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Biomedical subjects

J Pitt

Publications and source records attributed to J Pitt.

At least 73 records · Page 4Linked to original sources
PubMed1987

Low red cell arachidonic acid in hemolytic uremic syndrome.

A defect in prostacyclin generation has been proposed in hemolytic uremic syndrome (HUS): prostacyclin is formed from arachidonic acid derived from phospholipid and low levels of some phospholipids have been described in HUS cell membranes. Therefore fatty acid content of the red blood cell membranes of 8 children with HUS was compared with 32 children with other renal disease, with 33 patients with non-renal disease and with 8 normal adults. Children with HUS consistently had lower proportions of arachidonic acid (2.7-8.4%) than all other groups (10.1-18.8%) and the mean arachidonic acid level in HUS was very significantly reduced (p less than 0.0001). These findings suggest a reduced availability of arachidonic acid for prostaglandin synthesis in HUS and are consistent with the proposition that arachidonic acid is lost through peroxidative change.

Adolescent↗
PubMed1985

Deficiency of two human leukocyte surface membrane glycoproteins (Mo1 and LFA-1).

Structural and functional features of a novel disorder characterized by recurrent bacterial infections are reviewed. This disease is associated with a number of phagocyte adhesion defects. In 10 patients, phenotypic analysis with monoclonal antibodies (MAb) revealed the same basic defect in all patients: deficiency of at least two leukocyte surface glycoproteins, Mo1 and LFA-1. These two antigens have distinct alpha subunits (Mo1 alpha = 155 kilodaltons, LFA-1 alpha = 177 kilodaltons) noncovalently linked to a common beta subunit (94 kilodaltons). Mo1 is closely associated with or identical to a receptor for the iC3b fragment of the third component of complement. LFA-1 is involved in lymphocyte proliferation, cytotoxicity, and natural killing. MAb directed to this family of glycoproteins induce functional defects in normal cells similar to those observed in deficient cells. In normal cells, the surface expression of these glycoproteins is regulated by the state of cell activation. Mitogens and alloantigens significantly increase the surface expression of LFA-1 on T lymphocytes. Stimuli that induce degranulation in neutrophils increase the surface expression of Mo1. In all patients with combined Mo1, LFA-1 deficiency, the predominant clinical manifestations were more characteristic of a phagocyte than a lymphocyte disorder. In vitro studies, however, reveal significant defects in phytohemagglutinin-induced proliferation that are more apparent at lower concentrations of the lectin. In some families, more than one sibling is affected. Intermediate levels of Mo1 were observed on granulocytes from both parents of one child. In one family, however, only the mother had significantly reduced levels of Mo1, which indicates heterogeneity in the inheritance of this disorder.

Animals↗
PubMed1984

Deficiency of a surface membrane glycoprotein (Mo1) in man.

Deficiency of a granulocyte surface glycoprotein of 150,000-D had been associated with defective C3- and IgG-dependent phagocytosis in a patient with recurrent bacterial infections. By using monoclonal antibodies, we found that this patient's granulocytes, monocytes, and null cells were deficient in Mo1 (equivalent to OKM1 and Mac-1), a cell surface molecule consisting of two noncovalently linked glycoproteins of 155,000 and 94,000 D. The 155,000-D subunit is closely associated with the human complement receptor that recognizes C3bi and/or a further degradation product termed C3dg (C3bi receptor); the 94,000-D subunit has been shown to be shared, on normal cells, by two other surface membrane glycoproteins: lymphocyte function-associated antigen-1 (LFA-1) and P-150, 95. Both subunits of Mo1 were deficient on the patient's granulocytes as determined by immunoprecipitation with subunit-specific monoclonal antibodies as well as fluorescence analysis. Mol-deficient monocytes, like granulocytes, had defective C3-and IgG-dependent phagocytosis. Natural killing activity by the patient's peripheral blood leukocytes was normal. Mo1-deficient granulocytes and monocytes rosetted normally with sheep erythrocytes coated with C3bi. This rosetting was totally inhibited by a mixture of anti-Mo1 and anti-C3b (the major fragment of C3) receptor antibodies but not by either antibody alone. Since monoclonal antibodies to the 155,000-D subunit of Mo1 can inhibit C3bi receptor binding, immune phagocytosis, opsonized zymosan-induced degranulation, and superoxide generation by normal phagocytes (functions which are defective in Mo1-deficient cells), it appears likely that Mo1 deficiency may in part underlie the functional aberrations leading to recurrent bacterial infections in man.

Animals↗
PubMed1984

Deficiency of a leukocyte surface glycoprotein (LFA-1) in two patients with Mo1 deficiency. Effects of cell activation on Mo1/LFA-1 surface expression in normal and deficient leukocytes.

Mo1, a phagocyte surface glycoprotein heterodimer, is involved in a number of phagocyte adhesion functions such as binding and ingestion of serum-opsonized particles, zymosan-induced degranulation, and superoxide generation. Deficiency of this antigen in humans has been associated with increased susceptibility to recurrent bacterial infections. The beta subunit of Mo1 is shared by another surface glycoprotein named LFA-1, which is involved in lymphocyte proliferation, cytolytic T cell, and natural killing activities. Two unrelated patients with Mo1 deficiency were found to be deficient in LFA-1 as well as in the common beta subunit. Investigation of lymphocyte functions in these two patients revealed normal mixed leukocyte culture-generated cytolytic T cell and natural killing activities and significantly reduced proliferative response to phytohemagglutinin. LFA-1-deficient cells also proliferated in response to soluble antigen and different alloantigens. These responses were partially blocked by anti-LFA-1 antibody. Whereas LFA-1 was undetectable by immunofluorescence and immunoprecipitation on the patients' resting T cells, significantly reduced (approximately 5% of normal) but detectable amounts of the heterodimeric LFA-1 antigen were found on mitogen and alloantigen-activated T cells. On granulocytes, Mo1 surface expression was also dependent on the state of cellular activation. The amount of surface Mo1 present on resting normal granulocytes increased by 3-10-fold following exposure to stimuli that induced degranulation, suggesting the presence of a major intracellular pool for this antigen. Analysis of subcellular fractions from granulocytes showed that intracellular Mo1 is located primarily in the specific granule fraction. Activated granulocytes had little or no increase in their surface expression of LFA-1 antigen. Deficient granulocytes had significantly increased numbers of Mo1 antigen expressed on the surface following stimulation with calcium ionophore (1 microM). However, the amount expressed continued to be significantly reduced compared with normal cells. Quantitation of surface Mo1 on granulocytes exposed to calcium ionophore (1 microM) showed that both parents in one family but only the mother in the other family had significantly reduced levels of Mo1, suggesting heterogeneity in the inheritance of this disorder. Whereas LFA-1 deficiency on lymphocytes was associated with normal alloantigen-induced cytolytic T cell and natural killing activities in these two patients, functions which were in part dependent on small amounts of detectable LFA-1 antigen, the Mo1 deficiency state led to significant defects in phagocyte adhesion functions. Hence, the clinical symptoms associated with this combined deficiency state reflect a more profound phagocyte than lymphocyte disorder.

Animals↗
PubMed1983

Correlation between low natural killing of fibroblasts infected with herpes simplex virus type 1 and susceptibility to herpesvirus infections.

Natural killer cells capable of lysing herpes simplex virus type 1 (HSV-1)-infected fibroblasts were studied in three groups of patients unusually susceptible to severe herpes-virus infections. Cord blood was evaluated because of the known susceptibility of neonates to disseminated infections due to herpes simplex virus type 2 at birth. Only 30% of the cord blood specimens tested demonstrated normal lysis of HSV-1-infected fibroblasts and a normal increment in the lysis of infected over uninfected cells. Five out of six patients with Wiskott-Aldrich Syndrome (WAS) also were found to have abnormally low responses by these criteria. The one WAS patient with normal responses had had little difficulty with infections and had survived much longer than usual. Five patients with severe herpesvirus infections and no known primary cellular immunodeficiency had natural killer cell function significantly below normal (P less than 0.001). These data suggest that natural killer cells probably play an important role in human resistance to herpesvirus infection and that deficiencies of this system may result in unusual susceptibility to herpesvirus infections.

Adolescent↗
PubMed1980

Hemagglutination typing of Escherichia coli: definition of seven hemagglutination types.

A hemagglutination (HA) typing system has been developed for demonstrating and characterizing the mannose-sensitive and mannose-resistant hemagglutinins produced by Escherichia coli isolated from human sources. HA typing is performed by testing CFA agar-grown E. coli cells for HA with human, bovine, adult chicken, African Green monkey, and guinea pig erythrocytes in the presence and absence of mannose. Seven major HA types, designated HA type I through HA type VII, have been defined according to the HA patterns produced by 1,334 test cultures consisting of 33 colonization factor antigen I (CFA/I)-positive enterotoxigenic E. coli (ETEC), 37 CFA/II-positive ETEC, 614 isolates belonging to the classical enteropathogenic E. coli, or EPEC, serogroups, 446 non-ETEC, non-EPEC stool isolates, and 204 bacteremia-associated E. coli. Facultatively enteropathogenic E. coli (FEEC) serogroups, which are the causative agents of extraintestinal infections but also sporadic cases of enteritis, comprised 38% of the stool isolates and 91% of the blood isolates examined. Previous observations concerning the HA patterns of CFA-positive ETEC and the EPEC were confirmed. A significant correlation was found between FEEC serogroups and the production of mannose-resistant HA with human, monkey, and usually chicken erythrocytes (the HA patterns designated HA type VI). A large majority (80.2%) of the FEEC strains belonging to the most frequently isolated serogroups from cases of bacteremia (O1, O2, O4, O6, O7, and O18) produced type VI HA patterns. Stool isolates belonging to these same serogroups were 59.2% positive for HA type VI patterns. In contrast, only 17.4% of the non-FEEC stool isolates and 1.9% of the EPEC isolates belong to HA type VI. Of the blood isolates, the HA type VI phenotype was two times more prevalent among K1-positive E. coli than among K1-negative E. coli, 70.6 versus 31.1%. These results suggest that surface-associated hemagglutinins of E. coli, many of which are known to be fimbriae, should be considered in addition to serotype (O:K:H antigenicity) in the description of isolates.

Animals↗
PubMed1979

Virulence of Escherichia coli K1 in adults.

Of 137 cases of Escherichia coli bacteremia in adults at a general hospital, 16 (12%) were caused by E. coli K1. The case records of 15 patients with E. coli K1 and 48 patients with other E. coli revealed that the patients with E. coli K1 had an average age of 54, while those with other E. coli had an average age of 61 (P greater than 0.05). There was no significant difference between the profiles of underlying disease in the two groups. No patients with E. coli K1 bacteremia died, while 16 of 48 patients with non-K1 bacteremia died (P =0.006). This difference was statistically significant in those patients with ultimately fatal disease (P = 0.038) but not in those with non-fatal disease (P = 0.16). These findings suggest that E. coli K1 is cleared more easily by adults than are other E. coli.

Adolescent↗
PubMed1978

K-1 antigen of Escherichia coli: epidemiology and serum sensitivity of pathogenic strains.

K-1 Escherichia coli are far more frequent in neonatal sepsis (36% of E. coli sepsis) and meningitis (80% of E. coli meningitis) than would be expected by the frequency of K-1 E. coli colonization in neonates (11 to 25%). There is no apparent parallel in cases of sepsis in adults. To study further this apparent age-related difference in virulence, E. coli K-1 clinical isolates were tested for their sensitivity to sera. Strains isolated from cases of neonatal meningitis were more sensitive to serum bactericidal activity than those from cases of neonatal or adult sepsis or adult meningitis (P < 0.01). Serum sensitivity did not appear to be determined by K or O antigens. Four isolates sensitive to serum bactericidal activity obtained from neonatal cerebrospinal fluid were killed by adult serum chelated with 0.05 M Mg(2+) ethyleneglycol-bis (beta-aminoethyl ether)-N,N-tetraacetic acid (EGTA), suggesting that the alternative pathway was activated. Although untreated neonatal sera killed these strains as well as adult sera did, EGTA-treated neonatal sera were less effective than EGTA-treated adult sera. This suggests that the alternative pathway function was not activated in neonatal sera. The bactericidal defect of neonatal EGTA-treated serum was partially corrected by addition of either A or B hyperimmune equine meningococcal antiserum.

Adult↗
PubMed1977

Protection against experimental necrotizing enterocolitis by maternal milk. I. Role of milk leukocytes.

A rat model of necrotizing enterocolitis of the neonate in which maternal milk had been protective was studied to determine what components of the milk afforded protection and by what mechanism. Frozen and thrawed rat milk was not protective, but formula supplemented with rat milk cells was. It was concluded that the cells provided protection. The cells, which are principally mononuclear phagocytes, can phagocytize and kill the Klebsiella pneumoniae strain used in the animal model. Animals with necrotizing enterolitis had peritonitis and bacteremia caused by this bacillus.

Animals↗
PubMed1976

Synthesis and release of polyribophosphate by Haemophilus influenzae type b in vitro.

Polyribophosphate, the capsular polysaccharide antigen of Haemophilus influenzae type b, can be assayed in crude bacterial extracts by a combination of immunoprecipitation, hot-acid extraction, and colorimetry. In vitro, the antigen is synthesized during growth and, in well-buffered media, in early stationary phase as well. It is shed from the cell throughout the course of synthesis, and at 37 C almost all the extractable antigen has been released spontaneously within several hours after synthesis. Various strains are similar in extent of synthesis and gross composition of the antigen; however, strains differ in the rate of release during exponential phase. The antigen is released as (or as part of) a very large structure, although under certain culture conditions much smaller antigenic units are found.

Antigens, Bacterial↗
PubMed1974

Lipid peroxidation in the killing of phagocytized pneumococci.

To directly examine the role of hydrogen peroxide in the killing of bacteria after ingestion by granulocytes, we have studied some of the events of phagocytosis of a mutant strain of pneumococci which is relatively deficient in peroxide production. The hydrogen peroxide-deficient pneumococci and the otherwise identical wild type were grown with [(14)C]arachidonic and [(3)H]palmitic acid labels to label their lipids with unsaturated and saturated fatty acids, respectively. They were then incubated with both normal and chronic granulomatous disease granulocytes. The rates of ingestion and bacterial killing and the stability of fatty acids in the cell-bacteria complex were followed. Radioactive carbon dioxide released from glucose was also independently followed to measure glucose oxidation. Ingestion was similar for all cell-bacteria combinations. Chronic granulomatous disease cells killed the peroxide-positive wild pneumococci much more effectively (20-fold) than the peroxide-deficient mutant. Normal cells killed both peroxide-positive and -negative strains effectively. A considerable loss of [(14)C]arachidonic acid ( approximately 40%) consistent with lipid peroxidation of this unsaturated fatty acid was observed in all normal cells and in chronic granulomatous disease cells with peroxide-positive pneumococci. However, no loss of [(14)C]arachidonic acid occurred in chronic granulomatous disease cells with the peroxide-deficient pneumococci. No loss tritiated palmitic acid occurred in any cell-bacteria combination. Glucose oxidation was impaired in the chronic granulomatous disease cells in comparison to normal cells at rest and was especially impaired in chronic granulomatous disease cells ingesting the peroxide-deficient mutant pneumococci. This defect was partially corrected after phagocytosis of the peroxide-positive strain. These data directly support the hypothesis that bacterial killing is partially dependent upon an intact peroxide-generating system in the leukocyte-bacteria complex. Moreover, they indicate that bacterial lipid peroxidation is associated with the generation of peroxide during phagocytosis. Finally, they suggest that such peroxidation may contribute to effective phagocytic bacterial killing.

Animals↗
PubMed1974

Role of peroxide in phagocytic killing of pneumococci.

Two mutants of a pneumococcus type I with diminished peroxide production were selected from a population of nitrosoguanidine-treated cells. White cells of normal patients killed the mutant pneumococci as well as the otherwise isogenic wild-type strain. In patients studied with chronic granulomatous disease, however, the peroxide-poor strain was killed far less well than the wild type. These studies indicate that the removal of a peroxide-generating system in the phagocytic vacuole specifically brings forth the killing defect in chronic granulomatous disease.

Animals↗