Biomedical subjects
Publications and source records attributed to A Mazzone.
Two cases of moderate granulocyte adhesion glycoproteins complex deficiency are briefly discussed. These patients presented a clinical history of serious infections at various tissues and organs. Recently, the studies with monoclonal antibodies identified a new group of congenital granulocyte diseases.
This report summarizes the clinical and laboratory findings from a group of our patients and literature reviews from several families who have a genetic deficiency in three related leukocyte membrane surface antigens known as CR3,LFA-1, and p150,95. Each surface antigen has an identical beta-chain noncovalenty linked to one of three distinct alpha-chain types. Patients affected by this autosomal recessive disease have now been identified by several investigators. The patients have an increased susceptibility to bacterial infections that is similar to patients who have other types of neutrophil functional deficiencies or neutropenia. Laboratory tests have indicated that isolated neutrophils from these patients have two major types of functional deficiencies that probably contribute to their reduced ability to overcome bacterial infections. This review focuses exclusively on the phagocytic and cytotoxic abnormalities of neutrophils from these patients.
Isosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10(-7)-10(-6) vs. 10(-6)-10(-5) M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10(-7) M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p less than 0.05) and TX production (-36%, p less than 0.01) by ADP. At 10(-6) M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p less than 0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.
Inhibition of human granulocyte chemotaxis towards casein was observed in the presence of both the mu and kappa opioid receptor agonists, which, per se, exhibited chemokinetic activity. Naloxone was found to prevent both the opioid-related and opioid-unrelated increase in granulocyte migration. Moreover, morphine inhibited the aggregation response of granulocytes in a naloxone-sensitive way, while the opioid peptides were ineffective. Although opioid agonists with different receptor specificity were capable of strongly modifying human granulocyte migration, no conclusion can be drawn on the role of opioid receptors in regulating migrating activity. On the other hand, opioid receptor activation by morphine is likely to be responsible for aggregation inhibition.
We investigated two possible reasons for the greater antiplatelet efficacy of isosorbide dinitrate (ISDN) in vivo as compared to in vitro. ISDN and its two main hepatic metabolites, isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were compared for their ability to inhibit platelet aggregation and thromboxane B2 generation in vitro in response to threshold concentrations of ADP, adrenaline, collagen, thrombin and arachidonic acid. We also determined the concentration of prostacyclin required to inhibit by 50% platelet aggregation (IC50) in response to supra-threshold doses of aggregating agents. Out of the three nitrates tested, IS-2-MN was more effective than ISDN in inhibition of platelet aggregation and thromboxane B2 formation after ADP (minimum effective concentration: 10(-7) M) and adrenaline (minimum effective concentration: 10(-6) M). In addition, ISDN 10(-4)-10(-6) M decreased IC50 for prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active species, IS-2-MN, and synergism with prostacyclin are novel properties of ISDN and may account for in vivo-in vitro differences in antiaggregatory properties and in vivo mechanism of action.
Indexes of in vivo platelet activation, beta-thromboglobulin and platelet factor 4 were measured in triplicate in plasma from venous blood of 69 patients with proven ischaemic heart disease (IHD), discarding samples with a ratio of the plasma concentrations of the two proteins less than 2.6, in order to rule out sampling artifacts. Compared with 60 control volunteers, differences were not significant [for beta-thromboglobulin controls (ng ml-1, mean +/- SD) 27.8-8.6, ischaemic patients 32.3 +/- 17.1; for platelet factor 4 controls 4.3 +/- 1.4, ischaemic patients 5.9 +/- 5.7]. However, when patients were stratified according to disease activity (Group I--patients without spontaneous ischaemic episodes at rest during 4 days of continuous electrocardiographic monitoring; Group II--patients with less than 1 ischaemic episode/day; Group III--patients with greater than 1 episode/day), these indexes were increased in 'active' patients (for beta-thromboglobulin, in Group II--32.4 +/- 10.5 ng ml-1, P less than 0.05 vs. Group I; in Group III--42.6 +/- 14.6 ng ml-1, P less than 0.01 vs. Group I, P less than 0.05 vs. control. Platelet factor 4 was increased only in Group III--8.9 +/- 7.2 ng ml-1, P less than 0.05 vs. control). Beta-thromboglobulin and platelet factor 4 were 25.0 +/- 6.7 ng ml-1 and 4.9 +/- 4.8 ng ml-1, respectively, in Group I (P = NS vs. control). A relationship with the number of spontaneous ischaemic episodes at rest was confirmed by linear regression analysis (in Group III patients for beta-thromboglobulin: r = 0.76, P less than 0.01, and for platelet factor 4 r = 0.62, P less than 0.01). Levels were not elevated in patients with previous myocardial infarction without ischaemia at rest and/or patients with stable angina, and were not influenced by the occurrence of a positive exercise stress test. Coronary angiograms of ischaemic patients were analyzed to assess the extent and severity of atherosclerotic involvement: for both extent and severity, involvement was similar in the three groups. These data support the hypothesis of the occurrence of platelet activation in patients with spontaneous angina at rest, but not in other subsets of IHD patients, and establish the possibility of detecting in vivo platelet activation in IHD by means of such circulating markers.
Twenty four patients with acute infective exacerbations of chronic bronchitis received amoxycillin alone or in combination with erdosteine (a mucolytic agent) for a week in a double blind, placebo controlled study. Clinical assessment scores, body temperature, serum and sputum amoxycillin concentrations, and sputum culture results were recorded in each group. Erdosteine significantly increased antibiotic concentrations in sputum but not in serum. The combined treatment also caused a more rapid decrease in sputum viscosity and in body temperature and faster sterilisation of the sputum. These results show that erdosteine increases amoxycillin concentration in sputum in patients with acute exacerbations of chronic bronchitis. This effect may be due to a reduction in the viscosity of the bronchial secretions produced by erdosteine.
Serum and bronchial concentrations of erythromycin were determined in 30 chronic bronchitic patients during an exacerbation phase of bacterial infections. The levels were measured after single and multiple oral treatments with erythromycin-propionate-N-acetylcysteinate (EPAC) or erythromycin stearate (ES) in a double-blind design. EPAC showed higher and longer-lasting erythromycin levels in serum, sputum and pure bronchial mucus than ES. It is believed that EPAC is better absorbed because of its greater stability in the gastrointestinal juices. Higher concentrations in bronchial secretions not always depend on the blood levels. It seems to be possible that the N-acetylcysteine moiety in the molecule of EPAC drug can facilitate antibiotic penetration because of its mucolytic activity. The clinical response (disappearance of fever, clearance of bacterial pathogens from sputum, reduction of quantity and viscosity of sputum) also occurred faster in the EPAC than in the ES group.
We evaluated the hypothesis that leukotriene (LT) B4, a potent chemotactic and endothelium-permeabilizing autacoid, may be a factor in the progression of the atherosclerotic lesion. Human vascular fragments, freshly obtained at vascular surgery from saphenous veins, atrial appendages, normal aortas and atherosclerotic lesions (histologically classified as fibrous plaques, fatty plaques and complicated lesions) were incubated at 37 degree C with mechanical agitation, for various times ranging between 5 and 60 minutes, sequentially, with buffer (basal), ionophore A23187 (IONO), and arachidonic acid (AA). After each step medium was assayed for LTB4 production by radioimmunoassay. Incubations were also performed in a chamber allowing selective exposure of the endothelial surface to the medium. Basal production (15 minute incubation, ng/g, mean +/- SD) was lowest for fibrous plaques (0.9 +/- 0.2, n = 38) and saphenous veins (1.0 +/- 0.3, n = 32) and much higher (P less than 0.01) for fatty plaques (7.3 +/- 2.2, n = 35) and complicated lesions (5.3 +/- 3.0, n = 28). A virtual abolition of production was observed after boiling of the vascular fragment. Production was increased in the presence of AA and IONO (in atheromas: 11.5 +/- 4.2 AND 14.3 +/- 5.3, respectively, with 15 minutes incubation), and decreased after incubation with 5-lipooxigenase inhibitors. Peak of ionophore or arachidonic acid-stimulated production in kinetic studies was reached at 20 minutes. LTB4 production was able to reach the luminal surface in both basal and stimulated conditions. There was no relationship with concomitantly measured prostacyclin production (mainly endothelial), while a correlation was found between LTB4 levels and degree of white cell infiltration in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of short-term (2 weeks) administration of the anticonvulsant drug phenytoin on humoral and cellular immune function and phagocytic cell system activity was tested in nine healthy volunteers. No change either in the absolute or relative counts of leukocytes was found after drug treatment. Moreover, immunoglobulin serum concentration and lymphocyte subsets positive for OKT3, OKT4, OKT8, OKDRIA, OKB2, Leu 7, Leu 11a, anti-beta 2-microglobulin and antitransferrin monoclonal antibodies were not affected by phenytoin administration. A significant impairment of both polymorphonuclear neutrophil migrating activity and stimulated metabolism as measured by nitro blue tetrazolium reduction and superoxide anion generation was found after drug treatment or when phenytoin was added in vitro to the cells at concentrations lying within the anticonvulsant therapeutic range. Monocyte function was unaffected both after phenytoin administration and after direct application to the cells. The phenytoin-induced changes of polymorphonuclear neutrophil function was completely reverted within 2 weeks after drug withdrawal. The phenytoin-induced alterations of the phagocytic cell system are discussed in relation not only to the possible implications in the pathogenesis of adverse effects of anticonvulsant therapy but also to the potential therapeutic exploitation in immunologically mediated disorders.
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Cellular locomotion is a crucial function for conditioning the arrival to and the behavior of neutrophils in the inflammatory site. It can be spontaneous or stimulated by chemical agents, along chemical gradient (chemotaxis) or in absence of a gradient (chemokinesis). The availability of in vitro and in vivo assays has permitted the definition of specific congenital and acquired neutrophil abnormalities, which are associated with defective host resistance. The appreciation of complex and often adverse effects of certain systemic diseases and drugs on neutrophil locomotion as well as the use of new approaches to therapy suggest the importance of assessing the role of the neutrophil in states of impaired host defense.
Ciprofloxacin is a new quinolone carboxylic acid derivative which exerts its antibacterial activity at very low concentrations against a wide spectrum of microorganisms. Ciprofloxacin serum and urine concentrations were studied in 10 healthy volunteers after a single 250 and 500 mg oral dose. The concentration in ascitic fluid was determined in four male patients undergoing paracentesis after a single oral 250 mg dose (two patients) and 500 mg dose (two other patients). The penetration of ciprofloxacin into the human tonsils and turbinate bones was also determined in eight patients undergoing tonsillectomy or turbinectomy 3 h after a single oral 250 mg administration. Ciprofloxacin concentrations were determined by an agar diffusion test utilizing E. coli as reference strain. Ciprofloxacin is rapidly absorbed after oral administration (Ka = 2.67 and 1.93 mcg/ml) and its serum concentration does not vary significantly with sex and dosage (Cmax = 2.61 and 1.99 mcg/ml after a single 500 mg and 250 mg oral dose). Urinary concentrations of ciprofloxacin are twice higher after a single 500 mg dose than after a 250 mg one and are still high after 24 h (37.2 and 25.3 mcg/ml). The concentrations of ciprofloxacin in ascites, tonsils and turbinate bones are several times higher than its MICs against the majority of Gram+ and Gram- aerobic bacteria. The in vitro activity of ciprofloxacin and its human pharmacology suggest a twice daily 250 of 500 mg dosing for infections caused by multiple antibiotic-resistant bacteria, and a once a day dose in the treatment of urinary tract infections.
The relationship between JA and phagocyte function has often been reported in the literature. The action of JA may either inhibit or stimulate PMNs function depending on the concentration. On the basis of this experience, the efficacy of JA action, both directly and mediated after incubation was studied. In particular phagocytosis, NBT, superoxide production and chemotaxis were studied in basal conditions and after incubation with hyaluronic acid. In particular chemotaxis was also performed to assay the chemotactic action of the medium in which the monocytes were incubated with JA and the technique was found to produce a distinct progressive improvement in the chemotactic index. In conclusion, it is hypothesised that monocytes incubated with JA produce a chemotactic factor for PMNs.
In autoimmune disorders there is usually only one cell-type involved but occasionally there are more. The cell associated-IgG and -C3 in these disorders are sequestered normally in the spleen and removed by phagocytosis in the reticulum endothelial system (RES). Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease and normally presents only thrombocytopenia. Infrequently, neutropenia is associated. Recently high doses of intravenous gammaglobulin (HDIGG) have been used to block the cell destruction by RES in these diseases. The patient presented with ITP and associated neutropenia and was treated with HDIGG. We studied some neutrophil function, in relation to therapy (chemotaxis, random migration, latex phagocytosis, NBT reduction, superoxide generation), and performed some cytochemical stains (LAP and myeloperoxidase). We also determined the presence of antiplatelet and antineutrophil functions and resulted in an increase in the platelet and neutrophil count.
Patients suffering from myeloproliferative diseases are frequently susceptible to infection. We studied granulocyte function and cytogenetics in 32 patients with different myeloproliferative syndromes. In vivo granulocyte function was studied in 10 patients using the skin window technique. Our data demonstrate a deficit in chemotaxis (p less than 0.001) which does not seem to correlate with any specific chromosomal anomaly. Patients showing a deficit in myeloperoxidase activity, phagocytosis, O2- production or NBT reduction also had a much lower median survival with respect to other patients treated with the same protocol but without these deficits (p less than 0.01). By conducting granulocyte function studies at diagnosis one may therefore isolate those patients with an increased risk of contracting infections and a decreased probability of complete remission.
Twelve patients given more than 1 year phenytoin monotherapy and 12 healthy control subjects taking no drugs and matched for sex and age were examined for polymorphonucleate (PMN) functions. To assess PMN activity, cell locomotion and directed migration, phagocytosing ability and bactericidal activity were investigated. No change either in the absolute or relative counts of PMN leucocytes was found in the patients. However, a significant impairment of both PMN chemotaxis and stimulated Nitro Blue Tetrazolium reduction or superoxide anion generation was observed in the patients as compared with the control group of subjects.
The inflammatory process of rheumatoid arthritis is characterized by an alteration in neutrophil function and an accompanying increase in the number of these cells within the joint space. Both inhibition of peripheral neutrophil chemotaxis and the paradoxic and concomitant deleterious effects of overreactive synovial neutrophils are expressions of an imbalance within the immune system. Levamisole and methisoprinol have been found to improve the alterations in cellular function and immune response. We studied the in vitro effect of these drugs on neutrophil function in four patients with rheumatoid arthritis whose basal chemotaxis was seriously inhibited. Levamisole and methisoprinol improved neutrophil chemotaxis by inducing, in monocytes incubated with these drugs, the production of an important chemotactic factor effective on the altered neutrophils. We suggest that the use of these drugs is beneficial in the treatment of rheumatoid arthritis.