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Biomedical subjects

F G Cosio

Publications and source records attributed to F G Cosio.

At least 19 recordsLinked to original sources
PubMed1992

Atrial vulnerability.

The electrophysiologic substrates of atrial flutter and fibrillation (AFF) have been studied in patients with paroxysmal arrhythmias. Atrial repetitive responses to extrastimuli are a nonspecific response, even though they can precipitate AFF. AFF inducibility is rather sensitive, but not very specific, in separating patients from controls. There is no established protocol to explore vulnerability in this fashion. Atrial refractoriness is abnormal in some patients. Some authors have found a tendency toward short effective refractory periods (AERP) and others have found a poor adaptation of AERP to decreases in cycle length. Unfortunately, these abnormalities are neither sensitive nor specific enough. Atrial conduction may be abnormal basally, but subtler abnormalities are shown by premature stimulation. Early extrastimuli are conducted with increased conduction delays in patients with paroxysmal AFF in relation to controls. Again, there is not enough sensitivity and specificity in the findings to make them of diagnostic value. Electrophysiologic abnormalities are detectable in patients with AFF, but larger studies, including reproducibility and the effect of drugs on the abnormal parameters, will be necessary to develop clinical applications.

Atrial Fibrillation↗
PubMed1992

Electrophysiologic studies in atrial flutter.

The clinical electrophysiologic approaches to atrial flutter (F) have been activation mapping and the observation of changes induced by programmed stimulation. Sequential endocardial activation mapping has recently yielded information indicating that common F is produced by a large right atrial (RA) reentry circuit, with counterclockwise rotation in the frontal plane, including the inferior vena cava in its center. Functional block in the crista terminalis and conduction slowing in the approaches to the atrioventricular node seem to be important to support reentry. F inscribing positive deflections in the inferior leads usually follows the same path, but in a clockwise direction. Atypical F may be produced by left atrial circuits. Atrial stimulation during F entrains the circuit, resetting it with each stimulus. Collision between antidromic and orthodromic activation during entrainment produces fusion that can be identified in the surface electrocardiogram. The last paced activation restarts F, unless circuit penetration has been enough to modify it by block or disorganization. Entrainment may result in F acceleration, with changes in activation sequence, suggesting a different type of reentry, possibly based on functional factors.

Atrial Flutter↗
PubMed1992

Stimulating erythropoiesis increases complement receptor expression on primate erythrocytes.

Erythrocyte complement receptors (CR) are unique to primates and play a role in the clearance of immune complexes from the circulation. Immune complex-mediated diseases (e.g., systemic lupus erythematosus, SLE) cause decreased erythrocyte CR levels, resulting in decreased capacity of the erythrocytes to bind immune complexes that form in the circulation. Thus, raising erythrocyte CR levels might benefit patients with immune complex-mediated diseases. Because young erythrocytes express more CR than old erythrocytes, increasing erythropoiesis should increase the average number of CR expressed per erythrocyte. The present study was undertaken to test that hypothesis. Erythropoiesis was stimulated in nine cynomolgus monkeys (CYN) by weekly phlebotomy (30% of blood volume was removed, erythrocytes were discarded, and leukocytes were returned to the animal) for 8 weeks. Sham phlebotomy (30% of blood removed, then all components returned to the animal) was carried out weekly in four additional CYN for a period of 4 to 8 weeks. Sham phlebotomy did not change any of the parameters measured. However, phlebotomy resulted in a progressive increase in the mean number of CR expressed per erythrocyte (CR/erythrocyte): 2780 +/- 700 to 4230 +/- 820, P less than 0.0005. The increase in erythrocyte CR was first detected at about 2 weeks after the start of phlebotomy and was sustained through the course of phlebotomy. The increase in CR/erythrocyte included an increase in the percentage of erythrocyte expressing CR in clusters (37.9 +/- 6.4 vs 50.8 +/- 8.7%, P less than 0.01) as demonstrated by a flow cytometry study of the binding of fluorescent beads coated with anti-CR1 antibody. No significant change in leukocyte or platelet counts were observed. We conclude that stimulating erythropoiesis causes an increase in CR/erythrocyte. The magnitude of the increase suggests that it could be biologically significant.

Animals↗
PubMed1992

Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells.

Diabetic glomerulosclerosis is characterized by the accumulation of the matrix protein fibronectin in the glomerular mesangium and could result from increased mesangial cell fibronectin synthesis induced by hyperglycemia. To test this hypothesis, we cultured human mesangial cells for up to 14 days in media containing normal (5 mM) or high glucose (20 to 115 mM) concentrations and assessed cellular proliferation and fibronectin synthesis. When compared to 5 mM glucose, high glucose levels significantly inhibited cellular proliferation in a dose dependent fashion, as assessed by direct cell counting and thymidine incorporation. After eight days in culture, tissue culture supernatant fibronectin levels, as assessed by ELISA, were significantly higher from cells cultured under high glucose conditions than cells exposed to normal glucose levels. After 14 days and when compared to 5 mM glucose, matrix fibronectin levels and fibronectin mRNA expression (by Northern analysis) were also increased by 20 mM glucose. To control for the osmotic effects of high glucose, mesangial cells were also cultured in the presence of 20 mM or 50 mM mannitol. Mannitol had no effect on cellular proliferation but significantly increased tissue culture supernatant fibronectin levels and fibronectin gene expression. These studies demonstrate that, in vitro, high glucose suppresses human mesangial cell proliferation and stimulates fibronectin synthesis. The increase in fibronectin synthesis may in part result from changes in osmolality induced by high glucose. These data suggest that increased mesangial cell fibronectin synthesis may play a role in the accumulation of glomerular fibronectin common to diabetic glomerulosclerosis.

Cell Division↗
PubMed1991

Complement activation induces the expression of decay-accelerating factor on human mesangial cells.

In the present study we evaluated the effect of complement activation by immune complexes (IC) on the expression of decay-accelerating factor (DAF) on human mesangial cells (MC). MC in culture were incubated with an Ag (DNP-Gelatin) that binds to fibronectin present in the MC matrix. Subsequently, MC were incubated with anti-DNP antibodies in the presence of human serum. By immunoperoxidase staining we showed that these incubations resulted in IC formation and deposition of human C3 and terminal complement components (C5b-9) on the mesangial matrix and on the surface of MC. By immunoperoxidase staining and by RIA we showed that IC formation and complement activation significantly increased DAF expression on the MC plasma membrane. The induction of DAF expression was a consequence of deposition of terminal complement components on the MC because, zymosan-activated serum and IC formation in the presence of C5- or C8-deficient serum failed to increase MC DAF expression. Furthermore, the observed increased DAF expression was the consequence of increased DAF synthesis by MC. Thus, both cycloheximide and actinomycin D blocked the increase on MC DAF observed after incubation with IC and serum. MC DAF had biophysical and functional characteristics similar to DAF in other cells. Thus, 1) MC DAF was resistant to trypsin but was removed from the MC membrane by pronase; 2) phosphatidylinositol-specific phospholipase C removed 48 +/- 4% of MC DAF indicating that MC DAF is anchored in the cell membrane by phosphatidylinositol groups; 3) DAF isolated from MC-inhibited complement-mediated hemolysis and demonstrated a molecular mass of 83 kDa. In conclusion, deposition of terminal complement components on human MC trigger new synthesis and membrane expression of DAF. Because DAF protects cells against complement-mediated lysis, we postulate that DAF may protect glomerular cells during IC and complement-mediated glomerulonephritis.

CD55 Antigens↗
PubMed1991

Diagnostic significance of hypocomplementemia.

Hypocomplementemia is an important marker for the presence of IC-mediated disease and can be used to assess disease activity. However, in interpreting the clinical significance of hypocomplementemia, the following must be kept in mind: 1) There are numerous non-immunologic conditions that also can cause hypocomplementemia. Furthermore, some of these conditions can cause a multisystem disease that, along with the hypocomplementemia, can closely resemble an IC-mediated systemic vasculitis. Furthermore, these nonimmunologic conditions that lower serum complement levels can complicate the course of patients with inactive IC-mediated disease, spuriously indicating that the disease is active. The most relevant of these differential diagnostic problems are listed in Table 2. 2) There are a few conditions (for example, pregnancy) that can raise serum complement levels, thereby possibly obscuring the presence of a disorder (such as, active SLE) that is lowering complement levels. 3) There are some conditions that might be expected to lower serum complement levels, because of their effect on protein metabolism, but do not. Nephrotic syndrome, and moderately poor nutrition are examples. All of these factors should be considered when interpreting results of serum complement levels in a given patient.

Complement System Proteins↗
PubMed1991

Measurement of SC5b-9 in urine in patients with the nephrotic syndrome.

In passive or active Heymann nephritis (HN) in the rat, the immune complexes that form in the glomerular subepithelial space result in complement activation and the urinary (U) excretion of S protein-membrane attack complex (SC5b-9, MAC). Because of the similarities between HN in rats and membranous nephropathy (MN) in humans, it has been suggested that measurement of SC5b-9 in urine (UMAC) could be useful in assessing the immunologic activity of MN in patients. The present study was undertaken in normal individuals and in patients with nephrotic syndrome to determine: 1) the conditions of urine collection and preservation needed for accurate measurement of UMAC for clinical purposes; and 2) whether UMAC levels are a sensitive and/or specific test for MN. In studies conducted on urine specimens from patients with increased UMAC levels, we found that UMAC in freshly voided urine was stable for at least three hours at 37 degrees C, with or without the addition of the enzyme inhibitors that were used to stabilize UMAC levels in the studies of HN in the rat. Urine pH, leukocytes and erythrocytes, over the ranges usually encountered, did not influence UMAC levels. However, freezing urine at -70 degrees C artifactually raised UMAC levels (1500 +/- 550 to 1800 +/- 580 SE ng/ml, P less than 0.001 by paired t-test). Normal urine contained low UMAC levels: 80 +/- 3 ng/mg urinary creatinine (UCr). By contrast, patients with glomerulopathies tended to have elevated UMAC levels: 18 of 38 patients had levels that ranged from 200 to 20,000 ng/mg UCr.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

This study was undertaken to develop a model of immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate that could be used in subsequent studies to examine critically the role of the erythrocyte complement receptor (E-CR) in the pathogenesis of IC-mediated disease. Cynomolgus monkeys were chosen for study because they constitutively express E-CR levels that are either less than, equal to, or greater than that seen in normal man. After immunization with bovine gamma globulin (BGG), the GN induction protocol was begun in 10 cynomolgus by initiating daily i.v. administration of BGG in amounts sufficient to achieve or exceed antigen/antibody equivalence (assessed by the quantitative precipitin assay) for precipitating antibody present in the plasma volume. We found that within eight weeks of daily BGG administration of all the cynomolgus developed IC-mediated GN, irrespective of the initial E-CR level of the animals. However, the high E-CR cynomolgus tended to receive the higher BGG doses because of higher initial antibody levels to BGG. When the total number of glomerular deposits (determined by morphometric studies) per total BGG dose for each animal was plotted against the initial CR/E of that animal, there was a tendency for the animals with higher CR/E levels to have a lower number of glomerular deposits/BGG dose (r = 0.62, P = 0.06). Also, the total number of glomerular deposits correlated with the severity of the GN. During the early weeks of the GN induction protocol, the IC that formed in vivo (assessed by infusion of 125I-BGG) bound in large amounts to the circulating erythrocytes of the cynomolgus with medium or high E-CR levels. However, when tested after the onset of heavy proteinuria, which occurred between weeks 5 and 8 of daily BGG administration, the IC that formed in the circulation bound only poorly to circulating erythrocytes. By this time the E-CR levels had declined to 43 +/- 9% of initial values (P less than 0.01). This study demonstrates that: 1) A workable model of IC-mediated GN has been developed in the nonhuman primate. 2) During the induction of GN, CR/E and the ability of the erythrocyte to bind IC in vivo are decreased significantly. This suggests that an intact E-CR system could play a role in the protection against IC-mediated disease. However, further study will be needed to test that hypothesis critically. The present model should be useful in such studies.

Animals↗
PubMed1991

Suppression of Torsades de Pointes with verapamil in patients with atrio-ventricular block.

Experimental data have suggested a relation between Torsades de Pointes and early post-depolarization (EPD). We have studied the effect of intravenous verapamil in three patients with atrioventricular block (AVB) and Torsades de Pointes (TP), to obtain indirect evidence of slow membrane channel involvement in the TP mechanism. In two cases TP were completely suppressed and in one there was marked, albeit partial, suppression. In two cases verapamil did not shorten QT, while in the third suppression verapamil was related to junctional escape acceleration and QT shortening. In one of the cases where QT was not changed, the abolition of long pauses may have played a role in TP suppression. The affect of verapamil on TP in our patients is consistent with a combination of mechanisms, including direct membrane effects (EPD inhibition) and junctional pacemaker acceleration. Verapamil might be of therapeutic value in this clinical setting.

Aged↗
PubMed1990

Evaluation of the mechanisms responsible for the reduction in erythrocyte complement receptors when immune complexes form in vivo in primates.

Patients with immune complex-(IC) mediated diseases frequently have low levels of CR1 on E. The present study was undertaken to determine the role of circulating IC in causing low E-CR1 levels. E-CR1 were enumerated by measuring the binding of anti-CR1 mAb (E11) and rabbit anti-CR1 antibodies (RbaCR1) to E. In addition, the distribution of CR1 among E was assessed by flow cytometry of E stained with E11 and RbaCR1 and by evaluating the binding of E11-coated fluorescent beads (E11-beads) to E. E11-beads bind to clusters of CR1 on E. Five cynomolgus monkeys (CYN) were preimmunized to bovine gamma-globulin (BGG). E-CR1 changes in these animals were assessed: 1) acutely, during the first 60 min after an infusion of BGG and 2) chronically, during daily administration of BGG infusions over 2 wk. Acutely, there was a decrease in the number of E-CR1 as measured by E11 binding to E (E11/CR1). This decrease was not attributable to occupancy of CR1 by IC because the decrease in E11/CR1 number persisted after the IC had been cleared from E. By comparing the E11/CR1 levels in arterial blood to hepatic vein blood (n = 5), or in pulmonary artery blood (n = 1), we determined that the acute decrease in E11/CR1 number did not occur whereas E circulated through liver, spleen, or lung. The decrease in E11/CR1 number required the binding of IC to E because it did not occur after BGG was infused into nonimmunized CYN (n = 2) or into a preimmunized complement-depleted CYN. The decrease in E11/CR1 number was not due to loss of CR1 from E because E11/CR1 number recovered 24 h after infusion of BGG and in addition, enumeration of E-CR1 with RbaCR1 and E11-beads did not reflect a decrease in E-CR1 number. After several daily BGG infusions there was a persistent decrease in E-CR1 levels and that decrease appeared to be mainly the result of loss of CR1 from E because the decrease was confirmed with all methods of E-CR1 measurement and because E-CR1 levels recovered only slowly after BGG infusions were discontinued. Both in vitro and in vivo IC bound preferentially to subpopulations of E, identified by their ability to bind multiple E11-beads and by their high intensity staining with the anti-CR1 antibodies E11 and RbaCR1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Immune complexes bind preferentially to specific subpopulations of human erythrocytes.

Primate erythrocytes have complement receptors (CR1) that, both in vivo and in vitro, bind immune complexes (IC) opsonized with C3b. The present study was undertaken to determine whether the ability of human erythrocytes to bind IC is a characteristic shared by all erythrocytes. Binding of IC to erythrocytes probably involves the interaction of several C3b molecules with several CR1 clustered in small areas of the erythrocyte surface. To identify IC binding CR1 clusters, we first assessed the binding to erythrocytes of fluorescein-labeled polystyrene beads coated with monoclonal anti-CR1 antibodies (anti-CR1-beads) and second, performed IC. The binding of these ligands to erythrocytes was evaluated by immunofluorescence microscopy and flow cytometry. We found that only a fraction of erythrocytes from normal individuals bound anti-CR1-beads specifically and the percentage of erythrocytes able to bind beads increased with increasing numbers of CR1 per erythrocyte. However, the number of anti-CR1-beads bound per erythrocyte varied among cells from the same individual. We demonstrated further that the erythrocyte binding sites for anti-CR1-beads are also binding sites for opsonized IC. This was shown by demonstrating that anti-CR1-beads inhibited the binding of opsonized IC to erythrocytes and opsonized IC inhibited the binding of anti-CR1-beads to erythrocytes. Incubation of erythrocytes with opsonized IC, followed by FITC-labeled secondary antibodies, confirmed that indeed only a fraction of erythrocytes is capable of binding opsonized IC and that the binding sites for IC occupy small regions on the erythrocyte membrane. By contrast, we demonstrated that greater than 90% of erythrocytes express CR1. In conclusion, only some erythrocytes have the capacity to bind IC. Differences in the ability of erythrocytes to bind IC are probably related to differences in the clustering of CR1 in the erythrocyte membrane. Anti-CR1-beads identify erythrocyte binding sites for IC. These beads should prove useful to assess the changes that occur in the erythrocyte CR1 after exposure to IC in vivo.

Antibodies, Monoclonal↗
PubMed1990

Role of precipitating and nonprecipitating antibodies in glomerular immune complex formation.

The present study compared directly the ability of precipitating and nonprecipitating antibodies to form and sustain glomerular immune deposits. The antigen phenylated gelatin (DNP-GL) was injected i.v. into rats. DNP-GL is cleared from the circulation rapidly and becomes localized in glomeruli. Two hours later, rats received either precipitating or nonprecipitating mouse monoclonal anti-DNP antibodies. These antibodies were comparable with respect to size, affinity, number of antigen combining sites and isoelectric point. However, in vitro, nonprecipitating antibodies demonstrated a faster dissociation rate from antigen than precipitating antibodies. Control rats received DNP-GL alone or antibody alone. Antibody deposition in glomeruli was quantitated by Computerized Image Analysis (CIA) of immunoperoxidase stained tissue sections and by glomerular radioactive counts in experiments using 125I labelled antibodies. We demonstrated that glomerular uptake of anti-DNP antibody was similar two hours after injection of precipitating and nonprecipitating antibodies. However, six or more hours after injection, significantly less antibody was present in the glomeruli of rats injected with nonprecipitating antibodies. These differences could not be explained by a greater rate of antigen removal from kidney in rats injected with nonprecipitating antibodies. To assess whether nonprecipitating antibodies modify the glomerular binding and retention of precipitating antibody, in a separate series of experiments rats were injected with equal amounts of precipitating and nonprecipitating antibodies. Both types of antibody bound to glomeruli. However, with time glomerular antibody levels paralleled those found in rats injected with nonprecipitating antibody alone. We conclude that the precipitating characteristics of antibodies do not affect their ability to deposit in kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cellular receptors for matrix proteins in normal human kidney and human mesangial cells.

In the present study we evaluated the distribution of cell adhesion molecules, referred as very late antigens (VLA), in the normal human kidney and in mesangial cells in culture (MC). In addition, we assessed the functional properties of VLA proteins on MC. Normal human kidney and MC were stained by immunoperoxidase with mouse monoclonal antibodies to VLA proteins. We demonstrated that VLA-3, a protein that binds FN, laminin and collagen, is the predominant VLA protein in the human glomerulus and on MC. VLA-3 is located in the mesangium and on the glomerular visceral epithelial cell and endothelial cell surfaces in contact with the glomerular basement membrane. VLA-1 was demonstrated in the glomerular mesangium and VLA-5, an FN specific receptor, was present in the mesangium on glomerular endothelial cells and on MC. VLA-2 and VLA-4 were not present in the normal glomerulus nor on MC. In functional studies we evaluated the binding of MC to FN coated surfaces and the binding and phagocytosis of FN coated fluorescent beads by MC. We showed that MC bind to FN coated surfaces and that the binding is inhibited by anti-FN antibodies, EDTA and peptides containing the amino acid sequence Arg-Gly-Asp (RGD). In addition, anti-VLA-5 but not anti-VLA-3 antibodies inhibited significantly the binding of MC to FN, MC demonstrated binding and phagocytosis of FN coated beads and, purified FN inhibited both phenomena. By affinity chromatography and immunoprecipitation we demonstrated that MC FN binding proteins and MC VLA proteins are composed of two distinct protein chains that have Mr characteristics similar to those of normal human fibroblasts VLA proteins. In conclusion, the glomerular distribution of VLA-3 suggests that this protein is primarily involved on the adhesion of glomerular cells to basement membranes and matrix. MC FN receptors (VLA-5) mediate the binding of MC to FN and could mediate the phagocytosis of FN coated antigen or immune complexes by mesangial cells.

Binding Sites↗
PubMed1990

Intracardiac coiling of permanent atrial leads.

We have observed intracardiac movement of permanently implanted atrial pacing leads in two patients with AAI pacemakers. This resulted in looping of the lead body into the right atrium and ventricle, without displacement of the tip or changes in the pacing or sensing thresholds. At surgery only a single fixation ligature was found and allowed sliding of the lead through the suture sheath, in both cases. The position was corrected by gently pulling the lead. Multiple ligature fixation may avoid this complication.

Aged↗
PubMed1990

The effects of ciclosporin in experimental glomerulosclerosis.

The acute and chronic effects of daily, oral ciclosporin (CS) therapy (25 mg/kg) on proteinuria, blood pressure, renal function and histology were studied in rats subjected to unilateral nephrectomy and 3 weekly intraperitoneal injections of the aminonucleoside of puromycin (PAN). PAN therapy resulted in heavy proteinuria by week 4 which declined by weeks 8 and 16. When CS therapy was started weeks after the last dose of PAN, acute, transient reductions in proteinuria and reversible rises in blood urea nitrogen (BUN) were observed. When CS or oil therapy was started with PAN and continued for 8 or 16 weeks, there were no differences in proteinuria; however, after 16 weeks, CS treated rats had significantly higher BUN levels [65 +/- 11 (23.2 +/- 3.9) vs. 41 +/- 5 mg/dl (14.6 +/- 1.8 mmol/l); p = 0.001], a higher percentage of sclerotic glomeruli (47 +/- 7 vs. 28 +/- 10%; p less than 0.0001) and extensive interstitial fibrosis. There was a strong correlation between glomerulosclerosis and extent of interstitial fibrosis (r = 0.951; p less than 0.0001). These studies demonstrate that rats with experimental focal glomerulosclerosis treated with CS show an acute, transient reduction in proteinuria; however, chronic (for 16 weeks) CS therapy significantly increases azotemia and results in an increase in glomerulosclerosis and interstitial fibrosis.

Animals↗