Search PubMed⌕ Search

Biomedical subjects

C J McCabe

Publications and source records attributed to C J McCabe.

At least 19 recordsLinked to original sources
PubMed2003

Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour.

OBJECTIVE: Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor-2 (FGF-2). Given this background, we have determined the expression of PTTG, PBF, FGF-2 and its receptor FGF-R-1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour. PATIENTS AND METHODS: We used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analyses to measure PTTG, PBF, FGF-2 and FGF-R-1 expression in ex vivo pituitary tumours (N = 121). Clinical data, including accurate radiological assessment of tumour characteristics, were used to determine any associations between gene expression and tumour behaviour. RESULTS: PTTG was increased significantly (fivefold, P = 0.005) in adenomas compared with normal pituitaries. We also demonstrated that PBF was similarly raised in adenomas (sixfold, P = 0.0001), and was significantly correlated with PTTG expression. FGF-2 and its receptor FGF-R-1 were also raised in adenomas compared with normal pituitary tissue. Moreover, significantly enhanced expression of FGF-R-1 was observed in invasive adenomas compared with other pituitary tumours. CONCLUSIONS: Our data support a fundamental role for PTTG-mediated upregulation of FGF-2 signalling in pituitary tumorigenesis and growth, and suggest that receptor-mediated mechanisms of growth factor action may be critically important. Further prospective studies are required to determine whether measurement of FGF-R-1 mRNA will be of clinical use as a prognostic marker in patients with pituitary adenomas.

Adenoma↗
PubMed2002

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours.

OBJECTIVE: Thyroid hormones (THs) perform essential roles in pituitary function. They regulate anterior pituitary hormone secretion and are also key determinants of pituitary cell proliferation and differentiation. The critical role of deiodinase enzymes, which serve as prereceptor regulators of TH action, remains largely unexplored. Three deiodinase enzymes metabolize active and inactive THs and thereby determine tissue concentrations of the biologically active ligand, tri-iodothyronine (T3). We hypothesized that aberrant expression of deiodinase enzymes and/or altered enzyme activity in pituitary tumours may change tissue concentrations of THs and influence their growth and secretory characteristics. STUDY DESIGN AND PATIENTS: We studied 105 pituitary tumours and 10 normal pituitaries for expression of deiodinase enzyme mRNAs encoding types 1 (D1), 2 (D2) and 3 (D3) using real-time RT-PCR. Enzyme activity data from 20 pituitary samples were also obtained. RESULTS: Pituitary tumours expressed significantly increased D3 mRNA (6.5-fold, P < 0.0005) compared with normal pituitaries. D2 mRNA was also increased 2.6-fold (P = 0.005) in pituitary tumours compared with normals. The rare TSH-secreting pituitary tumour subtype expressed a 13.1-fold excess of D3 mRNA and reduced D2 mRNA (0.1-fold of normal pituitaries). D2 mRNA expression in ACTH-secreting tumours was similarly reduced to 0.1-fold that in normal pituitaries. CONCLUSIONS: Pituitary adenomas express abnormal levels of deiodinase enzymes compared to normal pituitaries. These abnormalities may have functional consequences on pituitary tumour growth. In the case of TSH-secreting pituitary adenomas, the observed pattern of deiodinase mRNA expression may explain the 'resistance' of this tumour type to TH feedback.

Adenoma↗
PubMed2002

Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors.

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.

Adenoma↗
PubMed2001

Ultrasonography by emergency physicians in patients with suspected cholecystitis.

This article investigates the use of bedside abdominal ultrasonography (BAU) performed by emergency physicians (EPs) to screen patients for cholelithiasis and cholecystitis. In this prospective study EPs performed BAU on 116 patients. Agreement between BAU and formal abdominal ultrasound (FUS) performed in the radiology department for detecting cholelithiasis and cholecystitis was determined using Kappa statistics. Test characteristics of BAU for detecting cholelithiasis and acute cholecystitis were calculated. Agreement between BAU and FUS was 0.71 for cholelithiasis and 0.46 for acute cholecystitis. Test characteristics of BAU for cholelithiasis were sensitivity 92%, specificity 78%, positive predictive value (PPV) 86%, negative predictive value (NPV) 88%. Test characteristics of BAU for acute cholecystitis compared with clinical follow-up were sensitivity 91%, specificity 66%, PPV 70%, NPV 90%. BAU may be used to exclude cholelithiasis and is sensitive for cholecystitis. However, when EPs with limited experience identify cholecystitis a confirmatory test is warranted before cholecystectomy.

Acute Disease↗
PubMed2000

Expression of pituitary-tumour transforming gene in colorectal tumours.

BACKGROUND: Basic fibroblast growth factor promotes angiogenesis and mitogenesis in colon carcinomas. Pituitary-tumour transforming gene (PTTG1) causes in-vitro and in-vivo transformation, regulates secretion of basic fibroblast growth factor, and inhibits chromatid separation. Most normal tissues show little or no PTTG1 expression but cancer cells express the gene abundantly. We postulated that PTTG1 expression in colorectal tumours is related to tumour invasiveness. METHODS: PTTG1 gene and protein expression were assessed in 68 colorectal tumours and compared with invasive characteristics, such as lymph-node invasion, evidence of metastases, tumour vessel density, and expression of basic fibroblast growth factor. PTTG1 expression is given in terms of the fold-increase over that in normal-adjacent colorectal tissue. FINDINGS: PTTG1 was overexpressed in all of 48 colon carcinomas (median fold-increase 2.2 [IQR 1.8-3.3]) and in 19 of 20 colonic polyps (2.2 [1.6-3.1]) compared with normal colonic tissue. Invasion of surrounding lymph nodes was associated with higher PTTG1 expression than in carcinomas limited to the bowel wall (3.4 [2.1-5.9] vs 1.9 [1.7-2.4], p=0.007), and higher PTTG1 expression was seen in more vascular than in less vascular tumours (2.6 [1.9-5.1] vs 1.9 [1.8-2.5], p=0.04). INTERPRETATION: Increased tumour PTTG1 expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target.

Colorectal Neoplasms↗
PubMed2000

Tissue-specific regulation of thyroid hormone receptor mRNA isoforms and target gene proteins in domestic ducks.

Skeletal muscles are important target tissues for thyroid hormone action. The present study examines the influence of thyroid status on muscle growth and tissue-specific expression of thyroid receptor (TR) mRNA isoforms in a commercial strain of the domestic duck (Anas platyrhynchos). Four groups (n=5) of 1-week-old ducklings were rendered either hypothyroid by treatment with methimazole (6 mg 100 g(-1) body mass or 12 mg 100 g(-1) body mass), or hyperthyroid by treatment with methimazole (6 mg 100 g(-1) body mass) in combination with thyroid hormones (5 microg thyroxine (T(4)) and tri-iodothyronine (T(3)) 100 g(-1) body mass or 10 microg T(4) and T(3) 100 g(-1) body mass). Serum and tissue samples (cardiac, pectoralis and semimembranosus leg muscle, liver, pituitary and cerebral cortex) were collected from these four groups, and from a group of untreated controls, at 8 weeks of age. Development of duckling morphology was retarded in methimazole-treated birds compared with that in euthyroid controls, as evidenced by differences in skeletal dimensions, primary feather length, and body and muscle masses. Body mass was lower by 18%, and relative masses of cardiac and pectoralis muscles were lower by 28% and 32% respectively. Heterologous oligonucleotides for TR alpha, TR beta 0, TR beta2 and the housekeeping gene beta-actin were derived from chicken sequences. RT-PCR showed that TR alpha mRNA was expressed in all tissues but was not significantly affected by any of the experimental treatments. TR beta 0 mRNA expression was significantly lower in the leg muscles of ducklings treated with 12 mg methimazole 100 g(-1) body mass (0.109+/-0.047 TR:beta-actin ratio, P<0.05) compared with that in euthyroid controls (0.380+/-0.202), but was unaltered in the pectoralis and cardiac muscles. Expression of TR beta 0 mRNA was significantly higher in pectoralis (by 3.5-fold, P<0. 05), cardiac (by 4.2-fold, P=0.003) and leg (by 4.0-fold, P<0.001) muscles of ducklings treated with thyroid hormones compared with those in euthyroid controls (0.098+/-0.019, 0.822+/-0.297 and 0. 38+/-0.202 TR:beta-actin respectively). Only the pituitary gland expressed significant levels of TR beta 2 mRNA.

Animals↗
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↗