Major histocompatibility complex class II association and induction of T cell responses by carbohydrates and glycopeptides.
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Acetylglucosamine↗
Biomedical subjects
D Thomson
Publications and source records attributed to D Thomson.
Neurotoxicity of peptide analogues of the transactivating protein tat from Maedi-Visna virus and human immunodeficiency virus.
Infection by lentiviruses such as human immunodeficiency virus, Maedi-Visna virus and Caprine Arthritis Encephalitis Virus, is associated with a variety of neurological syndromes, but the mechanism by which the damage occurs to the nervous system is not known. The viruses do not infect neurons and so the neurotoxic actions must be mediated indirectly. Here we applied synthetic peptide analogues derived from basic regions of Maedi-Visna virus and human immunodeficiency virus transactivating protein, tat, to rat brain in vivo and found them to be potent neurotoxins. The toxicity of the Maedi-Visna virus peptide was demonstrated to be reduced by blockade of nitric oxide synthase and of N-methyl-D-aspartate channel opening. These experiments suggest that peptides derived from lentiviral tat may share a common neurotoxic action.
Amino Acid Oxidoreductases↗
Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma.
In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzer's QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.
Adult↗
Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum.
The determination of peptide stability in human serum (HS) or plasma constitutes a powerful screening assay for eliminating unstable peptides from further development. Herein we report on the stability in HS of several major histocompatibility complex (MHC)-binding peptides. Some of these peptides are in development for the novel treatment of selected autoimmune disorders such as rheumatoid arthritis and insulin-dependent diabetes. For most of the l-amino acid peptides studied, the predominant degradation mechanism is exopeptidase-catalyzed cleavage. Peptides that were protected by d-amino acids at both termini were found to be more stable than predicted, based on additivity of single substitutions. In addition, N-acetylglucosamine glycopeptides were significantly stabilized, even when the glycosylation site was several amino acids from the predominant site(s) of cleavage. This indicates that long-range stabilization is possible, and likely due to altered peptide conformation. Finally, the effect of single amino acid substitutions on peptide stability in HS was determined using a model set of poly-Ala peptides which were protected from exopeptidase cleavage, allowing the study of endopeptidase cleavage pathways.
Acetylglucosamine↗
Evaluation of a computerized assessment package for general practitioner trainees.
A computerized assessment package for general practitioner trainees has been developed in order to measure the impact of teaching during the trainee year and to help identify areas of possible weakness in the knowledge base of trainees. The programme consists of an electronic questionnaire asking for background educational details, confidence rating scales, 60 multiple choice questions divided into 11 educational areas and a patient management problem to add variety and interest and to test decision making skills. A printout is produced at the end of the test summarizing the trainee's results and comparing these with the previous cohort of trainees. The programme was designed to be interesting and stimulating to the trainee by using colour and graphics, ensuring it was easy to use and providing instant feedback of results in comparison with their peer group. It was also designed to require the minimum intervention by trainers. Three sets of 70 trainees undertook the test in consecutive years with each trainee completing the assessment twice, once at the beginning of the trainee year and again towards the end of the year. In addition, a group of trainees completed a manual questionnaire asking them to rate certain aspects of the test. The results of the assessments showed a significant increase in knowledge in nearly all topic areas between the first and second tests. In general, the trainees' response to the test was positive with 63% stating it was useful in pinpointing areas of possible knowledge deficiency. The computer package described has been shown to be an effective and acceptable method for some aspects of trainee assessment.
Adult↗
Nephrotic syndrome associated with chronic lymphocytic leukaemia.
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Aged↗
Problem drug use in a central London general practice.
OBJECTIVE: To describe the profile of problem drug users presenting in general practice and to determine whether they can be cared for in general practice. DESIGN: Study of consultations by problem drug users. SETTING: Central London general practice. SUBJECTS: 150 problem drug users presenting over two years. MAIN OUTCOME MEASURES: Stopping drug use, alterations in lifestyle, obtaining paid work, and stopping drug related crime. RESULTS: Of the 150 patients, 111 were men and 39 women, and 106 were unemployed. 121 patients used heroin, 112 of whom injected. 145 patients accepted a methadone reduction programme and 81 completed it. A further 25 were stabilised on reducing doses of methadone, until places became available for them as inpatients at drug dependency units or rehabilitation projects. CONCLUSION: Withdrawal programmes for patients who misuse drugs can be successfully managed in general practice.
Family Practice↗
MHC interaction and T cell recognition of carbohydrates and glycopeptides.
The T cell independence of complex polysaccharide Ag has suggested the possibility that carbohydrates may be incapable of T cell recognition because of a failure to interact with MHC restriction elements and/or a failure of MHC/carbohydrate complexes to interact with and be recognized by Ag-specific TCR. We have used two approaches to obtain information about T cell recognition of carbohydrate. First, we have determined the capacity of a series of oligosaccharides and glycolipids to bind a murine class II MHC molecule, IAd. No significant binding was observed with the 26 compounds tested, but the limitation to these studies was that there was a relatively limited collection of synthetic carbohydrate and glycolipid structures of limited complexity available for analysis. The second approach involved the study of the effect of glycosylation of a known peptide T cell epitope (OVA 323-339) on MHC binding of the peptide and on T cell recognition. Three patterns of effects were observed: 1) no effect on either binding or T cell recognition. This pattern was observed when the carbohydrate was located at residues removed from the core MHC-binding region. When the carbohydrate was located within the core MHC-binding regions, either 2) glycosylation destroyed both MHC binding and T cell recognition; or 3) glycosylation did not ablate MHC binding or T cell recognition. In this latter instance, there was evidence to indicate that the carbohydrate moiety was an important part of the antigenic determinant recognized by T cells.
Animals↗
Inhibitory effects of glyceryl trinitrate on alpha-adrenoceptor mediated contraction in the human internal mammary artery.
1. Sympathomimetic amines have been considered to be related to vasospasm. Previous studies showed that the human internal mammary artery (IMA) was capable of weak beta-adrenoceptor mediated relaxation and that alpha-adrenoceptor agonists may induce contraction in the human IMA. 2. We investigated the effects of glyceryl trinitrate (GTN), a vasodilator agent often used perioperatively, on alpha-adrenoceptor mediated contraction in the human IMA. 3. Discarded human IMA segments were taken from 37 patients who underwent IMA--coronary artery bypass graft operations and equilibrated in an organ bath. 4. A specially designed technique was used to normalize the vessel segments under the pressure similar to the in vivo situation. Noradrenaline (NA), phenylephrine (PE), and methoxamine (MO) were used to contract the vessel segments. 5. GTN fully relaxed PE or MO (submaximal concentration) induced precontraction. Therapeutic plasma concentration of GTN relaxed 40-90% of the PE induced contraction (2.82 g, EC50 = 7.92 +/- 0.06 -log M) and 20-90% of the MO induced contraction (1.8 g, EC50 = 7.63 +/- 0.16 -log M). Pretreatment by the therapeutic plasma concentration of GTN inhibited the contraction induced by NA, PE in a different range. It reduced the NA induced contraction (6.9 g) by 14.8-38% (P greater than 0.05) and the PE induced contraction (4.3 g) by 7.9-39.3% (P greater than 0.05). The alpha 1-adrenoceptor antagonist prazosin, at the therapeutic plasma concentration, nearly totally abolished the NA or PE induced contraction (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
Triple therapy for advanced squamous cell cancer of the head and neck.
This study presents the results of treatment for Stage III and IV squamous cell carcinoma of the head and neck at the Princess Alexandra Hospital and Queensland Radium Institute, Brisbane. Patients were treated using a programme of sequential chemotherapy, surgery and radiotherapy. Between 1980 and 1988, 116 patients commenced the programme and 85 completed the treatment as planned. The Price-Hill regimen of chemotherapy was used until 1986 after which time it was replaced by cisplatin/5-fluorouracil (5FU). Two courses were usually given achieving an overall response rate of 36% (12% complete response). Cisplatin/5FU produced an overall response rate of 56% compared with 24% for the Price-Hill regimen. Radical surgical resections were performed using a free flap reconstruction in the majority of patients. Radiotherapy fields usually covered the primary site and both cervical lymph node areas to a dose of 50-60 Gy in 5-6 weeks. The lengthy treatment was generally well tolerated although there were two chemotherapy and two perioperative deaths. The overall actuarial survival for the 85 patients completing the triple therapy was 60%. These patients were analysed in more detail for possible prognostic factors.
Antineoplastic Combined Chemotherapy Protocols↗
A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam.
NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.
Adolescent↗
Heterogeneity of glutathione S-transferase isoenzyme expression in renal disease.
Recent work has suggested that glutathione S-transferase (GST) enzymuria may be used to assess renal injury in transplant kidneys. There is little work investigating the possibility of using glutathione S-transferase enzymuria to assess other renal diseases and this study was undertaken to evaluate the localisation of GST isoenzymes in various glomerular and tubular pathologies so that the specificity of these enzymes as markers of tubular injury could be defined. Immunostaining was carried out to establish the location of alpha and pi class GST in renal biopsies from patients with a wide variety of renal diseases including membranous glomerulonephritis, minimal-lesion glomerulonephritis, mesangial proliferative glomerulonephritis, loin pain haematuria syndrome, and renal allograft rejection. In the cases of glomerulonephritis studied, alpha class GST was detected in proximal tubules and pi class GST in distal convoluted tubules, podocytes, and Bowman's capsule. The majority of cases of glomerulonephritis showed a heterogeneous pattern of expression of both isoenzymes: that is, there was variation in intensity of staining both in single tubules and also between tubules as opposed to the uniform staining pattern observed in normal kidneys. The location of enzymes in the cases of glomerulonephritis was the same as that in normal kidneys and we were unable to demonstrate any de novo expression of GST isoenzymes. However, seven out of ten renal allograft biopsies showed expression of pi class GST in proximal tubules which were atrophic. Provided there is no significant tubular atrophy, urinary release of these enzymes may be used to localise renal tubular injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Midazolam and flumazenil: the agonist-antagonist concept for sedation and anaesthesia.
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Anesthesia, Intravenous↗
Effective salvage chemotherapy with etoposide, dactinomycin, and methotrexate in refractory germ cell cancer. Australasian Germ Cell Trial Group.
Fifty-one patients with advanced germ cell malignancy who had either failed to achieve complete remission with initial cisplatin, vinblastine, and bleomycin chemotherapy or who had relapsed after complete response (CR) to this therapy and then proven refractory on retreatment, were treated with etoposide (75 mg/m2 for 3 days), dactinomycin (1 mg/m2 day 1), and methotrexate (30 mg/m2 day 1) (EAM) every 3 weeks. Courses were continued until maximum response without empirical limit, and if complete remission was achieved, two courses of consolidation therapy were given before cessation of treatment. Thirteen patients (25%) were complete responders with residual masses containing fibrosis or benign teratoma being subsequently resected in seven patients. Two patients had persisting viable carcinoma within residual masses that were completely resected, leaving no evidence of disease (NED); the combined CR plus NED rate was 29%. The only pretreatment factor significantly influencing this response rate was tumor volume. Toxicities were moderate, with leukopenia being observed in 28% of patients, but it was severe in only 2%. There was one death from septicemia. Severe nausea and vomiting occurred in only 9% of patients and treatment-related stomatitis was observed in 42%. All patients achieving CR plus NED have been followed for a minimum of 5 years and no relapses have occurred, suggesting that these patients are cured. Unlike other regimens of salvage chemotherapy, this treatment program did not contain cisplatin and it is contended that a completely noncrossresistant drug regimen based on etoposide provides the opportunity to further improve the curability of patients with advanced germ cell cancer.
Antineoplastic Combined Chemotherapy Protocols↗
The bidirectional cavopulmonary shunt.
The bidirectional cavopulmonary shunt improves systemic arterial oxygen saturation without increasing ventricular work or pulmonary vascular resistance. Since 1983, 17 patients have undergone a cavopulmonary shunt procedure (five primary operations, 12 secondary operations). Diagnoses were single ventricle complex (n = 4), hypoplastic right heart syndrome (n = 10), and hypoplastic left ventricle (n = 3). Age at primary operation ranged from 3 1/2 to 30 months (median 6 months). Weight ranged from 3.5 to 9.7 kg. Age at secondary operation ranged from 10 months to 14 years (median 15 months). Seven cavopulmonary shunt operations were performed without cardiopulmonary bypass (six via thoracotomy and one via sternotomy) and 10, with cardiopulmonary bypass. All patients in the bypass group had additional procedures: takedown of modified Blalock-Taussig shunt, seven patients; revision of right ventricular outflow tract, four patients; reconstruction of pulmonary arteries, four patients; tricuspid valvuloplasty, one patient; and Damus procedure, one patient. There was one (1/17) operative death (Damus procedure). One patient required early revision. Follow-up ranges from 1 to 53 months (median 23 months). Twelve of 16 had a good to excellent late result, with a rise in mean arterial oxygen saturation from 69% to 83%. Three patients died late (4 to 53 months) (pulmonary vascular disease, pulmonary arteriovenous malformations, and pneumonia, one patient each). There was one late failure (converted to Glenn shunt). The cavopulmonary shunt is an excellent palliative procedure when right atrium-pulmonary artery connection (modified Fontan) must be deferred because of age, weight, or anatomic considerations. Five patients have undergone right atrium-pulmonary artery connection later. In addition, at the time of the modified Fontan operation, the cavopulmonary shunt approach may optimize the anatomic connection (eight additional patients).
Adolescent↗
Studies of the Australasian Germ Cell Trial Group: the management of advanced testis cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
The importance of age as a predictor of atrial fibrillation and flutter after coronary artery bypass grafting.
The purpose of this study was to identify factors associated with atrial fibrillation and flutter after coronary artery bypass grafting. The study group consisted of a consecutive series of 5807 patients who underwent coronary artery bypass grafting alone and who were in sinus rhythm preoperatively. Atrial fibrillation and flutter were identified during continuous monitoring or by clinical symptoms and signs; they occurred in 17.2% of the patients. The prevalence of atrial fibrillation and flutter was directly related to age at operation, varying from 3.7% in patients aged less than 40 years to 27.7% in patients aged 70 and over. In a multivariate analysis, age remained the most important independent predictor of atrial fibrillation and flutter (p less than 0.001). Other independent predictors of atrial fibrillation and flutter were chronic airflow limitation (p = 0.006), preoperative beta-adrenergic blockers (p = 0.011), and chronic renal failure (p = 0.04). Extent of coronary disease at catheterization, history of a previous myocardial infarction, heart size on chest x-ray film, and all operative factors measured, apart from year of operation, were unassociated with atrial fibrillation and flutter. Thus atrial arrhythmias after coronary artery bypass operations are most strongly related to advanced age and are unassociated with preoperative left ventricular function and extent of coronary disease.
Age Factors↗
[3H]MK-801 binding sites in neonate rat brain.
[3H]MK-801 binding sites are present in neonate rat brain as early as 3 days after birth. Immature hippocampus and cortex contain approximately one sixth the concentration of binding sites of the adult, while brainstem concentration is twice as high as that of adult. [3H]MK-801 binding is stimulated by glutamate and glycine and blocked by phencyclidine and Mg2+ both in 7-day-old neonate and adult, indicating that as early as 7 days postnatally, the N-methyl-D-aspartate-type glutamate receptor and MK-801 binding site are functionally coupled.
Animals↗