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Biomedical subjects

R Stevens

Publications and source records attributed to R Stevens.

At least 55 records · Page 3Linked to original sources
PubMed1999

Immune response to a recombinant human TNFR55-IgG1 fusion protein: auto-antibodies in rheumatoid arthritis (RA) and multiple sclerosis (MS) patients have neither neutralizing nor agonist activities.

A substantial number of patients enrolled in clinical studies of TNFR55-IgG1 in TNF-neutralizing treatment of rheumatoid arthritis and multiple sclerosis developed antibodies to the recombinant human protein. To enable more detailed investigation subgroups of patients donated small blood samples. TNFR55-IgG1 reactive antibodies were affinity purified from plasma; IgM and IgG class antibodies reactive with TNFR55-IgG1 were found which varied considerably in titer and kinetics of appearance among individual patients. The affinity purified antibody fractions included specificities to the receptor moiety of TNFR55-IgG1, but also rheumatoid factor and other pre-existing antibodies directed to the IgG1 moiety. The antibodies bound to Fc receptors, but not detectably to TNFR55 at the human cell surface. No agonistic nor neutralizing activities of these antibodies were detected. Major linear epitopes clustered in the TNFR55 sequence in close proximity to the IgG1 fusion site. The relative content of antibodies to linear and conformational epitopes was highly variable among patients. Route and frequency of administration rather than underlying disease appeared to influence the major linear B cell epitopes selected.

Antigens, CD↗
PubMed1999

A circumcision service for religious reasons.

OBJECTIVE: To review the results of a pioneering service introduced under National Health Service (NHS) cover, providing circumcision on religious grounds. SUBJECTS AND METHODS: The service was offered to all male babies aged 6-14 weeks. Circumcision was carried out using the Plastibell technique under 1% lignocaine ring block/penile block anaesthesia. Between July 1996 and August 1998, 168 circumcisions were performed and assessed postoperatively by telephone enquiry, visiting at home by the nurse and review at the hospital if and when required. RESULTS: Of the 168 babies, 31 required some follow-up care. In six babies the separated ring tracked back onto the shaft of the penis and had to be removed using a ring-cutter. Ten babies were referred for incomplete separation of the Plastibell ring; only two required removal, the rest of the rings detaching spontaneously within a few days. Two babies were reviewed for early separation of the ring and seven were reviewed for bleeding within 24 h of the operation. Two of these were immediately after circumcision, when the bleeding was seen to be from the torn frenulum. They were converted to a more formal circumcision without the Plastibell under the same anaesthesia. Surveillance with no intervention was required in the others, except one who needed a compression dressing. One baby had apyrexia, requiring antibiotics. Four babies had suspected wound infection but none was clinically significant. One parent remained dissatisfied and complained about the inadequate removal of the foreskin. CONCLUSION: The aim of the service was to provide safe circumcision requested on religious grounds. The technique was simple and easily learned by nurses. Parents have generally been very satisfied and the complication rate was acceptable, with most problems occurring early in the series, suggesting an improvement with experience.

Child Health Services↗
PubMed1999

An ontology for bioinformatics applications.

MOTIVATION: An ontology of biological terminology provides a model of biological concepts that can be used to form a semantic framework for many data storage, retrieval and analysis tasks. Such a semantic framework could be used to underpin a range of important bioinformatics tasks, such as the querying of heterogeneous bioinformatics sources or the systematic annotation of experimental results. RESULTS: This paper provides an overview of an ontology [the Transparent Access to Multiple Biological Information Sources (TAMBIS) ontology or TaO] that describes a wide range of bioinformatics concepts. The present paper describes the mechanisms used for delivering the ontology and discusses the ontology's design and organization, which are crucial for maintaining the coherence of a large collection of concepts and their relationships. AVAILABILITY: The TAMBIS system, which uses a subset of the TaO described here, is accessible over the Web via http://img.cs.man.ac.uk/tambis (although in the first instance, we will use a password mechanism to limit the load on our server). The complete model is also available on the Web at the above URL.

Animals↗
PubMed1999

UCLA's outreach program of science education in the Los Angeles schools.

The UCLA School of Medicine's Interactive Multi-media Exercises (IMMEX) Project began its outreach into pre-college education in the Los Angeles area in 1993. The project provides a model in which software and technology are effectively intertwined with teaching, learning, and assessment (of both students' and teachers' performances) in the classroom. The project has evolved into a special collaboration between the medical school and Los Angeles teachers. UCLA faculty and staff work with science teachers and administrators from elementary, middle, and high schools. The program benefits ethnically and racially diverse groups of students in schools ranging from the inner city to the suburbs. The project's primary goal is to use technology to increase students' achievement and interest in science, including medicine, and thus move more students into the medical school pipeline. Evaluations from outside project evaluators (West Ed) as well as from teachers and IMMEX staff show that the project has already had a significant effect on teachers' professional development, classroom practice, and students' achievement in the Los Angeles area.

Community-Institutional Relations↗
PubMed1999

Ternary complex structure of human HGPRTase, PRPP, Mg2+, and the inhibitor HPP reveals the involvement of the flexible loop in substrate binding.

Site-directed mutagenesis was used to replace Lys68 of the human hypoxanthine phosphoribosyltransferase (HGPRTase) with alanine to exploit this less reactive form of the enzyme to gain additional insights into the structure activity relationship of HGPRTase. Although this substitution resulted in only a minimal (one- to threefold) increase in the Km values for binding pyrophosphate or phosphoribosylpyrophosphate, the catalytic efficiencies (k(cat)/Km) of the forward and reverse reactions were more severely reduced (6- to 30-fold), and the mutant enzyme showed positive cooperativity in binding of alpha-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and nucleotide. The K68A form of the human HGPRTase was cocrystallized with 7-hydroxy [4,3-d] pyrazolo pyrimidine (HPP) and Mg PRPP, and the refined structure reported. The PRPP molecule built into the [(Fo - Fc)phi(calc)] electron density shows atomic interactions between the Mg PRPP and enzyme residues in the pyrophosphate binding domain as well as in a long flexible loop (residues Leu101 to Gly111) that closes over the active site. Loop closure reveals the functional roles for the conserved SY dipeptide of the loop as well as the molecular basis for one form of gouty arthritis (S103R). In addition, the closed loop conformation provides structural information relevant to the mechanism of catalysis in human HGPRTase.

Animals↗
PubMed1999

Nutritional status of adolescent girls in the eastern province of Saudi Arabia.

The aim of this study is to assess the nutritional status of Saudi adolescent girls using weight and height measurements. A cross-sectional sample of 676 girls aged 12 to 19 years were selected from Al-Khober city, in the Eastern Province of Saudi Arabia. At all ages median (50th percentiles) heights of Saudi girls are below the 50th percentiles of the international standards. However, the median weight falls between the 75th and 50th of the standards, which may indicate a trend toward obesity. Using the body mass index for determining the nutritional status of the girls, it was found that 11% of girls were underweight, 61% were normal and 28% were overweight or obese. The findings revealed that adolescent girls in Saudi Arabia face two contrasting nutrition situations, underweight and overweight. Similar findings were reported in other Arabian Gulf countries, indicating the need for intervention programmes to promote better nutrition among school children and adolescents in Saudi Arabia.

Adolescent↗
PubMed1998

The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties.

Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, -5, del(5q), -7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.

Acute Disease↗
PubMed1998

Porcine cerebroside sulfate activator (saposin B) secondary structure: CD, FTIR, and NMR studies.

Cerebroside sulfate activator protein (CSAct or saposin B) is one of a group of heat stable, low-molecular-weight proteins that appear to share a common structural motif. These have been referred to as saposin-like proteins and are thought to share a multiple amphipathic helical barrel structure with a conserved pattern of disulfide linkages. Porcine kidney CSAct was prepared in high purity and consisted of three major glycosylated subforms. The protein was studied by physical-chemical methods and evaluated by various methods for structural prediction. All suggest that CSAct has high amounts of alpha-helical conformation and little if any beta-sheet. Circular dichroism (CD) studies indicate 45-50% helical conformation depending on buffer and temperature. There was only a moderate loss in helical content with increasing temperature and no indication of thermal denaturation. Fourier transform infrared spectroscopy (FTIR) measurements on deuterium hydrated self-films also indicated a predominantly helical structure. Helical axis orientation was investigated by both oriented CD and FTIR dichroism, which suggested that the helical axes were roughly parallel and oriented along the axis of the surface on which the self-films had been deposited. One-dimensional nuclear magnetic resonance spectra showed large chemical shift dispersion, indicating a defined tertiary structure with little variation between 6 and 85 degrees C. NOESY spectra failed to show the strong NOE cross peaks expected for a highly helical conformation. This may indicate short-term conformational flexibility within the helices or molecular aggregation at the high protein concentrations employed. These observations are consistent with the 3-4-helix bundle motif suggested for saposin-like proteins by various predictive algorithms.

Algorithms↗
PubMed1998

Pharmacokinetic modeling of recombinant interleukin-2 in patients with human immunodeficiency virus infection.

A novel model was developed to characterize the time-varying clearance of recombinant interleukin-2 (IL-2). Sixty-eight patients with human immunodeficiency virus infection received 83 cycles of IL-2 either by continuous infusion or by subcutaneous injection for 5 days. IL-2 concentrations after intravenous infusions peaked at 24 hours and then declined by 55% to 78% during the remainder of the infusion. Soluble IL-2 receptors increased greater than 10-fold before gradually returning to baseline. Subcutaneous administration showed a dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5. A model was developed in 9 patients who had IL-2 concentrations and soluble IL-2 receptors determined by ELISA. Concentrations were fitted by an indirect stimulatory pharmacodynamic model. An additional 59 patients with only IL-2 concentrations were fitted to a simplified empiric model. Both models provided an overall r2 of 0.99 for the plot of observed versus fitted concentrations. The time-dependent increase in IL-2 clearance, likely receptor-mediated, was well described with use of an indirect-effects pharmacokinetic-pharmacodynamic model.

Adult↗
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

Immunolymphoscintigraphy in breast cancer: evaluation using 131I-labeled monoclonal antibody B72.3.

Noninvasive axillary lymph node staging was investigated using [131I]murine monoclonal antibody B72.3 in 16 patients with breast cancer scheduled for axillary dissection. [131I]B72.3 was injected into ipsilateral finger webs or around the breast biopsy. Scintigraphy to 72 h and gamma-counting/immunohistochemistry of nodes were performed. Specific antibody uptake (%ID/g) and the ratio of specific:nonspecific antibody uptake were not significantly different in tumor-positive versus tumor-negative nodes, suggesting that [131I]B72.3 is unsuitable to discriminate axillary node tumor involvement.

Antibodies, Monoclonal↗
PubMed1998

Prevalence of HIV, syphilis and genital chlamydial infection among women in north-west Ethiopia.

The prevalence of sexually transmitted diseases (STD) among women visiting antenatal (ANC) and gynaecological clinics in Gondar, north-west Ethiopia, was investigated. Between April and August 1995, 728 women consented to enter the study. Prevalence rates were 5.9% (41/693) for chlamydial antigen in cervix, 18.8% (113/600) for syphilis (Treponema pallidum haemagglutination assay [TPHA]) and 25.3% (150/593) for HIV. Active syphilis (RPR)+, TPHA+ was detected in 74% (44/597). HIV infection rate was higher among women with higher age of first marriage and low gravidity. It was significantly associated with young age, urban residence, and presence of genital ulcer (odds ratio [OR] = 6.3), and lymphadenopathy (OR = 2.8) on examination. Women seropositive for syphilis had married at an earlier age, were significantly older and had changed husbands. Low gravidity and age < 30 were independently significant risk factors for cervical chlamydial antigen positivity which was predominantly asymptomatic. Significant association was observed between HIV infection and syphilis (OR = 2.6). Active syphilis was associated with chlamydial (OR = 3.4) and HIV infection (OR = 4.1). The rate of 23.4% and 15.1% of HIV seropositivity among ANC attenders and rural women respectively is an indicator of the rapid progression of the HIV epidemic in the area.

Adolescent↗
PubMed1998

The fast flush test--is the clinical comparison equivalent to its in vitro simulation?

OBJECTIVE: An in vitro simulation of the fast flush (FL) test has previously been used to prove that the FL test-measures the dynamic response of entire the blood pressure monitoring system. This simulation has also been used to confirm that the FL test is equivalent to the "gold standard" test for determining dynamic response, namely the square wave (SW) test. The conditions of the in vitro simulation can be reproduced in vivo during cardiopulmonary bypass (CPB) and circulatory arrest. Therefore the present objective was to verify that the previous conclusions about the validity of the FL test, obtained from an in vitro model, are equally valid when applied to in vivo clinical conditions. A secondary objective was to determine whether the patient's arterial tree has any affect on the dynamic characteristics of fluid-filled manometers. METHODS: Fourteen patients were studied during surgery that required CPB. We measured the dynamic response of the fluid filled arterial manometer during pulsatile conditions prior to the initiation of CPB, and then repeated the measurements during non-pulsatile CPB. In four of the fourteen patients we measured the dynamic response during circulatory arrest. A manometer, consisting of a fluid-filled tubing component, measured the patient's arterial blood pressure as well as the damped sinusoidal wave form created by the fast flush tests. The fluid-filled tubing was connected to a transducer (Utah Medical Products, Inc., Midvale, UT). The arterial pressures and the results of flush testing were recorded and displayed by a monitor (Marquette 7010, Marquette Electronics Inc., Milwaukee, WI). In an additional three patients we measured the dynamic response of the manometer in vitro and then in vivo. RESULTS: The dynamic response of the arterial pressure measuring system was the same during normal pulsatile flow, CPB and circulatory arrest. In addition, the dynamic response of the fluid-filled manometer was the same in vivo as in vitro. CONCLUSIONS: The clinical conditions during CPB and particularly during circulatory arrest duplicate the in vitro FL test simulation model. These results confirm the validity of the FL test in vivo as well as proving that the dynamic characteristics of a fluid-filled manometer are independent of the patient's vasculature.

Blood Pressure↗
PubMed1998

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.

Adolescent↗
PubMed1998

Progression of human immunodeficiency virus disease is associated with increasing disruptions within the CD4+ T cell receptor repertoire.

The immunodeficiency caused by human immunodeficiency virus (HIV) infection may be related to loss of diversity in the T cell receptor (TCR) repertoire. A cross-sectional study of the CD4 TCR repertoire was done for patients at various stages of HIV infection. Semiquantitative polymerase chain reaction was used to study the relative usage of the variable chain beta (BV) subfamilies and the size distributions of transcripts (CDR3 size analysis) within these subfamilies. The relative usage of the TCRBV subfamilies of patients and controls was not significantly different. The proportion of subfamilies with abnormal CDR3 size patterns was higher in the HIV-infected patients (25%, 95% confidence interval [CI], 17%-33%) than in the controls (7.2%, 95% CI, 2.3%-12.1%; P < .001), with a significant negative correlation between the number of CD4 cells and the percentage of abnormal TCRBV subfamilies. These results indicate that progressive loss of CD4 T cells is accompanied by increasing disruptions within the T cell receptor repertoire.

CD4 Lymphocyte Count↗