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Biomedical subjects

F G Cosio

Publications and source records attributed to F G Cosio.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1990

Immune complex erythrocyte complement receptor interactions in vivo during induction of glomerulonephritis in nonhuman primates.

Multiple lines of evidence indicate that the erythrocyte complement receptor (E-CR) system, which is unique to the primate, may play an important role in the clearing of immune complexes (ICs) from the circulation. However, all previous investigations of IC/E-CR interactions in vivo have involved the study of small amounts of preformed or passively formed ICs interacting with E-CR that were numerically in vast excess. The present study was undertaken to assess IC/E-CR interactions under conditions in which large amounts of ICs were formed in the circulation, amounts that when sustained for several weeks by daily intravenous administration of antigen resulted in the development of active glomerulonephritis. Twelve cynomolgus monkeys with E-CR levels ranging from 25 to 5000 mean CRs per erythrocyte (CR/E) were actively immunized to BGG, and 6 to 12 weeks later they were studied first at low levels of IC formation in vivo (L-Protocol experiments, mean 125I-labeled BGG dose of 0.04 mg/kg given over 1 minute, a marked antibody excess state) and then at high levels of IC formation in vivo (H-Protocol experiments, mean 125I-labeled BGG dose 4.9 mg/kg given over 10 minutes, a state approximating antigen-antibody equivalence). Cynomolgus monkeys with fewer than 100 CR/E showed no evidence of binding of ICs to erythrocytes with either low-dose or high-dose 125I-labeled BGG. However, cynomolgus monkeys with greater than 450 CR/E showed significant binding of ICs to erythrocytes: mean peak binding of 125I-labeled BGG to erythrocytes was 22.1% +/- 1.1% in the L-Protocol experiments and 33.4% +/- 8.0% in the H-Protocol experiments. During H-Protocol experiments, mean CR/E, measured by using a monoclonal anti-human CR1 antibody, decreased acutely (mean decrease 36.2% +/- 14.1%, p less than 0.05), with recovery of E-CR levels within the next 24 to 72 hours. The acute decrease in E-CR levels could not be accounted for by occupancy of E-CR by ICs or by change in hematocrit. In summary, the present study demonstrates that during the development of glomerulonephritis, IC/E-CR interactions occur and the E-CR system is altered by these interactions. The present observations are consistent with the hypothesis that the E-CR system may play a role in the pathogenesis of IC-mediated disease in the primate.

Animals↗
PubMed1989

Characterization of the baboon erythrocyte C3b-binding protein.

E from primates demonstrate type 1 CR (CR1) with binding specificities for C3b and C4b. In the present study we characterized the E C3b-binding protein of baboons. We showed that three out of four mouse mAb and one polyclonal antiserum, raised against human E CR1, cross-reacted with baboon E. In addition, one anti-human CR1 mAb (1B4) and a polyclonal anti-human CR1 inhibited the binding of C3b opsonized immune complexes to baboon E. Finally, a mAb to human CR1 (E11) recognized epitopes on E of a variety of nonhuman primates, including baboons. SDS-PAGE analysis of biochemically purified baboon E membrane fractions reactive with E11 demonstrated a 65-kDa protein as a major component. Affinity absorption and elution experiments verified this protein to be E11 reactive as well as a C3b binding protein. E surface radiolabeling, followed by C3i affinity purification, confirmed that this 65-kDa protein is the only C3b-binding protein present on the baboon E membrane. We postulate that the baboon E 65-kDa protein is the equivalent of the human E CR1. In addition, there appear to be antigenic similarities between the baboon E 65-kDa protein and the human E CR1.

Animals↗
PubMed1989

Human erythrocytes inhibit complement-mediated solubilization of immune complexes.

Incubation of precipitable immune complexes (IC) with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed human E were added to human serum or guinea pig serum, binding of IC to the E occurred and IC solubilization was significantly inhibited. By contrast, SRBC did not bind IC nor inhibit IC solubilization. Because IC binding to human E is mediated by CR type 1 (CR1) we evaluated whether CR1 was responsible for the inhibition of IC solubilization. Human E were treated with trypsin or anti-CR1 mAb. Both treatments abrogated IC binding to human E but did not affect the ability of the human E to inhibit IC solubilization. Human E inhibited C activation by IC. Thus, incubation of IC in human serum caused significant activation of C3 and C5, but not C4. However, when IC were incubated in whole blood or with isolated human E and serum, C3 activation by IC was inhibited significantly. In addition, we demonstrated that the C3b generated during C activation by IC deposited on both IC and human E. Thus, human E may compete for nascent C3 generated during C activation by IC. In conclusion, human E inhibit both complement-mediated solubilization of IC and C activation by IC.

Antigen-Antibody Complex↗
PubMed1989

Localization of decay accelerating factor in normal and diseased kidneys.

Decay accelerating factor (DAF) is a cell membrane associated glycoprotein that inhibits C3 activation. In the present study we evaluated the presence of DAF in normal (N = 15) and diseased human kidneys (N = 76). Sections of frozen tissue were stained for DAF by immunoperoxidase, utilizing three mouse monoclonal anti-DAF anti-bodies. In normal kidneys, DAF was localized in the glomerular vascular pole, apparently in the juxtaglomerular apparatus (JGA). All other structures were negative for DAF. By contrast, in diseased kidneys, two types of abnormalities were detected. First, JGA-DAF was significantly decreased and this abnormality correlated with the pathologic diagnosis and with the presence of C3, IgM and/or fibrinogen in the glomeruli. Second, DAF was present in the glomerular mesangium (67%), renal interstitium (68%) and/or blood vessels (38%). The presence of DAF in the mesangium and interstitium of the kidney correlated with each other and correlated with C1q and C3 deposition in the glomerulus. Finally, vascular DAF was significantly more common in patients with electron dense deposits in the glomeruli. In summary, DAF is present in the normal kidney and is located exclusively in the glomerular vascular pole. In diseased kidneys, DAF tends to be lost from the JGA but is often present in glomerular mesangium, interstitium and blood vessels. This pattern is specially prominent in patients demonstrating complement deposition in the glomerulus. We speculate that kidney DAF may play a role in protecting the kidney against the products of complement activation.

CD55 Antigens↗
PubMed1988

Validation of double-spike electrograms as markers of conduction delay or block in atrial flutter.

Recent mapping studies of atrial flutter have shown that fragmented electrograms can be found in most cases from the posterior, posteroseptal and posterolateral walls of the right atrium. The fragmentation pattern most often consists of a double spike. To further assess double-spike electrograms as a possible marker of conduction delay, bipolar electrograms were continuously recorded during atrial overdrive pacing of common flutter from the right atrium (7 patients) and from the proximal coronary sinus (5). Baseline double-spike separation of 50 to 130 ms was unchanged in 1 patient and slightly increased (5 to 25 ms) in 4 by coronary sinus pacing. The electrogram sequence was unchanged and the surface morphology was similar to that of basal flutter. Right atrial pacing decreased double-spike separation by 25 to 85 ms from basal values of 45 to 175 ms (23 to 83%), suggesting fusion in the area of fragmented electrograms. These findings suggest that double-spike electrograms represent activation on both sides of a conduction delay zone. The changes induced in these electrograms by pacing from the anterior right atrium and the coronary sinus are consistent with flutter circuits rotating counterclockwise (frontal plane) in the posterior right atrial wall in common atrial flutter.

Atrial Flutter↗
PubMed1988

Cyclosporine nephrotoxicity in spontaneously hypertensive rats.

In the present study, we investigated the combined, nephrotoxic effects of cyclosporine (CsA) and hypertension in young, spontaneously hypertensive rats (SHR). After 4 weeks of CsA therapy, SHR, compared with oil-treated SHR, showed an acceleration in the development of hypertension, mild renal insufficiency, and the accumulation of periodic-acid-Schiff-positive (PAS [+]) material in periglomerular arterioles. By electron microscopy, PAS(+) material was composed of intracytoplasmic inclusion bodies consistent with the accumulation of renin granules. This finding was demonstrated in SHR after 4 weeks of CsA therapy but not after 8 weeks of therapy. By contrast, CsA had no significant effect on blood pressure in Wistar-Kyoto rats, a normo-tensive control. To investigate the effect of unilateral nephrectomy (UNx) on the development of renal histopathologic changes in this model, SHR were subjected to uninephrectomy and CsA or oil therapy. UNx accelerated the development of hypertension in all SHR groups. SHR subjected to UNx demonstrated no renal histopathologic changes after CsA or oil treatment. In conclusion, CsA accelerates the development of hypertension in SHR, and this effect is probably renin-mediated. The combination of UNx and CsA therapy in the SHR does not result in significant renal histologic damage.

Animals↗
PubMed1987

Interactions between precipitating and nonprecipitating antibodies in the formation of immune complexes.

In the present study, we used monoclonal antidinitrophenol (DNP) antibodies to determine certain of the biophysical characteristics of precipitating and nonprecipitating antibodies. In addition, we studied the dynamics of immune complex (IC) formation when precipitating antibodies react with antigen in the presence of nonprecipitating antibodies. The antigen utilized in these studies was DNP-bovine serum albumin. All isolated nonprecipitating anti-DNP antibodies were of the IgG2b isotype, whereas all antibodies with other isotypes (IgG1, IgG3, IgM, IgA and IgE) were precipitating. Nonprecipitating antibodies did not differ significantly from precipitating antibodies in affinity, valence, or isoelectric point. Nonprecipitating antibodies inhibited the formation of precipitable IC between antigen and precipitating antibodies. In addition, preformed IC precipitates were solubilized by nonprecipitating antibodies. The solubilization of IC precipitates was influenced by the isotype of the precipitating antibody and by the antibody:antigen ratio in the IC precipitate. By isokinetic sucrose density centrifugation, we determined that solubilization of IC precipitates by nonprecipitating antibodies was associated with release of free precipitating antibody and formation of soluble IC between the antigen and the nonprecipitating antibody. In conclusion, in this study the nonprecipitating property of mouse anti-DNP antibodies is isotype-specific. Nonprecipitating antibodies compete and displace precipitating antibodies from the antigen, resulting in inhibition of IC precipitation and in IC solubilization. On the basis of the present results, we postulate that antibody-antibody interactions are important determinants of precipitating ability, and that these interactions are a characteristic of antibody isotype.

Animals↗
PubMed1987

Clearance of human antibody/DNA immune complexes and free DNA from the circulation of the nonhuman primate.

The present study evaluated the participation of the primate erythrocyte immune complex (IC) clearing mechanism in the clearance and organ uptake of double-stranded DNA (dsDNA) and of soluble ICs formed with human anti-DNA antibodies and dsDNA (dsDNA-ICs). Five baboons received 51Cr-labeled autologous erythrocytes and after a period of equilibration received separate intraarterial injections of [125I]free dsDNA and [125I]dsDNA-IC. Four of these five baboons were studied on a second occasion. To assess clearance from the arterial circulation and organ uptake, multiple blood samples were obtained from aorta, hepatic vein, and renal vein after injection of each probe. Two minutes after injection, a mean of 85% of dsDNA-ICs were bound to erythrocytes. By contrast, free dsDNA did not bind significantly to blood cells. The clearance rate of dsDNA-ICs from the arterial circulation was significantly faster than that of free dsDNA in all animals but one. Erythrocyte-bound dsDNA-ICs were cleared at a rate similar to that of total dsDNA-ICs. The liver was the major site of uptake of free dsDNA and of dsDNA-ICs. The hepatic uptakes of free dsDNA (17 +/- 8%/5 min) and dsDNA-ICs (27 +/- 8%/5 min) were not significantly different. 51Cr-labeled erythrocytes were not sequestered in the liver. There was not detectable uptake of free dsDNA or dsDNA-ICs by the kidney but with one exception. Thus, the primate erythrocyte IC clearing mechanism is involved in the clearance of dsDNA-ICs from the circulation but not in the clearance of free dsDNA.

Animals↗
PubMed1987

Junctional echoes with slow retrograde conduction without His bundle depolarization: further evidence of reentry within the atrioventricular node.

We report a case of intranodal reentry with slow retrograde conduction and atrial echoes in the absence of His bundle activation. Echoes were related to delay in intranodal conduction. Reentry using anomalous atrioventricular connexions is impossible without ventricular activation. This observation suggests reentry within the node without participation of neighboring structures.

Aged↗
PubMed1987

Combined nephrotoxic effects of cyclosporine and endotoxin.

This study presents experimental evidence that cyclosporine (CsA) potentiates the nephrotoxicity of endotoxin. This study was motivated by clinical observations in 4 cyclosporine (CsA)-treated renal allograft recipients who developed severe, and sometimes irreversible, nephrotoxicity after infections. CsA or vehicle was administered intramuscularly to rabbits for 5 days, and subsequently both groups of animals received one dose of endotoxin intravenously. Compared with controls, CsA-treated animals demonstrated significantly higher elevations of blood urea nitrogen and serum creatinine 24 hr after endotoxin. By contrast, both groups of animals developed similar degrees of thrombocytopenia. Histologic evaluation of kidney tissues 24 hr after endotoxin revealed significantly greater tubular toxicity and a higher glomerular polymorphonuclear leukocyte (PMN) infiltration in CsA-treated animals. Semiquantitative scores of tubular damage correlated directly with the mean number of PMN/glomeruli in both groups of animals. Immunofluorescent microscopy of kidney tissues was negative for fibrinogen and for complement deposition in both CsA and control groups. We conclude that CsA enhances endotoxin nephrotoxicity in rabbits. This effect does not appear to be mediated by activation of coagulation factors. However, a role for PMN is suggested. CsA should be used with caution in patients with deteriorating renal function who are suspected of having severe bacterial infections.

Animals↗
PubMed1987

Role of fibronectin on the clearance and tissue uptake of antigen and immune complexes in rats.

In the present study, we have evaluated how plasma fibronectin (FN) and tissue FN can affect the clearance from the circulation and organ uptake of antigen or immune complexes (IC) that have the capacity to bind to FN. Phenylated gelatin (DNP-GL) (a FN binding antigen) and IC composed of DNP-GL and monoclonal IgGl anti-dinitrophenol (DNP) antibodies were tested. These probes were compared with DNP-bovine serum albumin (BSA) (a non-FN-binding antigen) and DNP-BSA IC formed with the same anti-DNP antibody used for the preparation of DNP-GL IC. We found evidence that DNP-GL, but not DNP-BSA, formed complexes with soluble FN in vitro and the data strongly suggest that DNP-GL-FN complexes form in vivo. The formation of complexes with plasma FN aided in the clearance of DNP-GL from the circulation, as shown by the facts that DNP-GL was removed from the circulation much faster than DNP-BSA and that complexes of DNP-GL with plasma FN were removed from the circulation faster than uncomplexed DNP-GL. The sites of deposition of DNP-GL were also different from those of DNP-BSA. Thus, DNP-GL demonstrated higher hepatic, splenic, and renal uptake than did DNP-BSA. Renal uptake of DNP-GL was quite high despite the fact that DNP-GL is anionic. Indeed, expressed per gram of tissue, liver and kidney deposition of DNP-GL was not significantly different. By immunofluorescence microscopy, DNP-GL could be demonstrated in hepatic sinusoids and glomerular mesangium. In vitro, DNP-GL bound to FN in the mesangium of frozen sections of kidney tissue. IC formed with DNP-GL or DNP-BSA demonstrated virtually the same size, yet the fate of DNP-GL IC was strikingly different from that of DNP-BSA IC. The removal of DNP-GL IC from the circulation was mediated by the antigen and not by Fc receptors since gelatin (an inhibitor of DNP-GL clearance) but not aggregated IgG (an inhibitor of Fc receptors) inhibited the removal of DNP-GL IC from the circulation. In summary, these studies suggest that the ability of an antigen or IC to bind to FN markedly influences the fate of that antigen or IC. Specifically, binding to FN accelerates clearance from the circulation and favors hepatic and renal (primarily mesangial) uptake of the FN binding antigen of IC.

Animals↗
PubMed1986

Fragmented electrograms and continuous electrical activity in atrial flutter.

Multiple endocardial bipolar electrograms were recorded in 13 patients with atrial flutter (AF) to locate areas of fragmented electrical activity. Stable fragmentation patterns were found in each case, covering between 36% and 100% of the flutter cycle. Double or triple spike patterns were common. The direction of atrial activation was approximately defined in 11 patients, and in all of them at least part of the areas showing fragmentation was included in the circuit. In 1 patient an area of continuous electrical activity was found. AF circuits appeared to be included in the right atrium in 12 patients and in the left atrium in 1 patient. During atrial stimulation changes in fragmented electrograms coincided with changes in AF pattern before its interruption, while restoration of stable AF after stimulation was accompanied by reappearance of previous stable fragmented electrograms. In 6 patients electrograms were recorded after sinus rhythm was reestablished, and all showed marked decreases or disappearance of fragmentation. It is concluded that fragmented electrograms are often found in AF and may be related to abnormal local conduction in relation to the reentrant activation circuits.

Adult↗
PubMed1986

Effects of intravenous ajmaline on atrial excitability and conduction in man.

Slow conduction of early extrastimuli and short refractory periods are some of the factors underlying atrial fibrillation in man. In order to study the effect of ajmaline, a class I antiarrhythmic agent, on these variables, we have performed electrophysiologic studies in 13 patients with and without atrial arrhythmias, before and after the intravenous administration of 1 mg kg-1 of ajmaline chlorhydrate. During paced rhythm with a 600 ms cycle length, extrastimuli were applied to the right atrial appendage, and conduction to the low septal right atrium and the coronary sinus were measured. Ajmaline prolonged P wave duration from 111 +/- 15 to 140 +/- 24 ms (P less than 0.001), conduction of baseline stimuli to low septal right atrium from 69 +/- 14 to 95 +/- 21 ms (P less than 0.001) and to coronary sinus from 127 +/- 18 to 165 +/- 29 ms (P less than 0.001). Atrial effective refractory period increased from 207 +/- 23 to 255 +/- 27 ms (P less than 0.001). Maximum conduction delay of early extrastimuli decreased at the low septal right atrium from 43 +/- 22 to 29 +/- 16 ms (P less than 0.25) and at the coronary sinus from 47 +/- 22 to 21 +/- 14 ms (P less than 0.001). These results show interesting electrophysiologic effects of ajmaline on atrial tissue, with reversion of some of the abnormalities underlying atrial fibrillation, and suggest an antiarrhythmic effect.

Ajmaline↗
PubMed1986

Differential binding of immunoglobulin A and immunoglobulin G1 immune complexes to primate erythrocytes in vivo. Immunoglobulin A immune complexes bind less well to erythrocytes and are preferentially deposited in glomeruli.

Primate erythrocytes appear to play a role in the clearance of potentially pathogenic immune complexes (IC) from the circulation. This study was undertaken to compare the clearance from the circulation and tissue uptake of two monoclonal IC probes: one of which, IgG1-IC, was bound well by erythrocytes, the other of which, IgA-IC, was bound relatively poorly by erythrocytes. The IC probes were labeled with different iodine isotopes and infused either concomitantly or sequentially into the arterial circulation. The results indicate that, compared with IgG1-IC, IgA-IC bind less well to primate erythrocytes, are cleared from the circulation more quickly despite their smaller size, and show increased uptake in kidney and lung but decreased uptake in liver and spleen. Evidence is presented which suggests that this pattern of clearance from the circulation and systemic uptake of IgA-IC is the result of decreased binding of IgA-IC to circulating erythrocytes. These findings support the hypothesis that the primate erythrocyte-IC clearing mechanism may be critically important for the safe removal of IC from the circulation.

Animals↗
PubMed1986

Binding of human fibronectin to antigen-antibody complexes.

We examined the capacity of human fibronectin (FN) to bind to antigen-antibody (IgG) complexes (IC) in the absence of complement components. Binding of FN to IC was not significantly different at 37 degrees C and 4 degrees C and reached equilibrium after 60 minutes of incubation. The binding was markedly enhanced by decreasing the ionic strength and lowering the pH of the incubation media. The effect of ionic strength on binding was caused at least in part by an increase in the percent of the total FN able to bind to IC. Binding of radiolabeled FN to IC was saturable and was inhibited by the addition of an excess of unlabeled FN. In addition, soluble IC prepared in antigen excess but not antigen or antibody alone inhibited the binding of FN to precipitable IC. FN binding to precipitable IC increased with increasing antibody concentrations in the IC. Heparin and gelatin, which bind to specific locations in the FN molecule, did not inhibit the binding of FN to IC. In conclusion, human FN binds to IC in the absence of C1q, and the binding is enhanced under conditions of antibody excess.

Antigen-Antibody Complex↗