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Biomedical subjects

J Brown

Publications and source records attributed to J Brown.

At least 199 records · Page 11Linked to original sources
PubMed2000

Signature-tagged and directed mutagenesis identify PABA synthetase as essential for Aspergillus fumigatus pathogenicity.

Signature-tagged mutagenesis (STM) is a method that has been used to screen for genes required for in vivo survival of pathogenic bacteria, but has not been used to investigate a eukaryotic pathogen in an animal model of disease. We have adapted STM to identify genes required for in vivo growth of the opportunistic fungal pathogen Aspergillus fumigatus. Using a mouse model of invasive pulmonary aspergillosis, we have isolated several mutant strains with defects in their ability to replicate in vivo. One strain unable to cause lethal infection was further characterized and found to have an insertion into the promoter of a gene (pabaA) encoding para-aminobenzoic acid synthetase, an enzyme catalyzing a late step in the biosynthesis of folate. The complete inability of this strain, and other pabaA- strains constructed in this study by targeted gene deletion, to cause lethal infection in mice confirms the importance of the folate synthesis pathway for in vivo survival of this pathogen. The successful application of STM to A. fumigatus demonstrates that in vivo genetic analysis of eukaryotic pathogens is feasible and could result in the identification of potential targets, such as para-aminobenzoic acid synthetase, for novel antifungal therapies.

Animals↗
PubMed2000

Rationale for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study.

Journal Article↗
PubMed2000

Protocol for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

Journal Article↗
PubMed2000

Heparinless partial cardiopulmonary bypass for the repair of aortic trauma.

OBJECTIVE: We hypothesized that partial cardiopulmonary bypass with a heparin-bonded system would be a technically simple, effective adjunct for reducing paraplegia during repair of traumatic aortic rupture. It avoids the risk of heparin, but, unlike left atrial-arterial bypass, it can heat, cool, oxygenate, and rapidly infuse volume if needed. METHODS: A retrospective review was conducted of patients admitted for aortic trauma from July 1994 to December 1999. Bypass consisted of femoral venous (right atrial) cannulation, a centrifugal pump, and an oxygenator-heater/cooler. Arterial return was to the femoral artery or distal aorta. The entire system was heparin-bonded and no systemic heparin was given. RESULTS: Heparin-bonded partial bypass was established in 50 patients (mean age 43 +/- 17 years). Crossclamp time was 32 +/- 11 minutes (range 14-70 minutes), mean flow 3.0 +/- 0.8 L/min, and bypass time 64 +/- 43 minutes. During repair, 58% of patients received volume through the system (mean 1.1 +/- 1.9 L). Core temperature rose slightly (35.9 degrees C +/- 0.7 degrees C to 36.3 degrees C +/- 0.8 degrees C). Three of the 15 patients who underwent percutaneous femoral arterial and venous cannulation concomitant with their angiograms had vessel injury, with one limb loss, and this procedure was discontinued. Thirty-five patients underwent percutaneous femoral vein and direct distal aortic cannulation without event. The mortality rate for patients supported by bypass was 10%, and all deaths were due to other injuries. There were no new cases of paraplegia and no worsening of intracranial or pulmonary injuries. CONCLUSIONS: Heparin-bonded bypass is technically simple to use and avoids the risk of anticoagulation. Paraplegia was avoided. The ability to correct hypothermia, oxygenate, and rapidly infuse volume may simplify management and improve outcomes.

Adult↗
PubMed2000

A functional map of cervical metastases from oral squamous cell carcinoma.

A visual summary of underlying patterns in metastases from oral squamous cell carcinoma (SCC) was created by the mathematical technique of multidimensional scaling (MDS). MDS creates a "functional" map of the neck, such that adjacent sites share similar probabilities of disease. We mapped the metastases from 130 sequential cases of oral SCC in the UK. Binary Euclidean distances were calculated from tallies of metastases at all possible pairs of neck levels (I-V on each side) for each of seven different primary sites: buccal mucosa, lower alveolus, floor of mouth, ventral tongue/floor of mouth, lateral tongue, retromolar trigone, and oropharynx. A two-dimensional functional map of the neck was made from these distances. The map explains 82% of the input data (p < 0.01). This is the first functional mapping of neck levels. The technique can now be used to summarize and compare patterns of metastases in different populations.

Carcinoma, Squamous Cell↗
PubMed2000

Motor block during patient-controlled epidural analgesia with ropivacaine or ropivacaine/fentanyl after intrathecal bupivacaine for caesarean section.

We compared patient-controlled epidural analgesia (PCEA) with ropivacaine alone or combined with fentanyl in terms of analgesic efficacy, motor weakness and side-effects in patients who had received spinal anaesthesia for elective Caesarean section. ASA I patients received combined spinal-epidural anaesthesia and were randomly assigned, in a double-blind study, into two groups after operation: group R (n = 23) received PCEA ropivacaine 0.1%, bolus 5 mg, lock-out 15 min, 3 mg h-1 background infusion, and group RF (n = 24) received PCEA 0.1% ropivacaine/fentanyl 2 micrograms ml-1 at identical settings. Pain and satisfaction on a 100 mm visual analogue scale (VAS) and side-effects were noted. Incidence of motor weakness (Bromage grade 1 or higher) was 48% (11/23) at 8 h in group R compared with 13% (3/24) in group RF (P = 0.025). Pain scores on movement were lower in group RF at 8 and 12 h and at rest at 6 and 8 h (P < 0.05 for each comparison). Analgesic consumption was less in RF (P = 0.041), but there was no difference in time to first request for supplementary analgesia. Patient satisfaction with postoperative analgesia (mean (SD)) was higher in RF (79 (23) vs 57 (29) mm, P = 0.045). Caution should be exercised using ropivacaine PCEA after spinal bupivacaine for Caesarean section, because its reputed motor-sparing property may be unreliable.

Adult↗
PubMed2000

A B220(-), CD19(-) population of B cells in the peripheral blood of quasimonoclonal mice.

We describe a new population of non-naive B cells in the peripheral blood of quasimonoclonal (QM) mice. Surface Ig of switched isotypes is expressed, but not B220 nor CD19. These cells are larger and denser than naive B cells but smaller than blasts or plasma cells; they do not stain with syndecan, a marker for plasma cells. Telomerase, which is usually expressed in B cell blasts, was not present in this population. We sorted the switched, idiotype-positive, B220(-) B cells from the peripheral blood of QM mice and sequenced Ig H chain and lambda L chain cDNA. There were many point mutations but no V gene replacements, gene conversions or other type of diversifications. As they express switched isotypes and have mutated their Ig genes, cells in the B220(-), CD19(-) population must have been in an immune response and we suggest that it includes the memory B cell subset.

Amino Acid Sequence↗
PubMed2000

The effects of neonatal screening for sickle cell disorders on lifetime treatment costs and early deaths avoided: a modelling approach.

BACKGROUND: The aim of the study was to calculate the cost to the UK National Health Service of providing treatment services for patients with sickle cell disorders. The rates of differential morbidity and mortality, in the first 10 years of life, between screen-detected early diagnosed and clinically presenting late diagnosed cohorts of sickle cell disorder patients are also estimated. METHOD: A cost model was developed, based on predictions of survival and the incidence of sickle cell disorder-related events. Direct data from the NHS are lacking, so data were incorporated from disparate sources. Patients with sickle cell disorders were divided into two categories: those with sickle cell anaemia and those with sickle HbC disease. RESULTS: Differentiating between sickle cell anaemia and sickle HbC disorder patients, the results show that the undiscounted (discounted at 6 per cent) lifetime treatment costs range from pound sterling 92323 (pound sterling 24917) to pound sterling 185614 (pound sterling 53861). The number of early deaths avoided per 100 births, as a result of early diagnosis through screening, ranges from 0.57 to 1.25. CONCLUSIONS: The resulting estimates may act as a guide to those involved in the planning of health care provision with regard to the resources required to treat sickle cell disorder patients. Such information may also be incorporated into the evaluation of both antenatal and neonatal screening programmes for sickle cell disorders.

Adolescent↗
PubMed2000

Effect of reserpine treatment on low-density lipoproteins in arterial wall and internal organs of rats.

The effects were determined in rats of single injections of reserpine at increasing doses (0.5, 1.58, and 5.0 mg/kg) on low-density lipoprotein (LDL) and cholesterol in aortic wall, heart, liver, kidney, and adrenal gland. Catecholamine levels in plasma, heart, and liver, arterial blood pressure, and heart rate were also monitored. Reserpine was injected intraperitoneally, followed immediately by the administration of [3H]cholesterol by gavage. Twelve hours later, homologous 125I-tyramine cellobiose-labeled LDL (125I-TC-LDL) was injected intravenously. Twenty-four hours later, the rats were killed, and the radioactivities of aortic walls, heart, liver, kidney, and adrenal glands were determined. The results showed that after reserpine treatment the accumulation of both the 125I-TC label derived from LDL and total [3H]cholesterol was significantly reduced in aortic wall and heart, increased in liver, and unchanged in the kidney and adrenal gland. At higher doses (1.58 and 5.0 mg/kg), reserpine significantly accelerated the plasma clearance of radiolabelled LDL. Plasma noradrenaline in reserpine-treated animals decreased maximally (86%) by 12 h and by 61-71% at 36 h compared with the control. Plasma adrenaline increased transiently after injection of reserpine and then returned to the basal levels. Reserpine greatly decreased noradrenaline and adrenaline levels in heart and liver. Arterial blood pressure was decreased significantly (0.001 < p < 0.05) at 12 h by the two lower doses of reserpine and then returned to normal values over the next 24 h. The results indicate that reserpine decreases LDL cholesterol in artery wall and heart and increases it in liver. These findings suggest that reserpine could find a new use as a cholesterol-lowering drug for the prevention of atherosclerosis.

Adrenal Glands↗
PubMed2000

National estimates of HIV-related symptom prevalence from the HIV Cost and Services Utilization Study.

OBJECTIVES: The objectives of this study were (1) to estimate the prevalence, bothersomeness, and variation of HIV-related symptoms in a nationally representative sample of HIV-infected adults receiving medical care and (2) to evaluate new aggregate measures of symptom frequency and bothersomeness. METHODS: Beginning in January 1996, 76% of a multistage national probability sample of 4,042 HIV-infected adults receiving medical care were interviewed. Participants endorsed the presence and degree of bothersomeness of 14 HIV-related symptoms during the preceding 6 months. Sex-standardized symptom number and bothersomeness indices were constructed. After sampling weights were incorporated, symptom distributions were compared according to selected characteristics by analysis of variance and multiple linear regression modeling. RESULTS: Prevalence of specific symptoms in the reference population was as follows: fever/night sweats, 51.1%; diarrhea, 51%; nausea/anorexia, 49.8%; dysesthesias, 48.9%; severe headache, 39.3%; weight loss, 37.1%; vaginal symptoms, 35.6% of women; sinus symptoms, 34.8%; eye trouble, 32.4%; cough/dyspnea, 30.4%; thrush, 27.3%; rash, 24.3%; oral pain, 24.1%; and Kaposi's sarcoma, 4%. Aggregate measures were reliable (Cronbach's alpha > or =0.75) and demonstrated construct validity when compared with other measures of disease severity. After adjustment for CD4 count, both symptom number and bothersomeness varied significantly (P <0.05) by teaching status of care setting, exposure/risk group, educational achievement, sex, annual income, employment, and insurance category. However, the magnitude of variation was small. Symptoms were greatest in women and injection drug users, as well as in persons with lower educational levels, lower income, and Medicare enrollment or those who were followed up at teaching hospitals. CONCLUSIONS: The prevalence and bothersomeness of HIV-related symptoms are substantial and vary by setting of care and patient characteristics.

Adolescent↗
PubMed2000

Can 16-18-year-old elite ballet dancers improve their hip and ankle range of motion over a 12-month period?

OBJECTIVE: To determine the effect of a 12-month intensive ballet training regimen on hip and ankle range of motion in male and female, first- and second-year professional dancers. DESIGN: 12-month longitudinal follow-up. SETTING: National classical ballet school in Australia. PARTICIPANTS: 28 female and 20 male full-time ballet students with a mean +/- 1 SD, ages 16.8 +/- 0.8 and 17.7 +/- 1.2 years, respectively. MAIN OUTCOME MEASURES: Degrees of range of motion of left and right sides for the following movements: standing plié in parallel-passive ankle dorsiflexion (DF); standing turnout in the balletic first position--lower leg external rotation (LLER); supine hip external rotation (ER); supine hip internal rotation (IR). An additional range of motion was calculated: external rotation below the hip joint (BHER) derived by subtracting hip ER from LLER. MAIN RESULTS: In all subjects combined, hip and ankle ranges increased statistically on the right. However, the amount was generally minimal and most at the borderline of the amount of error associated with the measurement tool. While there was no change in LLER, there was a decrease in BHER. There were no overall gender differences, and year differences existed only for left hip ER and total hip ER with first-year dancers showing significant improvements in these ranges. For DF and sum of hip IR, first-year males and second-year females had increases in range. There was a negative relationship between baseline range and the amount of change over the 12 months. CONCLUSIONS: Dancers ages 16-18 years who enter full-time ballet training did not augment their ankle dorsiflexion to any appreciable degree. Some, but certainly not all, increased their hip active external rotation over 12 months without increasing their total lower limb turnout. Hip ER was more likely to improve in the first-year rather than second-year student in this elite full-time training school.

Adolescent↗
PubMed2000

A cost effectiveness analysis of goserelin compared with danazol as endometrial thinning agents.

OBJECTIVE: To analyse the cost, effectiveness and cost effectiveness of two endometrial thinning agents prior to laser ablation for dysfunctional uterine bleeding: danazol and goserelin. SETTING: A district general hospital. DESIGN: A retrospective cost effectiveness analysis, from the perspective of the health service, based on data from an open, randomised, parallel group comparative study of 160 pre-menopausal women with dysfunctional uterine bleeding. METHODS: Within the trial, length of operation and duration of hospital stay was recorded for each woman. Resource use due to complications of surgery and adverse drug events was evaluated by one of the authors (R.G.). Additional surgery after completion of the study was collected using a postal questionnaire which was distributed to every woman who had undergone surgery. Resource use was costed using detailed unit costs from a specific NHS trust and from published sources. A cost effectiveness analysis was undertaken relating differential cost to differential rates of amenorrhoea at women's last point of follow up. RESULTS: Information on amenorrhoea was available from 138 women, of whom 111 had completed the questionnaire to indicate longer term follow up. Women who did not complete the clinical trial were not included in this economic evaluation. On average, women randomised to goserelin spent less time in theatre and on the ward. Based on longer term follow up, rates of retreatment were similar in the two groups. The mean (SD) health service cost of women in the goserelin group was pound sterling 323.84 (pound sterling 309.94), compared with pound sterling 243.45 (pound sterling 265.23) in the danazol group; median (range) costs were pound sterling 220.29 (pound sterling 191-pound sterling 2127) and pound sterling 159.76 (pound sterling 140-pound sterling 1426) in the two groups, respectively. These costs were significantly higher for goserelin (P = 0.0001). The goserelin group also had a higher rate of amenorrhoea (38.8% vs 28.6%, P = 0.23). Based on mean differences in cost, the incremental cost of goserelin per additional woman with amenorrhoea was pound sterling 788; based on median differences in cost the ratio was pound sterling 590. CONCLUSIONS: The shorter duration in theatre and stay in hospital provided a modest offset of the higher acquisition cost of goserelin, but the overall cost of management remained significantly higher than managing women with danazol. The rates of amenorrhoea indicated that goserelin was more effective at 24 weeks and approximately two years after surgery, although statistical significance was only achieved at 24 weeks. The economic impact of women withdrawn from treatment was not considered, but sensitivity analysis indicates that these women may have had a large effect on the overall result of this study. Purchasers will need to decide whether the additional cost of management with goserelin is justified by the increased rates of amenorrhoea and the reduced withdrawals from treatment.

Adult↗
PubMed2000

The Comorbidity Symptom Scale: a combined disease inventory and assessment of symptom severity.

OBJECTIVES: To develop and evaluate a scale to quantify the presence and severity of symptoms arising from comorbid diseases in older people. DESIGN: A validation cohort study of hospital inpatients and outpatients aged 65 years and older. SETTING: A Hospital and community in Northeast England. PARTICIPANTS: Development of the Comorbidity Symptom Scale-Convenience sample of 50 hospital inpatients and outpatients aged 65 years and older. Evaluation of the Comorbidity Symptom Scale- Convenience sample of 183 patients aged 65 years and older either awaiting cataract surgery or attending a geriatric day hospital. MEASUREMENTS: For development of the Comorbidity Symptom Scale, 22 comorbid conditions were identified and incorporated into a questionnaire (the CmSS). Evaluation of the Comorbidity Symptom Scale-Assessments included the CmSS, activities of daily living, perceived health status, and anxiety and depression. RESULTS: A 23-item scale was developed. Reliability of the CmSS was demonstrated by a test-retest correlation coefficient for the total instrument score of r = 0. 87 (P < .001). The CmSS scores correlated with assessments of activities of daily living, perceived health status, and anxiety and depression. CONCLUSIONS: The CmSS is a simple interviewer-administered tool for use in older people and provides an objective measure of the presence of comorbid disease and the patient's perception of severity of associated symptoms.

Activities of Daily Living↗
PubMed2000

Cloning, characterization, controlled overexpression, and inactivation of the major tributyrin esterase gene of Lactococcus lactis.

The gene encoding the major intracellular tributyrin esterase of Lactococcus lactis was cloned using degenerate DNA probes based on 19 known N-terminal amino acid residues of the purified enzyme. The gene, named estA, was sequenced and found to encode a protein of 258 amino acid residues. The transcription start site was mapped 233 nucleotides upstream of the start codon, and a canonical promoter sequence was identified. The deduced amino acid sequence of the estA product contained the typical GXSXG motif found in most lipases and esterases. The protein was overproduced up to 170-fold in L. lactis by use of the nisin-controlled expression system recently developed for lactic acid bacteria. The estA gene was inactivated by chromosomal integration of a temperature-sensitive integration vector. This resulted in the complete loss of esterase activity, which could then be recovered after complementation of the constructed esterase-deficient strain with the wild-type estA gene. This confirms that EstA is the main enzyme responsible for esterase activity in L. lactis. Purified recombinant enzyme showed a preference for short-chain acyl esters, surprisingly also including phospholipids. Medium- and long-acyl-chain lipids were also hydrolyzed, albeit less efficiently. Intermediate characteristics between esterases and lipases make intracellular lactococcal EstA difficult to classify in either of these two groups of esterolytic enzymes. We suggest that, in vivo, EstA could be involved in (phospho)lipid metabolism or cellular detoxification or both, as its sequence showed significant similarity to S-formylglutathione hydrolase (FGH) of Paracoccus denitrificans and human EstD (or FGH), which are part of a universal formaldehyde detoxification pathway.

Amino Acid Sequence↗
PubMed2000

Saccharomyces cerevisiae RAI1 (YGL246c) is homologous to human DOM3Z and encodes a protein that binds the nuclear exoribonuclease Rat1p.

The RAT1 gene of Saccharomyces cerevisiae encodes a 5'-->3' exoribonuclease which plays an essential role in yeast RNA degradation and/or processing in the nucleus. We have cloned a previously uncharacterized gene (YGL246c) that we refer to as RAI1 (Rat1p interacting protein 1). RAI1 is homologous to Caenorhabditis elegans DOM-3 and human DOM3Z. Deletion of RAI1 confers a growth defect which can be complemented by an additional copy of RAT1 on a centromeric vector or by directing Xrn1p, the cytoplasmic homolog of Rat1p, to the nucleus through the addition of a nuclear targeting sequence. Deletion of RAI1 is synthetically lethal with the rat1-1(ts) mutation and shows genetic interaction with a deletion of SKI2 but not XRN1. Polysome analysis of an rai1 deletion mutant indicated a defect in 60S biogenesis which was nearly fully reversed by high-copy RAT1. Northern blot analysis of rRNAs revealed that rai1 is required for normal 5.8S processing. In the absence of RAI1, 5.8S(L) was the predominant form of 5.8S and there was an accumulation of 3'-extended forms but not 5'-extended species of 5. 8S. In addition, a 27S pre-rRNA species accumulated in the rai1 mutant. Thus, deletion of RAI1 affects both 5' and 3' processing reactions of 5.8S rRNA. Consistent with the in vivo data suggesting that RAI1 enhances RAT1 function, purified Rai1p stabilized the in vitro exoribonuclease activity of Rat1p.

Amino Acid Sequence↗
PubMed2000

Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis.

OBJECTIVE: To evaluate short and long term effects of giving nebulised budesonide early in respiratory syncytial viral (RSV) bronchiolitis. DESIGN: A multicentre randomised double blind placebo controlled trial. SUBJECTS: Infants admitted to hospital with their first episode of RSV positive bronchiolitis. INTERVENTION: Randomisation to receive either 1 mg of nebulised budesonide (Bud) or placebo (Pla) twice daily from admission until 2 weeks after discharge. Follow up was for 12 months. MAIN OUTCOME MEASURES: Duration of hospital admission, time taken to become symptom free, re-admission rates, general practitioner consultation rates, and use of anti-wheeze medication during follow up. RESULTS: 161 infants were studied. Both arms were similar with respect to initial clinical severity, age, sex, socioeconomic class, and tobacco exposure. Median time from first nebulisation to discharge: Bud and Pla, 2 days. Median number of days for 50% of infants to be symptom free for 48 hours: Bud, 10 days; Pla, 12 days. Respiratory re-admission rates in the 12 month follow up: Bud, 16%; Pla, 18%; median difference (95% confidence interval (CI)), -2 (-14 to 10). Median respiratory related general practitioner attendances: Bud, 4.0; Pla, 4.5; median difference (95% CI), -1 (-2 to 0). Percentage of infants receiving at least one prescription for anti-wheeze medication during follow up, corticosteroids: Bud, 50%; Pla, 60%; difference (95% CI), -10 (-26 to 6); bronchodilators: Bud, 60%; Pla, 67%; difference (95% CI), -7 (-22 to 8). CONCLUSIONS: There are no short or long term clinical benefits from the administration of nebulised corticosteroids in the acute phase of RSV bronchiolitis.

Acute Disease↗