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Biomedical subjects

G A Thomas

Publications and source records attributed to G A Thomas.

At least 19 recordsLinked to original sources
PubMed2005

Metallothionein crypt-restricted immunopositivity indices (MTCRII) correlate with aberrant crypt foci (ACF) in mouse colon.

Metallothionein (MT) crypt-restricted immunopositivity indices (MTCRII) are colonic crypt stem cell mutation markers that may be induced early and in abundance after mutagen treatment. Metallothionein is the endogenous reporter gene for MTCRII, but is not typically implicated in the classical pathway of colorectal tumorigenesis. Hence, the oncological relevance of MTCRII is unclear. This study tests the hypothesis that MTCRII induced by N-methyl-N-nitrosourea (MNU) and lambda carrageenan (lambdaCgN) associate with aberrant crypt foci (ACF) in mouse colon. Undegraded lambdaCgN and MNU were tested alone and in combination against MTCRII and ACF in Balb/c mice, at 20 weeks after the start of treatment. MTCRII were unaffected by lambdaCgN alone. Combined lambdaCgN/MNU treatments induced greater MTCRII (P < 0.01) as well as greater number (P < 0.001) and crypt multiplicity (P < 0.01) of ACF than MNU alone. MTCRII were approximately 10-fold more numerous than ACF, although linear correlations were observed between these parameters (r = 0.732; P < 0.01). MTCRII are induced by lambdaCgN/MNU interactions in sufficient numbers to provide statistical power from relatively small sample sizes and correlate with ACF formation. MTCRII could thus provide the basis for a novel medium-term murine bioassay relevant to early-stage colorectal tumorigenesis.

Animals↗
PubMed2005

Investigation of loss of heterozygosity and SNP frequencies in the RET gene in papillary thyroid carcinoma.

In both medullary carcinoma and papillary carcinoma of the thyroid, altered expression of the RET gene is implicated in tumorigenesis. Recent studies suggest that loss of heterozygosity (LOH) at the G691S SNP may be associated with tumors from patients with a history of radiation exposure. We investigated LOH for three RET SNPs (G691S, S904S, and L769L) in tumor and normal tissue from 46 patients from Ukraine and Belarus who were exposed to radioactive fallout following the Chernobyl nuclear accident and were operated for papillary thyroid carcinoma between 1995 and 2000. Normal tissue from 28 patients was heterozygous for at least one SNP; DNA from the corresponding tumor samples was also heterozygous, indicating that no LOH had taken place. To assess SNP frequencies in a radiation-associated thyroid cancer cohort, we investigated a further 68 unpaired post-Chernobyl samples. For G691S, there was considerable deviation from Hardy-Weinberg equilibrium; more detailed analysis showed that this was linked to age at onset of disease. Among younger patients, the distribution of genotypes conformed to Hardy-Weinberg equilibrium; among older patients, we observed marked deviation (p = 0.0072), with significant over-representation of the rare S allele relative to the younger groups (Fisher's exact, p = 0.0233). This suggests that SNPs in the RET oncogene may play a role in sporadic papillary thyroid carcinoma.

Adolescent↗
PubMed2004

Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness.

The large numbers of papillary thyroid carcinomas that have occurred in those exposed to high levels of short-lived isotopes in fallout after Chernobyl provide a unique opportunity to correlate latency and tumour biology. We show that short latency is associated with tumours with a phenotype that is significantly less structurally differentiated, shows significantly less peritumour fibrosis, and significantly more invasive spread when compared to tumours with a longer latent period. In contrast, the type of differentiation (papillary or follicular architecture) is associated with age at exposure. These findings suggest that the initial mutation at the time of exposure played a major role in tumour latency and aggressiveness. We and others have shown that RET-PTC3 rearrangements are associated with the solid morphology seen in these short latency tumours, while classical papillary carcinomas more often show RET-PTC1 rearrangements. Studies in transgenic mice show similar findings, and in vitro studies show that RET-PTC3 induces more rapid growth than RET-PTC1. We therefore suggest that the solid morphology, high frequency of RET-PTC3 rearrangements and aggressive behaviour noted in early investigations of post-Chernobyl tumours were characteristic of short latency rather than the nature of the mutagen, and that successive overlapping waves of papillary carcinoma with differing latency, differing patterns of mutations and differing clinical behaviour are occurring in those exposed to Chernobyl fallout.

Adolescent↗
PubMed2002

Analysis of the Ki-67 antigen at the invasive tumour front of human oral squamous cell carcinoma.

BACKGROUND: It is hypothesised that cell proliferation, as measured by the Ki-67 labelling index (LI) at the invasive tumour front (ITF) was directly related to the histological grade in human oral squamous cell carcinomas (SCCs). METHODS: Tissues from 42 human oral SCCs were collected and stained with an antibody directed against the Ki-67 antigen using an advanced polymer staining system. Quantitation of the immunopositive cells was performed on two parallel sections at the invasive tumour front (ITF), using an image analyser. The Ki-67 LI was expressed as the number of positive nuclei/mm2 of epithelium. The control tissue used was normal epithelium at the excision margin. RESULTS: The mean Ki-67 LI for oral SCCs at the ITF was significantly greater than that for the excision margin tissue (P < 0.0001). There was a positive association between increasing Ki-67 LI and increasing Broders' grade (P < 0.05), with a well-differentiated tumour having the lowest mean Ki-67 LI (1549 +/- 806) and a poorly differentiated tumour having the highest value (2232 +/- 771). A similar trend was observed between the mean Ki-67 LI and Bryne's multifactorial grading system. CONCLUSIONS: It was concluded from this study that cell proliferation (as measured by the Ki-67 antigen) at the ITF had a strong positive relationship with histological grading in human oral SCC.

Analysis of Variance↗
PubMed2001

Planning oral rehabilitation: case-based computer assisted learning in clinical dentistry.

The partially edentulous adult offers a unique and problem-rich resource as a basis for a case-based learning scenario in clinical dentistry in the field of planning oral rehabilitation. However, there is little resource material available to help students negotiate the territory between diagnosis and treatment options of discrete conditions and treatment sequencing once decisions have been made. To address the educational void surrounding the teaching and learning of oral rehabilitation strategies, the authors have developed a CD-ROM 'Interactive Learning in Dentistry: Decision making in the oral rehabilitation of the partially edentulous adult'. The disc emphasises the distinction between 'doing' and 'planning to do' in the decision-making process. After using the disc the students should be able to apply a generic framework to formulate a custom oral rehabilitation plan for their own patient. The disc was evaluated by final-year students from the Faculty of Dentistry, University of Sydney. Response to the program was essentially positive and comments from students have impacted on further development.

Adult↗
PubMed2001

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue.

Combretastatin-A4 phosphate (cis-CA-4) is a tubulin-binding agent currently undergoing clinical trials as an anti-tumour drug. We have investigated whether CA-4 functions as a tumour-specific anti-vascular agent using the hyperplastic thyroid as a novel in vivo model of neovascularization. CA-4 elicited pathological changes in normal tissue, manifested as the induction of multiple, discrete intravascular thrombi. These vascular-damaging effects indicate that CA-4P does not function as a tumour-specific agent but targets neovasculature irrespective of the primary angiogenic stimulus.

Animals↗
PubMed2001

Differences in susceptibility to colonic stem cell somatic mutation in three strains of mice.

Different species and different strains of animals commonly show very different sensitivities to carcinogenic regimes, which are often unexplained. A major possible contributory factor is variation in susceptibility to mutation, but this has not been directly demonstrated. This study therefore quantified the colonic stem cell mutation frequency in three strains of mice using two carcinogens. Stem cell mutations were identified using loss of function of glucose 6-phosphate dehydrogenase (G6PD) in individual crypts, a technique validated by several previous studies. The carcinogens dimethylhydrazine (DMH) and ethyl nitrosurea (ENU) were given to Balb/C, C57BL/6J, and C3H mice. In response to DMH, Balb/C mice were most susceptible, with approximately double the stem cell mutation frequency found in C3H and more than ten-fold that found in C57BL/6J (3.3+/-0.71 vs. 1.5+/-0.52 vs. 0.28+/-0.8x10(-4)). In response to ENU, Balb/C mice and C3H mice were equally susceptible, showing a stem cell mutation frequency approximately twice that of C57BL/6J (3.1+/-0.4 vs. 3.1+/-0.65 vs. 1.63+/-0.28x10(-4)). The observed differences among the strains with respect to somatic mutation following DMH treatment are likely to be due to the previously documented differences in metabolic conversion to the active metabolite. However, as ENU is a directly acting, rapidly inactivated mutagen, strain differences in response to ENU are unlikely to be due to strain-dependent metabolism of the mutagen and are likely to reflect differences in DNA repair efficiency, or possibly in stem cell kinetics among the strains studied. Susceptibility to the induction of colonic stem cell mutation is an important factor in susceptibility to carcinogens, whether due to differences in DNA repair or to other factors. Direct quantification of stem cell mutation frequency allows the separate identification of this component of the carcinogenic cascade and shows that it can make a major contribution to the differing susceptibility of different mouse strains.

1,2-Dimethylhydrazine↗
PubMed2001

Membranous nephropathy associated with chronic immune thrombocytopenic purpura in childhood.

Membranous nephropathy has been associated with many autoimmune diseases. We describe a child with membranous nephropathy associated with chronic immune thrombocytopenic purpura (ITP) and Coombs'-positive hemolytic anemia. After 3 years of ITP, the patient developed nephrotic syndrome during a flare of ITP. A biopsy specimen showed membranous nephropathy. Treatment with corticosteroids led to improvement of the thrombocytopenia and resolution of the proteinuria. Two years later, the patient again developed thrombocytopenia and proteinuria. Both conditions resolved after treatment with corticosteroids. This case suggests that ITP can cause membranous nephropathy.

Adrenal Cortex Hormones↗
PubMed2001

Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine.

INTRODUCTION: Constipation is a common side-effect of opioid therapy; in addition to their analgesic effect, opioids reduce intestinal secretion and motility with an increase in whole-gut transit time. Naloxone, a specific opioid antagonist, reverses these effects but may also cause symptoms of opioid withdrawal in patients on long-term therapy. AIM: To use an enteric-release formulation, designed to produce a topical effect in the gut, with minimum systemic effects. METHODS: Naloxone 10 mg b.d. and codeine 30 mg b.d. were used with identical placebo capsules in four sets of studies; 12 male volunteers were given the drugs alone and in combination, with a control study involving double placebo, during each of four study periods. Whole-gut transit time was calculated and compared for each treatment period. RESULTS: Naloxone, both alone and with codeine, significantly shortened the mean whole-gut transit time compared with the control period, respectively, from 53.1 to 42.1 h (P=0.005) and to 40.7 h (P=0.024). Urgency to defecate was reported by two volunteers on naloxone alone and by three on combination therapy. CONCLUSIONS: The results show that the naloxone formulation counteracts the effect of codeine on intestinal transit, suggesting that it may have useful clinical applications.

Administration, Oral↗
PubMed2001

Enteric-release glyceryl trinitrate in active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Mucosal ischaemia may contribute to the pathogenesis of Crohn's disease. Microvascular abnormalities have been found in colonic resection specimens, and mucosal levels of constitutive nitric oxide synthase are reduced. AIM: To assess the efficacy of a novel, enteric-release formulation of the nitric oxide donor, glyceryl trinitrate, aimed at increasing the mucosal circulation and relaxing smooth muscle in the affected bowel. METHODS: The trial was randomized, double-blind and placebo-controlled. Baseline disease activity was assessed by a structured symptom diary, with blood tests and a quality of life assessment. Patients with a Crohn's disease activity index of > or = 150 and < 450 were randomized to receive 12 weeks of either glyceryl trinitrate (initially 6 mg twice daily, increasing to 9 mg twice daily after 6 weeks) or an identical placebo. Assessments were repeated at 6 and 12 weeks. RESULTS: Seventy patients (22 male) entered the study; 34 were given glyceryl trinitrate and 36 placebo. At 12 weeks, there were no differences between the treatment groups in terms of Crohn's disease activity index, pain, stool frequency, inflammatory markers or quality of life scores. CONCLUSIONS: Enteric-release glyceryl trinitrate did not benefit patients with mild to moderately active Crohn's disease. Whilst ischaemia may contribute to the pathogenesis of Crohn's disease, our results fail to provide supportive evidence for this hypothesis.

Administration, Oral↗
PubMed2001

Fluorescence, reflectance, and light-scattering spectroscopy for evaluating dysplasia in patients with Barrett's esophagus.

BACKGROUND & AIMS: The aim of this study was to assess the potential of 3 spectroscopic techniques (fluorescence, reflectance, and light-scattering spectroscopy) individually and in combination, for evaluating low- and high-grade dysplasia in patients with Barrett's esophagus (BE). METHODS: Fluorescence spectra at 11 excitation wavelengths and a reflectance spectrum were acquired in approximately 1 second from each site before biopsy using an optical fiber probe. The measured fluorescence spectra were combined with the reflectance spectra to extract the intrinsic tissue fluorescence. The reflectance spectra provided morphologic information about the bulk tissue, whereas light-scattering spectroscopy was used to determine cell nuclear crowding and enlargement in Barrett's epithelium. RESULTS: Significant differences were observed between dysplastic and nondysplastic BE in terms of intrinsic fluorescence, bulk scattering properties, and levels of epithelial cell nuclear crowding and enlargement. The combination of all 3 techniques resulted in superior sensitivity and specificity for separating high-grade from non-high-grade and dysplastic from nondysplastic epithelium. CONCLUSIONS: Intrinsic fluorescence, reflectance, and light-scattering spectroscopies provide complementary information about biochemical and morphologic changes that occur during the development of dysplasia. The combination of these techniques (Tri-Modal Spectroscopy) can serve as an excellent tool for the evaluation of dysplasia in BE.

Barrett Esophagus↗
PubMed2001

Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit.

BACKGROUND & AIMS: The megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disease of childhood that presents early with intestinal hypoperistalsis, hydronephrosis, and hydroureters. Transgenic mice that lack the alpha3 subunit containing nicotinic acetylcholine (nAChR) have a phenotype similar to that of MMIHS. METHODS: We examined the expression of this subunit in control and MMIHS tissue derived from patients using in situ hybridization (ISH) and immunocytochemistry (ICC). RESULTS: In controls, both techniques showed a wide distribution of alpha3 nAChRs present in ganglion cells, muscle, and epithelium. By contrast, most MMIHS tissue gave negative staining with ISH and variable results with ICC. CONCLUSIONS: These observations are consistent with a lack of alpha3 nAChRs contributing to the pathogenesis of MMIHS.

Abnormalities, Multiple↗
PubMed2001

Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues.

Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

Adenoma↗