Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity.

BACKGROUND: Endoscopic surveillance of chronic colitis uses random biopsies to find dysplastic fields. Enhanced endoscopic methods are more sensitive for dysplasia detection, but their specificity for colorectal cancer risk is unknown. AIMS: To develop a mathematical model of the sensitivity of random biopsy surveillance, and determine the implications of negative, a single positive, or multiple positive biopsies for dysplasia, and compare the detection threshold to that detectable by enhanced endoscopy. METHODS: Using mathematical modelling, we calculated the confidence level with which dysplasia can be excluded, the dysplastic field size detection threshold, the predicted area of a dysplastic field, and the number of biopsies needed for a given dysplasia detection threshold and confidence level. RESULTS: 32 random biopsies provide only 80% confidence that dysplasia involving > or =5% of the colon can be detected. When a single biopsy of 18 is dysplastic, this predicts a dysplastic area (89 cm(2)) several orders of magnitude greater than dysplastic fields that are readily detectable by enhanced endoscopy (1 cm diameter), and the predicted field size increases rapidly with multiple positive biopsies. CONCLUSIONS: Random biopsy surveillance is sufficiently sensitive to detect large dysplastic fields with significant colorectal cancer risk. Enhanced endoscopy can detect much smaller dysplastic fields, but these have unknown (perhaps much lower) colorectal cancer risk. Small dysplastic fields should not be assumed to indicate a high colorectal cancer risk that warrants colectomy. Prospective studies are needed to define the colorectal cancer risk and optimal management of small dysplastic lesions.

Thyroid hormone regulation of myocardial Na/K-ATPase gene expression.

Employing published methods for isolation of cardiac myocyte nuclei from adult rat ventricular myocardium with the use of mechanical disruption without digestive enzymes, we obtained transcriptionally active cardiac myocyte nuclei with sufficient yield and purity. The relative content of Na/K-ATPase subunit mRNAs (alpha 1, alpha 2, and beta 1) in ventricular myocardium of euthyroid rats closely matched the relative rates of transcription of the respective subunit genes determined by nuclear run-on assay. Treatment of hypothyroid rats with T(3)to elicit hyperthyroidism was associated with 2.9-, 7.5-, and seven-fold increases in the contents of alpha 1-, alpha 2, beta 1-mRNAs, respectively. In contrast, rates of transcription of the subunit genes were not changed significantly by T(3), while transcription of the 18 S ribosomal gene was stimulated identical with three-fold by the treatment. A quantitative reverse transcription-polymerase chain reaction assay for measurement of primary RNA transcripts of the beta 1 gene was developed employing a rat genomic DNA fragment that contains the first exon and part of the first intron of the beta 1 gene. The relative abundance of beta 1 primary transcripts did not change in RNA isolated from hypothyroid, euthyroid, and hyperthyroid rats. It is concluded that: (1) The relative contents of Na/K-ATPase subunit mRNAs in euthyroid adult myocardium is primarily controlled at the transcriptional level, and (2) T(3)-induced increases in the contents of Na/K-ATPase subunit mRNAs in the heart is not associated with increased rates of transcription of the subunit genes, and the effect is mediated at the post-transcriptional level.