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Biomedical subjects

L A Boxer

Publications and source records attributed to L A Boxer.

At least 199 records · Page 11Linked to original sources
PubMed1978

Potentiation of polymorphonuclear leukocyte motile functions by 2,3-dihydroxybenzoic acid.

DHB potentiates PMN phagocytosis of opsonized lipopolysaccharide-coated PO droplets by 53% to 45% and chemotaxis by 36% to 10% at 10-3M and 10-4M concentrations, respectively. The effect is reversible in vitro. In the presence of DHB, PMNs released significantly less superoxide and H2O2 to the extracellular media but were able to oxidize 1-14C-glucose normally during phagocytosis. Although iodination of opsonized particles was decreased in the presence of DHB, the PMNs were able to kill Staphylococcus aureus 502A normally. These results support the hypothesis that directed cell movement and phagocytosis can be enhanced by protecting the PMN membrane against auto-oxidative damage from scavenging superoxide and H2O2 by means of DHB.

Cell Movement↗
PubMed1977

The effect of 2-deoxyglucose on guinea pig polymorphonuclear leukocyte phagocytosis.

The effects of 2-deoxyglucose (DOG), an inhibitor of glycolysis, on guinea pig polymorphonuclear leukocytes (PMN) obtained from peritoneal exudates was examined. ATP levels in PMN were reduced by 40% by one hour following an incubation with 2-deoxyglucose. When complement (C3) coated 14C-staphylococcus aureus, C3 coated lipopolysaccharide-paraffin oil droplets (LPS-PO), 14C-pneumococcus opsonized with IgG, or albumin coated paraffin oil droplets opsonized with IgG were added to cell suspensions containing DOG, the phagocytizing rate was 1,310+/-55 cpm/5 X 10(6) cells/15 minutes, 6+/-2 microng paraffin oil (PO)/10(7) cells/minute, 2,250+/-175 cpm/1 X 10(6) cells/20 minutes or 0.037+/-0.01 mg PO/10(7) cells/minute compared to control values of 5,970+/-275 cpm/5 X 10(6) cells/15 minutes, 35+/-3 microng PO/10(7) cells/15 minutes, 4,510+/-200 cpm/1 X 10(6) cells/20 minutes and 0.067+/-0.01 mg PO/10(7) cells/minute. In parallel studies the phagocytic index for latex was 0.74+/-0.28 in DOG compared to control of 2.36+/-1.13 and the phagocytic rate of albumin coated paraffin oil droplets was 0.029+/-0.01 mg PO/10(7) PMN/minute in DOG compared to control of 0.048 mg PO/10(7) cells/minute. When ATP levels were maintained by the simultaneous addition of 5 mM glucose or pyruvate to media containing DOG, latex ingestion was improved to 1.15+/-0.3 with glucose and 1.59+/-0.64 with pyruvate and albumin coated particles to 0.045+/-0.01 mg PO/10(7) PMN/minute with pyruvate. There was no improvement in the uptake of either the C3 dependent particles or IgG coated Pneumococci in media containing DOG and glucose and/or pyruvate. Following the removal of DOG from the extracellular medium and the addition of pyruvate or glucose, phagocytosis of C3 dependent LPS-PO was restored to normal values. Neither the binding of C3 or IgG coated particles to the PMN nor the lateral movement of glycoprotein utilizing concanavalin A capping was affected by DOG. Thus, the presence of DOG in the PMN containing adequate amounts of ATP will selectively and reversibly inhibit those surface events required for phagocytosis of C3 and IgG bound particles but not latex particles or albumin particles which non-specifically bind to PMN.

Adenosine Triphosphate↗
PubMed1977

Abnormal platelet function in Chediak-Higashi syndrome.

Platelets in an infant with Chediak-Higashi (C-H) syndrome without bleeding manifestations and not in the accelerated phase showed abnormal function consistent with storage pool disorder as shown by abnormal aggregation, decreased storage capacity and release of [14C]5-HT, low endogenous 5-HT, reduced ATP and ADP with an increased ATP/ADP ratio, increased specific radioactivity of ADP after [14C]adenine labelling, decreased release of adenine nucleotides after stimulation, impaired secretion of acid hydrolases despite normal stores, and decreased calcium content. Incorporation of [14C]adenine into metabolic pool adenine nucleotides was normal. Nucleotide conversion to hypoxanthine in stimulated platelets was mildly impaired. Platelet cyclic-AMP (c-AMP) was initially elevated, but even when c-AMP returned to normal levels after ascorbate treatment, platelet function was not improved. Elevated intracellular c-AMP was not solely responsible for the abnormal platelet function.

Adenosine Diphosphate↗
PubMed1977

Mechanisms of microtubule diassembly in vivo: studies in normal and chronic granulomatous disease leucocytes.

Microtubule assembly in human polmorphonuclear leucocytes is a dynamic process that can be initiated by binding of the plant lectin Concanavalin A to surface receptors. Colchicine inhibits lectin-induced microtubule assembly and promotes the movement of Concanavalin A into surface caps. Inhibition of microtubule assembly and enhanced Concanavalin A cap formation also follow treatment of normal leucocytes with two specific glutathione-oxidizing agents, 'diamide' and tertiary butylhydroperoxide. Our objective here was to determine if microtubule inhibition is mediated via glutathione disulphide or via hydrogen peroxide that is generated in Concanavalin A-treated leucocytes and may accumulate when cells are depleted of reduced glutathione. We show that exogenous hydrogen peroxide induces Concanavalin A capping on normal polymorphonuclear leucocytes but only at concentrations that simultaneously oxidize glutathione. We also show that 'diamide' and tertiary butylhydroperoxide cause Concanavalin A cap formation in leucocytes from patients with chronic granulomatous disease. These cells cannot generate significant amounts of superoxide or hydrogen peroxide. Thus, it seems likely that the reversible inhibition of microtubule assembly and function caused by glutathione oxidants requires only increased glutathione disulphide and is not dependent on subsequent accumulation of other metabolites.

Child↗
PubMed1977

Improvement of Chediak-Higashi leukocyte function by cyclic guanosine monophosphate.

The addition of cholinergic agents and cyclic 3'5'-guanosine monophosphate (cGMP) to polymorphonuclear leukocytes in vitro from a patient with Chediak-Higashi syndrome corrected the impaired release of the lysosomal enzyme, beta-glucuronidase, to normal. Coinciding with the improvement in degranulation, the bactericidal capacity was enhanced to normal. Similar concentrations of cholinergic agents potentiated chemotaxis to control values. On the other hand, the phagocytic rate of lipopolysaccharide-coated paraffin-oil droplets was not altered by the cholinergic agents. The improvement in Chediak-Higashi syndrome polymorphonuclear leukocyte function by the addition of cholinergic agents and dibutyryl cGMP suggested disturbed intracellular cyclic nucleotide levels.

Blood Bactericidal Activity↗
PubMed1977

Bone marrow transplantation for an infant with neutrophil dysfunction.

A child with severe neutrophil dysfunction and intractable infections received bone marrow transplants from histocompatible siblings. After a first transplant preceded by cyclophosphamide (CY), antithymocyte serum (ATS) and procarbazine (PCB) preconditioning, there was no evidence for engraftment and autologous marrow function rapidly returned. Cell mediated lysis showed no evidence of patient sensitization against the marrow donor suggesting that graft rejection did not cause the transplant failure. A second transplant was performed utilizing another matched sibling donor. Total body irradiation was added to CY, ATS, and PCB for preconditioning after in vitro studies of the colony forming capacity (CFUc) of the patient's marrow cells showed normal sensitivity to radiation. Full engraftment ensued with correction of granulocyte function abnormalities. The patient eventually died of intractable pulmonary disease. Our experience with this child suggests that cyclophosphamide alone may be insufficient preparation for marrow transplantation in some patients with non-neoplastic hematologic disorders. Experimental and clinical data supporting this contention are reviewed.

Antilymphocyte Serum↗
PubMed1977

Autooxidation as a basis for altered function by polymorphonuclear leukocytes.

To investigate the possibility that human polymorphonuclear leukocytes (PMN) elaborate sufficient amounts of hydrogen peroxide (H2O2) and other radicals of reduced oxygen to be autotoxic and retard directed cell movement and phagocytosis, the rate of ingestion of opsonized lipopolysaccharide-paraffin oil particles and movement through Nuclepore filters were studied. Ingestion rates were increased under anaerobic conditions and in normal aerobic conditions in the presence of extracellular catalase but not superoxide dismutase (SOD) or scavengers of singlet oxygen or hydroxyl radicals. Conversely, ingestion rates were decreased when cells were exposed to H2O2 or a superoxide anion (O2-)-H2O2 generating system of xanthine-xanthine oxidase. Catalase, but not SOD, prevented the effect and also enhanced the directed movement of PMN in normal aerobic conditions. PMN from volunteers administered 1600 U/day of the membrane lipid antioxidant alpha-tocopherol were hyperphagocytic but killed Staphylococcus aureus 502A less effectively than controls, suggesting that less H2O2 was available to damage PMN or kill bacteria. H2O2-dependent stimulation of the hexose monophosphate shunt, H2O2 release from phaogytizing PMN, and fluoresceinated concanavalin A cap formation promoted by H2O2 damage to microtubules were all diminished, but the release of O2- from phagocytizing PMN was not diminished in the vitamin E group. These results support the hypothesis that directed movement and phagocytosis by PMN are attenuated by autooxidative damage to the cell membrane by endogenously derived H2O2 and that the administration in vivo of vitamin E may prevent this damage by scavenging H2O2.

Aerobiosis↗
PubMed1976

Correction of leukocyte function in Chediak-Higashi syndrome by ascorbate.

Because ascorbate potentiates chemotaxis of normal leukocytes, we examined the effect of ascorbate on polymorphonuclear leukocytes from a patient with the Chediak-Higashi syndrome. Chemotactic migration was 104+/-16 leukocytes per 10 fields (mean+/-S.D.) initially and 258+/-44 (P less than 0.001) after ascorbate, as compared to 182+/-10 in controls. There was no bactericidal activity by 40 minutes in the patient's untreated leukocytes. After ascorbate bactericidal activity of patient and untreated control cells was the same. The addition of ascorbate reduced cAMP levels in the patient's cells from a mean of 34.5 pmoles per 10(7) polymorphonuclear leukocytes to 5.9, as compared to a control value of 3.1+/-1.4. The association of elevated cAMP and impaired function in the polymorphonuclear leukocytes of patients with the Chediak-Higashi syndrome may be related to abnormal microtubular assembly.

Ascorbic Acid↗
PubMed1976

Chronic neutropenia in childhood. Analysis of 16 cases and a review of the literature.

We analyzed the clinical histories and hematologic information concerning 16 persons in whom chronic neutropenia was discovered early in life. Only two of them, those with the lowest mean neutrophil counts, had frequent and severe pyogenic infections. Almost all the infections were caused by Staphylococcus aureus or by enteric microorganisms and involved the skin, respiratory tract or gastrointestinal system. The prognosis in our subjects or in patients described in the literature could not be predicted from the bone marrow morphology, presence or absence of blood monocytosis, pattern of genetic transmission or results of special tests of neutrophil function. We propose that the complex nomenclature associated with chronic neutropenic states be discarded until a better basis for classification becomes available.

Adolescent↗
PubMed1976

The acute and transient nature of idiopathic immune hemolytic anemia in childhood.

The records of 22 children with the diagnosis of idiopathic immune hemolytic anemia were reviewed. Fifty per cent of the children had a history of an antecedent infection and 32% had underlying immune deficiency or lymphoproliferative diseases. The majority (77%) of the patients had an acute self-limited disease which was frequently associated with a positive complement or nongamma Coombs test. The anemia was usually severe, and a number of the children had reticulocytopenia at the time of diagnosis. These children responded rapidly to transfusions and corticosteroids and generally remained well on follow-up. Immunosuppressive drugs did not prove useful in two patients refractory to prednisone, but splenectomy was apparently beneficial in three of four patients so treated. Mortality rate was 18%, with most of the deaths related to an underlying disease.

Acute Disease↗
PubMed1976

Interactions of actin, myosin, and an actin-binding protein of chronic myelogenous leukemia leukocytes.

Actin, myosin, and a high molecular weight actin-binding protein were purified from chronic myelogenous leukemia (CML) leukocytes. CML leukocyte actin resembled skeletal muscle and other cytoplasmic actins by its subunit molecular weight, by its ability to polymerize in the presence of salts, and to activate the Mg2+-ATPase activity of rabbit skeletal muscle myosin. CML leukocyte myosin was similar to other vertebrate cytoplasmic myosins in having heavy chains and two light subunits. However, its apparent heavy-chain molecular weight and Stokes radius suggested that it was variably degraded during purification. Purified CML leukocyte myosin had average specific EDTA- AND Ca2+-activated ATPase activities of 125 and 151 nmol Pi released/mg protein per min, respectively and low specific Mg2+-ATPase activity. The Mg2+-ATPase activity of CML myosin was increased 200-fold by rabbit skeletal muscle F-actin, but the specific activity relative to that of actin-activated rabbit skeletal muscle myosin was low. CML leukocyte myosin, like other vertebrate cytoplasmic myosins, formed filaments in 0.1 M KCl solutions. Reduced and denatured CML leukocyte-actin-binding protein had a single high molecular weight subunit like a recently described actin-binding protein of rabbit pulmonary macrophages which promotes the polymerization and gelation of actin. Cytoplasmic extracts of CML leukocytes prepared with ice-cold 0.34-M sucrose solutions containing Mg2+-ATP, dithiothreitol, and EDTA at pH 7.0 underwent rapid gelation when warmed to 25 degrees C. Initially, the gel could be liquified by cooling to ice-bath temperature. With time, warmed cytoplasmic extract gels shrunk ("contracted") into aggregates. The following findings indicated that CML leukocyte actin-binding protein promoted the temperature-dependent gelation of actin in the cytoplasmic extracts and that CML leukocyte myosin was involved in the contraction of the actin gels: (a) Cytoplasmic extract gels initially contained actin as their major polypeptide component and consistent of tangled thin filaments; (b) Contracted aggregates of cytoplasmic extract gels contained by large quantities of myosin as well as actin; (c) Purified actin-binding protein underwent a temperature-dependent, reversible aggregation and caused low concentrations of purified muscle or CML leukocyte actins to gel in sucrose solutions; (d) The gels formed from purified actin plus purified actin-binding protein slowly contracted in the presence but not in the absence of purified CML leukocyte myosin; (e) Rabbit antiserum against purified CML leukocyte actin-binding protein but not against purified CML leukocyte myosin inhibited the gelation of warmed CML leukocyte extracts. Antiserum against CML leukocyte myosin had no effect on the gelation of CML leukocyte extracts but partially curtailed the contraction of the CML leukocyte extract gels and of gels formed from purified CML leukocyte actin-binding protein plus rabbit skeletal muscle actin.

Actins↗
PubMed1976

The biochemical basis of nitroblue tetrazolium reduction in normal human and chronic granulomatous disease polymorphonuclear leukocytes.

Normal human polymorphonuclear leukocytes (PMN) placed in anaerobic chambers reaching pO2's of less than 5 mm Hg fail to generate O2-, iodinate ingested particles, and stimulate glucose-1-14C oxidation through the hexose monophosphate shunt. The observation that anaerobic cells are incapable of generating O2- or reducing nitroblue tetrazolium (NBT) to formazan supports the idea that NBT reduction in phagocytizing PMN is due exclusively to oxygen-dependent O2- generating oxidase which is deficient in chronic granulomatous disease leukocytes, despite their hyperphagocytic capacity.

Granulomatous Disease, Chronic↗
PubMed1975

Autoimmune neutropenia.

Serologic tests for antineutrophil antibodies were used to determine if autoantibodies cause neutropenia. The serums of five patients with idiopathic neutropeniaopsonized normal neutrophils, causing them to be ingested by rabbit macrophages or else to activate glucose oxidation rates of other normal neutrophils by at least twice the rate of controls. Some of the serums inhibited the ability of normal neutrophils to ingest by 62 to 56 per cent. At splenectomy in two of the patients splenic macrophages contained ingested neutrophils, suggesting that the opsonic activity of the serum demonstrated in vitro had pathogenetic importance. In two adults, and possibly in an infant, corticosteroids raised the neutrophil count, although antibody activity remained in the serum of the adults. The findings indicate that autoantibodies are the basis of some cases of idiopathic neutropenia, and that they act by promoting the clearance of neutrophils by mononuclear phagocytes.

Adult↗
PubMed1975

Myelofibrosis-myeloid metaplasia in childhood.

A child with idiopathic myeloid metaplasia is described and her course contrasted with another child having myeloid metaplasia secondary to reticulum cell sarcoma. Despite prior reports the idiopathic form of illness may pursue a relatively indolent course in children. A thorough search should be made for underlying disease when myeloid metaplasia is first diagnosed.

Child↗