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Biomedical subjects

F C Schmalstieg

Publications and source records attributed to F C Schmalstieg.

At least 55 records · Page 3Linked to original sources
PubMed1988

Substrate inhibition of adenosine phosphorylation in adenosine deaminase deficiency and adenosine-mediated inhibition of PP-ribose-P dependent nucleotide synthesis in hypoxanthine phosphoribosyltransferase deficient erythrocytes.

The metabolism of adenosine and its effects on phosphoribosylpyrophosphate, PP-ribose-P, dependent nucleotide synthesis were studied using erythrocytes from patients with adenosine deaminase and hypoxanthine phosphoribosyltransferase deficiency as models. The phosphorylation of adenosine was progressively inhibited by concentrations of adenosine greater than 1 mumol L-1 for control and ADA deficient erythrocytes. There was essentially no initial rate of phosphorylation at 30 mumol L-1 adenosine. Adenosine, 1 mumol L-1, also caused a 60% reduction in PP-ribose-P concentration in ADA deficient erythrocytes. For HPRT deficient erythrocytes in which ADA activity was blocked by coformycin, 10 mumol L-1 inosine stimulated PP-ribose-P dependent nucleotide synthesis from adenine, whereas, 10 mumol L-1 adenosine inhibited nucleotide synthesis. These observations suggest that adenosine phosphorylation and PP-ribose-P dependent nucleotide synthesis are inhibited under conditions in which adenosine accumulates, such as in hereditary or pharmacologically induced ADA deficiency.

Adenosine↗
PubMed1988

Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration.

Human neutrophil (PMN) attachment to human umbilical vein endothelial cells (HUVEC) was evaluated in vitro using two MAbs, R6-5-D6 and RR1/1, that recognize intercellular adhesion molecule-1 (ICAM-1), and one MAb, TS1/18, that recognizes CD18. Pretreatment of the HUVEC with anti-ICAM-1 MAbs produced greater than 50% inhibition of attachment to HUVEC, and IL-1 (0.5 U/ml)- or lipopolysaccharide (LPS) (10 ng/ml)-stimulated HUVEC, and greater than 99% inhibition of f-Met-Leu-Phe (0.5 nM) enhanced adherence. Anti-ICAM-1 MAbs also inhibited by greater than 85% the transendothelial migration induced by 4-h IL-1 (0.5 U/ml) and LPS (10 ng/ml) activation of the HUVEC. That these effects involved a CD18-dependent mechanism is supported by the following results: pretreatment of PMN with TS1/18 produced the same degree of inhibition of attachment and migration as seen with R6-5-D6. In addition, the use of both MAbs together did not further increase the inhibition of cell attachment to stimulated HUVEC. The attachment of PMN from patients with CD18 deficiency to stimulated HUVEC was not reduced by R6-5-D6, and both R6-5-D6 and TS1/18 revealed the same time course for appearance and disappearance of an adherence component on stimulated HUVEC not blocked by either MAb. These results demonstrate that attachment and transendothelial migration of PMN in vitro depend substantially on both CD18 on the PMN and ICAM-1 on the endothelial cell.

Antibodies, Monoclonal↗
PubMed1988

The motility of human milk macrophages in collagen gels.

The hypothesis that the diminished motility of human milk leukocytes is due to a decrease in adherence was tested by using a collagen gel system in which leukocyte movement is less dependent on adherence. Unfractionated human milk leukocytes (HML) or fractionated peripheral blood leukocytes were placed on collagen gels in microwells and the leading edge of migration was determined by inverted phase microscopy. The mean rates of invasion of HML, blood neutrophils, and mononuclear blood leukocytes were 14, 240, and less than 1 mu/h, respectively (p less than 0.01). We then examined the identity of motile HML by immunoperoxidase techniques using antibodies to selected cell markers. Motile HML were positive for a specific macrophage marker (cathepsin B) and a neutrophil and monocyte marker (Mac-1) but were negative for specific neutrophil (cathepsin G) or lymphocyte markers (CD3 and CD5). The directed motility of these cells was not enhanced by exposure to the chemoattractant, N-formyl-L-methionyl-L-phenylalanine, but was inhibited by a T cell lectin, phytohemagglutinin. The movement was actin dependent but was not dependent on calcium or Mac-1 surface glycoproteins. Thus, the diminished motility of milk neutrophils does not appear to be due to decreased adherence per se, and those HML that are motile are macrophages. This suggests a dichotomy for the function of HML. Neutrophils may be relegated to the lumen of th alimentary tract, whereas macrophages may penetrate into mucosal sites for host defense.

Cell Migration Inhibition↗
PubMed1987

Periodontal manifestations of the heritable Mac-1, LFA-1, deficiency syndrome. Clinical, histopathologic and molecular characteristics.

The clinical, histopathologic and functional consequences of the genetic deficiency of leukocyte Mac-1, LFA-1 and p150,95 were assessed among three affected patients, heterozygotes and unaffected individuals among two generations of a single kindred. Longitudinal assessments of this family afforded the unique opportunity to characterize the natural history of severe periodontal manifestations associated with this disorder. Features uniformly observed among each patient included recurrent, necrotic soft tissue infections, impaired pus formation, delayed wound healing, constant granulocytosis, severe abnormalities of adhesion-dependent granulocyte functions and a profound deficiency (3%-6% of normal) of Mac-1 glycoproteins on granulocyte surfaces. Characteristic features of generalized prepubertal periodontitis including rapidly progressive alveolar bone loss affecting the primary and permanent dentitions (leading to premature tooth loss), recession, clefting and migration in association with intense gingival inflammation were uniformly observed. Biopsies of inflamed periodontal tissues in these individuals demonstrated dense infiltrates of mononuclear leukocytes but a striking absence of extravascular neutrophil granulocytes. Heterozygous family members demonstrated approximately half normal Mac-1 protein expression but no susceptibility to systemic infections and normal, adhesion-dependent leukocyte functions. Prepubescent heterozygotes demonstrated no periodontal manifestations but a 31-year-old heterozygous female exhibited clinical and radiographic features typical of postjuvenile periodontitis. The profound periodontal manifestations recognized in this clinical-pathologic model emphasize the physiologic importance of leukocyte adhesion reactions in defense of the periodontium and further suggest a possible pathologic role for Mac-1 proteins in other forms of early-onset periodontitis.

Adult↗
PubMed1986

Contributions of the Mac-1 glycoprotein family to adherence-dependent granulocyte functions: structure-function assessments employing subunit-specific monoclonal antibodies.

MAb directed at the alpha-subunits of Mac-1 (alpha M), LFA-1 (alpha L), p150,95 (alpha X), or their common beta-subunit were used to characterize the contributions of the Mac-1 glycoprotein family to granulocyte adherence reactions. Inhibitory effects of these MAb in incubation experiments with normal granulocytes indicated distinct adhesive contributions of each subunit. Significantly greater adherence, and inhibition of adherence by anti alpha M, alpha X, and beta MAb, was observed under chemotactic conditions designed to "up-regulate" the surface expression of the alpha M beta and alpha X beta complexes. Adherence to protein-coated glass and binding of albumin-coated latex beads were significantly inhibited by anti-beta greater than anti-alpha M (OKM-10, M1/70, LM2/1.6 and OKM-1) greater than anti-alpha X greater than anti-alpha L MAb, but no effects of anti-HLA, AB, or anti-CR-1 MAb were evident. A similar rank order of inhibition was observed in granulocyte aggregation assays in response to C5a, PMA, or f-Met-Leu-Phe. Significant inhibition of directed migration by anti-beta or anti-alpha M (OKM-1 or OKM-10) MAb was observed in subagarose but not Boyden chemotaxis assays; inhibition was dependent on a continuous cell exposure to anti-Mac-1 alpha or beta during the assay, suggesting that a continuum of new Mac-1 expression is required for directed translocation. Phagocytosis of Oil-Red-O paraffin or zymosan selectively opsonized with C3-derived ligands was significantly inhibited by anti-alpha M MAb (OKM-10 greater than LM2/1.6 greater than M1/70 greater than OKM-1) or by combinations of anti-alpha M + anti-CR-1 MAb, but only minimal inhibitory effects of anti-beta MAb and no effects of anti-alpha L or anti-alpha X MAb were seen. Similarly, complement-dependent phagocytosis-associated lactoferrin release, ingestion, and intracellular killing of Staphylococcus aureus 502A, and binding of iC3b-opsonized SRBC, were significantly inhibited by anti-alpha M (OKM-10, M1/70) or combinations of anti-alpha M + anti-CR-1 MAb, but not by anti-beta, alpha L, or alpha X MAb. Notably, none of the anti-Mac-1 MAb demonstrated inhibitory effects in assays of adherence-independent functions including shape change, specific f-Met-Leu-3H-Phe binding, O-2 generation, chemiluminescence evolution, or lactoferrin release in response to PMA.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Binding of the adhesive protein complex (LFA-1/Mac-1/p150,95) to concanavalin A.

At least 30 proteins from human PMNL plasma membranes capable of binding concanavalin A (Con A), can be identified after surface labeling with 125I and subsequent sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Immunoprecipitation of the labeled proteins after solubilization in non-ionic detergents, with monoclonal antibodies (MAbs) directed against a family of leukocyte membrane proteins (LFA-1, Mac-1, p150,95, and the beta subunit these glycoproteins share), indicated that Mac-1 and p150,95 were bound by Con A. Dissociation of the alpha and beta subunits with sodium dodecyl sulfate, electrophoresis, transfer to nitrocellulose paper, and subsequent binding of these proteins by Con A demonstrated Con A retention by Mac-1-alpha, p150,95-alpha, and the common beta subunit. Affinity of Con A for LFA-1-alpha from human peripheral blood PMNL could not be confirmed by direct binding or electroblotting. Similar experiments in a patient deficient in LFA-1, Mac-1, p150,95, and the beta subunit confirmed that Mac-1-alpha and the beta subunit were important Con A-binding proteins.

Antigens, Surface↗
PubMed1986

Two-dimensional and three-dimensional movement of human polymorphonuclear leukocytes: two fundamentally different mechanisms of locomotion [corrected].

Patients with an inherited deficiency of the adherence glycoproteins LFA-1, Mac-1, and p150,95 are unable to mobilize polymorphonuclear leukocytes (PMNLs) to peripheral sites of inflammation. LFA-1/Mac-1/p150,95-deficient PMNL exhibited profoundly impaired movement stimulated by chemotactic factors when the cells were required to move over two-dimensional surfaces. Less impairment of movement was demonstrated in three-dimensional movement through cellulose filters. A possible explanation for this difference in cell translational mobility is that movement in cellulose filters is less adherence dependent than movement over a two-dimensional plastic surface. Movement of PMNL in collagen gels is known to be relatively independent of adherence. No deficiency of translational mobility of PMNL from LFA-1/Mac-1/p150,95-deficient patients was observed in collagen gels. Antibodies against the common beta subunit effectively blocked two-dimensional movement but had little effect on three-dimensional movement through cellulose filters or collagen gel matrices. HL-60 cells were employed as a model to investigate the effects of adherence on cell movement. Treatment of HL-60 cells with phorbol myristate acetate resulted in the appearance of Mac-1 and p150,95 on the cell surface. Concurrently, the cells exhibited increased adherence to glass and plastic. In spite of increased adherence, HL-60 cells showed no translational movement, indicating factors other than the ability to adhere were important in cell motility. These experiments implied that PMNLs undergo two fundamentally different kinds of motion, one adherence dependent (two-dimensional movement) and the other largely adherence independent (three-dimensional movement). These findings are consistent with the view that egress of PMNLs from the vascular space is adherence dependent. Movement through extravascular tissues may be adherence independent.

Antigens, Surface↗
PubMed1986

Primary idiopathic cutaneous pustular vasculitis.

Pustular cutaneous vasculitis results from a heterogeneous group of disorders characterized by pustules on purpuric bases. Although the cause of this group of conditions is diverse, the histopathologic picture of the lesions is the same, showing a Sweet's-like or leukocytoclastic vasculitis. These distinctive lesions may occur in patients with Behçet's syndrome, bowel-associated dermatosis-arthritis syndrome, or chronic gonococcemia. We describe, for the first time, a patient with primary idiopathic cutaneous pustular vasculitis. This patient had evidence of both circulating immune complexes and serum enhancement of neutrophil migration. Extensive evaluation failed to reveal any underlying systemic disease. A classification of the pustular vasculitides is proposed.

Adolescent↗
PubMed1986

Thalidomide effects in Behçet's syndrome and pustular vasculitis.

Pustular vasculitis is a new disease concept that links cutaneous, and possibly systemic, aspects of Behçet's, bowel bypass, bowel-associated dermatosis-arthritis, and disseminated gonorrhea syndromes. The pathomechanism of pustular vasculitic lesion generation may relate to circulating immune complex (CIC)-mediated vessel damage and serum enhancement of neutrophil migration. Thalidomide, an oral pharmaceutical available on strict protocol, has therapeutic effects based on proposed modulation of CIC- and neutrophil-mediated cytotoxicity. Thalidomide therapy was started for four patients with significant morbidity from Behçet's syndrome and for one patient with bowel-associated dermatosis-arthritis syndrome. Clinical benefit was dramatic in all patients who completed sequential four-week "on" and "off" thalidomide therapeutic cycles. In three of four patients, in vivo testing for CIC after histamine injection immunopathology converted from positive (immunoreactant deposition in dermal vasculature [four hours after histamine] and CIC-mediated vasculitis [24 hours after histamine]) to negative during therapy. No effects were noted on neutrophil migration or on the LFA-1/Mac-1/p150,95 family of glycoproteins associated with neutrophil adherence as assessed qualitatively by tritium labelling of neutrophil cell surfaces. In this small patient group, thalidomide was a clinically effective, safe (with rigid monitoring) therapy whose mechanism of action may relate more to inhibitory effects on CIC-induced vasculitis than to effects on neutrophil-mediated cytotoxicity.

Antigen-Antibody Complex↗
PubMed1985

Urinary excretion of modified purines and nucleosides in immunodeficient children.

Studies have been carried out using an XAD-4 resin and ion-exchange chromatography for determination of urinary purines and nucleosides in seven children with severe combined immunodeficiency and in six normal children. These studies have included analyses for five methylated purines or nucleosides produced by catabolism of nucleic acids. The following compounds have been quantitatively determined: 1-methyladenosine, 1-methylinosine, 1-methylguanosine, 1-methylguanine, 3-methylcytidine, adenosine, methylthioadenosine sulfoxide, cytidine, and deoxycytidine. 1-Methyladenosine and 1-methylinosine were most consistently elevated in the urine of immunodeficient children. Methylthioadenosine sulfoxide was very markedly increased in urine of two of the immunodeficient children while more moderate increases were noted with a number of other nucleosides. The germ-free child with severe combined immunodeficiency showed consistently lower excretion levels of these compounds when compared to normal children.

Child↗
PubMed1985

Complex aphthosis: a forme fruste of Behçet's syndrome?

The evaluation of the rare patient who presents with oral and genital aphthae or almost constant, multiple (greater than 3) oral aphthae, but no systemic signs or symptoms (i.e., complex aphthosis), is difficult because no laboratory test is available to exclude Behçet's syndrome. Six patients with complex aphthosis were evaluated. In addition, patients with simple aphthosis, those with seronegative arthritis, and normal controls were assessed for circulating immune complexes (CIC) by in vitro and in vivo assays and for neutrophil migration by subagarose methods, since these tests have given significant results in patients with Behçet's syndrome. Patient 1, with complex aphthosis, had Raji cell evidence for CIC (51.2 mg aggregated human gamma globulin Eq/ml), C1q, and C3 in dermal blood vessels 4 hours post intradermal histamine injection and had a Sweet's syndrome-like vasculitis 24 hours post histamine injection. In addition, her serum enhanced the migration of patient neutrophils (3.6 +/- 0.6 to 4.6 +/- 0.5; N = 6, p less than or equal to 0.01). All other test and control patients had negative or normal CIC and neutrophil migration determinations. Sixteen-month clinical follow-up has confirmed that Patient 1, but not Patients 2 to 6, has developed overt manifestations of Behçet's syndrome.

Adult↗
PubMed1985

Familial exercise-induced anaphylaxis.

An 18-year-old hispanic male, his two brothers, father, two paternal uncles, and paternal grandfather experienced cutaneous and cardiorespiratory symptoms during vigorous exercise beginning at about 10 years of age. The propositus was challenged by running to exhaustion and by immersion in hot water. In neither case were allergic signs or symptoms noted; however, plasma histamine rose from undetectable levels to 1.0 and 3.7 ng/ml, respectively. Furthermore, C2 and C5 were significantly reduced and fell during exercise.

Adolescent↗
PubMed1985

Leukocyte LFA-1, OKM1, p150,95 deficiency syndrome: functional and biosynthetic studies of three kindreds.

Three patients (2 female, 1 male) with recurrent infection, granulocytosis, impaired pus formation, and/or delayed umbilical cord separation were identified. Assessments of polymorphonuclear leukocytes (PMN)/monocyte function in each patient revealed profound abnormalities of adherence and adherence-dependent functions. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of their PMN lysates demonstrated a deficient or absent protein(s) of 138 kilodaltons (gp 138). Na3HB4 labeling demonstrated the absence of a major cell surface glycoprotein complex in each patient. Among parental and sibling PMN suspensions, functional assessments revealed no consistent abnormalities, although variably diminished gp138 was identified by SDS-PAGE and Na3HB4 labeling. Analysis by fluorescence-activated cell sorting and monoclonal antibodies (MAb) to LFA-1 alpha, OKM1 alpha, and their common beta subunit demonstrated a severe or total deficiency of PMN/monocyte surface expression of each protein among all patients; intermediate values were observed for parental and affected sibling suspensions, findings consistent with an autosomal recessive mode of inheritance for this disorder. Cell surface labeling (125I) and immunoprecipitation with the same MAb demonstrated the absence of these glycoproteins in addition to a 150-kilodalton protein (p150,95). Identical abnormalities of surface expression of patient lymphocytes blast-transformed with phytohemagglutinin (PHA) or Epstein-Barr virus were demonstrated. Further, significantly diminished natural killer cell cytotoxicity was observed for each patient tested. PHA blast-transformed patient lymphocytes labeled with [35S]methionine demonstrated a total absence of the beta molecule but indicated the presence of an LFA-1 alpha precursor. These findings indicate that LFA-1 alpha synthesis and surface expression require beta association. It is concluded that impaired inflammatory function in this disorder is casually related to a heritable deficiency of critical "adhesive" leukocyte glycoproteins.

Adolescent↗
PubMed1985

Heritable lymphocyte function-associated antigen-1 deficiency: abnormalities of cytotoxicity and proliferation associated with abnormal expression of LFA-1.

The effect of heritable LFA-1 deficiency on T lymphocyte function was measured. After primary mixed lymphocyte stimulation, all six patients studied showed diminished allospecific T lymphocyte cytolytic and NK activity as compared with kindred and normal controls. MLR and mitogen-induced proliferative responses were consistently depressed. LFA-1-deficient, EBV-transformed B cell lines were poor stimulators of T cell responses. Primary cytolytic responses by lymphocytes from severely LFA-1-deficient patients (less than 0.2% of normal surface expression) were consistently more profoundly depressed than those by lymphocytes from moderately deficient patients (about 5% of normal surface expression). These results demonstrate the importance of LFA-1 in lymphocyte function. After repeated MLR restimulation, proliferative and cytolytic capacity improved and CTL lines could be established from all patients. Cytolysis by lines from one but not a second severe patient, and by four of four moderate patients, was inhibited by anti-LFA-1 MAb, and at 10-fold lower concentrations than required for inhibition of killing by control CTL lines. The locus of inhibition was on the target cell for the severely deficient CTL line, and on both the target and effector cells for moderately deficient CTL lines. In contrast, the locus of inhibition for normal CTL is on the effector cell. These findings show that LFA-1 can participate bidirectionally in cell interactions. The in vitro results are discussed in terms of the clinical findings in patients.

Antibodies, Monoclonal↗