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Biomedical subjects

R J Falk

Publications and source records attributed to R J Falk.

At least 91 records · Page 5Linked to original sources
PubMed1992

Treatment of progressive membranous glomerulopathy. A randomized trial comparing cyclophosphamide and corticosteroids with corticosteroids alone. The Glomerular Disease Collaborative Network.

OBJECTIVE: To determine if deterioration in renal function could be ameliorated by adding cyclophosphamide to corticosteroid therapy in patients with progressive membranous glomerulopathy. DESIGN: Randomized, controlled treatment trial. Patients were followed for a mean of 29.2 +/- 17.1 months. SETTING: Collaborative network of 120 university and private-practice nephrologists. PARTICIPANTS: Patients with membranous glomerulopathy whose renal function deteriorated (as evidenced by doubling of the serum creatinine level, a 50% fall in the glomerular filtration rate, or a sustained serum creatinine level of greater than 2.0 mg/dL [reciprocal creatinine value, 0.5], or whose nephrotic range proteinuria persisted in association with morbid complications. Of 156 patients with biopsy-proven membranous glomerulopathy, 36 became eligible for randomization. Twenty-six of these 36 patients were randomly assigned to receive one of the two treatments. INTERVENTIONS: Pulse methylprednisolone, oral corticosteroids, and 6 months of intravenous cyclophosphamide or alternate-day corticosteroid therapy alone. MAIN RESULTS: At entry, no statistical differences were found between the treatment groups in duration of renal disease, age, gender, serum creatinine level, 24-hour urine protein excretion, or biopsy stage. The groups showed no difference in mean arterial blood pressure during follow-up. Four of the 13 patients receiving corticosteroids alone and 4 of the 13 patients receiving corticosteroids plus intravenous cyclophosphamide progressed to end-stage renal disease during follow-up. Reciprocal creatinine values tested at 6-month intervals showed no statistical differences between treatment groups at any time point. The log of the 24-hour protein excretion values showed no statistical differences between treatment groups after treatment. The power to detect a substantial improvement in renal function, defined as a doubling of the reciprocal of the serum creatinine, at the 0.05 significance level was 0.92. CONCLUSIONS: Combination therapy with intravenous cyclophosphamide and corticosteroids, when compared with corticosteroid therapy alone, does not improve renal function in patients with progressive membranous glomerulopathy.

Adult↗
PubMed1992

Reactivity of antineutrophil cytoplasmic autoantibodies with mononuclear phagocytes.

Antineutrophil cytoplasmic autoantibodies (ANCA) react with proteins found in the granules of neutrophils and the peroxidase-positive lysosomes of monocytes, including myeloperoxidase (MPO), proteinase 3 (PR-3), and elastase. ANCA-associated diseases, such as Wegener's granulomatosis and polyarteritis nodosa, are characterized by necrotizing vascular inflammation. The inflammatory lesions typically contain both neutrophils and mononuclear phagocytes, with the latter sometimes predominating, for example, in the granulomatous lesions of Wegener's granulomatosis. We investigated the presence of the ANCA target antigens PR3, MPO, and elastase in mononuclear phagocyte cytoplasm during the course of differentiation in vitro and in alveolar and peritoneal macrophages. We observed that ANCA antigens were down-regulated during mononuclear phagocyte differentiation, with the loss corresponding to that of peroxidase-positive granules. This suggests that ANCA can directly interact only with monocytes and early exudative macrophages and not with mature macrophages.

Autoantibodies↗
PubMed1992

Isolated prolactin deficiency: a case report.

A 36-year-old woman, with lifelong oligomenorrhea and immeasurable serum PRL levels, conceived and had normal deliveries after ovulation induction with CC. Alactogenesis followed both deliveries. Evaluation of other pituitary hormones were within normal limits, and attempted stimulation of PRL levels by TRH was unsuccessful. The clinical significance of isolated hypoprolactinemia is discussed.

Adult↗
PubMed1992

Clinical and pathologic features of fibrillary glomerulonephritis.

A diagnosis of fibrillary glomerulonephritis was made in 31 renal biopsies from 28 patients on the basis of the electron microscopic identification of glomerular deposits of randomly arranged fibrils that resembled amyloidosis but were larger. This accounted for approximately 1% of all nontransplant renal biopsy diagnoses. Renal biopsy specimens with parallel arrays of 30 nm to 50 nm microtubules (that is, immunotactoid glomerulopathy) were not included in the study. The patients had a mean age of 49 years with a range of 21 to 75. The male to female ratio was 1:1.8 and the ratio of Whites to Blacks was 8.3:1, which differs from the 3:1 ratio in our overall biopsy population. All patients had proteinuria (mean 6.0 g/day), and most had hematuria and renal insufficiency. After a mean follow-up of 24 months, there was 48% renal survival. The light microscopic appearance of the fibrillary glomerulonephritis was quite varied. Capillary wall thickening and matrix expansion were the most frequent alterations. Nineteen percent of specimens had crescents. Morphometric ultrastructural analysis demonstrated a mean fibril diameter of 22.4 +/- 7.4 nm. Immunofluorescence microscopy revealed that IgG was the dominant and often the only immunoglobulin class in immune deposits, and subclass analysis revealed that IgG4 was the dominant or exclusive subclass in all specimens tested. We hypothesize that the relatively homogeneous nature of the immunoglobulin in the immune deposits is the basis for the fibril formation.

Adult↗
PubMed1992

Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells.

Anti-myeloperoxidase autoantibodies are found in association with idiopathic necrotizing glomerulonephritis and systemic vasculitis. It is not known if their presence is an epiphenomen or an integral part of the pathogenic process. To further delineate their hypothesized pathogenicity, we studied their ability to stimulate neutrophils to damage human umbilical vein endothelial cells in vitro. Anti-myeloperoxidase antibodies from human, rabbit and mouse sources were utilized. These antibodies stimulated neutrophils to damage endothelial cells as determined by 51Cr release. The effect was dependent on priming the neutrophils with tumor necrosis factor-alpha, and further enhanced with the addition of endotoxin. The amount of endothelial cell damage was dependent on the dose of anti-myeloperoxidase, the source of the neutrophils, the concentration of TNF, and the presence of endotoxin. Under identical conditions, control antibodies did not stimulate neutrophils to damage endothelial cells. The effect was confirmed by labeling the endothelial cells with 3H-adenine which yielded the same results. These results provide further in vitro evidence that anti-myeloperoxidase autoantibodies may play a significant role in the pathogenesis of idiopathic pauci-immune glomerulonephritis and vasculitis.

Adenine↗
PubMed1992

Anti-myeloperoxidase autoantibodies react with native but not denatured myeloperoxidase.

We wondered whether anti-myeloperoxidase (MPO) autoantibodies (MPO-ANCA) found in patients with systemic vasculitis react with a conformational epitope or epitopes on the MPO molecule. Sera from 15 human MPO-ANCA, and a polyclonal and a monoclonal anti-MPO antibodies were reacted with MPO in native and denatured states. Human MPO-ANCA and mouse monoclonal anti-MPO reacted with native MPO, and a 120-kD band representing the MPO hologenzyme, but not with denatured MPO fragments; however, MPO-ANCA and mouse anti-MPO did not demonstrate competitive inhibition of binding to MPO. Polyclonal rabbit anti-MPO reacted with both native and denatured MPO. All MPO-ANCA tested showed the same patterns of reactivity with native and denatured MPO in dot blot and Western blot analyses. Both polyclonal and monoclonal anti-MPO antibodies inhibited MPO's protein iodination by over 90%, whereas MPO-ANCA IgGs, normal IgGs and disease control IgGs did not. These data suggest that (i) MPO-ANCA interact with a conformational epitope on the MPO molecule; and (ii) MPO-ANCA from different patients have similar reactivity with native versus denatured MPO.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

Acute renal failure secondary to leukocyte-mediated acute glomerular injury.

Acute glomerulonephritis can cause acute renal failure. Activated neutrophils and monocytes are major effectors of glomerulonephritic renal failure. Adhesion molecules, granule enzymes, reactive oxygen radicals, lipid metabolites, and cytokines of activated neutrophils and monocytes mediate glomerular capillary constriction, occlusion, and destruction. Injurious products and biologically active mediators released by activated leukocytes have profound functional effects on mesangial cells and endothelial cells, which in turn participate in the disturbance of glomerular function, for example, by altering capillary diameter and surface area. The glomerular inflammatory events result in decreased glomerular capillary ultrafiltration coefficient and glomerular filtration rate, as well as other functional perturbations.

Acute Kidney Injury↗
PubMed1992

Studies on complement deposits in epidermolysis bullosa acquisita and bullous pemphigoid.

Epidermolysis bullosa acquisita (EBA) is an inflammatory subepidermal blistering disease characterized by circulating and tissue-bound autoantibodies specific for type VII collagen of the basement membrane zone. The antibodies consist of both complement- and noncomplement-binding populations and belong to all four subclasses of IgG. We investigated the presence of the membrane attack complex C3b, C5, and S protein in EBA and compared C3b and C5 in EBA and bullous pemphigoid. In 10 patients with EBA, these components were detected at the basement membrane zone as follows: membrane attack complex, 90%; S protein, 90%; direct C5, 90%; C3b, 100%; and C5 binding, 90%. In the patients with bullous pemphigoid, the results were as follows: direct C5, 58%; C3b, 33%; and C5 binding, 19%. These results provide additional evidence for complement activation at the basement membrane zone in EBA, show that complement activation in EBA proceeds to activation of terminal complement components, and suggest that EBA antibodies are more potent activators of C5 than are bullous pemphigoid antibodies.

Basement Membrane↗
PubMed1992

Serum beta-human chorionic gonadotropin, estradiol and progesterone as early predictors of pathologic pregnancy.

We prospectively studied 110 asymptomatic female infertility patients with serial serum measures of beta-human chorionic gonadotropin (hCG), estradiol (E2) and progesterone (P) to determine their sensitivity, specificity, predictive value and test efficiency, alone or in combination, for the prediction of pathologic gestations prior to five weeks after ovulation. Circulating levels of serum beta-hCG, E2 and P were measured at 48- or 72-hour intervals. Seventy-four patients (67%) had viable pregnancies, for which the abnormal changes in steroid levels were defined as: a beta-hCG rise of less than 66% in 48 hours or less than 120% in 72 hours, an E2 decline of greater than 15% in 48 hours or greater than 20% in 72 hours, or a P decline of greater than 25% in 48 hours or greater than 33% in 72 hours. Thirty-six women (33%) had pathologic pregnancies, which included ectopic pregnancies (8), spontaneous or missed abortions (7), blighted ova (anembryonic gestation, 20) and hydatidiform mole (1). For the detection of pathologic pregnancies in this asymptomatic infertility population, the sensitivity of beta-hCG, E2 and P, singly or in combination, ranged from 34% to 78%, and the test efficiency ranged from 68% to 88%. Beta-hCG alone provided the highest sensitivity (78%) and test efficiency (88%). When compared to measuring serial beta-hCG alone, serum E2 or P did not enhance the test efficiency and lowered the sensitivity for the detection of pathologic pregnancies in an asymptomatic infertility population.

Adult↗
PubMed1992

Disease associations and pathogenic role of antineutrophil cytoplasmic autoantibodies in vasculitis.

Antineutrophil cytoplasmic autoantibodies are a useful diagnostic serologic marker for a variety of well-known vasculitic syndromes, including Wegener's granulomatosis, polyarteritis nodosa (especially microscopic polyarteritis nodosa), Churg-Strauss syndrome, and pulmonary-renal syndrome with alveolar capillaritis. Although most patients with antineutrophil cytoplasmic autoantibody-associated disease have systemic disease, disease limited to one organ does occur, eg, isolated necrotizing glomerulonephritis, isolated respiratory tract disease, or isolated orbital disease. Antineutrophil cytoplasmic autoantibody titers may be useful in modulating treatment regimens. There is in vitro evidence that antineutrophil cytoplasmic autoantibodies are directly involved in the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitides.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Antibodies against granule proteins activate neutrophils in vitro.

Polymorphonuclear leukocyte (PMN) respiratory burst was stimulated by heterologous antibodies against PMN granule proteins but not by control antibodies. Fluorescence-activated cell sorter (FACS) analysis of activated PMN demonstrated the presence of two primary granule proteins, proteinase 3 (PR-3) and cationic protein 57 (CAP-57) at the membrane surface. The presence of myeloperoxidase (MPO) at the cell surface of primed and unprimed PMN was confirmed by immunoelectron microscopy. Priming doses of recombinant tumor necrosis alpha (rTNF alpha) enhanced the rate of superoxide (O2-) production by these antibodies and increased the amount of surface protein accessible to these antibodies. Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificities for PMN granule proteins are present in patients with Wegener's granulomatosis, polyarteritis nodosa, and idiopathic and crescentic glomerulonephritis. The demonstration that antibodies against granule proteins activate PMN supports the hypothesis that the vasculitis seen in these diseases is due in part to PMN mediated oxidative injury following PMN stimulation by ANCA.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch-Schönlein purpura: diagnostic value and pathogenic implications. The Glomerular Disease Collaborative Network.

IgA nephropathy is a common form of glomerulonephritis that has varied clinical expressions, ranging from asymptomatic hematuria to rapidly progressive nephritis. We report the strong association (P less than 0.0001) of circulating IgA-fibronectin aggregates with IgA nephropathy. Of 30 patients with IgA nephropathy, 93.3% had serum IgA-fibronectin aggregates detected with an enzyme immunoassay using collagen as a substrate to bind the aggregates. Among the patients with IgA-fibronectin aggregates were patients with Henoch-Schönlein purpura and recurrent crescentic IgA nephropathy in transplants. Only 11.7% of 103 patients with other types of glomerular disease and 6.7% of normal controls had positive IgA-fibronectin aggregate assay levels. IgA-fibronectin aggregates also were detected in serum using an antifibronectin antibody capture assay; and could be depleted from serum by heparin-agarose affinity chromatography. The circulating IgA-fibronectin aggregates had the same unusual predominance of lambda relative to kappa light chains that is observed in the glomerular deposits of IgA nephropathy. The data indicate that IgA-fibronectin aggregates are a useful serologic marker for IgA nephropathy, Henoch-Schönlein purpura, and recurrent IgA nephropathy in transplants. The presence of fibronectin in the circulating aggregates may play an important role in the preferential deposition of nephritogenic IgA-containing immune complexes in the mesangium of patients with IgA nephropathy.

Antigen-Antibody Complex↗
PubMed1991

Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides.

Antineutrophil cytoplasmic autoantibodies (ANCA) are in the circulation of patients with a variety of clinically and pathologically distinctive forms of necrotizing vasculitis. Some patients have classic manifestations of well-recognized clinicopathologic syndromes, such as Wegener's granulomatosis, microscopic polyarteritis nodosa, and Churg-Strauss syndrome, but many patients are difficult to assign to a diagnostic category. The Ad Hoc Nomenclature Committee of The Third International Workshop on ANCA is attempting to identify a working classification system for ANCA-associated vasculitides. This system takes into account the many shared clinical and pathologic features, and relies on prerequisite positive and negative findings for diagnostic categorization.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

The pathogenic role of antineutrophil cytoplasmic autoantibodies.

Antineutrophil cytoplasmic autoantibodies (ANCA) are found in the sera of patients with systemic necrotizing vasculitis and glomerulonephritis. Their role in the pathogenesis of these diseases is not clearly understood; however, there is a growing body of data that supports a pathogenic function for these antibodies. In vitro they can activate neutrophils and monocytes to produce reactive oxygen species (ROS), degranulate, and damage target cells. The antigens to which they are directed stimulate T lymphocytes from patients with these diseases. The ANCA directed against proteinase 3 (PR3) may also play a role in growth regulation of monocytes by inactivating the enzymatic function of its antigen. The proposed model of ANCA-induced disease takes into account both the in vitro data and the natural history of these diseases.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Reconstitution of an epithelial chloride channel. Conservation of the channel from mudpuppy to man.

We have previously shown that monoclonal antibody E12 (MAb E12), one of several such antibodies raised against theophylline-treated Necturus gallbladder (NGB) epithelial cells, inhibits the chloride conductance in the apical membrane of that tissue. Since chloride channels are critical to the secretory function of epithelia in many different animals, we have used this antibody to determine whether the channels are conserved, and in an immunoaffinity column to isolate the channel protein. We now demonstrate that MAb E12 cross-reacts with detergent-solubilized extracts of different tissues from various species by enzyme-linked immunosorbent assay (ELISA). Western blot analysis shows that this monoclonal antibody recognizes proteins of Mr 219,000 in NGB, toad gallbladder, urinary bladder, and small intestine, A6 cells, rat colon, rabbit gastric mucosa, human lymphocytes, and human nasal epithelial cells, and inhibits the chloride conductance in toad gallbladder, rat colon, and human nasal epithelium. Detergent-solubilized protein eluted from an immunoaffinity column and then further purified via FPLC yields a fraction (Mr 200,000-220,000) which has been reconstituted into a planar lipid bilayer. There it behaves as a chloride-selective channel (PCl/PNa = 20.2 in a 150/50 mM trans-bilayer NaCl gradient) whose unit conductance is 62.4 +/- 4.6 pS, and which is blocked in the bilayer by the antibody. The gating characteristics of this channel indicate that it can exist as aggregates or as independent single channels, and that the antibody interferes with gating of the aggregates, leaving the unit channels unchanged. From these data we conclude that the protein of Mr 219,000 recognized by this monoclonal antibody is an important component of an epithelial chloride channel, and that this channel is conserved across a wide range of animal species.

Animals↗
PubMed1991

Vitronectin: effects on keratinocyte motility and inhibition of collagen-induced motility.

Epibolin, a plasma protein, was initially purified on the basis of its ability to enhance spreading of keratinocytes. It is now known that epibolin is identical to serum spreading factor, S protein, and vitronectin, and the current name for the protein is vitronectin. Studies of vitronectin on cultured keratinocytes showed that it caused spreading and epiboly but not cellular adhesion to the substratum. In studies with other types of cells, vitronectin increased migration of several types of cells in a Boyden chamber. Because some agents that enhance spreading and adhesion, such as collagen and fibronectin, also increase motility, we tested whether vitronectin increased motility of keratinocytes. By photographing and quantitating motility of keratinocytes plated on a bed of colloidal gold particles, we determined that vitronectin increased local movement of keratinocytes in a concentration-dependent fashion, resulting in clearing of gold particles in a circular pattern around the cells, but did not cause the production of tracks found in cultures plated on collagen or fibronectin. The small increases in clearing of the gold particles that occurred in the presence of vitronectin were abolished by antibody to vitronectin. Furthermore, the marked increase in motility produced by type I collagen was significantly reduced when the keratinocytes were treated with vitronectin. Antibody to vitronectin also abrogated the vitronectin-induced reduction in collagen-stimulated motility, confirming that this action was specific for vitronectin. Serum, which contains vitronectin, stimulated motility in a fashion identical to purified vitronectin, but serum lacking vitronectin was inactive. These studies show that vitronectin causes a localized increase in movement associated with spreading resulting in a halo around individual cells, that vitronectin does not enhance directional motility of keratinocytes in this assay but in contrast antagonizes such motility produced by collagen, and that vitronectin is the factor in serum responsible for this effect. The findings with vitronectin and collagen show that these agents stimulate different types of motility. The roles in wound healing of agents stimulating different types of motility are unclear and require further study.

Blood Physiological Phenomena↗