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L C Paul

Publications and source records attributed to L C Paul.

At least 73 records · Page 4Linked to original sources
PubMed1996

Identification of differentially expressed genes in rat aortic allograft vasculopathy.

Graft vasculopathy is an important complication of long-surviving organ transplants, but its pathogenesis has remained elusive. We investigated rat aortic transplants with vasculopathy, aortic transplants without vasculopathy, and normal aortas for differentially expressed mRNA transcripts to gain further insight into the molecular mechanisms involved. Aortic transplants were performed in allogeneic or syngeneic recipients followed by removal after 1 or 5 months, RNA isolation, and differential display to identify mRNA transcripts the expression of which was modulated in conjunction with the transplant procedure and the development of vasculopathy. Using 80 random primers, 57 differentially displayed polymerase chain reaction products were identified, 18 of which were found in allografts but not in syngeneic grafts or normal vessels, whereas 15 were expressed in normal vessels and syngeneic grafts but not in allografts. Of the differentially displayed amplicons, 13 were successfully reamplified and used as probes for Northern analysis; differential expression was confirmed in 6 instances. DNA sequence analysis of these PCR products revealed identity with the immunoglobulin J chain in 2 instances, the ferritin heavy chain, a sequence related but not identical with Ras, and an established sequence tag recently isolated from a human fetal heart library; 1 sequence was not related to any known gene. To assess whether differential mRNA expression of the J-chain gene, a gene expressed in cells of B lymphocyte lineage, was associated with infiltration of the graft by B lymphocytes, tissue sections were stained with an antibody against the B cell marker CD45RA. Although the number of CD45RA-positive cells was low, there was a significant increase in the number of CD45RA-positive cells in the adventitia and intima of grafts with vasculopathy. Furthermore, immunostaining with anti-ferritin antiserum confirmed the presence of ferritin-positive cells within the inner layer of the graft vessel wall and dispersed in the intima, media, and adventitia. The question remains as to which of these genes are critically relevant in the pathogenesis of graft vasculopathy and whether they serve as targets for therapeutic interventions.

Animals↗
PubMed1995

Chronic renal transplant loss.

Chronic rejection results from recurrent episodes of subclinical or clinically evident acute rejection, with or without involvement of chronic rejection-specific allogeneic immune mechanisms. The tissue damage occurs over a prolonged period of time, which allows the emergence of antigen-independent tissue repair mechanisms and intrarenal adaptations in response to progressive loss of renal mass (Fig. 1). The combination of these mechanisms leads, very likely, to the tissue remodeling of chronic rejection. The heterogeneous expression of chronic rejection may result from different types and specificities of allogeneic immune reactions as well as different contributions of antigen-independent factors that modulate the antigen-dependent tissue responses to injury. The extent to which these mechanisms participate in the overall picture is presently unknown as immunological parameters are not measured routinely in the follow-up of patients with chronic graft dysfunction. Furthermore, some grafts may undergo tissue remodeling as a consequence of predominantly antigen-independent mechanisms. Therefore, the term chronic allograft dysfunction may clinically be preferable over chronic rejection to describe the gradual decline in graft function months or years after transplantation in the absence of a well-defined mechanism or an accepted treatment.

Animals↗
PubMed1995

Immunobiology of chronic renal transplant rejection.

With improvements in short-term renal transplant survival, concerns regarding the long-term outcome are becoming more important. Chronic rejection is the single most important cause of graft failure in the first posttransplant decade, but its pathophysiology remains poorly understood. It has been suggested that chronic rejection is the tissue remodelling that is initiated by smoldering foci of inflammation initiated by acute rejection episodes, perhaps in conjunction with chronic rejection-specific allogeneic immune reaction. The chronicity of these processes leads to concurrent activation of tissue repair mechanisms and changes in renal hemodynamics, which contribute to the tissue remodelling that is characteristic for chronic rejection.

Animals↗
PubMed1995

Post-transplant hypertension and chronic renal allograft failure.

Chronic renal allograft dysfunction is often associated with hypertension, but it is unknown to what extent this affects graft structure and function. We investigated the effect of antihypertensive drug treatments on the course and histopathology of chronic renal allograft rejection in a rat model. Recipient animals were treated with a combination of reserpine, hydralazine and hydrochlorothiazide, the angiotensin converting enzyme inhibitor cilazapril, or the angiotensin II receptor blocker L158,809. Systemic blood pressures and tubular stop-flow pressures were measured on day 50 after transplantation; the histopathology was assessed semiquantitatively in kidneys not used for micropuncture studies. Grafts removed from untreated recipients showed inflammation and structural vascular and glomerular lesions consistent with chronic rejection. All treatment regimens decreased the systemic and glomerular capillary pressures and were associated with improved graft survival, decreased proteinuria and a tendency to improved graft function; the histopathology showed a significant amelioration of glomerular mesangiolysis and glomerulosclerosis but no effect was found on the tubulointerstitial lesions; the angiotensin receptor blocker also inhibited graft atherosclerosis. We conclude that hemodynamic and angiotensin II-mediated processes may play a pivotal role in the expression of immune-mediated glomerular lesions of chronic allograft dysfunction.

Animals↗
PubMed1994

Cardiac allograft atherosclerosis in the rat. The effect of histocompatibility factors, cyclosporine, and an angiotensin-converting enzyme inhibitor.

Cardiac transplant atherosclerosis is thought to result from immune-mediated vessel wall injury. The present experiments were designed to test whether CsA alone or in combination with the ACE-inhibitor cilazapril has any effect on graft atherosclerosis in a rat cardiac transplant model. Cardiac grafts were transplanted heterotopically into either syngeneic or allogeneic recipients and followed by daily palpation; long-surviving grafts were removed after 100 days and the extent and degree of atherosclerosis was assessed using computerized morphometry. Atherosclerosis was more extensive in grafts removed from untreated allogeneic recipients compared with syngeneic recipients; CsA treatment increased the extent of atherosclerosis in syngeneic transplants. The extent and degree of vascular occlusion in allogeneic grafts from recipients treated with 15 mg/kg of CsA every other day was not different from that in grafts removed from recipients that received initially higher CsA doses. Cilazapril had no effect on the extent of graft atherosclerosis but decreased the degree of luminal narrowing in grafts from CsA-treated recipients significantly. Some grafts showed neovascularization in the subendocardial region adjacent to organized intraventricular clots, suggesting the release of angiogenic factors from such clots; such growth factors may contribute to the atherosclerotic vessel wall reaction in this model. We conclude that CsA promotes the development of graft atherosclerosis in heterotopically transplanted syngeneic cardiac grafts in the rat. We furthermore found that cilazapril has a beneficial effect on the degree of atherosclerosis in CsA-treated recipients.

Animals↗
PubMed1994

Functional and histologic characteristics of chronic renal allograft rejection.

Chronic allograft rejection very probably results from the interactions between allogeneic immune injury, tissue reactions in response to injury, and local intragraft hemodynamic adaptations to the progressive loss of functioning organ mass. We examined each of these components in a rat model of chronic renal allograft rejection. Although immunofluorescence studies of renal allografts with chronic rejection usually reveal nondiagnostic patterns of immunoglobulin deposits, we found, using Western blot analysis, donor-directed antibodies against novel glomerular basement membrane antigens in the sera of animals with chronic rejection-associated transplant glomerulopathy. Stop-flow micropuncture studies have shown that the glomerular capillary pressure in transplanted kidneys resembles that of the donor strain kidney in response to renal ablation. Northern blots for growth factor transcripts showed induced expression of mRNA levels for various growth factors in long-surviving renal transplants. Reduction in intraglomerular pressure was associated with increased recipient survival, preservation of renal function, decreased amounts of proteinuria, and less severe structural lesions in the glomeruli. We conclude that the glomerular lesions of chronic rejection may arise from a combination of antiglomerular (allo) antibodies in conjunction with increased intraglomerular pressures and local production of growth factors. The vascular lesions and interstitial scarring of chronic rejection may arise from previous episodes of graft vasculitis and interstitial inflammation, respectively.

Animals↗
PubMed1994

Chronic renal allograft rejection in the rat. Transplantation-induced antibodies against basement membrane antigens.

BACKGROUND: To obtain understanding of the immunologic mechanism of chronic rejection-associated glomerular and interstitial renal damage, we investigated the humoral immune response against donor type glomerular and tubular basement membrane proteins in rats with long-surviving renal transplants with and without chronic rejection. EXPERIMENTAL DESIGN: Sera from Lewis and Fisher 344 rats with long-surviving Fisher 344 and Lewis renal allografts were investigated by enzyme-linked immunosorbent assay and Western blot analysis using collagenase-digested renal basement membrane preparations from various strains of rats. RESULTS: Kidneys from F344 strain donors transplanted into Lewis recipients developed glomerular lesions consistent with transplant glomerulopathy as well as chronic tubulointerstitial inflammation and fibrosis. Indirect immunofluorescence studies of the Lewis anti-Fisher 344 post-transplant sera showed the presence of antibodies that gave punctate staining in the glomeruli and bright, linear staining of the proximal tubular basement membrane. Dot blot analysis of the sera showed the presence of antibodies against Fisher and third party Brown Norway glomerular basement membranes, whereas no reactivity was found with recipient strain basement membranes. Western blot analysis with glomerular basement membrane preparations showed that the antibodies recognized several antigens under nonreducing (> 200 and approximately 100 kilodaltons) and reducing (> or = 200, approximately 200, approximately 90, approximately 50 to 60, and < 45 kilodaltons) conditions. Western blots with tubular basement membrane proteins showed antibodies against various antigens. Anti-basement membrane antibodies were not found after conventional immunizations with kidney homogenates or after transplantation of cardiac allografts. Fisher 344 rats with long-surviving Lewis renal transplants produced antibodies against laminin fragments, but these antibodies were not associated with transplant glomerulopathy. CONCLUSIONS: We found that Lewis rats that carry a Fisher 344 renal allograft with transplant glomerulopathy produce antibodies against one or more novel antigen(s) of donor glomerular and tubular basement membranes. The role of these antibodies in the pathogenesis of transplant glomerulopathy and chronic rejection-associated tubulointerstitial inflammation remains to be established.

Animals↗
PubMed1993

Post-transplant conversion from cyclosporin to azathioprine: effect on cardiovascular risk profile.

The benefits of long-term cyclosporin (CyA) therapy are not yet established and must be weighed against its toxicity. We studied cardiovascular risk factors in 25 patients who received a kidney transplant between 1985 and 1989 and in whom CyA was discontinued. The protocol for discontinuing CyA involved starting azathioprine (Aza) and then weaning CyA over 6 weeks without changing the prednisone dose. Parameters collected from the patients' charts 3 months before (pre) and 3 months after conversion (post) and at the most current follow-up (cur) included serum creatinine, cholesterol, blood pressure, and anti-hypertensive medication. The severity of the hypertension was graded, based on a hypertension index reflecting the nature and dose of the anti-hypertensive medication. Of the 25 patients in whom CyA was discontinued, 2 experienced a rejection episode during conversion and were switched back to CyA; 1 patient had a rejection episode after conversion but remained on Aza. Converted patients demonstrated improved renal function (1/Cr pre 0.69 +/- 0.20, post 0.84 +/- 0.23, P < 0.05), lower serum cholesterol levels (pre 6.8 +/- 1.0, post 5.8 +/- 1.2, P < 0.05), lower mean arterial pressure (pre 111 +/- 14, post 102 +/- 8, P < 0.05) and a lower hypertension index (pre 2.45 +/- 2.77, cur 1.62 +/- 1.70, P < 0.05). Although conversion may carry some risk of acute rejection, it improves graft function and the cardiovascular risk profile significantly.

Adult↗
PubMed1993

Restless sleep, illness intrusiveness, and depressive symptoms in three chronic illness conditions: rheumatoid arthritis, end-stage renal disease, and multiple sclerosis.

Restless sleep was compared across 110 out-patients with rheumatoid arthritis (RA), 101 with end-stage renal disease (ESRD), 94 with multiple sclerosis (MS), and an unselected control group of 176 individuals attending their family practitioners (FP). It was also investigated in the three chronic illness groups as a contributor to illness intrusiveness--the extent to which one's illness and/or its treatment interfere with continued involvements in valued activities and interests--a determinant of depression and emotional distress in chronic conditions. Reported frequencies of restless sleep were highest in RA, lower in ESRD, and lowest in MS; FP patients reported frequencies that were similar, overall, to those observed in MS. These differences were evident among nondepressed, (chi 2 9, N = 309, p < 0.0001), but not depressed, individuals. The occurrence of restless sleep correlated significantly with increased illness intrusiveness, r (279) = 0.31, p < 0.001, in RA, ESRD, and MS. Results supported the hypothesis that the relation between restless sleep and emotional distress is mediated by illness intrusiveness. Treatment of restless sleep may offer the added benefit of diminishing illness intrusiveness and may, thereby, enhance quality of life in chronic physical illness.

Activities of Daily Living↗
PubMed1993

Excitation-contraction coupling in rat heart: influence of cyclosporin A.

OBJECTIVE: The aim was to investigate the steps in the excitation-contraction coupling process by which chronic exposure to cyclosporin A (cyclosporin) affects twitch force development by rat cardiac trabeculae. METHODS: The interval dependence and [Ca2+]o dependence of twitch force development by intact trabeculae isolated from myocardium of untreated rats and rats treated with cyclosporin (15 mg.kg-1.d-1 for 21 d) were studied in Krebs-Henseleit solution (K-H; pH 7.4 and 25 degrees C) and the force-pCa relation was examined in all trabeculae. RESULTS: The force-[Ca2+]o relation of cyclosporin treated trabeculae was shifted leftward compared to that of controls, but these trabeculae generated 35% less stress (force/cross sectional area) at optimal [Ca2+]o. Unlike control trabeculae, cyclosporin treated trabeculae showed spontaneous activity at all diastolic intervals, even at low [Ca2+]o. Treated and control trabeculae generated the same maximum stress [control: 78.1 (SEM 7.7) mN.mm-2, cyclosporin treated: 70.2(7.4) mN.mm-2] in the presence of extracellular Sr2+ ions in the Krebs-Henseleit medium. Maximum stress observed in the presence of Sr2+ was similar to the stress generated by maximum activation of chemically skinned trabeculae in both groups [control: 70(4.6) mN.mm-2; cyclosporin treated: 73(6.2) mN.mm-2). The force-pCa relation of cyclosporin treated muscles and control muscles after skinning were also indistinguishable [control pCa50 = 5.56(0.04); cyclosporin treated pCa50 = 5.58(0.03)]. The twitch force-interval relation at 0.7 mM [Ca2+]o in intact control trabeculae revealed postrest potentiation with a maximum [equivalent to 70% of twitch force at optimal [Ca2+]o -61.0(2.1) mN.mm-2] at 100 s and subsequent rest depression. Under the same conditions, twitch force development by cyclosporin treated trabeculae was closer to optimal force [41.4(7.1) mN.mm-2] at all intervals, and rest potentiation was reduced. Pronounced rest potentiation (as well as postextrasystolic potentiation) was still observed in cyclosporin treated trabeculae at [Ca2+]o < 0.7 mM. Postextrasystolic potentiation was reduced at 0.7 mM [Ca2+]o in these trabeculae, but the rate of decay of postextrasystolic potentiation and the rate of relaxation of the twitch force were unaffected. CONCLUSIONS: These results suggest that the changes in the sensitivity of intact rat myocardium to [Ca2+]o and in maximum force development induced by cyclosporin are not due to changes in myofilament properties. The increased twitch force development as well as the spontaneous activity at low [Ca2+]o may be due to facilitated Ca2+ release from the sarcoplasmic reticulum due to altered properties of the sarcoplasmic reticular Ca2+ release channel, as both are observed when twitch force is submaximal, suggesting that the sarcoplasmic reticulum was not overloaded with Ca2+. The decline in peak stress with cyclosporin at [Ca2+]o > approximately 1.0 mM can be explained on the basis of spontaneous release of Ca2+ during the interval between twitches which leaves less Ca2+ for release from the sarcoplasmic reticulum with each action potential.

Animals↗
PubMed1993

Live and learn: patient education delays the need to initiate renal replacement therapy in end-stage renal disease.

During a longitudinal study of the quality of life of end-stage renal disease, 204 patients with deteriorating renal function were identified before dialysis or transplantation was required to preserve their lives. These patients were randomly assigned to either an enhanced or a standard education condition. The enhanced education condition consisted of a specially prepared slide-lecture show concerning kidney diseases and their treatment that was delivered by a trained research assistant. The standard education condition consisted of whatever educational procedures were routinely available at the participating hospital. All but six patients have now started treatment by maintenance dialysis. Individuals in the enhanced education condition survived an average of 4.6 months longer than did those in the standard education group without requiring the initiation of renal replacement therapy. This effect could not be attributed to physical differences between the groups, to cohort effects, to delays in contacting the patients, or to when or where they were identified. Possible mechanisms for this effect are discussed.

Attitude to Health↗
PubMed1993

Differences in illness intrusiveness across rheumatoid arthritis, end-stage renal disease, and multiple sclerosis.

Illness intrusiveness derives from illness-induced lifestyle disruptions that interfere with continued involvements in valued activities and interests and is hypothesized to represent a fundamental determinant of the psychosocial impact of chronic conditions. The present investigation compared reported levels of illness intrusiveness across 305 individuals from three chronically ill populations: rheumatoid arthritis (N = 110), end-stage renal disease (N = 101), and multiple sclerosis (N = 94). Although multiple sclerosis was significantly more intrusive, overall, into lifestyles, activities, and interests as compared with rheumatoid arthritis and end-stage renal disease (which did not differ), a significant illness group x life domain interaction indicated that intrusiveness into eight individual life domains differed significantly across the groups and that the pattern of differences varied as a function of the particular life domain involved. Differences in the constellations of signs, symptoms, and treatment regimens associated with a given condition were hypothesized to account for observed differences in illness intrusiveness.

Adult↗
PubMed1993

Glomerular capillary pressures in long-surviving rat renal allografts.

Many renal transplants undergo gradual deterioration in structure and function in the months or years after transplantation. The processes that underlie this progressive decline have not been defined, and may include immunological and nonimmunological mechanisms. The present experiments were designed to investigate the glomerular capillary hydrostatic pressure in long-surviving rat renal transplants with or without chronic rejection. Stop-flow glomerular pressures were measured in F344 renal allografts with chronic rejection, syngeneic F344 grafts, and long-surviving syngeneic and allogeneic LEW grafts without chronic rejection; control measurements were done in nontransplanted intact animals or after subtotal renal ablation. Renal ablation or transplantation resulted in increased glomerular pressure in F344 but not LEW kidneys; the glomerular pressure in syngeneic F344 grafts was not different from that in allogeneic F344 grafts. There was no correlation between the mean arterial pressure and the glomerular capillary pressure. Our data suggest that the glomerular capillary pressure is determined by local intrarenal factors. The glomerular capillary pressure in allotransplanted kidneys resembles that of the donor kidney after subtotal renal ablation. The importance of increased glomerular pressure in the progressive decline of graft function of chronic rejection remains to be established.

Animals↗