Search PubMed⌕ Search

Biomedical subjects

R J Johnson

Publications and source records attributed to R J Johnson.

At least 181 records · Page 10Linked to original sources
PubMed1995

Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity.

Chronic cyclosporine (CsA) nephrotoxicity is a major complication of solid organ transplantation, and is characterized histologically by striped tubulointerstitial fibrosis, tubular atrophy, and hyalinization of the afferent arteriole, a highly specific finding in cyclosporine injury. The salt-depleted rat model of chronic cyclosporine nephropathy mimics these lesions in humans. We conducted sequential studies of this model in groups of pair fed rats (N = 6) treated with CsA (15 mg/kg, s.q.) or an equivalent dose of olive oil. Proliferation of tubular and interstitial cells was documented early in the medulla by day 5 (3.2 +/- 2.1 vs. 0.81 +/- 0.4 cells/HPF in CsA vs. control, P < 0.02), and was maximal in areas of interstitial fibrosis by day 35 (7.9 +/- 3.7 vs. 0.52 +/- 0.2 cells/HPF in CsA vs. control, P < 0.005). The interstitial fibrosis was associated with a significant macrophage influx by day 35 (13.9 +/- 3.5 vs. 1.5 +/- 0.32 cells/HPF, CsA vs. control, P < 0.005), which correlated with increased cortical tubular staining for the macrophage adhesion protein, osteopontin. Elevated serum creatinine correlated with interstitial fibrosis at day 35 (0.85 +/- 0.11 vs. 0.40 +/- 0.03 mg/dl Cr, CsA vs. control, P < 0.005) by linear regression (r = 0.9, P < 0.05). Medullary proliferation and interstitial fibrosis correlated with decreased tubular concentrating ability, and higher urinary volume. Cortical interstitial fibrosis was maximal at day 35 and was associated with an increase in type I and type IV collagen deposition, while tubular injury was associated with increased vimentin expression. Tubular interstitial cells also expressed increased vimentin early in the medulla (day 10) and later in the cortex. Both groups remained normotensive despite significantly elevated juxtaglomerular (JG) apparatus renin expression in CsA treated animals, implicating the intrarenal-renal renin-angiotensin system in this disease. We conclude that cyclosporine nephrotoxicity is associated with early tubular and interstitial cell proliferation, and a significant macrophage influx that precedes the development of cortical interstitial fibrosis and afferent arteriolar hyalinosis. These early cellular changes correlate with functional abnormalities including decreased creatinine clearance (CCr) and decreased medullary concentrating ability, which stabilized despite progressive fibrosis. These cellular events may be important in the pathogenesis of chronic CsA nephrotoxicity.

Animals↗
PubMed1995

Thrombospondin 1 is expressed by proliferating mesangial cells and is up-regulated by PDGF and bFGF in vivo.

Thrombospondin 1 has been shown to be linked to PDGF-mediated mesangial cell proliferation and migration in vitro, but little is known regarding its expression or regulation in glomerular disease. Experimental mesangial proliferative nephritis was induced in rats by injection of anti-Thy1 antibody. Mesangial cell proliferation was associated with de novo expression of thrombospondin 1 mRNA (detected by Northern blot and in situ hybridization) and protein (by Western blot and immunostaining). Although some thrombospondin 1 was expressed by platelets and macrophages, double labeling showed that most thrombospondin 1 mRNA and protein were expressed by proliferating alpha-actin-positive mesangial cells. Thrombospondin 1 expression in anti-Thy1 nephritis was complement-dependent and could be reduced by treatment with anti-PDGF or anti-bFGF antibodies. Thrombospondin 1 could also be induced in normal rats by infusion of PDGF and in rats which were primed with low dose anti-Thy1 antibody by infusion of PDGF of bFGF. Thus, this study demonstrates that proliferating mesangial cells express thrombospondin 1 de novo in disease and that thrombospondin 1 expression in vivo is regulated by PDGF and bFGF.

Animals↗
PubMed1995

Modulation of experimental mesangial proliferative nephritis by interferon-gamma.

The observation that interferon-gamma (IFN-gamma) inhibits cell proliferation and collagen synthesis of a variety of cell types in culture has suggested that IFN-gamma may be useful in the treatment of fibroproliferative diseases. We administered recombinant IFN-gamma subcutaneously (10(5) U/kg/day for 3 days) to rats, beginning one day after the induction of mesangial proliferative nephritis with anti-Thy 1 antibody. IFN-gamma reduced glomerular (primarily mesangial) cell proliferation by 44% at days 2 and 4 compared to vehicle injected control rats with anti-Thy 1 nephritis (that is, proliferating cells that excluded the macrophage marker, ED-1, P < 0.001). Despite the inhibition of mesangial cell proliferation, IFN-gamma did not reduce the overall extracellular matrix deposition (by silver stain) or deposition of type IV collagen or laminin (by immunostaining) at 4 or 7 days, and glomerular type IV collagen and laminin mRNA levels were increased (1.4 and 1.7-fold) at 4 days relative to controls. The inability of IFN-gamma treatment to reduce mesangial matrix expansion may relate to the fact that IFN-gamma treated rats had a twofold increase in glomerular macrophages (that is, ED-1 positive cells, P < 0.001 at 2 and 4 days) with an increase in oxidant producing cells (day 2, P < 0.05) and a 1.6-fold increase in glomerular TGF-beta mRNA expression (4 days). This suggests that the effect of IFN-gamma to inhibit mesangial cell proliferation in glomerulonephritis may be offset by the ability of IFN-gamma to increase glomerular macrophages and TGF-beta expression. These data also show that IFN-gamma can partly dissociate the mesangial proliferative response from the extracellular matrix expansion in glomerulonephritis.

Animals↗
PubMed1995

Changes in physician utilization over time among older adults.

Although much is known from cross-sectional studies about the use of physician services among older adults, little is known about the consistency of or changes in that utilization over time. Hierarchical multivariable regression analysis of data on the 2,430 older adults who were enrolled in the LSOA and successfully reinterviewed in 1986, 1988, and 1990 is used to model changes in the number of physician visits between 1984 and 1990 based on the predisposing, enabling, and need (including functional status) characteristics measured in 1984, and subsequent changes in functional status. Overall, 19 percent of the variance in physician utilization is explained, with 8 percent coming from the introduction of the need characteristics, 4.7 percent from the subsequent introduction of the number of physician visits at baseline, and 4.9 percent from the subsequent introduction of changes in functional status. Declines in each of the functional status measures are significantly associated with increases in physician utilization, although improvements are fundamentally unrelated.

Activities of Daily Living↗
PubMed1995

Hospital utilization profiles among older adults over time: consistency and volume among survivors and decedents.

Medicare claims data are used to model hospital utilization patterns for the 4,660 survivors and 2,867 decedents of the Longitudinal Study on Aging (LSOA). When the volume of hospital utilization was collapsed into four categories based on the mean annual number of hospital episodes and consistency was defined as a maximum absolute deviation from that mean of 1.5 or less, 42.6 percent of the LSOA respondents were found not to have any hospital admissions, and another 24.7 percent were found to be consistently low users. Only 4.8 percent were consistently high users, with an additional 6.8 percent being inconsistently high users. Multiple regression identified prior physician and hospital utilization, as well as poor perceived health, as the most important predictors of the volume and consistency of hospital utilization among survivors, as well as of the volume of hospital utilization among decedents. Among decedents, consistency was primarily related to geographic region and prior physician utilization.

Activities of Daily Living↗
PubMed1995

Hepatitis C virus-associated glomerulonephritis.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with a variety of extrahepatic manifestations, including cryoglobulinemia and glomerulonephritis. Epidemiologic evidence suggests that HCV infection may be a major risk factor for both cryoglobulinemic and type I membranoproliferative glomerulonephritis (MPGN). Clinical symptoms and laboratory data may or may not reflect the presence of chronic liver disease. Most patients have evidence of hypocomplementemia, circulating rheumatoid factors, and cryoglobulinemia. The pathogenesis of HCV-associated MPGN is probably a result of glomerular deposition of circulating HCV and anti-HCV antibodies. Treatment with interferon-alpha has been shown to improve proteinuria, suppress viremia, and stabilize renal function. However, patients often relapse after therapy is stopped. The optimal therapy remains to be defined but may involve different dosage regimens of interferon-alpha or the combination of several antiviral agents.

Glomerulonephritis↗
PubMed1995

Urinary tract obstruction and nephrostomy drainage in pelvic malignant disease.

OBJECTIVE: To determine the survival of patients after percutaneous nephrostomy drainage (PND) for obstructive uropathy secondary to pelvic malignant disease. PATIENTS AND METHODS: The records of 77 patients undergoing PND for obstructive uropathy were reviewed. Patients were classified according to the nature of the obstructing lesion: Group I (primary untreated malignancy, 31 patients); Group II (recurrent malignancy with further treatment, 15 patients); Group III (recurrent malignancy with no further treatment, 12 patients); and Group IV (benign disease as a consequence of previous treatment, 19 patients). Outcome was assessed by survival over a mean follow-up of 20 months (range 2 days-8.3 years). RESULTS: Overall median survival was 26 weeks, with a 5-year survival of 22%. The survival in Groups I and II was not significantly different (median survival 27 and 20 weeks, respectively; 5-year survival, 10% and 20%, respectively). Group III patients had a poor prognosis (median survival 6.5 weeks) with no patient surviving beyond one year, whilst Group IV patients fared best with a 5-year survival of 64%. The commonest primary tumour type was carcinoma of the cervix (42 patients), and these patients were analysed as a subset. Benign post-radiation fibrosis was found in 16 of 27 patients (59%). Survival was related to the diagnostic group. CONCLUSION: The nature and extent of the obstructing lesion and its potential for further treatment are the major determinants of post-nephrostomy survival. Every effort should therefore be made to identify the nature of the obstruction before deciding on PND.

Adult↗
PubMed1995

The effects of soluble recombinant complement receptor 1 on complement-mediated experimental glomerulonephritis.

Complement is a major mediator of tissue injury in several types of glomerulonephritis. However, no therapeutic agents that inhibit complement activation are available for human use. sCR1 (TP10, BRL 55736) is a recombinant, soluble human complement receptor 1 (CR1) molecule lacking transmembrane and cytoplasmic domains that inhibits C3 and C5 convertase activity by preferentially binding C4b and C3b. To test the efficacy of sCR1 on complement-mediated glomerulonephritis, rats were pretreated with sCR1 (60 mg/kg per day) before and during the induction of three models of complement-dependent glomerulonephritis (concanavalin A and antithymocyte serum models of proliferative glomerulonephritis, passive Heyman nephritis). Daily sCR1 and complement hemolytic activity levels were measured, and renal histology and urine protein excretion were examined. Mean serum sCR1 levels of 100 to 200 micrograms/mL were maintained with a reduction in complement hemolytic activity to less than 15% in most animals. In the antithymocyte serum model, sCR1-treated animals had significant reductions in mesangiolysis, glomerular platelet and macrophage infiltrates, and proteinuria at 48 h. In the concanavalin A model, sCR1 significantly reduced glomerular C3 and fibrin deposits, platelet infiltrates, and proteinuria at 48 h. In passive Heymann nephritis, proteinuria was also significantly reduced (199 +/- 8.5 versus 125 +/- 16 mg/day, P < 0.002) at 5 days. It was concluded that sCR1 significantly reduces both morphologic and functional consequences of several different types of complement-mediated glomerulonephritis and deserves evaluation as a potential therapeutic agent in complement-mediated immune glomerular disease in humans.

Animals↗
PubMed1995

Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan.

The prevalence of hepatitis C virus (HCV) infection was determined in 146 adult patients with various types of glomerulonephritis and renal diseases monitored between 1990 and 1993. Serum HCV antibody (HCV Ab) was evaluated, and positive cases were tested for HCV RNA by polymerase chain reaction. HCV infection was present in 1 (1.7%) of 58 cases of immunoglobulin A nephropathy, 0 (0%) of 14 cases of lupus nephritis, 0 (0%) of 12 cases of minimal change nephrosis, and 0 (0%) of 28 cases of other renal diseases, which is similar to the 2% prevalence observed in healthy blood donors in Japan. In contrast, HCV Ab was observed in 2 (8.3%) of 24 cases of membranous nephropathy and 6 (60%) of 10 cases of membranoproliferative glomerulonephritis (MPGN) Type I. The prevalence of HCV infection in MPGN patients was significantly higher than the frequency of HCV infection observed in the other patients with renal diseases (P < 0.001). HCV RNA was present in all cases in which HCV Ab was present. The six patients with HCV-MPGN were similar to the four patients with idiopathic MPGN with respect to age, presence of nephrotic syndrome, and renal dysfunction, but had a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (low C3). HCV infection is present in a large percentage of patients with MPGN in Japan and clinically may differ slightly from other cases of MPGN.

Adolescent↗
PubMed1995

Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis.

In many glomerular diseases severe injury to the mesangium may occur, leading to matrix dissolution and damage to the glomerular capillaries. Although the destruction of glomerular architecture may lead to permanent injury, in some cases spontaneous recovery occurs. The mechanisms that mediate this recovery are unknown. In this study we provide evidence for glomerular capillary repair (angiogenesis) in the adult injured glomerulus. Injection of anti-Thy 1 antibody into rats results in severe mesangiolysis with capillary ballooning, microaneurysm formation, and loss of endothelial cells in addition to mesangial cells. Although mesangial proliferation is a major response to injury, proliferation of endothelial cells also can be documented from days 2 to 14 in association with repair of the capillaries. The endothelial cell proliferation peaks on days 2 and 7, when it is seven- to ninefold greater than normal. Many of the endothelial cells display morphological features of angiogenesis. The initial wave of endothelial cell proliferation can be reduced by 40% with neutralizing anti-basic fibroblast growth factor antibodies (P < 0.001). The later glomerular endothelial cell proliferation is associated with upregulated expression of vascular permeability factor/endothelial cell growth factor (VPF/VEGF) and an increase of flk, a VPF/VEGF receptor. Although PDGF is expressed in this model, anti-PDGF antibody treatment did not affect the endothelial cell proliferative response. In summary, glomerular endothelial cells have an active role in the glomerular response to injury. Glomeruli are capable of healing microaneurysms, and the mechanism involves basic fibroblast growth factor- and VPF/VEGF-mediated endothelial proliferative responses.

Animals↗
PubMed1995

Multiple roles for platelet-derived growth factor in renal disease.

Platelet-derived growth factor (PDGF) is a pleiotropic cytokine, that is synthesized by various resident renal cells and also by infiltrating cells. The best established role for PDGF in the kidney is the mediation of glomerular mesangial cell proliferation. There is also evidence to suggest an involvement of PDGF in the regulation of renal extracellular matrix turnover, the chemoattraction of mesangial cells and/or other cells to sites of injury, the regulation of glomerular hemodynamics, and lipoprotein uptake in the glomerulus. The first studies investigating the efficacy of anti-PDGF therapy in glomerular disorders point to a potentially novel approach to treat progressive renal disease.

Animals↗
PubMed1995

The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: the glomerular cytokine theory.

Numerous studies have suggested that tubulointerstitial disease has a major impact on the overall function and prognosis of glomerular disease. The mechanism by which tubulointerstitial disease develops in patients with glomerular and other diseases is unknown. In this review, we discuss the hypothesis that factors released from injured glomeruli act on tubules and interstitial cells to induce expression of chemotactic and adhesive factors that attract mononuclear cells into the interstitium. Evidence is provided that osteopontin is one candidate leukocyte adhesive factor involved in this process, but others are likely involved. The recruited leukocytes (primarily macrophages) then release inflammatory mediators that injure tubular cells and activate interstitial fibroblasts, resulting in tubulointerstitial injury with eventual fibrosis.

Animals↗
PubMed1995

Effect of anterior cruciate ligament reconstruction with patellar tendon or prosthetic ligament on the morphology of the other ligaments of the knee joint. An experimental study in dogs.

The effect of anterior cruciate ligament replacement on the other ligaments of the knee, including the medial or lateral collateral and posterior cruciate ligaments, was studied histologically in the canine knee. The anterior cruciate ligament was replaced either with the medial third of the patellar tendon or with a prosthetic ligament. Histologic analysis was performed 3 months after prosthetic ligament implantation and 1 year after patellar ligament reconstruction. In all ligaments, numerous pathologic alterations were found. Degenerative changes such as glycosaminoglycan accumulation, metachromasia, collagenolysis, collagen necrosis, and lipomatosis were similar after 3 months and after 1 year. Granulation tissue, a sign that characterizes tissue repair, was seen only in those ligaments taken 3 months after anterior cruciate ligament surgery. Similar degenerative changes also were found in the ligaments of the knees with only a large medial arthrotomy (sham). In the contralateral control knees, the pathologic alterations were rare. Thus, open arthrotomy alone or with anterior cruciate ligament reconstruction seems to result in longstanding degenerative changes in all ligaments of the canine knee joint.

Animals↗
PubMed1995

Hepatitis C virus associated membranous glomerulonephritis.

Hepatitis C virus infection has been associated with a variety of extrahepatic disorders. We report four patients with membranous glomerulonephritis and hepatitis C virus infection. In contrast to patients previously reported with HCV infection and membranoproliferative glomerulonephritis, these patients have normal or minimally reduced complement levels and no evidence of rheumatoid factor or cryoglobulinemia. A liver biopsy in one patient was consistent with chronic active hepatitis although liver enzymes were only minimally elevated and coagulation studies normal. Three patients were treated with alpha-interferon with some success. Treatment with alpha-interferon may have a beneficial effect in reducing proteinuria and improving liver function and may be related to the ability of interferon to suppress viremia. Future studies need to focus on clarifying the role of the virus in causing glomerular disease and improving dosing strategies for alpha-interferon. Randomized, controlled studies need to be performed to determine whether the beneficial effect of alpha interferon is significant, and if so, if it is superior to conventional therapies.

Adult↗
PubMed1995

Detection of clonal immunoglobulin gene rearrangements in the PBPC harvests of patients with acute lymphoblastic leukaemia.

We have used a fluorescently based PCR technique to detect rearrangements in the immunoglobulin heavy chain (IgH) gene in the presentation BM of five patients with adult ALL and have looked for similar rearrangements in their PBPC. Using this approach we have been able to demonstrate clonal rearrangements in the PBPC of two of five patients. Remission BM samples taken 6-12 weeks prior to leucapheresis failed to show a clonal rearrangement in either patient. The significance of these results is discussed.

Base Sequence↗