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Biomedical subjects

J Symons

Publications and source records attributed to J Symons.

At least 19 recordsLinked to original sources
PubMed2006

Fitness costs limit escape from cytotoxic T lymphocytes by influenza A viruses.

The use of cytotoxic T lymphocyte (CTL)-inducing vaccines could afford both homo- and heterosubtypic immunity. However, amino acid variation in CTL epitopes associated with escape from CTL-mediated immunity might undermine the use of these vaccines. To assess the impact of amino acid substitutions in highly conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of various CTL epitopes. Our findings indicated that fitness costs limited variation in functionally constrained epitopes, especially at anchor residues.

Amino Acid Sequence↗
PubMed2005

Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes.

Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in CTL epitopes. Also for influenza A viruses a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from CTL. However, other previously identified influenza A virus CTL epitopes are highly conserved, including the immunodominant HLA-A*0201-restricted epitope from the matrix protein, M1(58-66). We hypothesized that functional constraints were responsible for the conserved nature of influenza A virus CTL epitopes, limiting escape from CTL. To assess the impact of amino acid substitutions in conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of CTL epitopes. Both alanine replacements and more conservative substitutions were introduced at various positions of different influenza A virus CTL epitopes. Alanine replacements for each of the nine amino acids of the M1(58-66) epitope were tolerated to various extents, except for the anchor residue at the second position. Substitution of anchor residues in other influenza A virus CTL epitopes also affected viral fitness. Viable mutant viruses were used in CTL recognition experiments. The results are discussed in the light of the possibility of influenza viruses to escape from specific CTL. It was speculated that functional constraints limit variation in certain epitopes, especially at anchor residues, explaining the conserved nature of these epitopes.

Amino Acid Substitution↗
PubMed2004

A European multi-center trial investigating the anti-restenotic effect of intravascular sonotherapy after stenting of de novo lesions (EUROSPAH: EUROpean Sonotherapy Prevention of Arterial Hyperplasia).

BACKGROUND: Intravascular sonotherapy (IST) reduces neointimal hyperplasia post-stenting in animal studies. Euro-SPAH is a multi-center, double blind, randomized trial investigating the efficacy of IST to reduce in-stent late loss. METHODS: Patients with angina or silent ischaemia with stented de novo lesions were randomised to sham or IST. The sample size had a 90% power to detect a late loss difference of 0.21 mm at 6 months. The secondary endpoints were MACE at 1, 6, 12 months and neo-intimal hyperplasia on IVUS at 6 months. RESULTS: At 23 sites in Europe, 403 patients were randomized, with successful treatment with sham or IST in 95.6%. There were no significant differences between the groups in terms of baseline demographics or lesion characteristics. Angiographic follow-up was obtained in 89%. In-stent late loss was not significantly different. The restenosis rate at 6 months was 23% in the IST group versus 25% in the sham group. The IVUS measurements confirm the absence of effect of IST on neointimal hyperplasia. At one year, the event-free survival did not significantly differ between the two groups. CONCLUSION: The use of sonotherapy following stent implantation in de novo lesions does not reduce intra-stent neointimal hyperplasia, or effect the angiographic restenosis rate compared to sham treatment.

Aged↗
PubMed2001

Home-based factor infusion therapy and hospitalization for bleeding complications among males with haemophilia.

Information from the medical records of 2650 US males with haemophilia living in six states was used to examine the influence of infusing factor concentrate at home (home therapy) and other variables on rates of hospitalization for a haemorrhagic bleeding complication (HBC) over a 4-year period. Bleeding complications included actual and suspected haemorrhagic events but excluded elective admissions for procedures necessitated by haemorrhage (e.g. joint synovectomy). Other risk determinants considered in the analyses included age, race, employment status, health insurance type, care received in federally funded haemophilia treatment centres (HTCs), factor deficiency type and severity, amount of factor prescribed, prophylactic treatment, and presence of inhibitors at baseline. Survival analysis methods were used to evaluate relationships between baseline risk factors and subsequent hospitalization rates. During 8708 person years (PYs) of follow-up, 808 subjects (30.5%) had a total of 1847 bleeding-related hospitalizations; an overall rate of 21.2 admissions per 100 PYs. Using proportional hazards regression to adjust for all of the studied factors, we found that home therapy use (among residents of four of the states) and care in HTCs were independently associated with a decreased risk for a first HBC. Patients who had government-sponsored health insurance or who had no insurance, those of minority race or ethnicity, those with higher levels of factor use, and those with inhibitors were at increased HBC risk. We conclude that the use of home therapy and receipt of care in HTCs are each associated with a substantially lower risk for HBC among males with haemophilia.

Adolescent↗
PubMed2000

Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators.

OBJECTIVE: To determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women. METHODS: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting. RESULTS: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1. CONCLUSION: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.

Adult↗
PubMed1998

Safety of tacrine: clinical trials, treatment IND, and postmarketing experience.

The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.

Adult↗
PubMed1996

The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial.

OBJECTIVE: To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol (EE2) combinations with matching unopposed EE2 or placebo. DESIGN: A 2-year, double-blind, placebo-controlled, parallel-group clinical trial. SETTING: Outpatients at 65 centers. PATIENTS: Asymptomatic or mildly symptomatic women aged 40 years or older who had undergone the onset of spontaneous menopause within the last 5 years and who had an intact uterus. INTERVENTIONS: Patients were equally randomized to placebo or 1 of 8 treatment groups: 0.2 mg of NA and 1 microg of EE2; 0.5 mg of NA and 2.5 microg of EE2; 1 mg of NA and 5 microg of EE2; 1 mg of NA and 10 microg of EE2; 1 microg of EE2; 2.5 microg of EE2; 5 microg of EE2; or 10 microg of EE2. PRIMARY OUTCOME MEASURES: Bone mineral density (BMD) measured by quantitative computed tomography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status. RESULTS: Twelve hundred sixty-five patients entered the study. Bone mineral density increased significantly from baseline (P<.001) in the 1 mg NA-5 microg EE2 and the 1 mg NA-10 microg EE2 treatment groups at each annual assessment. Among the unopposed EE2 groups, only the 10-microg group had increased BMD above baseline, but also was accompanied by an unacceptably high rate of endometrial hyperplasia. The NA-EE2 treatment groups had a significant linear dose-response trend for increasing BMD. Increased endometrial proliferation and hyperplasia occurred with increasing unopposed estrogen doses. The combination of NA and EE2 effectively protected the endometrium against hyperplasia. The percentage of change in the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol was positive for all treatment groups. The increase in triglyceride levels associated with EE2 was attenuated with NA-EE2 treatment. CONCLUSIONS: Daily treatment with NA-EE2 was well tolerated and protected the endometrium from EE2-induced proliferation and hyperplasia. The NA-EE2 treatments produced a dose-related significant increase in BMD that was not present with unopposed EE2 treatment. The overall effect of NA-EE2 treatments on lipid measures was favorable.

Adult↗
PubMed1995

Inflammatory cytokine responses in juvenile chronic arthritis.

The inflammatory cytokines interleukin 1 beta (IL-1 beta) interleukin 6 (IL-6), tumour necrosis factor alpha (TNF alpha) and the anti-inflammatory peptide--the interleukin 1 (IL-1) receptor antagonist--were measured in the plasma of children with juvenile chronic arthritis (JCA). In the two subgroups studied (polyarticular JCA and systemic JCA), there was good correlation between laboratory measures of disease activity C-reactive protein (CRP), erythrocyte sedimentation rate and clinical scores for disease activity. Despite higher levels of CRP in the systemic group IL-1 beta levels were lower and regression analysis recorded a difference in the relationship between CRP and IL-1 beta within the two clinical groups. In contrast, IL-6 levels were high in the systemic group and correlated with disease activity. No such correlation was observed in the polyarticular group. Five children with systemic JCA were studied during the febrile phase of their illness. IL-6 levels rose and fell with the fever. TNF alpha levels also rose and fell but out of phase with the fever. In contrast IL-1 beta levels were either undetectable throughout the febrile episode or only became detectable as the temperature reduced to normal. The IL-1 receptor antagonist was usually found in 1000-fold excess over IL-1 beta, levels rising and falling with the fever. These results demonstrate difference in the cytokine profiles and acute phase protein responses in polyarticular and systemic JCA. This would suggest different pathogenic mechanisms for these two groups of JCA with IL-6 being the more important cytokine in systemic JCA.

Acute Disease↗
PubMed1995

Making staff aware of risks.

Outlines the essential steps in establishing risk management as an effective process in any organization and relates to management claims, complaints and adverse incidents. Discusses the way to elicit and use information from patients and staff. Emphasizes the need to learn from all those involved in delivery and receipt of care.

Data Collection↗
PubMed1993

Contrasting levels of in vitro cytokine production by rheumatoid synovial tissues demonstrating different patterns of mononuclear cell infiltration.

Synovial membrane samples obtained at knee arthroplasty from 22 patients with rheumatoid arthritis (RA) were characterized histologically. Two groups were identified. Tissue samples from 15 patients demonstrated multiple focal lymphoid aggregates of mononuclear cells (group A). Samples from the remaining seven patients demonstrated diffuse mononuclear cell infiltration (group B). Samples of each synovial membrane (0.25 g) were cultured for cytokine production. The highest levels of IL-1 beta and IL-6 were produced by group A tissues: 19.1 +/- 19.6 ng/ml IL-1 beta (mean +/- s.d.) and 264.4 +/- 301.9 ng/ml IL-6, versus 3.8 +/- 6.6 ng/ml and 54.7 +/- 42.6 ng/ml respectively. Small quantities of IL-2 and IL-4 were measured in both groups: the levels of IL-2 in group A cultures were highest (P = 0.04). Moreover, using MoAbs, the most intense cytokine staining in the tissues was detected in group A. Similar total numbers of each cell subpopulation and similar quantities of immunoglobulin and rheumatoid factor synthesis were measured in both groups. It is suggested that the presence of multiple focal lymphoid aggregates associated with higher levels of cytokine production observed in group A represent a greater degree of immunological activation, and may represent a subgroup of patients with a greater potential for articular destruction.

Adult↗
PubMed1989

An economic approach to fertility in Britain since 1860.

This paper utilizes a dynamic economic approach to examine movements in fertility in Britain since 1860. The analysis and results indicate that fertility has responded positively to change in incomes. However, this positive effect has been more than offset by the increase in the opportunity cost of female time which has followed closely the educational attainment of women.

Adolescent↗