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Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 163 records · Page 9Linked to original sources
PubMed1985

Opsonization of Legionella pneumophila in human serum: key roles for specific antibodies and the classical complement pathway.

Legionella pneumophila has previously been shown to require serum factors for efficient uptake by phagocytic cells. In this investigation, the roles of specific antibody and complement in phagocytosis of L. pneumophila by human polymorphonuclear leucocytes (PMN) and tissue macrophages were determined. Opsonization was assessed by quantitating the uptake of [3H]-labelled Legionellae. Compared to other Gram-negative and to Gram-positive bacterial species, L. pneumophila was highly resistant to the opsonic activity of normal pooled human serum (PHS). Of 12 donor sera tested, only four promoted significant L. pneumophila uptake when used at full strength. Experiments with immune antibody, and with human sera deficient in immunoglobulins, or the complement components C2, C3, or C5, revealed that L. pneumophila opsonization was dependent on antibody-mediated activation of the classical complement pathway; activation of the alternative pathway could not be detected. At high concentrations, immune antibody alone could adequately opsonize L. pneumophila. Human alveolar and peritoneal macrophages required very similar amounts and types of opsonins for L. pneumophila phagocytosis as did human PMN. Heating L. pneumophila to temperatures greater than or equal to 80 degrees abolished its resistance to opsonization by diluted PHS; however, activation of complement via the alternative pathway or via other antibody-independent routes remained undetectable. These studies show that, in addition to immune antibody, the classical pathway of complement plays an important role in the opsonization of L. pneumophila. The limited ability of these bacteria to interact with human complement provides a likely explanation for their resistance to opsonization and may be partly based on heat-sensitive structures on the surface of L. pneumophila.

Antibodies, Bacterial↗
PubMed1985

Adriamycin-induced chronic proteinuria: a structural and functional study.

Focal, segmental glomerulosclerosis is frequently associated with chronic proteinuria and progressively declining renal function in humans as well as in experimental models of glomerular disease. Although little is known regarding the pathogenesis of this lesion, persistent, massive proteinuria has been associated with a poor prognosis. The administration of adriamycin to rats results in proteinuria of glomerular origin. We used this model to study the glomerular functional and structural alterations associated with proteinuria of 4 to 5 weeks duration. Studies of single nephron function revealed a 34% reduction in nephron plasma flow and a 50% decline in the glomerular ultrafiltration coefficient in rats given adriamycin. Single nephron glomerular filtration rate, however, was only modestly reduced (27%), because of an 8.0 mm Hg elevation of mean transcapillary hydraulic pressure difference (P less than 0.05). Morphologically, glomeruli of adriamycin-treated rats demonstrated significantly increased mesangial matrix and cellularity. In addition, glomerular capillaries frequently appeared enlarged, and epithelial cell bleb formation was evident. Focal glomerulosclerosis, however, was only rarely seen. The functional and morphologic characteristics of chronic adriamycin nephrosis are different from those associated with chronic proteinuria induced by repetitive administration of aminonucleoside of puromycin. Comparison of the two models suggests that the development of focal glomerulosclerosis can be dissociated from proteinuria and elevations of intraglomerular hydraulic pressures.

Animals↗
PubMed1985

Relationship among altered glomerular barrier permselectivity, angiotensin II, and mesangial uptake of macromolecules.

Clinical and experimental studies suggest that accumulation of phlogogenic macromolecules in the glomerular mesangium may lead to mesangial expansion and eventual glomerulosclerosis. In focal glomerulosclerosis and nephrotic syndrome entrapment of macromolecules is observed in areas of glomerulosclerosis. To determine whether mesangial uptake of radiolabeled, heat-aggregated IgG (AG125I), a biologically active macromolecular protein, is influenced by increased glomerular filtration barrier permeability, we evaluated the glomerular uptake of AG125I in three models of proteinuria: aminonucleoside of puromycin nephropathy (PAN), adriamycin nephropathy, and Heyman's nephropathy. Rats were studied approximately 1 week after onset of proteinuria. AG125I was measured in preparations of isolated glomeruli and compared to simultaneous blood, liver, and spleen levels. Only rats with PAN had a marked increase in glomerular AG125I compared to control rats, 7.8 versus 2.6 micrograms/mg of glomeruli, respectively. We then evaluated whether a continuous infusion of a competitive inhibitor of angiotensin II, saralasin (300 micrograms/kg of body weight/minute), influenced mesangial uptake of AG125I in PAN rats. Strikingly, glomerular AG125I in rats with PAN was reduced to levels comparable to that observed in control rats infused with only saralasin, 2.8 versus 3.0 micrograms/mg of glomeruli, respectively. This effect on glomerular AG125I content was independent of any significant effect of saralasin on blood, hepatic, or splenic levels of AG125I. Moreover, these changes in glomerular AG125I in saralasin-infused rats with PAN did not appear to directly correlate with changes in whole kidney function. These studies also demonstrated that proteinuria per se did not influence mesangial uptake of macromolecules. Thus, these data indicated that angiotensin II had an important effect on intraglomerular factors that modulate mesangial localization of phlogogenic macromolecules.

Angiotensin II↗
PubMed1985

Age is a determinant of the glomerular morphologic and functional responses to chronic nephron loss.

Loss of renal mass results in a compensatory increase in growth and function of remaining nephrons. Renal ablation also accelerates the expansion of mesangial matrix and the development of focal glomerulosclerosis (FGS) associated with aging. To determine whether age at the time of nephron loss influences the compensatory changes in function and the severity of subsequent glomerular lesions, immature rats (group I) and adult rats (group II) underwent right unilateral nephrectomy (Nx). Four weeks after Nx, compensatory renal growth and single nephron function showed a similar pattern in both groups. Five months after Nx, however, group I displayed significantly greater compensatory growth than group II, although both groups exhibited similar single nephron function. Moreover, group II demonstrated a significant increase in mean transcapillary hydraulic pressure difference (delta P) of approximately 5 mm Hg. Although both groups experienced accelerated expansion of mesangial matrix, significant FGS was detectable only in group I. Thus glomerular injury after Nx may result from factors other than alterations in glomerular hemodynamics.

Aging↗
PubMed1985

Effects of genetic obesity on renal structure and function in the Zucker rat.

Although hyperphagia and obesity in the Zucker rat strain have been reported to be associated with spontaneous focal glomerulosclerosis (FGS), little is known about the age of onset and the natural history of hypertension, albuminuria, renal function, and glomerular injury in this model. We systematically investigated renal structure and function in obese male Zucker rats. Lean male littermates were used as controls. Obese rats developed glomerular mesangial matrix expansion and albuminuria by 14 weeks of age. These changes occurred despite normal inulin clearance (2.2 +/- 0.6 ml/min obese vs. 2.0 +/- 0.4 ml/min lean, P greater than 0.1) and filtration fraction (0.32 +/- 0.08 obese vs. 0.34 +/- 0.06 lean, P greater than 0.1), suggesting that increased glomerular filtration and renal plasma flow were not a prerequisite for the development of FGS. By 28 weeks of age, FGS was evident in seven of eight obese rats, and at 68 weeks of age all obese rats had marked FGS. Mean systolic blood pressure was elevated by 11 to 25 mm Hg in obese rats at all ages. Although the pathogenesis of glomerular injury is unknown, our data demonstrate that microalbuminuria, mild hypertension, and mesangial matrix expansion precede the development of progressive FGS in obese Zucker rats.

Albuminuria↗
PubMed1985

Effects of genetic obesity on renal structure and function in the Zucker rat. II. Micropuncture studies.

The obese Zucker rat is a model of nonimmune glomerular disease characterized by spontaneous proteinuria and focal glomerulosclerosis. Mechanisms important in the pathogenesis of glomerular injury in obese Zucker rats are unknown, but may involve hemodynamic and metabolic factors. Micropuncture studies of superficial nephron function were performed prior to the development of FGS in male obese Zucker rats and lean littermates 9 to 13 weeks of age. Compared with lean littermates, obese Zucker rats demonstrated small increases in superficial nephron glomerular filtration rate (32.3 +/- 2.3 nl/min vs. 27.8 +/- 2.0, P greater than 0.05) and plasma flow (87.1 +/- 7.2 nl/min vs. 79.0 +/- 5.1, P greater than 0.05). Intraglomerular hydraulic pressures were not significantly different between groups. Despite similarities in superficial nephron glomerular function, obese Zucker rats displayed increases in glomerular area and mesangial matrix. These morphologic changes occurred in both superficial and deep nephrons. We conclude that increases in glomerular pressures and flows are not a prerequisite for the initiation of glomerular injury in the obese Zucker rat.

Albuminuria↗
PubMed1984

Acute glomerulonephritis. A clinical overview.

Acute glomerulonephritis is a syndrome characterized by the abrupt onset of hematuria often accompanied by proteinuria, hypertension, edema, and renal dysfunction. Acute glomerulonephritis can be subdivided into primary glomerular disease, postinfectious glomerulonephritis, and glomerulonephritis associated with systemic disease. With few exceptions, the underlying mechanism of acute glomerulonephritis is an immunologic one. To differentiate clinically the specific etiology of the glomerulonephritis, attention must be focused on the presence of signs or symptoms of systemic disease, changes in the environment of the patient, family history of renal disease, and recent history of infectious disease.

Adult↗
PubMed1984

Opsonic deficiency of peritoneal dialysis effluent in continuous ambulatory peritoneal dialysis.

Staphylococcus epidermidis peritonitis frequently complicates the clinical course of patients treated with continuous ambulatory peritoneal dialysis (CAPD). Since bacterial opsonization is critical to the effective defense of the peritoneal cavity by phagocytic cells, we prospectively evaluated the opsonic activity of peritoneal dialysis effluent obtained from 17 CAPD patients during 102 patient months. Samples of peritoneal dialysis effluent contained concentrations of opsonins against S. epidermidis that were less than 2% of that observed in serum. Moreover, heat-labile opsonic activity against Escherichia coli was absent from all dialysis effluents. During the study, there were ten episodes of peritonitis in nine CAPD patients (1 per 10.2 patient months). S. epidermidis was isolated in seven episodes, a gram-negative bacillus in one, and two episodes were culture negative. the incidence of S. epidermidis peritonitis was 1 per 62 patient months in the patients with "high" peritoneal dialysis effluent opsonic activity against S. epidermidis but was nearly tenfold greater in patients with "low" opsonic activity (1 per 6.7 patient months). We conclude that peritoneal dialysis effluent opsonic activity predicts which CAPD patients are at an increased risk to develop S. epidermidis peritonitis.

Aged↗
PubMed1984

Hemodialysis elimination rates and clearance of gentamicin and tobramycin.

The apparent hemodialyzer elimination rate constant and clearance for gentamicin and tobramycin were determined during 100 routine hemodialysis treatments in 49 patients. Three different dialyzers (CDAK 3500, CF 1211, and CF 1511), which vary in membrane composition, surface area, and thickness, were evaluated. The elimination rate constant in each patient was calculated from the slope of the log serum concentration-time curves. Two different elimination rate constants for each patient were derived, one during hemodialysis (KT) and one off hemodialysis (K). The hemodialyzer elimination rate constant (KD) for each dialyzer was calculated as the difference between these two values. The hemodialyzer clearance (Cd) was calculated by multiplying the hemodialyzer elimination rate constant by the volume of distribution of the patient. The KDS of gentamicin and tobramycin by the three dialyzers were significantly different. The gentamicin KD of the CDAK 3500 was lower than the values of the CF 1211 and CF 1511 (0.086 versus 0.123 versus 0.131 h-1, respectively). The Cd of the CDAK 3500 for gentamicin was also significantly lower than that of the CF 1511. Although the CdS of tobramycin for the CF 1211 and CF 1511 were 24 and 43% greater than that for the CDAK 3500, these differences were not statistically significant. The KD and Cd of tobramycin were greater than those of gentamicin for all three dialyzers. These data demonstrate that commonly used hemodialyzers vary markedly with respect to their elimination and clearance characteristics of gentamicin and tobramycin. Clinically, these observations may be helpful in designing the correct dose of gentamicin and tobramycin to achieve maximum drug safety and efficacy in hemodialysis patients.

Aged↗
PubMed1984

Pharmacokinetics of vancomycin in patients with various degrees of renal function.

The pharmacokinetics of vancomycin were characterized in 56 patients with different degrees of renal function after an intravenous dose of 18.4 +/- 4.7 mg kg-1 (mean +/- standard deviation). Seven subjects had a creatinine clearance (CLCR) of greater than 60 ml min-1 (group I), 13 had a CLCR of 10 to 60 ml min-1 (group II), and 36 had a CLCR of less than 10 ml min-1 (group III). Serial serum samples (range, 3 to 8) were collected during the 168 h after drug administration. The serum concentration-time profile in all patients demonstrated monoexponential decay. The mean half-lives were 9.1, 32.3, and 146.7 h in groups I, II, and III, respectively. A significant decline in serum clearance (CLS) was also noted (62.7 to 28.3 to 4.87 ml min-1 in groups I, II, and III, respectively). The steady-state volume of distribution varied from 0.72 to 0.90 liter kg-1. There was no significant relationship between the steady-state volume of distribution and CLCR. The observed relationship between CLS and CLCR (CLS = 3.66 + 0.689 CLCR; r = 0.8807) can be utilized to devise dosage schedules for patients with any degree of renal impairment. This relationship was utilized to develop a nomogram for initial and maintenance dosing of vancomycin.

Adolescent↗
PubMed1984

Polyamino acid enhancement of bacterial phagocytosis by human polymorphonuclear leukocytes and peritoneal macrophages.

Cationic polyamino acids are known to enhance a variety of cell-cell interactions by virtue of their ability to alter electrostatic forces of cell surfaces. In this study, the effect of polyamino acids on phagocytosis of 3H-labeled bacteria by human polymorphonuclear leukocytes (PMNs) and peritoneal macrophages was investigated. Negatively charged and neutral polyamino acids did not influence phagocytosis of unopsonized Staphylococcus epidermidis, whereas protamine, poly-L-arginine, and poly-L-lysine stimulated phagocytosis in a dose-dependent manner. At 50 micrograms/ml, greater than 30% uptake by PMNs was seen with each of these cationic polyamino acids. Although cationic polyamino acids promoted PMN and peritoneal macrophage phagocytosis of unopsonized S. epidermidis, Staphylococcus aureus M (encapsulated) and M variant (unencapsulated), and Escherichia coli J5, little effect was seen with the parent E. coli O111:B4 or a serotype O222:H16 strain. Pretreatment of bacteria and phagocytes separately demonstrated that the phagocytosis-promoting property of polyamino acids is manifest predominantly on the bacteria. Bacteria pretreated with cationic polyamino acids also elicited a PMN chemiluminescent response, and PMN-associated bacteria were killed, as determined by a fluorochrome microassay. Thus, cationic polyamino acids promote the phagocytosis and killing of many but not all bacterial strains, and in this respect polyamino acids function as opsonins.

Escherichia coli↗
PubMed1984

Bacterial growth and killing in chronic ambulatory peritoneal dialysis fluids.

We determined the ability of Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli to survive and grow in peritoneal dialysis fluids from patients undergoing chronic ambulatory peritoneal dialysis. Staphylococci did not survive in commercially available dialysis solutions but grew readily in peritoneal effluents obtained from patients after the dialysis dwell time. The number of CFU doubled 6 and 13 times in 24 h for S. epidermidis and S. aureus, respectively. E. coli grew well in both the pre- and postdialysis peritoneal fluid. Peritoneal macrophages as well as peripheral blood leukocytes inhibited bacterial growth in peritoneal dialysis fluid. However, 10(6) phagocytes per ml were minimally required to obtain a bacteriostatic effect. The addition of serum to peritoneal dialysis fluid increased the antibacterial activity of macrophages and blood leukocytes. The capacity of the aminoglycoside antibiotic tobramycin to reduce bacterial CFU in peritoneal dialysis fluid was only 10% of its bactericidal capacity in standard Mueller-Hinton brush. Peritoneal dialysis fluid had no effect on the antibacterial activity of imipenem.

Blood Bactericidal Activity↗
PubMed1984

Glomerular hemodynamic and structural correlations in long-term experimental diabetic rats.

The glomerular functional and histologic alterations present in rats after 1 year of severe experimental diabetes mellitus were examined. Determination of single nephron function revealed a significant decline (27%) in glomerular plasma flow, primarily as a consequence of a significant increase in afferent arteriolar resistance. Single nephron filtration rate was not decreased proportionate to the decline in glomerular plasma flow, principally because of a significant increase (33%) in the ultrafiltration coefficient. As a result, single nephron filtration fraction was significantly increased by 24%. These functional changes in diabetic rats were similar to those observed after only 1 month of experimental diabetes; however, considerable progression in the glomerular histopathologic characteristics was evident in rats diabetic for 1 year. These changes were characterized by an increased glomerular mesangial matrix, focal glomerulosclerosis, and intense staining for rat IgG and C3 in mesangial regions. We propose that these histologic changes may be a consequence of long-term increases in the filtration fraction particularly associated with decreases in nephron blood flow, functional changes that may favor mesangial localization of phlogogenic macromolecules.

Animals↗
PubMed1983

Peritoneal macrophages and opsonins: antibacterial defense in patients undergoing chronic peritoneal dialysis.

The antibacterial activity of phagocytic cells and opsonins in peritoneal dialysis effluents from 21 patients undergoing chronic peritoneal dialysis (CPD) was studied. Effluents contained an average of 12 x 10(6) cells per liter that were predominantly macrophages. Macrophages phagocytized and killed opsonized Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli as efficiently as did polymorphonuclear neutrophils (PMNs) from healthy donors. Macrophage chemiluminescence was one-third of that observed with donor PMNs. In the absence of opsonins, macrophages efficiently phagocytized and killed S. aureus by binding S. aureus cell wall protein A to macrophage surface IgG. Nine (43%) of 21 effluents failed to opsonize S. epidermidis, and none opsonized E. coli. When present, titers of S. epidermidis opsonins were 50- to 100-fold lower than that of normal serum. IgG and C3 concentrations in effluent reflected its opsonic capacity. Macrophages from patients undergoing CPD thus have intact phagocytic and bactericidal functions. However, the low level of opsonic molecules and inadequate numbers of macrophages in the peritoneal cavity may predispose patients undergoing CPD to peritonitis.

Ascitic Fluid↗
PubMed1983

Human peritoneal macrophage cytotoxicity mediated by cytophilic IgG.

Cells of the human mononuclear phagocyte system have recently been shown to possess cytophilic IgG molecules that promote phagocytosis of staphylococci bearing cell-wall protein A. In the present study, the possible mediation of a cytotoxic response to 51Cr-labeled sheep erythrocytes coated with protein A by cytophilic antibodies on human peritoneal macrophages was evaluated. The target cells were readily lysed by peritoneal macrophages. Cytotoxicity was blocked by pretreatment of macrophages with soluble protein or with anti-Fc F(ab')2 fragments. In contrast, cytotoxicity was not affected by cytochalasin B; this finding suggests that cytolysis is an extracellular event. Perturbation of cytophilic IgG with particle-bound protein A elicited a chemiluminescent response from peritoneal macrophages; however, experiments with scavengers of reactive oxygen species indicated that toxic oxygen radicals may not be required for cytotoxicity. The results indicate that cytophilic antibody-mediated cytotoxicity may contribute to cellular injury as well as host-defense aspects of the inflammatory process.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1983

Cefsulodin pharmacokinetics in patients with various degrees of renal function.

The pharmacokinetics of cefsulodin were characterized in 19 patients with different degrees of renal function after a single 500-mg, 30-min intravenous infusion. Six subjects had a creatinine clearance (Clcr) of greater than 100 ml min-1 (group I), eight had a Clcr of between 12 and 42 ml min-1 (group II), and five had a Clcr of less than 10 ml min-1 (group III). Nine plasma and four urine samples were collected in the first 36 h. The plasma concentration-time data were fitted to a two-compartment open model. The mean beta-phase half-life was 1.77, 6.37, and 10.12 h in groups I, II, and III, respectively. A significant decline in plasma clearance (Clp) was also noted between the three groups: 136 to 49.6 to 27.2 ml min-1 in groups I, II, and III, respectively. Steady-state volume of distribution was 0.26 liter kg-1, regardless of renal function. The observed linear relationship between Clp and Clcr (Clp = 24.09 + 0.765 Clcr; r = 0.9566) can be utilized to revise dosage schedules for patients with any degree of renal impairment. The nonrenal clearance of cefsulodin was also noted to be significantly lower in groups II and III than in group I. Further investigations will be necessary to elucidate the mechanism(s) responsible for the decrease in the nonrenal clearance of cefsulodin.

Adult↗