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Biomedical subjects

C J McCabe

Publications and source records attributed to C J McCabe.

At least 37 records · Page 2Linked to original sources
PubMed1999

Estrogen receptor beta mRNA expression in normal and adenomatous pituitaries.

Estrogen (E2), acting via its nuclear receptors, has been implicated in tumor development and growth, particularly in the pathogenesis of breast cancer. E2 also modulates anterior pituitary hormone production and is a potent cell mitogen. Until recently, the actions of E2 were thought to be mediated by a single estrogen receptor (ER) isoform (ER alpha), and currently little is known of the pathophysiological relevance of the ER beta isoform. The presence of ER beta mRNA has been demonstrated by RT-PCR in the normal human pituitary, although expression of ER beta mRNA in human pituitary tumors has now been described. We have used semiquantitative RT-PCR to determine the relative levels of expression of ER beta mRNA in normal human pituitaries, non-functioning pituitary adenomas and GH-secreting tumors. ER beta mRNA was detected in normal pituitaries and all pituitary tumors examined. The ratio of ER beta mRNA to beta-actin mRNA expression was significantly reduced in non-functioning pituitary tumors (NFTs; 0.92 +/- 0.09; mean +/- SE; n = 23) compared with findings in normal pituitaries (1.56 +/- 0.21; mean +/- SE; n = 5; p < 0.05 Student's t-test). Studies of ER beta protein expression are required to determine the functional significance of reduced ER beta mRNA expression in NFTs.

Adenoma↗
PubMed1999

Increased MEN1 mRNA expression in sporadic pituitary tumours.

BACKGROUND: The MEN1 gene on chromosome 11q13 encodes a tumour suppressor gene, mutations in which cause multiple endocrine neoplasia (MEN) type 1 syndrome. Loss of heterozygosity (LOH) at this locus is a common finding amongst sporadic pituitary tumours. We have therefore screened the MEN1 gene for mutations in sporadic pituitary tumours and, as the gene is a putative tumour suppressor, have quantified mRNA expression in tumorous and normal pituitaries to assess the role of MEN1 in pituitary tumorigenesis. SUBJECTS AND DESIGN: Thirty-one nonfunctioning pituitary tumours, 8 GH secreting, 2 TSH-secreting tumours and 1 corticotrophinoma have been assessed for the presence of MEN1 mutations, to examine the hypothesis that MEN1 mutations may contribute to the pathogenesis of sporadic pituitary neoplasms. In addition, quantitative changes in the pretranslational expression of the tumour suppressor gene MEN1 have been determined in 42 pituitary tumours and 6 normal pituitaries using semiquantitative reverse transcriptase PCR. RESULTS: No novel or previously published mutations were apparent in the MEN1 coding regions of any tumours studied, although several polymorphisms were identified. Transcriptional changes of the gene, assessed by semiquantitative RT-PCR, indicated that nonfunctioning and GH-secreting pituitary tumours are associated with significantly increased pretranslational expression of the MEN1 gene. In addition, the single corticotrophinoma showed increased expression compared to normal, as did one of the two TSH-omas. CONCLUSION: Coding mutations of the putative tumour suppressor gene MEN1 are unlikely to contribute to pituitary tumorigenesis in sporadic nonfunctioning, GH-secreting and TSH-secreting adenomas. Changes in pretranslational expression of MEN1 were observed in pituitary tumours, suggesting that changes in the level of MEN1 expression, rather than coding changes, may be of functional importance in influencing sporadic pituitary tumorigenesis.

Adenoma↗
PubMed1999

Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment.

OBJECTIVES: To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment. DESIGN: Cohort life table method using data from outcome trials. MAIN OUTCOME MEASURES: The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from pound 100 to pound 800 per year. RESULTS: The costs per life year gained according to annual CHD event risk were: for 4.5%, pound 5100; 3.0%, pound 8200; 2.0%, pound 10 700; and 1.5%, pound 12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks. CONCLUSIONS: At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.

Coronary Disease↗
PubMed1999

Thyroid receptor alpha1 and alpha2 mutations in nonfunctioning pituitary tumors.

We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) alpha and beta isoforms, an observation that may account for abnormalities of T3-mediated negative regulation of the glycoprotein hormone common alpha-subunit. Reduced TR protein was associated with a parallel reduction in TRbeta messenger RNA (mRNA), although TRalpha1 and alpha2 mRNA levels were similar in nonfunctioning tumors and normal pituitaries. Because TRalpha shows aberrant posttranscriptional processing, and TRbeta is under ligand-dependent autoregulation, we hypothesized that aberrant TR expression in nonfunctioning tumors may reflect mutation in receptor coding and regulatory sequences, and therefore screened TRalpha mRNA and TRbeta T3 response elements and ligand binding domains for sequence anomalies. Screening TRalpha mRNA in 23 tumors and subsequently sequencing candidate fragments identified one silent change from published sequences and three novel missense mutations, two in the common TRalpha region (ser45ile and lys370asn) and one that was alpha2 specific (ser377leu). TRbeta response elements failed to show any differences from published sequences in 14 nonfunctioning tumors. Sequencing of TRbeta ligand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TRalpha mutations is unknown; definition of mutant TR action may provide insight into the role of TRs in the growth control of pituitary cells.

Adult↗
PubMed1999

PTTG--a new pituitary tumour transforming gene.

The pathogenesis of sporadic pituitary tumours remains elusive. Recently, a new candidate gene has been described which is able to induce pituitary cell transformation, and the expression of which appears to be strongly correlated with pituitary tumorigenesis. The so-called pituitary tumour transforming gene (PTTG) encodes a 23 kDa, 202 amino acid protein, and is located on chromosome 5q33, a locus previously associated with recurrent lung cancer and acute myelogenous leukaemias. Although the precise function of PTTG protein is unknown, in vitro experiments have demonstrated that it is capable of inducing fibroblast growth factor (FGF) expression. Mutation of the two proline-rich domains of the PTTG protein has also been shown to abolish subsequent FGF induction. Furthermore, in patients with pituitary adenomas, serum FGF concentrations fall post-operatively after successful excision of the tumour.

Adenoma↗
PubMed1998

Annual league tables of mortality in neonatal intensive care units: longitudinal study. International Neonatal Network and the Scottish Neonatal Consultants and Nurses Collaborative Study Group.

OBJECTIVE: To assess whether crude league tables of mortality and league tables of risk adjusted mortality accurately reflect the performance of hospitals. DESIGN: Longitudinal study of mortality occurring in hospital. SETTING: 9 neonatal intensive care units in the United Kingdom. SUBJECTS: 2671 very low birth weight or preterm infants admitted to neonatal intensive care units between 1988 and 1994. MAIN OUTCOME MEASURES: Crude hospital mortality and hospital mortality adjusted using the clinical risk index for babies (CRIB) score. RESULTS: Hospitals had wide and overlapping confidence intervals when ranked by mortality in annual league tables; this made it impossible to discriminate between hospitals reliably. In most years there was no significant difference between hospitals, only random variation. The apparent performance of individual hospitals fluctuated substantially from year to year. CONCLUSIONS: Annual league tables are not reliable indicators of performance or best practice; they do not reflect consistent differences between hospitals. Any action prompted by the annual league tables would have been equally likely to have been beneficial, detrimental, or irrelevant. Mortality should be compared between groups of hospitals using specific criteria-such as differences in the volume of patients, staffing policy, training of staff, or aspects of clinical practice-after adjusting for risk. This will produce more reliable estimates with narrower confidence intervals, and more reliable and rapid conclusions.

Cohort Studies↗
PubMed1998

Effect of computed tomography of the appendix on treatment of patients and use of hospital resources.

BACKGROUND: In patients with clinically suspected appendicitis, computed tomography (CT) is diagnostically accurate. However, the effect of routine CT of the appendix on the treatment of such patients and the use of hospital resources is unknown. METHODS: We performed appendiceal CT on 100 consecutive patients in the emergency department who, on the basis of history, physical examination, and laboratory results, were to be hospitalized for observation for suspected appendicitis or for urgent appendectomy. Outcomes were determined at surgery and by pathological examination in 59 patients, and by clinical follow-up two months later in 41 patients. Treatment plans made before CT were compared with the patients' actual treatment. We also determined the costs of surgery that revealed no appendicitis (from data on 61 patients), one day of observation in the hospital (from data on 350 patient-days in patients with suspected appendicitis), and appendiceal CT (from data on all pelvic CT examinations in 1996). RESULTS: Fifty-three patients had appendicitis, and 47 did not. The interpretations of the appendiceal CT scans were 98 percent accurate. The results of CT led to changes in the treatment of 59 patients. These changes resulted in the prevention of unnecessary appendectomy in 13 patients, admission to the hospital for observation in 18 patients, admission to the hospital for observation before necessary appendectomy in 21 patients, and admission to the hospital for observation before the diagnosis of other conditions by CT in 11 patients. The effects of performing appendiceal CT on the use of hospital resources included the prevention of unnecessary appendectomy in 13 patients (for a savings of $47,281) and the prevention of unnecessary hospital admission for 50 patient-days (for a savings of $20,250). After the cost of 100 appendiceal CT studies ($22,800) was subtracted, the overall savings was $447 per patient. CONCLUSIONS: Routine appendiceal CT performed in patients who present with suspected appendicitis improves patient care and reduces the use of hospital resources.

Adolescent↗
PubMed1998

Evaluation of a diabetic foot screening and protection programme.

We set out to evaluate a clinical foot-screening programme in terms of primary outcomes (reductions in the incidence of ulcers and lower limb amputation) and process outcomes (compliance with screening, the number of patients not completing the programme and the use of chiropody services and prescribed footwear and cost). All but 4 of 2001 patients attending a general diabetic out-patient clinic were allocated randomly to index and control groups. The exceptions were patients who presented with active ulcers and were placed in the index group. Primary and secondary screening programmes identified 128 high risk patients in the index group and these were admitted to the foot protection programme. At 2-year follow-up, 11 fewer ulcers were reported from the index group. There were 7 amputations (1 major, 6 minor) in the index group and 23 (12 major and 13 minor) in the control group. The differences were not statistically significant for ulceration or minor amputations but significant for major amputations (p < 0.01). The total cost of the 2-year programme was pounds sterling 100,372 (1991-92 costs), with a mean cost per patient of approximately pounds sterling 100. Taking pounds sterling 12,000 as a conservative estimate of the cost of a major amputation, the foot clinic was cost-effective in terms of amputations averted. The process outcomes were much less satisfactory. Cost-effectiveness could have been improved if it had been possible to improve patient compliance.

Ambulatory Care Facilities↗
PubMed1998

The computed tomography appearance of recurrent and chronic appendicitis.

The objective of this study was to determine computed tomography (CT) appearance of recurrent and chronic appendicitis. In 100 consecutive appendiceal CT examinations of proven appendicitis, 18 patients met criteria for recurrent (multiple discrete episodes) or chronic (continuous symptoms > 3 weeks, pathological findings) appendicitis. CT findings were reviewed. Ten patients had recurrent appendicitis, 3 had chronic appendicitis, 3 had both, and 2 had pathological chronic appendicitis. CT findings in 18 recurrent/chronic cases were identical to 82 acute appendicitis cases, including pericecal stranding (both 100%), dilated (> 6 mm) appendix (88.9% versus 93.9%), apical thickening (66.7% versus 69.5%), adenopathy (66.7% versus 61.0%), appendolith(s) (50% versus 42.7%), arrowhead (27.8% versus 22.0%), abscess (11.1% versus 11.0%), phlegmon (11.1% versus 6.1%), and fluid (5.6% versus 19.5%). CT findings in recurrent and chronic appendicitis are the same as those in acute appendicitis. Appendiceal CT can be beneficial for evaluating patients with suspected recurrent or chronic appendicitis.

Adult↗
PubMed1998

Retinoid X receptor expression in the normal pituitary and clinically 'non-functioning' pituitary tumours.

OBJECTIVE: The glycoprotein hormone common alpha-subunit is frequently expressed in clinically 'non-functioning' tumours (NFTs) of the anterior pituitary, despite normal levels of T3 and gonadal steroids. This observation suggests abnormal negative-feedback regulation of the alpha-subunit by T3 and gonadal steroids in NFTs. We have previously documented reduced expression of thyroid hormone receptor (TR) variants in NFTs compared to normals and proposed that this observation may, in part, explain the defective negative regulation. Due to the important role of retinoid X receptors (RXRs) in transactivating TR-mediated transcriptional regulation, via heterodimer formation, we hypothesize that aberrant RXR isoform expression in NFTs may contribute to the defective negative regulation of the alpha-subunit by T3. DESIGN: Comparison of RXR isoform protein and mRNA expression in NFTs and normal pituitaries. PATIENTS AND TUMOURS: Twenty clinically non-functioning pituitary tumours and 27 normal pituitaries were obtained for analysis. MEASUREMENTS: Immunocytochemistry and semiquantitative RT-PCR was performed on tumours and normal pituitaries to determine the relative levels of expression of RXR isoform proteins and mRNAs, respectively. RESULTS: RXR alpha was expressed in a similar proportion (approximately 50%) of both normal human pituitaries and NFTs, while RXR beta and gamma were each observed in 26% of normals but were undetectable in NFTs. The application of semiquantitative RT-PCR revealed similar levels of mRNAs encoding the RXR alpha and RXR beta isoforms in normals and NFTs but significantly reduced expression of RXR gamma mRNA was observed in NFTs. CONCLUSIONS: We propose that abnormal RXR isoform expression in clinically 'non-functioning' pituitary tumours may contribute to abnormal T3-mediated negative regulation of alpha-subunit production.

DNA-Binding Proteins↗
PubMed1998

Differential regulation of the human thyrotropin alpha-subunit promoter by thyroid hormone receptors alpha1 and beta1.

The differential tissue expression of thyroid hormone receptor (TR) isoforms implies that they fulfil different roles in mediating triiodothyronine (T3) regulation. We have examined the differential roles of TR isoforms in mediating T3-dependent repression of the human thyrotropin (TSH)-alpha subunit gene promoter in vitro, and have assessed TR binding characteristics using gel mobility shift assays. Expression of transfected TR in JEG-3 cells revealed that TRalpha1 and TRbeta1 differentially inhibited TSHalpha subunit expression in the presence of T3, with TRbeta1 twice as potent as TRalpha1. TRalpha2 antagonized T3-dependent repression when coexpressed with TRalpha1 and TRbeta1. Gel mobility shift assays, performed in the presence and absence of JEG-3 nuclear extract, demonstrated that TRbeta1 bound with higher affinity to the wild-type TSHalpha negative thyroid hormone response element (nTRE) than TRalpha1. In vivo, the differential DNA binding of TR variants to nTREs may determine the ability of receptors to mediate T3-dependent repression.

Cell Line↗
PubMed1998

An abnormality of thyroid hormone receptor expression may explain abnormal thyrotropin production in thyrotropin-secreting pituitary tumors.

Thyrotropin (TSH)-secreting pituitary adenomas cause hyperthyroxinemia in the presence of "inappropriately" elevated concentrations of TSH. TSH production under these circumstances escapes the normal negative feedback effect of thyroid hormone. We propose that this defective negative feedback is mediated by an abnormality of thyroid hormone receptor (TR) expression. Two TSH-secreting pituitary adenomas were analyzed by immunocytochemistry for TR isoform protein expression and by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) for TR isoform mRNA expression. The results obtained from these tumors were compared with the findings from six normal human pituitaries. Neither tumor examined expressed detectable levels of nuclear TRalpha or TRbeta proteins, in contrast to the normal pituitaries studied, which expressed all TR isoforms. Application of RT-PCR, however, revealed mRNAs encoding each TR isoform in all tumorous and normal tissues examined. Semiquantitative RT-PCR revealed similar levels of expression of TRalpha and TRbeta isoform mRNAs in tumors and normal tissue, in contrast to the observed difference in TR proteins. Absent TRalpha and TRbeta protein expression, in association with normal mRNA levels, implies a post-transcriptional defect in TR mRNA processing in TSH-secreting adenomas. Reduced TR expression in these tumors may explain defective negative feedback of thyroid hormone on TSH production, and may also contribute to uncontrolled tumor growth.

Adenoma↗
PubMed1998

Economic burden of environmental tobacco smoke on Hong Kong families: scale and impact.

STUDY OBJECTIVE: To examine the financial cost of doctor consultations for cough, phlegm, and wheeze in children living in a home where family members smoke compared with those not exposed to environmental tobacco smoke. To model these costs to provide the Territory of Hong Kong with estimates of potentially avoidable health care resource use. DESIGN: Cross sectional questionnaire survey. SUBJECTS AND SETTING: All children (10,615) in classes primary 3 to 6 (aged 8-13 years) attending 27 schools in two districts of Hong Kong in 1992 and their parents. MEASUREMENTS AND MAIN RESULTS: Doctor consultations during the previous three months for symptoms of either cough, phlegm or wheeze were higher in younger children, ranging from 22.9% in 8 year olds to 8.4% in those aged 12 or over. For those children living in homes with one, or more than one, smoker category (there were four categories of smokers: father, mother, siblings, others), the adjusted odds ratios (95% confidence intervals) for a doctor consultation for any of these symptoms were 1.15 (1.01, 1.31) and 1.38 (1.14, 1.67) respectively. Using US$15 as the minimum cost incurred per consultation, the expected direct cost per annum per child of doctor consultations was 14% higher for children living in a one smoker category home and 25% for two or more compared with exposure to no smokers in the home. Using these values on a territory wide basis, the annual avoidable direct cost associated with exposure to tobacco smoke in children from birth to 12 years of age ranged from US$338,042 to US$991,591. CONCLUSIONS: Exposure to environmental tobacco smoke not only provides a respiratory health risk for children but also an avoidable excess cost to the family's financial resources and health service providers.

Child↗
PubMed1998

Choice of NSAID and management strategy in rheumatoid arthritis and osteoarthritis. The impact on costs and outcomes in the UK.

OBJECTIVE: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective therapy for rheumatoid arthritis, they are associated with significant adverse effects, the management of which imposes additional costs on the healthcare system. Prescribing NSAIDs which have a lower risk of major adverse effects as the first-line NSAID for patients with rheumatoid arthritis and osteoarthritis may be expected to lead to an improvement in clinical outcomes and reduce overall treatment costs. This analysis examines data from a published randomised controlled trial of 5 NSAIDs to explore these hypotheses. DESIGN AND SETTING: Data from a clinical trial comparing 5 NSAIDs were combined with published cost data to construct 2 clinical decision models, reflecting alternative approaches to the management of major and minor adverse effects in the UK. INTERVENTIONS: The 5 NSAIDs evaluated in the analysis were nabumetone, diclofenac, ibuprofen, piroxicam and naproxen, although only the results for ibuprofen and nabumetone are reported. MAIN OUTCOME MEASURES AND RESULTS: The total cost of care per patient receiving nabumetone was estimated to be between 25 pounds sterling (Pound) and 41 Pounds more expensive than ibuprofen. In a hypothetical cohort of 100,000 patients, there were between 690 and 821 more major adverse effects using ibuprofen than nabumetone. The cost per life-year gained (LYG) from using nabumetone rather than ibuprofen ranged between 1880 Pounds and 2517 Pounds (1995 values), depending upon the management of adverse effects. CONCLUSIONS: These results indicate that: (i) prescribing the newer, currently more expensive, NSAIDs will not necessarily lead to cost savings; (ii) the management of adverse effects can have a significant impact on costs; and (iii) the additional cost may be justifiable in terms of the mortality and morbidity gains associated with the new lower-risk NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗