PubMed Health⌕ Search

Biomedical subjects

R J Powell

Publications and source records attributed to R J Powell.

At least 19 recordsLinked to original sources
PubMed2006

Tacrolimus immunosuppression in high-risk corneal grafts.

BACKGROUND: Unlike the immune privilege enjoyed by low-risk corneal grafts, high-risk corneal grafts experience rejection rates comparable to liver and kidney transplants. Systemic immunosuppression reduces the risk of rejection in high-risk corneal grafts. METHODS: Systemic tacrolimus, a specific T cell inhibitor, was used at a mean daily dose of 2.5 mg to immunosuppress 43 patients undergoing high-risk corneal transplantation. Immunosuppression was continued for a period of 18-24 months after the high-risk corneal graft. RESULTS: During a mean follow-up period of 33.7 months, clarity of the graft was maintained in 65% of patients. Eight patients experienced rejection episodes while on tacrolimus, and this led to graft failure in five patients. CONCLUSION: Tacrolimus is relatively safe and effective in reducing rejection and prolonging graft survival in patients with high-risk keratoplasty compared with other series where similar immunosuppression was not used.

Administration, Oral↗
PubMed2006

Offspring birthweight is not associated with paternal insulin resistance.

AIMS/HYPOTHESIS: Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight. SUBJECTS AND METHODS: The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee. RESULTS: Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=-0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight. CONCLUSIONS/INTERPRETATION: Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.

Adult↗
PubMed2006

Paternal insulin resistance and its association with umbilical cord insulin concentrations.

AIMS/HYPOTHESIS: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action. SUBJECTS, MATERIALS AND METHODS: To assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. RESULTS: As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16-0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors. CONCLUSION: Our results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring pre-natally before the homeostatic feedback loop between glucose and insulin is established.

Adult↗
PubMed2005

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.

Adult↗
PubMed2005

Determinants of insulin concentrations in healthy 1-week-old babies in the community: applications of a bloodspot assay.

BACKGROUND: Epidemiological research into insulin secretion and insulin action would be helped by improved ability to measure insulin concentrations in large groups of healthy babies in the neonatal period. Such research is often restricted by the invasive nature of blood sampling. AIMS: We assessed the use of an assay that can measure insulin from bloodspots taken during routine Guthrie testing 7 days after delivery. STUDY DESIGN AND SUBJECTS: Insulin and glucose were measured in 366 seven-day-old infants from heel-prick bloodspots. Time since last feed and type of feed were recorded. RESULTS: Bloodspot insulin concentrations in normal 7-day-old infants were much lower (median (IQR): 15.4 pmol/l (<10-28.5)) than fasting insulin concentrations in adult males (44.3 pmol/l (30.6-72.6)) (p<0.001). Insulin and glucose concentrations were correlated (r=0.33, p<0.001). Insulin and glucose fell significantly with time from feed. Bottle fed infants had higher insulin concentrations but similar glucose concentrations compared to breast fed infants. Detailed analysis to account for confounders was limited due to the skewed distribution of time since feed and the lower limit of the assay leading to non-continuous insulin data. CONCLUSIONS: In the largest study of normal 7-day-old children to date we have shown insulin concentrations are low compared to adults and vary with glucose, time from feed, and type of feed. This validates the use of the bloodspot insulin assay as a potential research tool for large-scale epidemiological studies. However, careful study design would be required in future use to reduce the variation caused by timing and type of feeding and the problem of one third of values being at or below the lower limit of this assay.

Blood Glucose↗
PubMed2005

The efficacy of sirolimus in the treatment of patients with refractory uveitis.

AIMS: To determine the efficacy of sirolimus in the treatment of patients with severe non-infectious uveitis. METHODS: Eight patients with severe non-infectious uveitis were recruited to an open study. Inclusion criteria were limited to patients whose disease was not controlled with at least two or more separate steroid sparing immunosuppressants (either because of unacceptable side effects or ineffectiveness of the drug) or who required regular doses of corticosteroids either as high dose systemic or orbital floor injections in order to control their disease. Intraocular inflammation, visual acuity, symptoms, corticosteroid burden, drug toxicity, and side effects were monitored. RESULTS: Sirolimus therapy was effective in five of the eight patients, all of whom had their dose of corticosteroids reduced or discontinued. Treatment in three patients was considered a failure as it caused intolerable side effects and/or failed to control the uveitis. Side effects were common and were typically gastrointestinal or cutaneous in nature. The severity of symptoms was dose dependent in most cases and occurred at trough blood levels above 25 ng/ml. CONCLUSION: Sirolimus is an effective and potent immunosuppressive treatment in the majority of patients with non-infectious uveitis and can reduce the need for long term supplementary corticosteroid therapy. Further studies are required to establish the long term efficacy and safety of sirolimus alone or in combination with other steroid sparing immunosuppressants.

Adult↗
PubMed2004

Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To describe the effect of Etanercept treatment in systemic AA amyloidosis in tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Etanercept therapy was given to a 27 year old woman, with systemic amyloidosis and nephrotic syndrome, and to her 51 year old father, also affected by TRAPS, who had previously undergone renal transplant for amyloidosis. Serum SAA levels, plasma cytokines, glomerular filtration rate and serum amyloid P scanning were monitored. RESULTS: Etanercept treatment resulted in initial clinical resolution of nephrotic syndrome in the 27 year old female. Both subjects demonstrated improvements in GFR and initial reduction or stabilisation of amyloid deposits on SAP scanning. CONCLUSION: Etanercept may reverse or slow the progression of systemic AA amyloidosis in subjects with C33Y TNFRSF1A mutation. Treatment may however need to be continuous and life-long to prevent progression to end stage disease.

Adult↗
PubMed2003

Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells.

It has been proposed that cytokines play a role in the pathogenesis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS). However, different studies have reported conflicting results using enzyme-linked immunosorbent assay or polymerase chain reaction to detect cytokines in these conditions. In the present study, for the first time, the production of inflammatory [interleukin (IL)-1alpha, IL-6, and TNF-alpha] and anti-inflammatory (IL-10) cytokines by CD14+ and CD14- peripheral blood mononuclear cells (PBMC) from chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients and sex- and age-matched normal subjects was investigated at the level of individual cells using the technique of intracellular cytokine staining and flow cytometry. Cultures were carried out in the presence of polymyxin B to inhibit the effect of endotoxins on cytokine production by monocytes. The mean intensity of fluorescence (MIF) and percentage of CD14+ (monocytes) and CD14- (lymphocytes) cytokine-producing mononuclear cells were comparable in patients and controls in either unstimulated or IFN-gamma-stimulated conditions. Our study indicates that dysregulation of cytokine production by circulating monocytes or non-monocytic cells (lymphocytes) is not a dominant factor in the pathogenesis of CFS/FMS.

Adolescent↗
PubMed2003

Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients.

OBJECTIVE: To assess the effects prospectively of tumour necrosis factor (TNF) receptor superfamily (TNFRSF) fusion proteins TNFRSF1B (etanercept) and TNFRSF1A (p55TNFr-Ig) in patients with TNF receptor associated periodic syndrome (TRAPS). METHODS: Seven patients with a clinical and genetic diagnosis of TRAPS received subcutaneous etanercept for 24 weeks. One of these patients had previously received an intravenous infusion of p55TNFr-Ig. Therapeutic response was assessed by comparing corticosteroid requirement, acute-phase response and an established scoring system over 20 weeks, both on and off etanercept. RESULTS: Etanercept was well tolerated. The five corticosteroid-responsive patients required significantly less corticosteroids and demonstrated reductions in acute-phase reactants on etanercept. The two patients not requiring corticosteroids had small reductions in disease activity scores. The effect of p55TNFr-Ig in a single patient with TRAPS remains unclear. CONCLUSIONS: Etanercept does not abolish inflammatory attacks but improves disease activity allowing corticosteroid reduction. Etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of TRAPS. A formal trial of etanercept to establish its role in clinical management is indicated.

Adult↗
PubMed2003

Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells.

Recent studies indicate that normal B cells can be primed to differentiate into two distinct cytokine-secreting effector subsets, Be1 and Be2. The aim of this study was to analyse, for the first time, Be1 and Be2 cells at the single cell level in SLE patients using the recently developed technique of flow cytometry for intracellular cytokines. Peripheral blood mononuclear cells (PBMC) from SLE patients and age- and sex-matched normal controls were cultured for 24 h in the presence or absence of phorbal myristate acetate and ionomycin (PMA/I) or lipopolysaccharide (LPS). The production of type I (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-6, IL-10, IL-13) cytokines by B cells (and IL-10 production by fractionated CD5+ and CD5- B cells) was investigated using an intracellular cytokine staining technique and flow cytometry. In the absence of PMA/I stimulation, the percentage of B cells from SLE patients was significantly lower than those of normal subjects and significantly more SLE B cells spontaneously produced IL-10 than controls. Moreover, CD5+ B cells from SLE patients were enriched for cells with signs of previous in vivo activation and for high levels of IL-10 production. A significant positive correlation was observed between the percentage of IL-10- and IL-6-producing PMA/I-stimulated B cells in SLE patients, but not in controls. There were no significant differences in the production of other cytokines by B cells of SLE patients and normal subjects. In conclusion, a general alteration of type 1 and type 2 cytokine production by B cells is not observed in SLE patients. The role of B cell cytokines in the pathogenesis of SLE appears to be exerted by elevated secretion of in vivo IL-10, which may play an important role in the immune dysregulation observed in SLE patients. Moreover, the cross regulation of IL-10 and IL-6 is disrupted in SLE patients.

B-Lymphocytes↗
PubMed2002

Clinically useful monoclonal antibodies in treatment.

Monoclonal antibodies have been used in clinical diagnosis for many years but it is only now that these agents are being licensed for clinical treatments. This review will focus on UK licensed monoclonal antibodies highlighting their clinical benefits, limitations, and side effects.

Antibodies, Monoclonal↗