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Biomedical subjects

A Hassell

Publications and source records attributed to A Hassell.

At least 19 recordsLinked to original sources
PubMed2005

Competence-based assessment of specialist registrars: evaluation of a new assessment of out-patient consultations.

OBJECTIVE: To implement and evaluate formal assessment of the performance of West Midlands rheumatology specialist registrars (SpRs) in conducting out-patient consultations. METHODS: SpRs conducted a full out-patient clinic while being observed by one or two consultants who scored each SpR's performance on a structured pro forma. The assessment was conducted within the examining consultant's hospital trust (in which the SpR was not working). The process was evaluated by trainees and trainers by means of a questionnaire. RESULTS: Sixteen SpRs were assessed. No trainee failed to reach the required standard. Six trainees scored 'borderline' for management planning and four had a borderline performance recorded for examination skills. Overall the process was valued by trainers and trainees, although consensus was that it would be more practicable for the trainee to be examined within the hospital in which they were working by a visiting consultant examiner. It was also felt that a broader range of scoring options would be preferable. CONCLUSION: Formal assessment, by direct observation, of the skills of SpRs in conducting an out-patient clinic is practicable and offers information which is useful to trainer and trainee. A culture of direct observation of performance can be achieved within the context of rheumatology higher medical training.

Ambulatory Care↗
PubMed2005

Patients with stable long-standing rheumatoid arthritis continue to deteriorate despite intensified treatment with traditional disease modifying anti-rheumatic drugs--results of the British Rheumatoid Outcome Study Group randomized controlled clinical trial.

OBJECTIVE: Patients with rheumatoid arthritis (RA) should start treatment early with the aim of suppressing the inflammatory process completely. It is not known if this strategy should, or can, be continued in later disease. METHODS: In a multicentre, randomized, observer-blinded, controlled trial, 466 patients with established RA (>5 yr), on stable therapy for at least 6 months, were randomized to adequate symptom control/shared care setting (SCSC) or aggressive treatment/hospital setting (ATH). All were reviewed annually by a rheumatologist. The primary outcome after 3 yr was the Health Assessment Questionnaire (HAQ). Others included the OMERACT core set and the Disease Activity Score (DAS) 28. RESULTS: Three hundred and ninety-nine patients completed the trial. There was a significant deterioration in HAQ in both arms. Only the physician global score differed between the arms. CONCLUSIONS: The trial showed no additional benefit of intensified treatment with traditional disease modifying anti-rheumatic drugs (DMARDs) in patients with stable, established RA. It proved hard to suppress C-reactive protein levels. Patients in the SCSC arm were able to initiate treatment changes when their symptoms deteriorated without frequent hospital assessment. Pending further evidence, the model of shared care with annual hospital review is as good as 4-monthly hospital review for these patients.

Aged↗
PubMed2003

Control perceptions in patients with rheumatoid arthritis: the impact of the medical consultation.

OBJECTIVE: To identify factors that patients perceive as influencing control in living with the symptoms of rheumatoid arthritis (RA). METHOD: A sample of 40 patients with RA were recruited randomly from an out-patient population. The participants of the sample were interviewed in depth by one researcher to identify perceptions of control. They also completed two self-administered questionnaires, the Health Assessment Questionnaire and the Rheumatology Attitude Index. RESULTS: Four major categories were identified that positively influenced perceptions of control in patients living with the consequences of RA. These included: (i) the reduction of physical symptoms; (ii) social support matching perceived need; (iii) the provision of information; and (iv) the medical consultation. Components of the consultation included patient involvement, provision of information, feedback and reassurance, empathy and access to an expert. CONCLUSION: The categories identified can be influenced by health-care professionals in the management of the patient, and if the medical consultation is utilized to its full potential it can play a major role in enabling patients with RA to manage the daily symptoms of their condition.

Adult↗
PubMed2002

Teaching consultation skills in higher specialist training: experience of a workshop for specialist registrars in rheumatology.

OBJECTIVES: To design, implement and evaluate an initial communication skills workshop for higher specialist trainees in rheumatology, and to determine their prior experience of and attitude towards such training. METHODS: The setting for this study was a rheumatology specialist registrar study day in the West Midlands region of the UK. The workshop was jointly facilitated by a hospital specialist and a general practitioner educationist, providing both the credibility of subject expertise and experience of teaching consultation skills to groups of doctors. Simple, structured observations of pre-recorded consultations and simulations, based on scenarios from within the specialist field, were used. RESULTS: There was strong agreement amongst the trainees that the workshop was enjoyable and useful, that prior training and experience in this area was inadequate, and that it is feasible and important to develop the communication skills of hospital specialists. CONCLUSIONS: Undergraduate teaching in communication skills has been inadequate in the past and it receives little or no attention in most specialist training. There is a compelling argument for the inclusion of communication skills teaching in higher medical training within rheumatology. More work is required to research the optimum methods of delivering teaching in this area in a postgraduate setting, and to assess the impact of communication skills teaching on clinical practice.

Communication↗
PubMed2001

Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.

Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.

Antineoplastic Agents↗
PubMed2000

Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase.

4-Anilinoquinazolines represent an important class of protein kinase inhibitor. Modes of binding for two members of this inhibitor class were determined by X-ray crystallographic analysis of one inhibitor (4-[3-hydroxyanilino]-6,7-dimethoxyquinazoline) in complex with cyclin-dependent kinase 2 (CDK2) and the other (4-[3-methylsulfanylanilino]-6,7-dimethoxyquinazoline) in complex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoquinazoline was bound in the ATP site with the quinazoline ring system oriented along the peptide strand that links the two domains of the protein and with the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoline accepted a hydrogen bond from a backbone NH (CDK2, Leu-83; p38, Met-109) of the domain connector strand, and aromatic hydrogen atoms at C2 and C8 interacted with backbone carbonyl oxygen atoms of the peptide strand. The anilino group of the CDK2-bound compound was essentially coplanar with the quinazoline ring system and occupied a pocket between Lys-33 and Phe-80. For the p38-bound inhibitor, the anilino group was angled out of plane and was positioned between Lys-53 and Thr-106 in a manner similar to that observed for the aryl substituent of the pyridinylimidazole class of inhibitor.

Adenosine Triphosphate↗
PubMed1999

Lack of effect of erythromycin and ketoconazole on the pharmacokinetics and pharmacodynamics of steady-state intranasal levocabastine.

The single-dose effects of the cytochrome P-450 inhibitors erythromycin and ketoconazole on the steady-state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1-receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open-label, placebo-controlled, two-way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half-life was approximately 45 and 44 hours, respectively. In both studies, mean steady-state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P-450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P-450 system is minimal.

Administration, Intranasal↗
PubMed1997

Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA.

We investigated whether tumor necrosis factor (TNF) microsatellite polymorphisms are associated with sex and age at disease onset in rheumatoid arthritis (RA). A case-control study was used to compare the frequencies of TNF microsatellite alleles in 181 Caucasian RA cases and 251 controls. TNF microsatellite genotyping was performed using fluorescent based polymerase chain reaction (PCR) techniques and HLA-DR typing using PCR based sequence specific oligonucleotide probing. The association of TNF microsatellite alleles a6, b5, and d4 with RA was confirmed. These polymorphisms were more frequent in female patients. Male patients with RA with young age at onset had a different TNF microsatellite profile, TNFa2, b1, and c2 being the most frequent. TNF microsatellite polymorphisms are different in male and female patients with RA. This difference was more obvious in patients stratified according to age at onset. Sex and age at onset should be considered in studies of genetic factors in RA.

Adult↗
PubMed1994

Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome.

OBJECTIVE: To test the hypothesis that genetic characterization of patients at the time they present with inflammatory arthritis can predict subsequent destructive disease. METHODS: We evaluated 177 patients with early arthritis. Patients were serologically tested for rheumatoid factor (RF) and were DNA oligotyped for the presence of conserved base sequences in the third hypervariable region (HVR3) of the DRB1 gene, previously shown to be associated with severe rheumatoid arthritis (RA). Homozygosity in the patient's genotype was confirmed using restriction fragment length polymorphism analysis. The main outcome measure was radiologic erosions at 1 year. RESULTS: At presentation, 120 patients fulfilled the American College of Rheumatology 1987 criteria for RA, 64% of whom possessed the conserved base sequences, compared with 45% of 347 healthy controls (P < 0.001) and with 56% of 57 patients with other inflammatory arthritis (P not significant). Within the RA population, the frequency of Dw4/Dw14 compound heterozygotes was disproportionately increased. The presence of either HVR3 or RF had a relative risk of 13.49 for erosions, with a sensitivity of 95% (specificity 39%); the presence of both HVR3 and RF had a relative risk of 8.13, with a specificity of 88% (sensitivity 53%). All but 1 patient with the Dw4/Dw14 genotype developed erosions within 1 year. CONCLUSION: Knowledge of a patient's HLA-DR type and RF status allows clinically useful prediction of erosive disease; patients possessing Dw4/Dw14 represent a particularly high-risk subgroup.

Alleles↗
PubMed1994

Sulfate metabolism is abnormal in patients with rheumatoid arthritis. Confirmation by in vivo biochemical findings.

OBJECTIVE: To independently confirm previous probe drug findings that patients with rheumatoid arthritis (RA) have defective oxidation of cysteine derivatives. METHODS: Measurement of cysteine dioxygenase substrate (cysteine) and product (sulfate) under controlled conditions, with elemental assessment by proton induced x-ray emission (PIXE). RESULTS: Plasma inorganic sulfate was significantly depressed in patients with rheumatoid arthritis (RA) compared to both controls and non-RA disease, 85 +/- 36 nm/ml vs 267 +/- 146 and 604 +/- 412 (mean +/- SD. RA patients vs non-RA disease p < 0.001). Fasting cysteine levels were significantly raised compared to controls (59 +/- 20 nm/ml vs 17 +/- 81 nm/ml p < 0.001). Synovial fluid (SF) sulfate was also significantly reduced in patients with RA compared to non-RA controls (202 +/- 117 nm vs 1041 +/- 700 p < 0.001). PIXE data confirmed the low sulfate levels in serum and SF while showing no reduction in the levels of other elements analyzed. CONCLUSIONS: These cysteine/sulfate findings confirm the validity of the previous probe drug abnormalities and the importance of defective cysteine dioxygenase activity in RA.

Adult↗
PubMed1993

Responses to gram negative enteric bacterial antigens by synovial T cells from patients with juvenile chronic arthritis: recognition of heat shock protein HSP60.

OBJECTIVE: To investigate the antigenic specificity of synovial T cells in juvenile chronic arthritis (JCA). METHODS: Synovial fluid and peripheral blood mononuclear cells from 24 patients with JCA were tested for their proliferative responses to recall antigens, enteric organisms associated with reactive arthritis, influenza A and a recombinant preparation of a mycobacterial heat shock protein, HSP65. To investigate further recognition of this last antigen, synovial T cells from one B27+ patient with pauciarticular disease were cloned using HSP65. The specificity of the resultant clones was then examined. RESULTS: Marked synovial T cell responses to enteric organisms and to HSP65 were noted, particularly in HLA-B27+, pauciarticular patients; these were similar to those seen in a B27+ patient with reactive arthritis. Responses to enteric organisms and to HSP65 were significantly correlated, suggesting recognition of an epitope common to these antigen preparations. However, all of the T cell clones obtained using HSP65 proved to recognize E. coli derived antigens contaminating the recombinant HSP65 rather than the mycobacterial antigen; these contaminants included the 60 kDa E. coli HSP, GroEL. The GroEL specific T cells did not respond to heat shocked human cells; this suggests (but does not prove) that they do not crossreact with human HSP60. CONCLUSION: Synovial T cell recognition of antigens from enteric organisms associated with reactive arthritis is a common feature in pauciarticular JCA. Among the target antigens is the GroEL HSP, but T cells recognizing this antigen do not necessarily crossreact with the homologous human HSP60.

Antigens, Bacterial↗
PubMed1992

Proteolysis of an active site peptide of lactate dehydrogenase by human immunodeficiency virus type 1 protease.

The muscle and heart lactate dehydrogenase (LDHs) of rabbit and pig are specifically cleaved at a single position by HIV-1 protease, resulting in the conversion of 36-kDa subunits of the oligomeric enzymes into 21- and 15-kDa protein bands as analyzed by SDS-PAGE. While the proteolysis was observed at neutral pH, it became more pronounced at pH 6.0 and 5.0. The time courses of the cleavage of the 36-kDa subunits were commensurate with the time-dependent loss of both quaternary structure and enzymatic activity. These results demonstrated that deoligomerization of rabbit muscle LDH at acidic pH rendered its subunits more susceptible to proteolysis, suggesting that a partially denatured form of the enzyme was the actual substrate. Proteolytic cleavage of the rabbit muscle enzyme occurred at a decapeptide sequence, His-Gly-Trp-Ile-Leu*Gly-Glu-His-Gly-Asp (scissile bond denoted throughout by an asterisk), which constitutes a "strand-loop" element in the muscle and heart LDH structures and contains the active site histidyl residue His-193. The kinetic parameters Km, Vmax/KmEt, and Vmax/Et for rabbit muscle LDH and the synthetic decapeptide Ac-His-Gly-Trp-Ile-Leu*Gly-Glu-His-Gly-Asp-NH2 were nearly identical, suggesting that the decapeptide within the protein substrate is conformationally mobile, as would be expected for the peptide substrate in solution. Insertion of part of this decapeptide sequence into bacterial galactokinase likewise rendered this protein susceptible to proteolysis by HIV-1 protease, and site-directed mutagenesis of this peptide in galactokinase revealed that the Glu residue at the P2' was important to binding to HIV-1 protease. Crystallographic analysis of HIV-1 protease complexed with a tight-binding peptide analogue inhibitor derived from this decapeptide sequence revealed that the "strand-loop" structure of the protein substrate must adopt a beta-sheet structure upon binding to the protease. The Glu residue in the P2' position of the inhibitor likely forms hydrogen-bonding interactions with both the alpha-amide and gamma-carboxylic groups of Asp-30 in the substrate binding site.

Amino Acid Sequence↗
PubMed1991

Peripheral nerve dysfunction in scleroderma.

Peripheral neuropathy in patients with scleroderma is thought to be rare. We have undertaken a quantitative assessment of peripheral nerve function in 29 patients with either limited cutaneous scleroderma or progressive systemic sclerosis. Tactile thresholds were raised in the fingers in 28 per cent of patients and in the foot in 50 per cent. Two-point discrimination was abnormal in 10 patients, thermal thresholds were abnormal in five and vibration thresholds were abnormal in one. Nerve conduction studies showed abnormalities in six patients, five of whom had clinical signs of a mild peripheral neuropathy: the mean duration of disease in these six patients was 10 years longer than that in the remainder of the patients. There was electrophysiological evidence of a subclinical carpal tunnel syndrome in two patients. The sympathetic skin response was recorded in 16 patients who had not been subjected to sympathectomy for Raynaud's phenomenon, and was abnormal in four. These results indicate that peripheral nerve dysfunction in scleroderma, though mild, is not as uncommon as previously thought. The abnormal cutaneous sensory thresholds may be partly due to altered viscoelastic properties of the skin, but abnormal responses in the lower limbs to tests of tactile sensitivity, the clinical findings and the disturbances of nerve conduction argue in favour of an additional neuropathic process in some patients. Low grade distal nerve trunk ischaemia may be responsible.

Adult↗
PubMed1991

Increased circulating levels of bromocriptine after vaginal compared with oral administration.

OBJECTIVE: To compare the circulating levels of bromocriptine after oral and vaginal administration of the drug. DESIGN: Experimental PARTICIPANTS: Seven ovulatory female volunteers and one hyperprolactinemic patient. INTERVENTIONS: Ovulatory volunteers were randomized to receive either oral or vaginal bromocriptine (2.5 mg). In a second session, the subjects were crossed-over to bromocriptine by the alternate route. An additional hyperprolactinemic patient received vaginal bromocriptine only. MAIN OUTCOME MEASURE: Serum bromocriptine and prolactin (PRL) levels were measured hourly for 12 hours in the normal volunteers and for 10 hours in the hyperprolactinemic patient. RESULTS: Circulating bromocriptine levels were significantly higher after vaginal bromocriptine after the 7th hour (P less than 0.05). The reduction in serum PRL was significantly greater after oral administration between 2 and 6 hours. CONCLUSIONS: Vaginally administered bromocriptine may result in a reduction in the overall dose required, thereby improving compliance without compromising therapeutic efficacy.

Administration, Oral↗