4 (n - 6) was not related to oxyradical formation, while the thapsigargin-sensitive Ca2+ mobilization induced by 20:4 (n - 6) may be involved in the initiation but not necessarily the maintenance of superoxide production. In conclusion, this is the first report to demonstrate a biological activity for the VLCFA and indicates that 30:4 (n - 6) influences second messenger systems in intact cells that differ from those affected by long-chain fatty acids such as 20:4 (n - 6).

Calcium↗
PubMed1995

Activation of mitogen-activated protein kinase by arachidonic acid in rat liver epithelial WB cells by a protein kinase C-dependent mechanism.

Arachidonic acid (20:4(n-6)), which is released by cells responding to a wide range of stimuli, may play an important role in intracellular signaling. We now report that incubation of WB cells with 20:4(n-6) resulted in the appearance of several tyrosine-phosphorylated cytosolic proteins. Two of the phosphotyrosine-containing proteins, migrating in SDS-polyacrylamide gels of approximately 43 and 45 kDa, corresponded in mobility to phosphorylated species of the 42- and 44-kDa mitogen-activated protein kinase (MAPK) isoforms. Immunoblots of soluble fractions from unstimulated WB cells with anti-MAPK antibodies revealed the presence of the 42- and 44-kDa isoforms of MAPK. Upon incubation with 20:4(n-6), the mobility of both isoforms was retarded, consistent with their activation by phosphorylation. Chromatography of soluble fractions from these cells on Mono Q columns revealed early and late eluting peaks of myelin basic protein kinase activity, which contained the 42- and 44-kDa MAPK isoforms, respectively. Activation of MAPK was transient, peaking at 5 min, and was detectable at 5 microM 20:4(n-6). Further studies into the mechanisms by which MAPK was activated by 20:4(n-6) strongly suggested the involvement of protein kinase C (PKC). Not only did incubation of WB cells with 20:4(n-6) result in the translocation of PKC alpha, delta, and epsilon to a particulate fraction, it was found that the fatty acid failed to activate MAPK in cells pretreated for 26 h with phorbol 12-myristate 13-acetate, which depleted WB cells of PKC alpha, delta and epsilon. In addition, fatty acids of the n-3 series were effective activators of MAPK. The present study, to our knowledge, is the first to report that polyunsaturated fatty acids can cause the activation of MAPK.

Animals↗
PubMed1995

Paroxystic hypertension in a long-term hemodialyzed patient. Successful adrenalectomy for a dopamine-producing pheochromocytoma.

Pheochromocytoma (Pheo) is an uncommon neoplasm producing blood pressure troubles and it may be undiagnosed in chronic dialyzed patients in whom hypertension is a common finding. The symptoms in Pheo syndrome depends on the prevalent catecholamine released, the most common being epinephrine (E) and norepinephrine (NE). Recently, a particular clinical picture has been described for dopamine (DA)-producing Pheos, in whom a normo-hypotensive status is more often observed. The authors report a case of mainly dopamine-producing Pheo in a long-term dialyzed patient, successfully treated with adrenalectomy. The main steps in diagnosis and preoperative management are described and debated also in view of the particular background produced by the end-stage renal failure. The common imaging techniques adopted for adrenal medullary neoplasms (US, CT, MIBG scintiscan) confirmed to be decisive for diagnosis; HPLC assay of plasma catecholamines is the only biochemical test available in these patients although its significance is questionable due to the poor knowledge of catecholamine metabolism in chronic renal failure. The clinical findings observed in this case seem in disagreement with those already reported in DA producing Pheos. Pheo in hemodialyzed patients is a rare event and it may be hidden by other more common causes of hypertension. However, more awareness from the medical staff allows to diagnose the neoplasm correctly by the currently available methods and to plan a safe surgical therapy also in high-risk patients.

Adrenal Gland Neoplasms↗
PubMed1995

Inhibitory effects of arachidonic acid (20:4,n-6) and its monohydroperoxy- and hydroxy-metabolites on procoagulant activity in endothelial cells.

The procoagulant response of endothelium to pathophysiological agents such as tumour necrosis factor alpha (TNF alpha) and phorbol myristate acetate (PMA) alters the expression of proteins such as tissue factor. The modulation of such procoagulant activity (PCA) by the polyunsaturated fatty acid arachidonic acid (20:4,n-6) and its 15-hydroperoxy (15-HPETE) and 15-hydroxy (15-HETE) metabolites was examined since this may have important implications in cardiovascular disease and atherosclerosis. Treatment of human umbilical vein endothelial cells (HUVEC) for 30 min with 20:4, 15-HPETE or 15-HETE before induction of PCA with TNF alpha (100 U) or PMA (10(-7) M) caused a significant inhibition of PCA. This inhibition was seen at 2-5 microM fatty acids. Dose response curves with TNF alpha indicated that the inhibition was greatest at higher concentrations of TNF alpha (> or = 250U TNF alpha/ml). The mode of administration of the fatty acid was not critical as fatty acids presented as DPC-fatty acid micelles or solubilised in ethanol gave similar inhibitions of PCA. 20:4, 15-HPETE or 15-HETE did not alter the binding of I125-labelled TNF alpha to its surface receptors on HUVEC, suggesting that the effect of these fatty acids was not mediated by events at the cell surface receptor level. In support of this, these fatty acids were found to inhibit PCA induced by PMA which bypasses cell surface receptors to activate protein kinase C directly.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1995

Effect of fatty acid structure on neutrophil adhesion, degranulation and damage to endothelial cells.

Neutrophils have been implicated in ischaemic heart disease, unstable angina pectoris and acute myocardial infarction. Alterations in dietary levels of specific 18- and 20-carbon polyunsaturated fatty acids have significant clinical benefits in cardiovascular disease. However, to date there has been no concerted effort to identify the structural basis for polyunsaturated fatty acid-induced alterations in key neutrophil functions. We have investigated the influence of fatty acid structure and involvement of lipoxygenase/cyclooxygenase pathways on fatty acid-induced neutrophil functions. When neutrophils were incubated with 18-carbon fatty acids containing one to four double bonds (10-33 mumol/l), a significant increase in adherence and release of specific granule constituents occurred compared with control cells. In general, as the number of double bonds in the 18-carbon fatty acid increased, so did its ability to stimulate these functions. There was less stimulation of adherence and specific granule release by 18:3(n-3) than its isomer 18:3(n-6). Smaller effects were seen on azurophilic granule release. A further increase in adherence and degranulation was observed with increasing carbon chain length (20:3(n-6) and 20:4(n-6)). Differences were found in the ability of isomers of 20:3 to stimulate neutrophil function. Of the fatty acids tested only 20:4(n-6) was able to induce significant neutrophil-mediated endothelial detachment. Introduction of either internal hydroperoxy or hydroxyl groups into 20:4(n-6) abolished its adherence stimulating activity and considerably reduced its ability to stimulate release of both specific and azurophilic granules. Preincubation of neutrophils with either lipoxygenase (caffeic acid) or cyclooxygenase (indomethacin) inhibitors had no effect on 20:4(n-6) stimulated function. These studies show that the number and position of double bonds, carbon chain length and oxidation state can be critical to the neutrophil stimulatory properties of these fatty acids.

Cell Adhesion↗