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Biomedical subjects

D C Anderson

Publications and source records attributed to D C Anderson.

At least 127 records · Page 7Linked to original sources
PubMed1995

Pretreatment with a blocking monoclonal antibody to P-selectin accelerates pharmacological thrombolysis in a primate model of arterial thrombosis.

It has been established that the fibrin content of a developing thrombus can be dramatically reduced with the use of the GA6 monoclonal antibody, which is directed against P-selectin (CD62p). This effect is probably related to diminished tissue factor activity on monocytes in the presence of P-selectin antagonism. Therefore, we hypothesized that an occlusive arterial thrombus formed in the presence of a P-selectin monoclonal antibody would be more susceptible to lysis with standard thrombolytic therapy. To test this hypothesis, 22 male cynomolgus monkeys were anesthetized and instrumented for induction of thrombosis of a femoral artery. Endothelial injury was induced by passing a 150-microA anodal current through a small electrode that was placed in the femoral artery. Blood flow through the artery was continuously monitored using an ultrasonic transit-time flowmeter. The GA6 monoclonal antibody (1 mg/kg) or control, isotype matched mouse IgG1 (P23 or P7) was administered i.v. 1 hr before electrolytic endothelial injury. In the P23 group (n = 11), an occlusive thrombus formed in 52.1 +/- 8.5 min, and in the GA6 group (n = 11), an occlusive thrombus formed in an average time of 52.0 +/- 8.1 min. After formation of an occlusive thrombus, the current was terminated and intravenous heparin (100 U/kg + 50 U/kg/hr) was administered to prevent clot extension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The dizzy patient: a review of etiology, differential diagnosis, and management.

BACKGROUND: Dizziness is a lay term used to describe a variety of sensations. Unfortunately, the term "dizziness" does not have a precise medical definition, and additional information is typically required to further define the patient's problem. METHODS: When dizziness is a presenting complaint, distinctions must be made between vertigo (a sense of false movement), near-syncope (a feeling of impending faint), disequilibrium (loss of balance), and ill-defined lightheadedness (an inability to concentrate or focus the mind). Possible causes of dizziness include conflicts between visual and vestibular information, vascular problems, adverse reactions to medication, psychological difficulties, systemic disease, and the effects of aging. RESULTS: Dizziness is a symptom of a physiological or psychological illness, and therefore management is typically directed toward treatment of the underlying illness. In some cases the cause of the dizziness cannot be found, however, or is untreatable. In these cases, management is directed toward symptom reduction. CONCLUSIONS: Dizziness is a relatively common problem that arises from a variety of causes. In many cases, optometrists can participate in the diagnosis and management of patients with complaints of dizziness.

Diagnosis, Differential↗
PubMed1995

Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1.

OBJECTIVE: A blocking monoclonal antibody to intercellular adhesion molecule-1 (ICAM-1), CL18/6, previously has been demonstrated to inhibit neutrophil attachment to isolated vascular endothelium and cardiomyocytes. Due to the well known participation of ICAM-1 in the inflammatory responses associated with myocardial ischemia/reperfusion injury, we investigated if CL18/6 could attenuate myocardial ischemia/reperfusion injury in vivo. METHODS: Saline (3-5 ml, i.v., n = 6), non-blocking control MAb CL18/1D8 or CL18/6 (both 0.5 mg kg-1, i.v., n = 4) were administered prior to coronary occlusion (1 h) and subsequent reperfusion (5 h) produced by inflation of a coronary balloon angioplasty catheter in isoflurane-anesthetized, closed-chest dogs. Heart rate and arterial pressure were measured, and regional myocardial blood flow (rMBF), and myeloperoxidase activity (MPO) to index local neutrophil sequestration, were determined. Myocardial infarct size (IS) was evaluated using the tetrazolium staining technique and expressed as a percent of area at risk (AR). RESULTS: Changes in heart rate and arterial pressure were insignificant throughout the experiment. rMBF (mean +/- s.e.m.) in the ischemic subendocardium for each treatment group was: Saline (0.07 +/- 0.02 ml min-1 g-1); CL18/1D8 (0.04 +/- 0.02); CL18/6 (0.06 +/- 0.02). IS/AR% was: saline (37 +/- 3%); CL18/1D8 (39 +/- 9%); CL18/6 (15 +/- 4%*); * = significantly different from CL18/1D8 and saline, P < 0.05. MPO assayed from AR immediately adjacent to the infarct was significantly reduced below infarct MPO only in the CL18/6 treated group-36%). CONCLUSIONS: The results indicate that CL18/6 antagonism of ICAM-1 provided cardioprotection associated with reduced neutrophil activity in vulnerable myocardium, and suggest that ICAM-1 mediated neutrophil sequestration in endangered cardiac tissue is an important mechanism of myocardial ischemia/reperfusion injury.

Animals↗
PubMed1995

Antibodies to intercellular adhesion molecule-1 ameliorate the inflammatory response in acetic acid-induced inflammatory bowel disease.

The transendothelial migration of leukocytes in many inflammatory responses is now believed to be dependent on the interaction of leukocyte and endothelial cell-derived adhesion molecules. To examine the role of intercellular adhesion molecule-1 (ICAM-1) in the development of inflammation in a rat model of colitis, we investigated the effects of antibodies to rat ICAM-1 given 24 hrs after inflammation was induced by acetic acid. Antibodies to rat ICAM-1 substantially ameliorated the inflammatory response as indicated by a reduction in gross inflammatory characteristics, tissue/body weight ratio, myeloperoxidase activity and superoxide levels. The results demonstrate that ICAM-1 plays an important role in the development of inflammatory bowel disease in rats. The use of antibodies to ICAM-1 to inhibit the adherence of leukocytes to endothelium, may be of potential therapeutic value in the treatment of inflammatory bowel disease in man.

Acetates↗
PubMed1995

NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment.

Leukocytes accumulate at sites of inflammation in response to the induced expression of endothelial cell adhesion molecules. The nuclear transcription factor kappa B (NF-kappa B) plays a critical role in the cytokine-induced expression of these genes in cultured endothelium. We examined the relationship between NF-kappa B activation and endothelial cell adhesion molecule gene expression in vivo during the initiation of acute inflammation. Nuclear NF-kappa B DNA-binding activity was rapidly increased within lung and heart tissues of rats administered endotoxin, consistent with the translocation of NF-kappa B complexes from the cytoplasm to the nucleus. This NF-kappa B was composed of p50 and p65 subunits, and could bind NF-kappa B elements in the E-selectin promoter. NF-kappa B activation was maximal within 30 min and persisted for at least 3 hr after endotoxin treatment. NF-kappa B activation preceded the transcriptional activation of the P-selectin, E-selectin, VCAM-1, and ICAM-1 genes. In the lung, increased expression of P-selectin and ICAM-1 protein was detected immunohistochemically. These molecular events were temporally associated with the sequestration of leukocytes and the development of pulmonary inflammation. NF-kappa B activation is therefore an early event in the initiation of acute inflammation in vivo. This molecular pathway may be of consequence in the pathogenesis of acute inflammatory disease.

Animals↗
PubMed1994

A sialoglycoprotein from human leukocytes functions as a ligand for P-selectin.

P-selectin (CD62P), a Ca(2+)-dependent lectin expressed on activated platelets and endothelial cells, functions as a receptor for myeloid and monocytoid cells. Previous reports have described a homodimeric sialoglycoprotein from human leukocytes and HL-60 cells specifically recognized by P-selectin. We describe here a panel of monoclonal antibodies prepared against high molecular weight fractions of HL-60 cell membranes. These antibodies are of IgM isotype, bind to a approximately 240-kDa protein from human leukocyte membranes which is also reactive with P-selectin. They recognize a Ca(2+)-dependent, sialidase-sensitive determinant on myeloid and monocytoid cell lines. Each antibody specifically inhibits adhesion of neutrophils or HL-60 cells to: 1) purified P-selectin, 2) thrombin-stimulated platelets, and 3) phorbol 12-myristate 13-acetate-activated endothelial cells. These results suggest that the sialoglycoprotein recognized by this panel of monoclonal antibodies may function as a cell surface ligand for P-selectin.

Amino Acid Sequence↗
PubMed1994

Cloning, sequence comparison and in vivo expression of the gene encoding rat P-selectin.

We have cloned the cDNA encoding rat P-selectin (Psel) and have examined the regulation of Psel expression in vivo. Sequence analysis of the complete Psel cDNA demonstrated significant nucleotide and amino-acid identity with human and mouse Psel. Similar to mouse Psel, the rat sequence lacks the equivalent of human complement regulatory protein-like repeat 2 (CR2). Seven potential N-linked glycosylation sites are conserved between the three species, suggesting that carbohydrate modification may play an important role in Psel function. To examine expression of Psel in vivo, levels of Psel mRNA were examined in several different tissues after systemic administration of lipopolysaccharide (LPS). Psel mRNA was undetectable in tissues of vehicle-treated animals. By 3 after LPS administration, Psel mRNA levels were elevated in all tissues examined, the highest levels being seen in the lung. Significant increases in Psel mRNA were also seen in the heart, thymus, spleen and kidney. By 24 h after LPS, mRNA levels for Psel remained elevated in the lung, heart, kidney, thymus and small intestine. Psel mRNA was not detectable in total RNA isolated from purified rat platelets, suggesting that the increased levels of Psel mRNA were the result of upregulation of endothelial gene expression. In addition, only minimal levels of platelet factor 4 mRNA (PF4), used as a platelet-specific marker, were observed in the tissues studied. These data demonstrate that part of the response to acute inflammation in vivo includes the rapid increase in endothelial Psel expression.

Amino Acid Sequence↗
PubMed1994

CD18-dependent and L-selectin-dependent neutrophil emigration is diminished in neonatal rabbits.

Human neonatal neutrophils manifest decreases in mobility, adherence, and emigration compared with adult neutrophils that may contribute to the increased susceptibility of neonates to infection. In a developmental rabbit model, we show a reduced ability of neutrophils from 1-day-old rabbit pups to emigrate to inflamed peritoneium (3.7 +/- 0.35 x 10(6) neutrophils/mL peritoneal exudate) compared with 14-day-old (8.5 +/- 0.7 x 10(6)/mL) and adult rabbits (9.4 +/- 1.4 x 10(6) mL, P < .05) despite significantly increased blood neutrophil counts. Because the reductions in functional Mac-1 (CD11b/CD18) as well as the amount of surface L-selectin are hypothesized to be primarily responsible for the differences in human neonatal neutrophil mobility, we examined CD11b/CD18 and L-selectin in our model. Using flow cytometric analysis we found that similar to human neonates, neutrophils from 1-day-old rabbit pups had 57% of adult rabbit levels of L-selectin and, in contrast with adults, failed to show significant decreases in L-selectin after chemotactic stimulation. In addition, neutrophils from 1-day-old pups compared with adults showed a significantly diminished capacity to upregulate CD11b/CD18 after chemotactic stimulation in vitro, or after emigration to the inflamed peritoneum. Systemic administration of anti-L-selectin monoclonal antibody (MoAb) resulted in significant reduction in peritoneal neutrophils in adult (47%, P < .05) and 14-day-old rabbits (47%, P < .05), but was without effect in 1-day-old rabbits. Administration of anti-CD18 MoAb resulted in significant reduction in peritoneal neutrophil accumulation in all age groups though less in 1 day and 14 day (58% and 65%, respectively) than in adults (91%, P < .05). Only in the 14-day-old rabbits was there an additive effect of anti-L-selectin and anti-CD18 MoAbs compared with anti-CD18 alone (84% v 65%, P < .05). The findings in this in vivo rabbit model support the hypothesis that the previously described in vitro defects in human neonatal L-selectin and CD11b/CD18 may be major contributors to human neonatal inflammatory deficits.

Age Factors↗
PubMed1994

Carotid stenosis in patients with atrial fibrillation. Prevalence, risk factors, and relationship to stroke in the Stroke Prevention in Atrial Fibrillation Study.

BACKGROUND: Several mechanisms contribute to the increased stroke rate of patients with atrial fibrillation (AF). We assessed the frequency of carotid artery stenosis in patients with AF and its relationship to stroke during aspirin or warfarin therapy. METHODS: Carotid ultrasonography was done in 676 patients with AF enrolled in the Stroke Prevention in Atrial Fibrillation Study to detect cervical carotid stenosis of 50% or more of the luminal diameter. The presence of carotid stenosis was correlated with patient features and subsequent stroke during a mean of 2.6 years of follow-up. RESULTS: In patients with AF who were older than 70 years, the frequency of carotid stenosis was 12% in men and 11% in women. Carotid stenosis was independently associated with systolic hypertension (relative risk, 2.4; P = .002), diabetes (relative risk, 1.8; P = .04), and tobacco use (relative risk, 1.8; P = .02). Carotid stenosis did not add significantly to prediction of stroke when analyzed with other clinical risk factors for stroke in patients with AF (relative risk, 1.3; 95% confidence interval, 0.5 to 3.6; P = .55). CONCLUSIONS: Carotid artery stenosis of 50% or more occurs in about 12% of elderly patients with AF, reflecting the substantial prevalence of hypertension and diabetes in these patients. Carotid stenosis was not usefully predictive of stroke in patients with AF who were given aspirin or warfarin. Routine ultrasonography to detect carotid stenosis does not appear warranted in patients with AF without previous symptoms of brain ischemia.

Aged↗
PubMed1994

Immunocomplexes stimulate different signalling events to chemoattractants in the neutrophil and regulate L-selectin and beta 2-integrin expression differently.

Neutrophils express receptors for numerous phlogistons which, when occupied, trigger distinct signal-transduction pathways. Previous studies have shown that stimulation of neutrophils with chemoattractants induces shedding of the adhesive molecule L-selectin and increased expression of the beta 2-integrin CD11b/CD18. We determined the effect of ligation of classic, G-protein-linked chemoattractant receptors [C5a, interleukin-8 (IL-8), formylmethionyl-leucylphenylalanine (FMLP) and substance P], receptors for the Fc portion of IgG (Fc gamma receptors) and receptors for transforming growth factor beta (TGF beta) on expression of adhesive molecules by neutrophils and the stimulus-transduction mechanisms thought to mediate these changes. We were surprised to observe that occupancy of Fc gamma receptors by immunocomplexes (BSA-anti-BSA) stimulated increased expression by neutrophils of CD11b/CD18 at concentrations which did not affect L-selectin expression (EC50 9 micrograms/ml versus 350 micrograms/ml respectively, P < 0.00001, n = 5). In contrast, similar to previous studies, recombinant C5a, recombinant IL-8 and FMLP all stimulated increased expression of CD11b/CD18 (170-260% of basal, P < 0.001, n = 5) and shedding of L-selectin (56-75% reduction from basal, P < 0.001, n = 5) at similar concentrations and with similar potencies (EC50 = 2, 5, and 3 nM respectively). In contrast, neither TGF beta 1 nor, surprisingly, substance P affected expression of CD11b/CD18 or L-selectin. The regulation of expression of CD11b/CD18 or L-selectin in response to FMLP or immunocomplexes was unaffected by cytochalasin B (5 micrograms/ml) or the tyrosine kinase inhibitor tyrphostin-25 (25 microM). Although occupancy of both chemoattractant (FMLP) and Fc gamma receptors stimulated increments in the second messenger diacylglycerol, disruption of actin microfilaments by cytochalasin B enhanced diacylglycerol generation in response to FMLP but not in response to ligation of Fc gamma receptors. Moreover, both FMLP and immune aggregates provoked fluxes of intracellular Ca2+ concentration which differed with respect to both magnitude and kinetics and did not correlate well with regulation of adhesive-molecule expression. As upregulation of CD11b/CD18 is tightly linked to exocytosis of specific granules, these results suggest that shedding of L-selectin by activated neutrophils is not linked to exocytosis. These studies provide further evidence that receptors for chemoattractants and immunocomplexes on the neutrophil are linked to multiple signalling pathways.

Actins↗
PubMed1994

Intravascular neutrophil activation in systemic lupus erythematosus (SLE): dissociation between increased expression of CD11b/CD18 and diminished expression of L-selectin on neutrophils from patients with active SLE.

Previous studies have shown that neutrophils in the circulation of patients with active systemic lupus erythematosus (SLE) are activated as judged by their increased surface expression of the beta 2-integrin CD11b/CD18. Since activation of neutrophils leads to altered expression of another adhesion molecule, L-selectin (LS), we examined neutrophils from patients with SLE for changes in the expression of CD11b/CD18 and LS by cytofluorographic analysis of immunofluorescent-labeled cells. Overall there was no difference between surface expression of CD11b/CD18 on neutrophils from SLE patients or controls [mean fluorescence 225 +/- 26 vs 225 +/- 13 relative fluorescence units (RFU), respectively]. However, as previously reported, neutrophils from patients with more active disease (activity score > or = 3, UCH Middlesex activity score) expressed greater CD11b/CD18 than neutrophils from controls (319 +/- 40 RFU, P < 0.03, n = 9) or from patients with less active disease (193 +/- 10 RFU, P < 0.006). Indeed, CD11b/CD18 expression correlated directly with disease activity (r = 0.54, P < 0.02). Stimulation of neutrophils ex vivo with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (100 nM) induced up-regulation of CD11b/CD18 in cells from both SLE patients and controls (205 +/- 12% vs 239 +/- 15% of basal, respectively), but neutrophils from the most active patients (score > or = 3) increased CD11b/CD18 expression less than controls (175 +/- 12% of basal, P < 0.003, n = 9). The magnitude of the stimulated increment in expression of CD11b/CD18 on neutrophils correlated inversely with SLE activity (r = -0.64, P < 0.003, n = 20). Surprisingly, we observed no change in LS expression on neutrophils from SLE patients compared to controls (143 +/- 14 vs 141 +/- 16 RFU, respectively) even in patients with the highest activity indices (154 +/- 21 RFU). In contrast to CD11b/CD18, there was no correlation between LS expression and disease activity (r = 0.12, P = NS). Stimulation of neutrophils reduced the expression of LS similarly in both controls and SLE patients (67 +/- 3% vs 58 +/- 4% reduction, respectively) and did not correlate with disease activity (r = 0.07, P = NS, n = 20). These results show, for the first time, that changes in CD11b/CD18 expression do not correlate with LS expression on neutrophils from patients with active SLE.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, CD↗
PubMed1994

Helicobacter pylori-induced microvascular protein leakage in rats: role of neutrophils, mast cells, and platelets.

BACKGROUND/AIMS: Previous studies indicate that a water extract of Helicobacter pylori (HPE) can promote neutrophil-endothelial cell interactions in vivo and in vitro. The objectives of this study were to assess whether HPE alters the rate of albumin leakage in rat mesenteric venules and identify the factors that mediate the HPE-induced microvascular dysfunction. METHODS: Intravital microscopy was used to continuously monitor leukocyte adherence and emigration and albumin leakage in rat mesenteric venules during superfusion with HPE. RESULTS: HPE increased leukocyte adherence and emigration and microvascular albumin leakage. The enhanced albumin leak could be subdivided into two components: an early (within 10 minutes) and a later (within 30 minutes) phase. HPE also elicited perivenular mast cell degranulation and the formation of platelet-leukocyte aggregates within post-capillary venules. The HPE-induced early phase of albumin leakage was attenuated by pretreatment with a mast cell stabilizer. The HPE-induced late phase of albumin leakage was reduced by monoclonal antibodies directed against either CD11b/CD18 or intercellular adhesion molecule 1. A monoclonal antibody against P-selectin also inhibited the HPE-induced platelet-leukocyte aggregation and reduced the later phase of albumin leak. CONCLUSIONS: HPE-induced microvascular dysfunction appears to be a consequence of interstitial and intravascular cell-cell interactions.

Albumins↗
PubMed1994

Role of neutrophil-endothelial cell adhesion in inflammatory disorders.

Polymorphonuclear leukocytes are armed with an impressive arsenal of bactericidal agents that allow these cells to play a vital role in host defense against invading pathogens. However, these same agents can produce extensive cellular damage in host tissues when leukocytes are activated during inflammatory conditions. Recognition of this fact, when coupled with the observation that leukocyte adhesion to post-capillary venules is a critical first step in the inflammatory process, has led to the development of the concept that inhibition of neutrophil-endothelial cell adhesion (NECA) may represent a novel therapeutic strategy for the prevention of leukocyte-dependent injury in inflammatory conditions. Indeed, pharmacological or immunologic inhibition of NECA reduces cellular injury, dysfunction, and necrosis induced by ischemia/reperfusion, circulatory shock and resuscitation, organ transplantation, cardiopulmonary bypass, frostbite, and thermal trauma. NECA also appears to play an important role in the pathobiology of airway inflammation and asthma, pulmonary oxygen toxicity, arthritis, bacterial meningitis, and cerebral malaria. The aim of this review is to summarize the evidence implicating NECA in the pathogenesis of these inflammatory conditions.

Antibodies, Monoclonal↗
PubMed1994

Complement receptor 3 (CR3, Mac-1, integrin alpha M beta 2, CD11b/CD18) is required for tyrosine phosphorylation of paxillin in adherent and nonadherent neutrophils.

Expression of the leukocyte (beta 2) integrins is required for many functions of activated neutrophils (PMN), even when there is no recognized ligand for any beta 2 integrin. To investigate the hypothesis that beta 2 integrins may be involved in a signal transduction pathway related to cytoskeletal reorganization, we examined whether beta 2 integrins have a role in tyrosine phosphorylation of the cytoskeletal protein paxillin. Treatment of PMN in suspension with phorbol esters, f-Met-Leu-Phe, and TNF-alpha resulted in paxillin tyrosine phosphorylation. However, treatment of beta 2-deficient (LAD) PMN failed to induce paxillin tyrosine phosphorylation. Normal PMN phosphorylated paxillin in response to adhesion to immune complexes, while the LAD PMN did not. Adhesion of phorbol ester activated-LAD PMN to the extracellular matrix proteins fibronectin, laminin, and vitronectin failed to induce paxillin tyrosine phosphorylation. Treatment of activated normal PMN with mAb directed against the beta 2 integrin alpha chains demonstrated that CR3 (alpha M beta 2) was required for paxillin phosphorylation. Transfection of the cell line K562 with CR3 confirmed that CR3 ligation resulted in paxillin tyrosine phosphorylation. As a control, K562 transfected with CR2 (CD21) which bound equally avidly to the same complement C3-derived ligand (C3bi) as the CR3 transfectants, showed no enhanced tyrosine phosphorylation of paxillin upon receptor ligation. While both CR2 and CR3 transfectants showed efficient adhesion to a C3bi-coated surface, only the CR3 transfectants spread during adhesion and phosphorylated paxillin. Together these data demonstrate that CR3 is required for paxillin phosphorylation during activation of both adherent and nonadherent PMN. Even PMN activated in suspension or by adhesion to immune complexes, when no CR3 ligand is apparent, still require CR3 for a signal transduction pathway leading to paxillin tyrosine phosphorylation. This pathway is likely to be important for PMN function in inflammation and host defense.

Adolescent↗