Mucosal receptors and T- and B-cell immunity.
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Animals↗
Biomedical subjects
E Mitchell
Publications and source records attributed to E Mitchell.
Communicating the diagnosis of motor neurone disease.
Communication of the diagnosis of motor neurone disease (MND) is a particularly difficult task for doctors in view of the poor prognosis and the lack of significant treatment. This study examined patients' views of being given the diagnosis and of how it was communicated. Fifty people who had been diagnosed with MND more than six months previously were interviewed about their experience of the diagnosis. The majority reported positive aspects of being told, especially having a label for their condition. The most frequently mentioned critical aspect of how they were told was the directness and clarity with which they were given the information. Patients were more critical if the diagnosis was worse than expected (as it was for most patients) and more satisfied if they felt they had been able to ask questions. There was no evidence that unsatisfactory communications were associated with later mood disturbance. A longitudinal study is recommended to overcome limitations in this cross-sectional design.
Adaptation, Psychological↗
Identification and cloning in yeast artificial chromosomes of a region of elevated loss of heterozygosity on chromosome 1p31.1 in human breast cancer.
We have mapped a region of high loss of heterozygosity in breast cancer to a 2-cM interval between the loci D1S430 and D1S465 on chromosome 1p31.1. This region shows allelic imbalance in around 60% of breast tumors. As part of a strategy to clone the target gene(s) within this interval, we have generated a yeast artificial chromosome contig spanning over 7 Mb. YACs from the CEPH and Zeneca (formerly ICI) libraries have been obtained by screening with PCR-based STSs from the region for both previously identified loci and newly isolated STSs. The YACs have been assembled into a contig by a combination of approaches, including analysis of their STS content, generation of new STSs from the ends of key YACs, and long-range restriction mapping. These YAC clones provide the basis for complete characterization of the region of high loss in breast cancer and for the ultimate identification of the target gene(s).
Base Sequence↗
The crystal structure of cyclin A.
BACKGROUND: Eukaryotic cell cycle progression is regulated by cyclin dependent protein kinases (CDKs) whose activity is regulated by association with cyclins and by reversible phosphorylation. Cyclins also determine the subcellular location and substrate specificity of CDKs. Cyclins exhibit diverse sequences but all share homology over a region of approximately 100 amino acids, termed the cyclin box. From the determination of the structure of cyclin A, together with results from biochemical and genetic analyses, we can identify which parts of the cyclin molecular may contribute to cyclin A structure and function. RESULTS: We have solved the crystal structure, at 2.0 A resolution, of an active recombinant fragment of bovine cyclin A, cyclin A-3, corresponding to residues 171-432 of human cyclin A. The cyclin box has an alpha-helical fold comprising five alpha helices. This fold is repeated in the C-terminal region, although this region shares negligible sequence similarity with the cyclin box. CONCLUSIONS: Analysis of residues that are conserved throughout the A, B, and E cyclins identifies two exposed clusters of residues, one of which has recently been shown to be involved in the association with human CDK2. The second cluster may identify another site of cyclin A-protein interaction. Comparison of the structure of the unbound cyclin with the structure of cyclin A complexed with CDK2 reveals that cyclin A does not undergo any significant conformational changes on complex formation. Threading analysis shows that the cyclin-box fold is consistent with the sequences of the transcription factor TFIIB and other functionally related proteins. The structural results indicate a role for the cyclin-box fold both as a template for the cyclin family and as a generalised adaptor molecule in the regulation of transcription.
Algorithms↗
Has general practitioner computing made a difference to patient care? A systematic review of published reports.
OBJECTIVE: To review findings from studies of the influence of desktop computers on primary care consultations. DESIGN: Systematic review of world reports from 1984 to 1994. SETTING: The computerised catalogues of Medline, BIDS, and GPlit were searched, as well as conference proceedings, books, bibliographies, and references in books and journal articles. SUBJECTS: 30 papers met the inclusion criteria and were included for detailed review. INTERVENTIONS: A validated scheme for assessing methodological adequacy was used to score each paper. MAIN OUTCOME MEASURES: Papers were rated on sample formation, baseline differences, unit of allocation, outcome measures, and follow up. Differences in outcomes were also recorded. RESULTS: Four of the six papers dealing with the consultation process showed that consultations took longer. Doctor initiated and "medical" content of consultations increased at the expense of a reduction in patient initiated and "social" content. Each of the 21 studies which looked at clinician performance showed an improvement when a computer was used (from 8% to 50%, with better results for single preventive measures). Only one of the three studies looking at patient outcomes showed an improvement (diastolic blood pressure control 5 mm Hg better after one year, with fewer doctor-patient consultations). CONCLUSIONS: Using a computer in the consultation may help improve clinician performance but may increase the length of the consultation. More studies are needed to assess the effects on patient outcomes of using a computer in consultations.
Ambulatory Care Information Systems↗
Establishment of the marker order pter-NRAS-NGFB-D1S189-D1S252-D1S440-D1S453-D1S514-CEN-D1S442-D1S498-qte r in relation to the centromere on human chromosome 1.
Recent developments in genetic linkage mapping of the human genome have generated a large number of short tandem repeat polymorphic markers (Weissenbach et al. 1992, Gyapay et al. 1994), and eventual integration of these markers into a physical map is a logical progression. A number of Généthon microsatellite (CA repeat) markers have been provisionally localized to 1p13, but their exact position with respect to other sequences is unknown. In order to confirm the order of these markers and their position with respect to known genes within 1p13 and the centromere, we have isolated yeast artificial chromosomes (YACs) corresponding to the markers and have carried out double and triple fluorescence in situ hybridization (FISH) studies. Knowledge of both the order of microsatellite markers and their integration with a physical map of known genes can be an essential component in analysis of disease loci such as human cancer, where regions of chromosomes showing high levels of loss of heterozygosity need to be mapped in detail.
Centromere↗
A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration.
BACKGROUND: Mutations in the peripherin/retinal degeneration slow (RDS) gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation. METHODS: DNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods. RESULTS: A proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism. CONCLUSIONS: The authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant retinal degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.
Adolescent↗
Role of Bud3p in producing the axial budding pattern of yeast.
Yeast cells can select bud sites in either of two distinct spatial patterns. a cells and alpha cells typically bud in an axial pattern, in which both mother and daughter cells form new buds adjacent to the preceding division site. In contrast, a/alpha cells typically bud in a bipolar pattern, in which new buds can form at either pole of the cell. The BUD3 gene is specifically required for the axial pattern of budding: mutations of BUD3 (including a deletion) affect the axial pattern but not the bipolar pattern. The sequence of BUD3 predicts a product (Bud3p) of 1635 amino acids with no strong or instructive similarities to previously known proteins. However, immunofluorescence localization of Bud3p has revealed that it assembles in an apparent double ring encircling the mother-bud neck shortly after the mitotic spindle forms. The Bud3p structure at the neck persists until cytokinesis, when it splits to yield a single ring of Bud3p marking the division site on each of the two progeny cells. These single rings remain for much of the ensuing unbudded phase and then disassemble. The Bud3p rings are indistinguishable from those of the neck filament-associated proteins (Cdc3p, Cdc10p, Cdc11p, and Cdc12p), except that the latter proteins assemble before bud emergence and remain in place for the duration of the cell cycle. Upon shift of a temperature-sensitive cdc12 mutant to restrictive temperature, localization of both Bud3p and the neck filament-associated proteins is rapidly lost. In addition, a haploid cdc11 mutant loses its axial-budding pattern upon shift to restrictive temperature. Taken together, the data suggest that Bud3p and the neck filaments are linked in a cycle in which each controls the position of the other's assembly: Bud3p assembles onto the neck filaments in one cell cycle to mark the site for axial budding (including assembly of the new ring of neck filaments) in the next cell cycle. As the expression and localization of Bud3p are similar in a, alpha, and a/alpha cells, additional regulation must exist such that Bud3p restricts the position of bud formation in a and alpha cells but not in a/alpha cells.
Amino Acid Sequence↗
Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3.
The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.
Base Sequence↗
Generation of diversity in the hierarchy of T-cell epitope responses following different routes of immunization with simian immunodeficiency virus protein.
OBJECTIVES: To examine whether the route of immunization determines the hierarchy of T-cell epitope proliferative responses in macaques. DESIGN: Macaques were immunized with a recombinant simian immunodeficiency virus (SIV) p27 core protein by the intramuscular, male and female genital or rectal route, each of which was augmented by oral immunization, and by the novel targeted lymph-node immunization route. Overlapping peptides were used to identify the proliferative T-cell epitopes and to determine their hierarchy in the circulation, spleen and lymph nodes. METHODS: T-cell epitope mapping of the proliferative responses was studied in short-term cell lines. Dendritic cells and macrophages were enriched by metrizamide gradient and adherence to plastic, respectively. RESULTS: Intramuscular immunization elicited in the circulating T cells a hierarchy of T-cell epitopes within four peptides in the following descending order of frequency: peptides 121-140 (57.9%), 41-60 (28.9%), 61-80 (18.9%) and 101-120 (5.4%). The hierarchy of these four T-cell epitope responses differed significantly with each of the five routes of immunization, when circulating (P < 0.001), splenic (P < 0.02-< 0.001) or iliac lymph-node cells (P < 0.001) were analysed. The effect of antigen-presenting cells was then investigated and enriched dendritic cells were more effective than macrophages in processing and presenting the p27 antigen and the immunodominant (121-140) and 61-80 T-cell epitopes. CONCLUSIONS: The route of immunization may determine the hierarchy of T-cell epitopes in the lymph nodes draining the mucosa in the circulating and splenic lymphocytes. The diversity of T-cell epitopes may affect the control of HIV at different anatomical sites, the administration route of the vaccine, and selection of polypeptides or recombinant antigens for immunization.
Animals↗
Peak expiratory flow meters (PEFMs)--who uses them and how and does education affect the pattern of utilisation?
BACKGROUND: Asthma control may be assisted by educating patients to use peak expiratory flow meters (PEFMs). AIMS: To find out the sociodemographic and clinical characteristics of asthmatics attending an Emergency Room (ER) who owned PEFMs. METHODS: We undertook a study of 352 asthmatics aged seven to 55 years who attended an ER. The following were analysed: their pattern of peak flow monitoring (PFM), the factors associated with 'appropriate' or daily PFM on entry to the study and then prospectively; whether asthma education influenced utilisation and whether there was a reduction in ER use or admissions in those who acquired a PEFM. RESULTS: Those owning a PEFM at entry to the study (54%) had more asthma morbidity (p = 0.0001), had had asthma for longer (p = 0.0001), had seen their medical practitioners more often in the previous nine months (p = 0.0001), were on more asthma medications (p = 0.0001) and were more likely to have been to an Asthma Clinic (p = 0.0001). Those not owning a PEFM were more likely to be of lower social class (p = 0.016) and of Pacific Island origin (p = 0.0001) suggesting that distribution is not ideal and is influenced by disease severity, amount of health care use and sociodemographics. Patients with a self-management plan (35% of PEFM owners) and those receiving 'good care' or management, were more likely to use PFM 'appropriately' and to mention PFM in a scenario evaluating their response to worsening asthma control and argues for PEFMs to be distributed only in conjunction with a self-management plan, and therefore in close association with the patients' medical practitioners. Most patients (75%) appeared to prefer making management decisions based on symptoms rather than on their peak expiratory flow (PEF) and few (16%) performed daily PFM at entry to the study and fewer (6%) nine months later. There was an improvement in the pattern of PFM after education, but the acquisition of a PEFM made no difference to the frequency of ER use or admission. CONCLUSION: More realistic goals need to be defined in relationship to PFM which may improve patients' acceptance of the strategy, and therefore, hopefully their compliance. Such strategies need to be consistently reinforced over time for them to have an impact on asthma morbidity.
Adolescent↗
Prospective controlled evaluation of the effect of a community based asthma education centre in a multiracial working class neighbourhood.
BACKGROUND: Previous work has indicated a high rate of non-attendance at hospital based clinics among young, multiracial asthmatic patients of lower socioeconomic class. The efficacy of delivering asthma education from a community health centre established in a multiracial working class neighbourhood was evaluated. METHODS: A prospective controlled study was performed in which asthmatic subjects aged between two and 55 years attending a hospital emergency room with acute asthma and living within a defined geographical area of high emergency room users were randomised to the usual follow up or the education centre plus usual follow up. Measurements were taken at entry into the study and again nine months later. RESULTS: At nine months patients randomised to the education centre had more preventive medications, more peak expiratory flow meters and better flow meter technique, more self-management plans, better knowledge of appropriate action to take when confronted with worsening asthma, less nocturnal awakening, and better self-reported asthma control than the control group. There was no difference between the study groups in measurements of compliance, hospital admission, days lost from school or work, or emergency room use. CONCLUSIONS: The main effects of education were on asthma knowledge and self-management skills, whilst improvements in asthma morbidity were small. Potential reasons for this include heterogeneous study population (in terms of baseline self-management skills, asthma severity, ethnicity and age), pragmatic study design, insensitivity of many of the measurements of morbidity, the modest effectiveness of a single time limited education programme, and inability to limit the effects of such a large community based study to the intervention group (there was a 67% reduction in asthma admissions during the study period from the geographical area targeted compared with a 22% reduction for the rest of Auckland).
Adolescent↗
A prospective reevaluation of transient ischemic attacks as a risk factor for death and fatal or nonfatal cardiovascular events.
BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) is generally considered a risk factor for death and cardiovascular events. This assumption is based on comparisons of the survival of the TIA population with that of the general population. Such comparisons may provide biased estimates of the risk associated with TIA because the general population is usually more healthy than TIA patients. METHODS: Using a prospective case-control study design, we report the comparison of a TIA population (n = 280) and a control group (n = 399) with a comparable cardiovascular risk factor burden. Proportional hazards analysis was used to compare survival time and time to fatal or nonfatal stroke and/or myocardial infarction for the two study groups. Comparisons were made without adjustment for risk factors and after adjustment for age, race, sex, and major cardiovascular risk factors. RESULTS: Before adjustment for age-race-sex or risk factors, TIA proved to be a risk factor for early mortality, stroke, and myocardial infarction (P < .05). Adjustment for age-race-sex disparities between the case and control groups explained much of the differences in mortality, as the hazard ratio was reduced from 2.2 to 1.4. However, adjustment for age-race-sex or age-race-sex and risk factors did not markedly reduce the role of TIA as a risk factor for stroke or myocardial infarction. CONCLUSIONS: Although TIA proved to be a risk factor for stroke or myocardial infarction, it apparently plays a smaller role in the risk of death.
Age Factors↗
Piccadilly Circus legionnaires' disease outbreak.
BACKGROUND: An outbreak of legionnaires' disease occurred in central London in January and February 1989. An Infection Control Committee was established to investigate the outbreak and institute control measures. The objective of this paper is to describe the investigation and control of the outbreak. METHODS: An epidemiological survey and case-control study were carried out. The subjects were cases of community acquired pneumonia associated with central London with onset of illness in January and February 1989. RESULTS: Thirty-three confirmed cases, including five deaths, and ten suspected cases, including three deaths, were identified with dates of onset from 1 January to 11 February. A clustering of visits by cases to the vicinity of Piccadilly Circus was noted, and a case-control study demonstrated a strong association between illness and visits to this area in the two weeks before onset of symptoms. The causative organism, Legionella pneumophila serogroup 1, was isolated from six patients. Legionella pneumophila of the same serogroup was isolated from water samples from five wet cooling systems (cooling towers) in the area under investigation, but in only two systems was the organism indistinguishable by subtyping from the patients' strains. Many of the cooling towers examined were inadequately maintained, including one of the two above a building adjacent to Piccadilly Circus from which a strain indistinguishable from the outbreak strain was isolated. All cooling towers in the area were shut down until inspected, and only allowed to restart after appropriate maintenance had been instigated. CONCLUSIONS: This outbreak showed the continuing risk of legionnaires' disease posed by wet cooling systems, including cooling towers, and highlighted the need to assess this risk so that appropriate maintenance is carried out. Regulations have recently been introduced, under the Health and Safety at Work Act, requiring notification of all wet cooling systems to the local authority to facilitate the investigation of outbreaks of legionnaires' disease.
Adolescent↗
A large outbreak of human salmonellosis traced to a local pig farm.
An outbreak of Salmonella typhimurium definitive type (DT) 193 affecting 206 persons occurred in July and August 1989 in a small town in northern England. A descriptive study suggested that cold meats including pork from a butcher's shop in the town were vehicles of infection. An analytical study of a cohort attending a function in the town showed a significant association between illness and consumption of cold roast pork supplied by the butcher's shop (P = 0.00000004). S. typhimurium DT 193 with the same antibiotic resistance pattern (to ampicillin, streptomycin, sulphonamides and tetracyclines) as the outbreak strain, and possessing a single plasmid of 80 MDa was isolated from samples of meat bought from the shop and implicated in illness, and from samples of pig faeces taken from the farm supplying the shop. It was concluded that inadequate processing of infected pork meat at the shop may have contributed to this outbreak but that cross contamination also played an important part in transmission. Control measures included a temporary closure of the shop and subsequent implementation of a detailed protocol for meat processing and monitoring of all procedures at the shop.
Adolescent↗
Coping with motor neurone disease--an analysis using self-regulation theory.
Medicine and environmental changes have had tremendous success in controlling the infectious diseases that were the major causes of death in the last century. However, the consequential extension of life has been accompanied by an increase in the number of persons living with and dying of chronic illness. Despite these changes and their implications, the means by which people cope with such illnesses has only recently begun to receive the attention the subject warrants. Such diseases have a high prevalence in the population and self-detection and self-management are critical to the treatment and control of chronic disease and disability. This paper examines how people cope with motor neurone disease and sets this in the context of earlier research on psychological aspects of chronic disease and current theoretical approaches to coping with long-term ill health.
Adaptation, Psychological↗
Detection of thyrotropin binding inhibitory activity in neonatal blood spots.
Recent studies have suggested that maternal TSH receptor-blocking antibodies might be of primary etiological importance in some cases of transient congenital hypothyroidism (CH). Because these antibodies are extremely potent, we evaluated the feasibility of identifying babies at risk by using readily available newborn blood spots. Blood spots obtained from 84 normal babies (group 1) and from 354 infants whose initial T4 was less than the tenth percentile for the assay and whose TSH was 40 mU/L or more (group 2) were studied without knowledge of the diagnosis. Blood was eluted from spots overnight and evaluated for [125I]TSH binding inhibition (TBI) to solubilized porcine thyroid membranes. Four spots obtained from 3 group 2 babies, but none of those from the group 1 infants, exhibited TBI activity greater than 3 SD above the normal mean (33.9%). Four additional hypothyroxinemic infants whose mothers had Graves' disease were also negative. Subsequent follow-up revealed that all 3 positive babies had transient CH, and all 3 mothers had primary myxedema. Potent TBI activity was confirmed in the serum of all 3 mothers and in the 2 babies in whom it was evaluated at birth. We conclude that newborn blood spots can be used to detect potent maternal TBI activity, and that this identifies a baby likely to have transient, rather than permanent, CH. Because of their stability and ease of collection and handling, newborn blood spots should offer a convenient tool for future studies aimed at defining in more detail the incidence and clinical characteristics of this unique syndrome.
Autoantibodies↗
An outbreak of Salmonella dublin infection in England and Wales associated with a soft unpasteurized cows' milk cheese.
An outbreak of Salmonella dublin infection occurred in England and Wales in October to December 1989. Forty-two people were affected, mainly adults, and most lived in south-east England. Microbiological and epidemiological investigations implicated an imported Irish soft unpasteurized cows' milk cheese as the vehicle of infection. A case-control study showed a statistically significant association between infection and consumption of the suspect cheese (p = 0.001). Salmonella dublin was subsequently isolated from cheeses obtained from the manufacturer's premises. Initial control measures included the withdrawal of the cheese from retail sale and a Food Hazard Warning to Environmental Health Departments, as well as a press release, from the Department of Health. Subsequently, a decision was taken by the manufacturer to pasteurize milk used in the production of cheese for the UK market and importation of the cheese resumed in June 1990.
Adolescent↗