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Biomedical subjects

R C Atkins

Publications and source records attributed to R C Atkins.

At least 127 records · Page 7Linked to original sources
PubMed1993

Interferon-gamma stimulates the secretion of IL-1, but not of IL-6, by glomerular mesangial cells.

IL-1 activity in culture supernatant and cell lysate from rat mesangial cells stimulated with interferon-gamma (IFN-gamma) was measured by a thymocyte proliferation assay. While IFN-gamma alone had no effect on the secretion or the intracellular pool of IL-1, the enhancement by IFN-gamma of IL-1 secretion in response to lipopolysaccharide (LPS) was observed. The stimulatory effect of culture supernatant on thymocyte proliferation was abrogated by preincubation with the anti-IL-1 antibody. At least 4-h incubation with IFN-gamma and LPS was required to detect enhancing effect of IFN-gamma. The addition of as little as 1 U/ml IFN-gamma significantly increased IL-1 secretion in the presence of 10 micrograms/ml LPS. The IL-6 activity in culture supernatants was determined by measurement of thymidine uptake in mouse IL-6-dependent cell line (MH60.BSF2). Mesangial cells secreted IL-6 in culture supernatant without additional stimuli and LPS distinctly increased it as described previously. However, in contrast to IL-1 production, no effect of IFN-gamma on IL-6 secretion was observed in the presence or absence of LPS. Moreover, we determined whether enhanced IL-1 release is associated with Ia expression on mesangial cells. IFN-gamma alone and the combination with LPS induced marked expression of Ia antigen, whereas LPS alone did not. We conclude that IFN-gamma stimulates the production of IL-1, but not IL-6, by mesangial cells and suggest an important role of IFN-gamma in the pathogenesis of glomerulonephritis by regulating the mesangial production of IL-1 and the accessory cell function of mesangial cells.

Animals↗
PubMed1993

Suppression of experimental crescentic glomerulonephritis by deoxyspergualin.

Deoxyspergualin is an immunosuppressive drug which is effective in both preventing allograft rejection and suppressing steroid-resistant acute rejection. This study was designed to determine whether deoxyspergualin could suppress the development of rapidly progressive crescentic glomerulonephritis in antigen-primed animals. Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced by priming rats with rabbit immunoglobulin G (IgG), followed 5 days later by an injection of rabbit anti-rat GBM serum (day 0). Groups of five animals were treated with deoxyspergualin (5 mg/kg.day) or saline by daily ip injection from day 0 until euthanasia on days 1, 7, 14, or 21. Deoxyspergualin treatment resulted in a significant suppression of renal disease. Compared with saline-treated controls, deoxyspergualin treatment reduced proteinuria, resolved hematuria, and completely prevented a fall in creatinine clearance. Deposition of rabbit IgG along the GBM was unaffected by deoxyspergualin treatment, but glomerular deposition of rat IgG and C3 was significantly reduced from day 14 onwards, which was associated with a significant reduction of circulating rat anti-rabbit IgG. Deoxyspergualin treatment also produced a dramatic improvement in renal histology. Glomerular necrosis, fibrosis, and crescent formation were markedly suppressed, whereas tubulointerstitial lesions were completely prevented. This was associated with a marked suppression of mononuclear cell infiltration and activation. In the glomerulus, macrophage infiltration was suppressed by approximately 50%, whereas accumulation of macrophages and immune-activated (interleukin-2 receptor) T cells within the interstitium was almost completely abrogated by deoxyspergualin treatment. In conclusion, deoxyspergualin was found to be effective in suppressing the development of experimental crescentic glomerulonephritis in antigen-primed animals by acting on both the local cell-mediated response within the kidney and the systemic humoral immune response. Further work is warranted to determine whether this could be a useful drug for the treatment of human proliferative glomerulonephritis.

Animals↗
PubMed1993

Immune events in lymphoid tissues during experimental glomerulonephritis.

To investigate immune events within lymphoid tissues and their role in relation to glomerular disease, systemic lymphoid tissues from rats with accelerated experimental anti-GBM glomerulonephritis or with primed serum sickness glomerulopathy were studied. Following disease induction, changes in leukocytic populations within lymphoid tissues were analysed over a 28 day time course by immunoperoxidase labelling with monoclonal antibodies. In anti-GBM glomerulonephritis there was rapid and severe renal injury and pulmonary hemorrhage (Good-pasture's syndrome). In these rats, antigen (rabbit IgG) was deposited on the GBM and within germinal centres of lymphoid tissues. From day 3 onwards, there was a significant increase in the number of T cells, presumably CD4+ T helper cells, present within enlarged germinal centres of kidney draining lymph nodes, axillary lymph nodes and spleen (p < 0.05) which peaked at day 14 (up to 28% of total cells) when there was intense deposition of rat IgG and C3 on the GBM. Similarly, increased numbers of ED1+ macrophages were evident in both germinal centres and T cell areas (paracortex and periarteriolar lymphoid sheath). Notably, the appearance of IL-2R expression in germinal centres and T cell areas was apparent from day 7 onwards. This was the time when widespread renal interstitial infiltration, cellular immune activation and severe renal functional and histological injury developed. In addition, antigen deposited in germinal centres was found to be associated with CD4+, CD5-, ED1- cells, most probably antigen presenting dendritic cells. In contrast, in acute serum sickness there was no antigen deposited in germinal centres and only mild renal injury and minor changes within lymphoid tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Serum alpha 2-macroglobulin in haemodialysis patients: baseline and kinetic studies.

The pathogenesis of dialysis related amyloidosis remains unresolved despite the identification of beta 2-microglobulin (beta 2M) as the major protein constituent, as well as other proteins being present in the deposits. Among the latter we have assessed the serum concentrations of alpha 2-macroglobulin (alpha 2M) both in the baseline stage and during the haemodialysis (HD) procedure. We have also assessed the influence of the membrane on alpha 2M kinetics. Fifteen HD patients with histologically proven dialysis-related amyloidosis (DRA group) and 15 HD patients clinically and radiologically considered dialysis-related amyloidosis free (control group) were included in the baseline study. Blood was sampled the day before the second dialysis of the week and alpha 2M, beta 2M and alpha 1 antitrypsin were determined along with the routine biological analysis of these patients. Serum alpha 2M was greater in dialysis-related amyloidosis than in control patients (t = 2.35; P < 0.026). Serum beta 2M was similar in both groups. The serum alpha 2M and beta 2M correlated in patients with dialysis-related amyloidosis (r = 0.64; P < 0.01), while no correlation was found in controls (r = 0.17; NS). Stepwise analysis taking the presence of dialysis-related amyloidosis as the dependent variable retained the serum alpha 2M concentration as the first variable in the model (F = 4.4; partial r = 0.38; P < 0.046).(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloidosis↗
PubMed1993

Expression of VCAM-1 and E-selectin in an in vivo model of endothelial activation.

Vascular cell adhesion molecule 1 (VCAM-1) and E-selectin (or endothelial-leukocyte adhesion molecule 1) are inducible endothelial cell adhesion molecules that play a role in the recruitment of leukocytes into sites of inflammation. Information about the spatial and temporal pattern of induced expression of these leukocyte adhesion molecules in vivo is limited. This study reports the expression profile of VCAM-1 and E-selectin in various mouse tissues after lipopolysaccharide administration. Using rat complementary DNA probes for VCAM-1 and E-selectin, Northern blot analysis showed a marked increase in transcript levels for both adhesion molecules in lung, heart, and kidney. Maximal transcript levels for both VCAM-1 and E-selectin were observed at 3-6 hours and declined to low, constitutive levels of expression at 48 hours. Consistent with the Northern blot results, immunoperoxidase analysis revealed focal endothelial cell expression of VCAM-1 in control animals. Following lipopolysaccharide administration, VCAM-1 expression increased dramatically in all vascular beds examined, although the response was heterogeneous. Widespread induced expression of VCAM-1 on cells other than vascular endothelium was not seen. Neither basal nor induced expression correlated with leukocyte adhesion. Signals other than the expression of endothelial leukocyte adhesion molecules are required in vivo for leukocyte infiltration in this murine model of systemic endothelial activation.

Amino Acid Sequence↗
PubMed1993

Investigation of hematuria at a printing company.

An investigation was undertaken at a printing company into an apparently high prevalence of trace dipstick hematuria discovered during routine medical examinations. In both the printing employees (n = 225) and a control group (n = 118) from other industries, the prevalence of hematuria exceeded that described in most previous reports (31% and 25%, respectively, using the criterion of > 12 glomerular red cells or > 2 nonglomerular red cells/microliter of urine). No focus of abnormality was identified within the printing plant and no association was identified between reported exposure to potentially toxic substances and the degree of hematuria. An occupational hygiene inspection and medical follow-up of selected workers did not reveal any significant abnormalities. The limitations of available information concerning "normal" urinalysis results suggests that hematuria may not be a useful test for the screening of occupational groups at risk of bladder cancer.

Adolescent↗
PubMed1992

Epidermal growth factor and transforming growth factor alpha stimulate or inhibit proliferation of a human renal adenocarcinoma cell line depending on cell status: differentiation of the two pathways by G protein involvement.

Transforming growth factor alpha production by renal tumors, acting through the epidermal growth factor receptor, has been implicated in malignant transformation by studies which compared gene expression in neoplastic and normal human tissue. We sought confirmation of this hypothesis by measuring the growth responses of a human renal tumor cell line to the addition of epidermal growth factor and transforming growth factor alpha. Surprisingly, it was found that both growth factors could induce either mitogenic or inhibitory signals depending on the growth status of the cultures. Confluent cultures were stimulated by both growth factors, and nonconfluent cultures were inhibited, as determined by thymidine incorporation, cell cycle analysis, and direct cell counting. These signals appear to use different transduction pathways, as growth factor induced inhibition was reversed by Bordetella pertussis toxin (which affects G protein signaling), whereas the stimulatory effects were not reversed. Two clones isolated from these cells responded in the same manner as the main cell isolate. These data show that the same cell may display opposite responses to equivalent concentrations of the same growth factor, depending on the transduction pathway used after triggering by receptor occupancy of either ligand (epidermal growth factor or transforming growth factor alpha).

Adenocarcinoma↗
PubMed1992

Nucleotide sequence of rat vascular cell adhesion molecule-1 cDNA.

Vascular cell adhesion molecule 1 (VCAM-1) is an inducible transmembrane protein which is expressed by vascular endothelium following cytokine activation. VCAM-1 mediated the adhesion of certain blood leukocytes and tumor cells via the interaction with its counter-receptor, the integrin VLA4. When initially cloned from interleukin-1 (IL-1) stimulated human umbilical vein endothelial cells, VCAM-1 was reported to contain six immunoglobulin-like domains. However, subsequent cDNA clones and structural analysis of the human gene evealed an alternatively spliced seventh immunoglobulin domain. This seven domain form appears to be the predominant transcript in IL-1 activated endothelium. In this report, the cloning and nucleotide sequence of rat VCAM-1 is described.

Amino Acid Sequence↗
PubMed1992

Campylobacter peritonitis in continuous ambulatory peritoneal dialysis: report of eight cases and a review of the literature.

Continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis remains the most common complication of this form of renal replacement therapy and the potential causative organisms are many and varied. Campylobacter bacteria are unusual causes of peritonitis in CAPD patients and we report our experience with eight cases and review those cases reported in the literature. In many episodes, there is a strong association with acute enterocolitis, which may precede the onset of cloudy dialysate by many days. The method of spread of these organisms from the gastrointestinal tract to the peritoneal cavity remains speculative. Bacteremic transfer would appear the most likely route, although it is probable that no single mode of spread explains all episodes. The treatment of choice of Campylobacter peritonitis is with intraperitoneal aminoglycoside in combination with oral erythromycin. An awareness of the potential for Campylobacter to cause CAPD-associated peritonitis, particularly when diarrhea is a prominent feature, has resulted in this organism becoming increasingly isolated in our unit.

Campylobacter Infections↗
PubMed1992

Renal allograft scintigraphy with Tc-99M-DTPA--its role during cyclosporine therapy.

There are no accurate noninvasive methods to distinguish renal allograft dysfunction due to rejection or cyclosporine nephrotoxicity. We have studied the value of Tc-99M-DTPA renal scanning in 90 episodes of renal allograft dysfunction occurring in 44 patients subjected to 57 renal biopsies in whom a clear diagnosis could be established. Renal scintigrams were assessed qualitatively and quantitatively by a blinded observer. Rejection was diagnosed when deterioration in perfusion occurred in the presence of maintained or declining radionuclide excretion. The diagnosis of cyclosporine nephrotoxicity was made by exclusion. The final diagnosis was based on the clinical response to therapy and/or the findings on renal biopsy. The scintigraphic diagnosis of rejection had a specificity of 87.9% and significantly contributed to the exclusion of cyclosporine nephrotoxicity (negative predictive value of 90.6%). Furthermore, a scintigraphic diagnosis compatible with cyclosporine nephrotoxicity, in the presence of a drug level above the therapeutic range, indicated a 90.4% probability of true nephrotoxicity. We conclude that, even in cyclosporine-treated renal transplant patients, Tc-99M-DTPA scintigraphy is of clinical value and can be incorporated into an effective diagnostic algorithm for allograft dysfunction.

Cyclosporine↗
PubMed1992

Rapid induction of intercellular adhesion molecule-1 on monocytes and myelomonocytic cell lines after interferon gamma treatment.

The ICAM-1 molecule is an important adhesion factor that facilitates lymphocyte activation as well as the movement of lymphocytes into solid tissues. It is poorly expressed on circulating monocytes but higher levels have been described following the use of some activation factors. While previous work has emphasized the role of interferon gamma in inducing increased ICAM-1 expression on nonleukocytic cells, we have demonstrated time- and dose-dependent increases on human monocytes and two myelomonocytic cell lines (Rc2A & U937). The increased level of ICAM-1 expression on the Rc2A cells was associated with higher accessory cell activity as determined by an increased mitogen and allogeneic response but specific antibody inhibition studies indicated only a partial dependence (up to 50%) on this molecule. Class II MHC expression and IL-1 production were not elevated by IFNg treatment of these cells, indicating that other factors account for the remainder of the incremental activity observed following this treatment.

Antigens, Surface↗
PubMed1992

Two new anti-rat macrophage monoclonal antibodies.

There are relatively few monoclonal antibodies (MAbs) to rat monocyte/macrophages available. We describe here 2 new such antibodies. The first, 109.2, recognizes most rat monocyte/macrophages and all polymorphs. The antigen recognized by this antibody is upregulated by 15 mins exposure to PMA (Phorbol myristate acetate) but down regulated by overnight exposure to LPS (lipopolysaccharide). It is probably an adhesion molecule and is likely to represent the rat equivalent of CD11b. The second antibody, 112.1, recognizes lysozyme in rat macrophages, particularly alveolar macrophages. In addition it also recognizes lysozyme in hen, rabbit and human macrophages. It also recognizes lysozyme in other tissues such as Paneth cells and proximal renal tubular cells.

Animals↗
PubMed1992

Involvement of activated periglomerular leukocytes in the rupture of Bowman's capsule and glomerular crescent progression in experimental glomerulonephritis.

BACKGROUND: In an experimental model of crescentic glomerulonephritis, we have investigated whether periglomerular leukocytes are involved in (a), the disruption of Bowman's capsule (BC), and (b) the progression of cellular crescents. EXPERIMENTAL DESIGN: Experimental crescentic glomerulonephritis was induced in inbred Sprague-Dawley rats using passive accelerated anti-glomerular basement membrane disease. Groups of 4 animals were sacrificed at 3, 7, 14, 21, and 28 days after administration of nephrotoxic serum. RESULTS: Periglomerular infiltration of macrophages and T cells was evident at day 3, although focal accumulation of activated mononuclear cells (IL-2R+) was not apparent in this area until day 14. BC rupture in some glomeruli was first evident at day 14, and this was seen in all 12 animals from days 14 to 28. Similarly, glomerular crescent formation was first apparent at day 14, and from days 14 to 28, 11 of 12 animals displayed crescent formation (25 to 74% crescentic glomeruli). Examination of glomeruli (> or = 200/animal) within periodic acid-Shiff stained sections found that BC disruption invariably occurred at sites of prominent focal periglomerular mononuclear cell infiltration. Monoclonal antibody labeling revealed that T cells and IL-2R+ cells were restricted to focal infiltrates at sites of BC rupture, whereas macrophages were more widely distributed throughout the periglomerular area. A key finding was that while BC disruption occurred in both the presence and the absence of crescent formation, it was always associated with prominent periglomerular leukocytic infiltration. In this model, most cellular crescents contained leukocytes (88.8 +/- 2.1%). In the presence of an intact BC, macrophages constituted the predominant leukocyte cell type within these crescents. However, when BC was ruptured, although the number of macrophages remained unchanged, a marked accumulation of both T cells and IL-2R+ cells occurred within crescents. Progressive fibrous organization of cellular crescents was observed only in those glomeruli in which BC was disrupted. CONCLUSIONS: The results suggest that: (a) activated periglomerular mononuclear cells may cause disruption of BC via a delayed-type hypersensitivity mechanism, (b) rupture of BC facilitates entry of activated periglomerular T cells and fibroblasts into Bowman's space leading to progressive fibrous organization of cellular crescents, and (c) disruption of BC may be a general mechanism of progressive glomerular damage mediated by periglomerular leukocytes irrespective of crescent formation.

Animals↗
PubMed1991

T-lymphocyte response to cytokines in B-chronic lymphocytic leukemia.

The mechanisms underlying abnormal T-cell function in B-chronic lymphocytic leukemia (B-CLL) are unknown. We have studied B-CLL T-cell activation pathways in the rigorous absence of leukemic cells and with controlled numbers of accessory cells present. The responsiveness to added recombinant IL-1 and IL-2 was assessed. We have found that under optimal culture conditions B-CLL T cells had a normal PHA-induced proliferative response in terms of incorporated 3H-thymidine per T cell. Also the capacity of mitomycin-C treated B-CLL monocytes to support autologous T-cell mitogenesis was normal. However, a subtle difference between normal and B-CLL T cells emerged with respect to cytokine responsiveness. While the PHA response of purified normal T cells in the absence of monocytes was augmented by rIL-1, this could not be demonstrated for B-CLL T cells. A much greater degree of augmentation occurred with added rIL-2 in the case of both normal and B-CLL T cells. In the presence of 20% autologous monocytes rIL-1 and rIL-2 had no effect on mitogenesis. We conclude that B-CLL T cells have an abnormal profile of cytokine responsiveness which is consistent with observed abnormalities of subset distribution, and which may contribute to the clinical immunodeficiency in B-CLL.

Cytokines↗