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Biomedical subjects

R J Powell

Publications and source records attributed to R J Powell.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma.

BACKGROUND: Cyclosporin and tacrolimus are immunomodulatory drugs which act predominantly on T cells. Improvements in certain manifestations, particularly skin tightness, have been observed in a number of patients with scleroderma treated with these drugs. However, to date there have been no reports of their use in a routine clinical setting. METHODS: Patients attending clinical immunology clinics who had progressive systemic sclerosis and related syndromes and who had received cyclosporin and/or tacrolimus were identified. Details of their treatment, including drug dosage, duration of and response to treatment, side-effects and reasons for withdrawal, were recorded. RESULTS: Sixteen patients had been given cyclosporin and 13 of these had been treated for skin tightness. Half noticed significant softening of their skin whilst on treatment, and resolution was observed in all four of the patients treated for digital vasculitis. Side-effects were common and dose-limiting, and contributed to withdrawal in 12 out of 13 patients. Eight patients had been treated with tacrolimus; two of these had stopped the drug because of progression of their disease, one developed diarrhoea, prompting withdrawal, one stopped tacrolimus following improvement, and four remained on the drug. Side-effects had occurred in three patients. CONCLUSION: Improvements in skin occur in approximately half of all cases of scleroderma treated with either cyclosporin or tacrolimus, suggesting a beneficial effect. Side-effects, especially hypertension, are common with cyclosporin and often necessitate withdrawal. Adverse effects are also observed with tacrolimus, but in the small cohort so far treated only one patient had stopped the drug for this reason.

Adult↗
PubMed2000

Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients of Afro-Caribbean and Asian origin living in the United Kingdom have a more severe spectrum of disease compared with the white population but whether this is attributable to genetic host factors or environmental factors is unclear. This study examines time from first symptom to onset of persistent proteinuria, as a marker of renal disease, to assess which factors are important. METHODS: The 189 patients studied were ascertained using multiple methods and included 161 white, 22 Afro-Caribbean and six Asian patients. Time of first observation of persistent proteinuria (>/=0.5 g/day) was taken as onset of renal SLE. Initial univariate analysis to determine which factors are associated with onset of renal disease was followed by using a Cox's proportional hazards regression model enabling analysis of several prognostic factors at the same time. Variables included three measures of socioeconomic status, ethnic group and the presence or absence of different autoantibodies. RESULTS: There was no effect from any socioeconomic variable. Using forwards stepwise selection, the following had independent effects (p<0.05) on the development of renal SLE: Afro-Caribbean race (hazard rate ratio 4.4 (1.9-10.2), compared with white population); and the presence of IgG anti-cardiolipin antibodies (hazard rate ratio 2.6 (1.2-5.7)). CONCLUSION: Differing socioeconomic factors do not explain the increased frequency of lupus nephritis in Afro-Caribbean patients with SLE, but rather there are important genetic or other host differences. The independent effect of IgG anti-cardiolipin antibodies warrants further investigation.

Adolescent↗
PubMed2000

An audit of cyclosporin for systemic lupus erythematosus and related overlap syndromes: limitations of its use.

OBJECTIVE: To establish the usefulness of cyclosporin for systemic lupus erythematosus (SLE) in a routine clinical setting. METHODS: Patients who had received cyclosporin for SLE, mixed connective tissue disease, and other overlap syndromes were identified. Data relating to treatment with cyclosporin, including dosage, concurrent steroid use, response to treatment, side effects, and reasons for withdrawal, were extracted from medical notes. RESULTS: A total of 43 patients had been treated with cyclosporin between 1995 and 1998. Cyclosporin, average dose 4 mg/kg/d, was started in patients whose disease was active despite previous use of alternative second line agents. On every occasion when cyclosporin was used for thrombocytopenia the response was good, but when arthritis was the indication, the response was good in 14/26. The success rates for symptoms of arthralgia, myalgia, and fatigue were lower. Side effects occurred in 28/43 (65%) cases, and on 39/47 (83%) occasions cyclosporin was withdrawn owing to either side effects or failure to control disease activity, after a median duration of treatment of only four months. CONCLUSIONS: The response to cyclosporin is mixed and usually short lived.

Adult↗
PubMed2000

Behçet's disease.

Behçet's disease is a systemic vasculitis of unknown aetiology characteristically affecting venules. Onset is typically in young adults with recurrent oral and genital ulceration, uveitis, skin manifestations, arthritis, neurological involvement, and a tendency to thrombosis. It has a worldwide distribution but is prevalent in Japan, the Middle East, and some Mediterranean countries. International diagnostic criteria have been proposed, however diagnosis can be problematical, particularly if the typical ulcers are not obvious at presentation. Treatment is challenging, must be tailored to the pattern of organ involvement for each patient and often requires combination therapies.

Adult↗
PubMed1999

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Amino Acid Sequence↗
PubMed1999

A caspase inhibitor decreases oxidized low-density lipoprotein-induced apoptosis in bovine endothelial cells.

BACKGROUND: Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Oxidized low density lipoprotein (oxLDL) is a putative cause of atherogenesis. We examined the effect of oxLDL on endothelial cell (EC) apoptosis and the ability of a caspase antagonist to inhibit oxLDL-induced EC injury. METHODS: Bovine ECs were plated at a concentration of 5.0 x 10(5) cells/ml and exposed to LDL oxidized by ultraviolet radiation at a concentration of 100 microgram oxLDL/ml for 20 h. Some ECs were pretreated with an irreversible caspase inhibitor (ZVAD). Samples were analyzed histologically. Apoptosis was measured using the Annexin V assay (flow cytometry) which detects phosphatidylserine on plasma membranes and confirmed by TUNEL assay (flow cytometry). Statistical assessments were performed using ANOVA. RESULTS: ECs treated with LDL were morphologically similar to untreated cells. Cells treated with oxLDL demonstrated cytoplasmic shrinkage, plasma membrane blebbing, chromatin condensation, and loss of adhesion. These effects were diminished after pretreatment with the caspase inhibitor ZVAD. The Annexin V assay showed: (a) cells exposed to LDL had a 12 +/- 1% apoptosis rate, (b) exposure to oxLDL induced apoptosis in 30 +/- 0.3% of the cells, and (c) pretreatment with the caspase inhibitor ZVAD decreased the oxLDL-induced apoptosis to 16 +/- 1% (P < 0.05). This decrease in apoptosis was also reflected by an increase in the percentage of alive cells from 34 +/- 7% after oxLDL exposure to 55 +/- 6% after apoptosis inhibition with ZVAD. TUNEL assay demonstrated a 2.5-fold reduction in mean fluorescence intensity between cells treated with oxLDL alone and those treated with ZVAD, suggesting a significant decrease in apoptosis in the latter group. CONCLUSIONS: We conclude that treatment of bovine ECs with oxLDL induces apoptosis which can be significantly reduced by a specific caspase inhibitor.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine.

OBJECTIVE: To assess the efficacy and side effects of tacrolimus, a potent immunosuppressive macrolide antibiotic, in the treatment of sight-threatening uveitis. DESIGN: A clinical study of tacrolimus in patients who required systemic immunosuppression for control of uveitis, but were refractory to cyclosporine. PARTICIPANTS: Six patients with uveitis were treated: three had Behçet disease, one had microscopic polyangiitis, one had pars planitis, and one had idiopathic retinal vasculitis. INTERVENTION: Patients with sight-threatening uveitis refractory to cyclosporine were treated with tacrolimus. MAIN OUTCOME MEASURES: Intraocular inflammation, visual acuity (VA), neovascularization. Adverse effects of tacrolimus were documented. RESULTS: The posterior uveitis remained controlled in all patients while they were taking tacrolimus. Five of the six patients showed improvement, defined as improvement of two or more lines of Snellen acuity or a decrease in the binocular indirect ophthalmoscopy score (P < 0.05, Sign test). One patient with Behçet disease showed a marked improvement in best-corrected VA from 1/60 to 6/24. Two patients with Behçet disease showed a modest improvement in VA in the affected eye and had no disease activity in the other eye. The patient with microscopic polyangiitis was symptomatically improved, and there was no progression of the posterior uveitis. The patient with pars planitis had an improvement in VA from 6/18 to 6/9. The patient with retinal vasculitis showed partial regression of neovascularization on tacrolimus. Side effects were less troublesome than with cyclosporine. CONCLUSIONS: Tacrolimus (FK506) has a useful role as an immunosuppressive agent for the treatment of sight-threatening uveitis in patients who did not respond to cyclosporine either because of lack of therapeutic effect or unacceptable adverse effects.

Adolescent↗
PubMed1999

A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia-reperfusion in mice.

PURPOSE: Apoptosis is a stereotypical pathway of cell death that is orchestrated by a family of cysteine endoproteases called caspases. This study examined the effect of apoptosis inhibition with a specific caspase inhibitor on murine intestinal viability after ischemia-reperfusion (IR). METHODS: C57Bl6 X SV129 mice underwent segmental small bowel ischemia by vascular isolation of 10 cm of terminal ileum. In separate experiments, the ischemic time was varied from 30 to 130 minutes with a reperfusion interval of 6 hours. The degree of small bowel injury was quantified from 1 to 5 (increasing severity) by standardized, blinded histologic grading. The degree of apoptosis was assessed with a specific assay (terminal deoxyamcleotydil transferase-mediated deoxyuridine triphosphate nick end labeling [TUNEL]) and quantified by calculating the apoptotic index (apoptotic cells/10 high-power fields). To evaluate for activation of interleukin-1beta converting enzyme we measured tissue mature interleukin-1beta levels using a specific enzyme-linked immunosorbent assay. To evaluate the effect of apoptosis inhibition on intestinal viability after IR, mice received 3.0 mg of the caspase inhibitor ZVAD (N-benzyloxycarbonyl Val-Ala-Asp-Ome-fluoromethylketone) subcutaneously before and after IR in five divided doses (n = 11), the same dose of ZFA (N-benzyloxycarbonyl Phe-Ala fluoromethylketone), a structurally similar molecule with no anticaspase activity (n = 9), or sham operation (n = 6). RESULTS: A linear relationship existed between ischemic interval and histologic grade (r = 0.69, P <.006). Increasing the ischemic interval from 0 to 50 minutes was associated with a fivefold increase in apoptotic index (P =.05). Ischemic bowel was measured to have an average of 57.3 +/- 7.8 pg/mL whereas normal bowel had an average of 1.8 +/- 0.5 pg/mL of mature interleukin-1beta present. Mice tolerated multiple injections of ZVAD and ZFA without signs of toxicity. Animals treated with ZVAD (apoptosis inhibitor) had little injury after 50 minutes of ischemia and 6 hours of reperfusion (injury grade 1.8) compared with sham controls (injury grade 1.2, P =.7) and had significantly less injury than mice treated with ZFA (placebo) (injury grade 3.0, P <.006). CONCLUSIONS: Increasing ischemic interval in a segmental small bowel murine IR model is associated with increased histologic injury and augmented apoptosis as evidenced by increased TUNEL staining and interleukin-1beta converting enzyme activation. Inhibition of apoptosis with a specific caspase inhibitor significantly diminishes the degree of small bowel injury.

Animals↗
PubMed1999

Antibodies from systemic lupus erythematosus (SLE) sera define differential release of autoantigens from cell lines undergoing apoptosis.

SLE is an autoimmune disease characterized by a wide range of anti-cellular and anti-nuclear autoantibodies. Many of these antigens are exposed or altered during apoptosis when the nucleus is dismantled in a controlled manner by caspases. We used Western blotting techniques to demonstrate that autoantibodies in SLE sera recognize antigens released during apoptosis. Reproducible bands, not seen in the untreated cells, with the characteristics of histones were seen when staining apoptotic cell lysates with SLE sera. Normal sera recognized some of these bands but much less strongly. Different triggers of apoptosis did not produce marked differences in the antigens recognized. We also compared different cell lines (Jurkat and U937) and found that the staining differed for one autoantigen in particular. The differential release of autoantigens by apoptotic cells may have relevance to the variety of autoantibodies seen in SLE.

Apoptosis↗
PubMed1999

Pregnancy outcome and family size in systemic lupus erythematosus: a case-control study.

OBJECTIVE: To establish pregnancy outcomes and family size in a geographically defined population of systemic lupus erythematosus (SLE) patients. METHODS: One hundred and thirty-eight SLE patients (all women satisfying at least four American Rheumatism Association criteria) and 276 age-matched female controls, from the Nottingham area, were interviewed by a single investigator. Demographic details and maternity histories were obtained, and the data collected were analysed statistically to calculate odds ratios (ORs) for risk of fetal loss (through miscarriage, stillbirth and abortion). Family size was also determined in White and non-White cases and controls. RESULTS: Women with SLE are at greater risk of spontaneous fetal loss than their healthy counterparts (OR = 2.21, 95% CI 1.46-3.35, P < 0.01) and they are more likely than controls to have a surgical abortion (OR 2.44, 95%, CI 1.22-4.87, P = 0.01). The excess risk of both of these outcomes exists both before and after diagnosis of SLE. The median number of children in White and non-White families of cases and controls is the same, i.e. two. White women with SLE, however, appear less likely than controls to have more than two children, whereas non-White lupus women tend to retain their propensity to have larger families, i.e. more than two children. CONCLUSIONS: We confirm that lupus women who have, or later develop, SLE are at greater risk of pregnancy loss by spontaneous or surgical means. We have also shown that race, and the inherent differences in social and cultural influences, appears to be an important determinant of ultimate family size; White women with SLE have fewer children than controls, whilst non-White lupus women tend to have larger families.

Abortion, Spontaneous↗
PubMed1999

Expression of recombinant enterotoxigenic Escherichia coli colonization factor antigen I by Salmonella typhimurium elicits a biphasic T helper cell response.

Protective immunity to enterotoxigenic Escherichia coli (ETEC) is antibody (Ab) dependent; however, oral immunization with purified ETEC fimbriae fails to elicit protective immunity as a consequence of antigenic alteration by the gastrointestinal (GI) tract. Unless unaltered ETEC fimbriae can reach the inductive lymphoid tissues of the GI tract, immunity to ETEC cannot be induced. To produce immunity, live vectors, such as Salmonella typhimurium, can effectively target passenger antigens to the inductive lymphoid tissues of the GI tract. By convention, oral immunizations with Salmonella vectors induce CD4(+) T helper (Th) cell responses by gamma interferon (IFN-gamma)-dominated pathways both to the vector and passenger antigen, resulting in serum immunoglobulin G2a (IgG2a) and modest mucosal IgA Ab responses. In the present study, mice orally immunized with a Salmonella vector engineered to stably express ETEC colonization factor antigen I (CFA/I) showed initially elevated serum IgG1 and mucosal IgA anti-CFA/I Ab responses. As expected, mice orally immunized with an E. coli-CFA/I construct elicited poor anti-CFA/I Ab responses. In fact, the addition of cholera toxin during oral E. coli-CFA/I immunization failed to greatly enhance mucosal IgA Ab responses. Seven days after immunization with the Salmonella-CFA/I construct, cytokine-specific ELISPOT showed induction of predominant Th2-type responses in both mucosal and systemic immune compartments supporting the early IgG1 and IgA anti-CFA/I Abs. By 4 weeks, the Th cell response became Th1 cell dominant from the earlier Th2-type responses, as evidenced by increased mucosal and systemic IFN-gamma-producing T cells and a concomitant elevation of serum IgG2a Ab responses. This biphasic response offers an alternative strategy for directing Salmonella vector-induced host immunity along a Th2 cell-dependent pathway, allowing for early promotion of mucosal and systemic Abs.

Animals↗
PubMed1999

Systemic lupus erythematosus (SLE) and hair treatment: a large community based case-control study.

OBJECTIVE: To investigate the association of hair treatment, including permanent and non-permanent dyes, bleach, highlights and lowlights on the development of systemic lupus erythematosus (SLE). METHODS: 150 SLE patients and 300 controls from Nottingham, UK were interviewed in a case-control study. Controls were matched to cases for gender and year of birth. All patients met at least four of the American Rheumatology Association criteria for SLE. Controls were randomly selected from the Nottingham Family Health Services Authority register. Information was collected via an interview-administered questionnaire concerning demographic variables and hair treatment. RESULTS: For hair treatment no significant associations were observed between ever using permanent colouring, non-permanent colouring, bleach or lowlights, and disease. Nevertheless a significant association (OR 0.55, 95% CI 0.31-0.95) was observed between 'ever having' used highlights and disease with cases having used highlights less frequently than their healthy counterparts. No significant differences were observed in duration of usage of hair bleach, permanent colouring, non-permanent colouring, highlights and lowlights between cases and controls. CONCLUSIONS: Hair treatment or duration of hair treatment usage is not significant in the aetiology of SLE. Although patients with SLE were less likely in this study to have highlights than controls, for all other hair treatments no differences were observed.

Case-Control Studies↗
PubMed1998

Ambient pulsatile pressure modulates endothelial cell proliferation.

Many studies over the last decade have indicated that circulatory forces such as shear stress and cyclic strain can influence the endothelial cell (EC) phenotype. However, very little is known about the in vitro effects of pressure on EC. To study this, cultured bovine aortic EC were grown in custom designed pressure chambers with carefully regulated CO2/air environment. EC were exposed to either atmospheric, static (135 mmHg) or pulsatile pressure (160/110 mmHg). A pulsed pressure frequency of 60 cycles/min was maintained by computer-controlled solenoid valves, placed in series with pressure lines. EC proliferation was determined both by cell count after trypsin release on days 1,3 and 5 and by 3H-thymidine incorporation. By day 5, a significant decrease in cell number occurred in both pressure groups, confirmed by the thymidine studies. No changes were observed in cell morphology and cell viability as assessed by LDH activity studies. To investigate the mechanism of this effect, EC conditioned media from the three pressure conditions were transferred to non-exposed, control EC. Significant cell growth inhibition was demonstrated in the control EC group treated with conditioned media from EC cultured under pulsatile pressure conditions. This finding suggests that EC exposed to pulsatile pressure secrete an autocrine factor with growth inhibitory properties. This effect was not mediated by the growth factors TGFbeta and IL-1 as shown by Northern blot analysis and antibody-neutralization studies.

Animals↗
PubMed1998

The differential effect of contrast agents on endothelial cell and smooth muscle cell growth in vitro.

PURPOSE: This study was designed to evaluate the effects of ionic and nonionic contrast agents on endothelial cell (EC) and smooth muscle cell (SMC) proliferation, and to determine the role of osmolality as the etiology of these effects. METHODS: Cultured bovine aorta EC and SMC were exposed to ionic (iothalamate meglumine) or nonionic (ioversol or iopamidol) contrast, or varying osmolar solutions of mannitol, for periods of 1, 3, 5, 10, or 20 minutes. Cells were then incubated in growth media at 37 degrees C and proliferation and structure were assessed 1, 3, 5, and 7 days later. RESULTS: Both EC and SMC showed decreased proliferation after brief exposure to both ionic and nonionic contrast. Proliferation was markedly decreased at 24 hours after exposure, and began to recover by day 3 after exposure. EC showed a significant decrease up to 7 days after exposure to ionic contrast (p < 0.03), whereas SMC showed a significant decrease up to 7 days after exposure to nonionic contrast (p < 0.001). The decrease in proliferation was directly dependent on the length of exposure to the contrast and the concentration of the contrast. EC proliferation decreased in proportion to increasing osmolality of the test solution (p < 0.05). SMC proliferation did not show a decrease proportional to osmolality. No change was observed in cell viability as assessed by LDH activity studies. After contrast exposure, bare areas with no cells present were noted in the previously confluent EC and SMC culture wells. Cell structure was altered immediately after exposure to contrast, with normal structure recovered by 24 hours after exposure. CONCLUSION: This study demonstrates that brief exposure to contrast agents injures EC and SMC, altering their structure and decreasing proliferation for up to 7 days in vitro. This response is both dose and time dependent. EC are more severely affected by ionic contrast, and SMC are more severely affected by nonionic contrast. EC injury appears to be mediated by the osmolar effect of the contrast, but the effects of contrast on SMC seem to be due to a different mechanism.

Animals↗
PubMed1998

Endothelial cells inhibit smooth muscle cell secretion of hyaluronanic acid.

OBJECTIVE: Hyaluronanic acid is a glycosaminoglycan that is present soon after arterial injury and that may augment the smooth muscle cell (SMC) response to injury. The effect of bovine endothelial cells (ECs) on bovine SMC hyaluronanic-acid synthesis was assessed with a bilayer coculture model. METHODS: Hyaluronanic acid was measured in conditioned media by means of radioimmunoassay and in the cell matrix by histochemistry and point hit quantitation. The receptor for hyaluronic acid-mediated motility (RHAMM) expression, which is increased by hyaluronanic acid, was measured by means of immunoblot. RESULTS: Hyaluronanic acid levels in the conditioned media of SMCs cultured alone (425+/-30 microg/ml/10(6) cells) were greater at 48 hours when compared with SMCs cocultured with ECs (212+/-30 microg/ml/10(6) cells; p < 0.01). Histochemical stain for hyaluronanic acid showed increased hyaluronanic acid in SMCs cultured alone at all time points studied. This finding was confirmed by point hit quantitation at all time points (p < 0.05). Cocultured SMCs had a 50%+/-17% reduction in RHAMM as compared with SMCs cultured alone (p=0.08). CONCLUSIONS: ECs inhibit SMC hyaluronanic acid synthesis and RHAMM expression. This inhibition may be an important mechanism by which ECs modify the SMC response to injury.

Animals↗
PubMed1998

Linkage of familial Hibernian fever to chromosome 12p13.

Autosomal dominant periodic fevers are characterized by intermittent febrile attacks of unknown etiology and by recurrent abdominal pains. The biochemical and molecular bases of all autosomal dominant periodic fevers are unknown, and only familial Hibernian fever (FHF) has been described as a distinct clinical entity. FHF has been reported in three families-the original Irish-Scottish family and two Irish families with similar clinical features. We have undertaken a genomewide search in these families and report significant multipoint LOD scores between the disease and markers on chromosome 12p13. Cumulative multipoint linkage analyses indicate that an FHF gene is likely to be located in an 8-cM interval between D12S77 and D12S356, with a maximum LOD score (Z max) of 3.79. The two-point Z max was 3.11, for D12S77. There was no evidence of genetic heterogeneity in these three families; it is proposed that these markers should be tested in other families, of different background, that have autosomal dominant periodic fever, as a prelude to identification of the FHF-susceptibility gene.

Chromosome Mapping↗