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Biomedical subjects

G R Williams

Publications and source records attributed to G R Williams.

At least 19 recordsLinked to original sources
PubMed1992

Benign epithelial neoplasms of the appendix: classification and clinical associations.

The nomenclature of non-carcinoid epithelial proliferations of the appendix is confused and many of the terms used have no histogenetic basis. A classification based on the well-established diagnostic categories of colonic epithelial polyps has been proposed recently. We have applied this classification to 42 benign epithelial lesions of the appendix in order to determine its suitability for routine diagnostic use, and in order to determine the prognosis of patients with these lesions. All lesions could be classified as either hyperplastic, adenomatous, mixed hyperplastic/adenomatous or dilated appendices. Six cases were associated with a synchronous carcinoma of the colon with all types of appendiceal histology being represented. Follow-up of the remainder of the patients revealed two subsequent colonic carcinomas, at 3 and 6 years post-appendicectomy respectively. In both of these patients, the appendix had shown adenomatous epithelium. We suggest that adenomas of the appendix may have a similar prognostic significance to adenomas elsewhere in the large bowel.

Adult↗
PubMed1992

Effect of acute ventricular dilatation on fibrillation thresholds in the isolated rabbit heart.

We examined the effects of ventricular dilatation on epicardial refractoriness and ventricular fibrillation threshold (VFT) in the isolated, retrograde-perfused rabbit heart. Ventricular size was modified by acutely changing the volume of a fluid-filled balloon secured within either the left or right ventricle. Left ventricular dilatation (to an end-diastolic pressure of 30-38 mmHg) significantly decreased left ventricular effective refractory period (ERP) and myocardial wavelength (calculated as ERP x conduction velocity). Left VFT (determined by scanning the vulnerable period with a train of pulses) decreased from 6.4 +/- 0.9 to 4.4 +/- 0.5 mA; P < 0.01) with left but not right ventricular dilatation. Right ventricular dilatation was associated with a decrease in the right ventricular ERP and myocardial wavelength, and right VFT decreased from 13.6 +/- 1.8 to 4.1 +/- 0.3 mA (P < 0.01). Changes in VFT correlated with the decrease in local refractoriness and shortening of local excitation wavelength.

Animals↗
PubMed1992

Differential capacity of wild type promoter elements for binding and trans-activation by retinoic acid and thyroid hormone receptors.

Retinoic acid receptor (RAR) and thyroid hormone receptor (T3R) are structurally similar and can bind as homodimers or T3R-RAR heterodimers to a single synthetic DNA response element. The interaction of these two types of receptors with wild type elements, however, has not been systematically investigated. Promoter elements from genes regulated by retinoic acid (RA) or thyroid hormone (T3) were tested for response to T3 and RA in transient transfections in both JEG and COS cells. The elements were classified as primarily responsive to RA or to T3 or responsive to both ligands. Binding of highly purified RAR alpha and T3R alpha to the various elements was assessed using the gel shift assay. Those elements predominantly responsive to one ligand showed preferential binding to the appropriate receptor. A series of point mutations were introduced into the rat GH T3 response element to further define sequence requirements for response to both RA and T3. Down-mutations in any of the three hexamers (previously demonstrated to be required for full response to T3 and full binding of T3R) also decreased RA induction and RAR binding. However, only one of two sets of up-mutations for T3 response also increased RA induction, demonstrating differences in hexamer preference between RAR and T3R. Variation in spacing of the three hexamers did not influence RA vs. T3 induction or RAR vs. T3R binding according to the predictions of a simple hexamer spacing model. There was a strong correlation between the extent of T3R dimer binding and strength of T3 induction for a subset of elements studied in JEG cells (r = 0.97, P < 0.01) and a weaker but significant correlation in COS cells (r = 0.65, P < 0.05)). In contrast, RAR dimer binding by the wild type elements did not quantitatively correlate with RA induction in either JEG (r = 0.13, P > 0.05) or COS cells (r = 0.21, P > 0.05). These results suggests that RAR interacts with a heterodimer partner(s) which influences binding site specificity, whereas T3R heterodimer partner(s) is less likely to alter binding site recognition. The observed difference in COS and JEG cells as well as the weak T3R binding-function relationship of the malic enzyme element, however, suggest that the influence of T3R heterodimer partner(s) on binding site specificity is likely to vary with cell type and the specific element tested.

Animals↗
PubMed1992

Capacity for cooperative binding of thyroid hormone (T3) receptor dimers defines wild type T3 response elements.

Thyroid hormone response elements (T3REs) have been identified in a variety of promoters including those directing expression of rat GH (rGH), alpha-myosin heavy chain (rMHC), and malic enzyme (rME). A detailed biochemical and genetic analysis of the rGH element has shown that it consists of three hexamers related to the consensus [(A/G)GGT(C/A)A]. We have extended this analysis to the rMHC and rME elements. Binding of highly purified thyroid hormone receptor (T3R) to T3REs was determined using the gel shift assay, and thyroid hormone (T3) induction was measured in transient tranfections. We show that the wild type version of each of the three elements binds T3R dimers cooperatively. Mutational analysis of the rMHC and rME elements identified domains important for binding T3R dimers and allowed a direct determination of the relationship between T3R binding and function. In each element two hexamers are required for dimer binding, and mutations that interfere with dimer formation significantly reduce T3 induction. Similar to the rGH element, the rMHC T3RE contains three hexameric domains arranged as a direct repeat followed by an inverted copy, although the third domain is weaker than in rGH. All three are required for full function and T3R binding. The rME T3RE is a two-hexamer direct repeat T3RE, which also binds T3R monomer and dimer. Across a series of mutant elements, there was a strong correlation between dimer binding in vitro and function in vivo for rMHC (r = 0.99, P less than 0.01) and rME (r = 0.67, P less than 0.05) T3REs. Our results demonstrate a similar pattern of T3R dimer binding to a diverse array of hexameric sequences and arrangements in three wild type T3REs. Addition of nuclear protein enhanced T3R binding but did not alter the specificity of binding to wild type or mutant elements. Binding of purified T3R to T3REs was highly correlated with function, both with and without the addition of nuclear protein. T3R dimer formation is the common feature which defines the capacity of these elements to confer T3 induction.

Animals↗
PubMed1991

Oligomeric binding of T3 receptor is required for maximal T3 response.

Receptors in the thyroid-steroid hormone superfamily bind preferentially as dimers to palindromic response elements containing two hexameric half-sites. The 23-base pair rat growth hormone (rGH) T3 response element (T3RE), however, contains three hexameric binding domains, all of which are required for maximal T3 response. We examined the binding of purified T3 receptor alpha (T3R alpha), overexpressed in Escherichia coli, to wild-type and up and down mutations of the rGH T3RE to evaluate whether transcriptional potency correlates with changes in T3R binding. T3R binds to the rGH T3RE as a monomer, dimer, or higher order oligomer. Cooperative T3R dimer binding was demonstrated to two hexameric domains of the rGH T3RE arranged as either direct or inverted repeats. Decreased binding was seen with point mutations in each domain as well as with mutations which altered hexamer orientation and spacing within the site. These results demonstrate that all three hexamers of the rGH T3RE are involved in binding T3R. Occupancy of all three hexamers by T3R in the gel shift assay was observed with functional up mutations of the T3RE, increasing receptor concentration or addition of nuclear extract. The transcriptional response potencies of T3RE up or down mutants in a transient transfection assay correlated closely with T3R binding. These results confirm our earlier hypothesis that all three hexamers of the rGH T3RE bind T3R in a novel binding arrangement and provide a model for the interaction of T3R and other nuclear proteins with the DNA sequences of thyroid hormone-regulated genes.

Animals↗
PubMed1991

Polyacrylamide gel electrophoresis of reducing saccharides labeled with the fluorophore 8-aminonaphthalene-1,3,6-trisulphonic acid: application to the enzymological structural analysis of oligosaccharides.

Mono- and oligosaccharides, each containing a reducing end group, were labeled with the charged fluorophore 8-aminonaphthalene-1,3,6-trisulphonic acid and the resulting derivatives were separated with high resolution by polyacrylamide gel electrophoresis using a method developed recently (P. Jackson, Biochem. J. 1990, 270, 705-713) but with an alternative electrophoretic buffer system. The fluorescent derivatives of glucose and all its straight chain, alpha 1-4 linked, oligomers from maltose to maltoheptaose were well resolved. Various isomers such as maltose and lactose could be separated, as were maltose and cellobiose and some epimers, for instance glucose and galactose. The method was applied to the analysis of the partial sequential degradation of a complex oligosaccharide with neuraminidase and beta-galactosidase. Gels showing fluorescent saccharide band patterns were recorded in picomolar quantities either photographically or using an imaging system based on a cooled charge-coupled device.

Electrophoresis, Polyacrylamide Gel↗
PubMed1991

Thyroid hormone and glucocorticoid regulation of receptor and target gene mRNAs in pituitary GH3 cells.

We have examined the effects of triiodothyronine (T3), in dose-response and time-course studies, on T3 receptor (T3R) alpha and beta and glucocorticoid receptor (GR) mRNAs in rate pituitary GH3 cells, in parallel with T3 actions on expression of the growth hormone (GH) target gene. Modulatory influences of dexamethasone (dex) on T3 action were studied by treatment with dex before and during T3 treatment. T3 treatment (1-100 nM) for 24 h reduced T3R alpha mRNA, while the presence of dex (1 microM) enhanced the T3 effect on T3R alpha mRNA and induced T3 inhibition of T3R beta mRNA. Stimulatory effects of T3 treatment on GH mRNA and release were seen in the face of inhibition of T3R mRNAs; these effects on GH were also enhanced by the presence of dex. T3 treatment for 24 h increased GR mRNA; this effect was inhibited by the presence of dex. We next examined the influence of dex on GR and T3R alpha and beta mRNAs, in parallel with effects of dex on the prolactin (PRL) target gene. Modulatory influences of T3 on dex action were studied by treatment of cells with T3 before and during dex treatment. Treatment with dex (0.1-10 microM) for 24 h reduced GR mRNA, an action enhanced by the presence of T3 (100 nM). Dex treatment resulted in inhibition of PRL mRNA and release despite parallel inhibition of GR mRNA by dex; these effects were enhanced by the presence of T3. In contrast to actions on GR, dex has no effect on T3R mRNAs. These effects of T3 and dex on receptor mRNAs suggest that glucocorticoid modulation of T3 action is not related to direct actions on T3R synthesis. In contrast, the mechanism of T3 modulation of glucocorticoid action may be due in part to alteration of GR mRNA expression. Effects of T3 and dex on target gene expression were observed in the presence of parallel reduction of their respective receptor mRNAs. This provides new evidence that interactions between these hormones are likely to be mediated by mechanisms other than regulation of receptor gene expression.

Animals↗
PubMed1991

Hydrogen peroxide decreases effective refractory period in the isolated heart.

Although previous investigations have concluded that reactive oxygen metabolites contribute to reperfusion arrhythmias, the experimental models employed also had a significant amount of tissue injury, which may have contributed to the observed electrophysiologic effects. We studied whether exposure of the intact heart to a reactive oxygen metabolite at doses that are not associated with histologic evidence of cell necrosis would alter myocardial refractoriness, suggesting that subtle and reversible oxidative stress could alter myocardial electrophysiologic properties and perhaps contribute to ventricular arrhythmias. Isolated rabbit hearts were perfused for 30 min with low doses of hydrogen peroxide (H2O2), either 10(-5), 5 x 10(-6), or 10(-6)-M H2O2 versus vehicle alone; followed by a 30-min washout period without H2O2. Infusion of H2O2 for 30 min decreased ventricular epicardial effective refractory period (ERP) in a dose-dependent manner compared to saline controls (delta ERP). The delta ERP versus time curves during the last 10 min of H2O2 infusion were different (p less than 0.01) for each of the three H2O2 doses. Creatine phosphokinase and reversible oxidized glutathione release occurred during 10(-5)-M H2O2 infusion, but not with lower H2O2 doses. Exposure of the intact heart to low concentrations of H2O2, in a range that caused subtle oxidative injury, decreased ventricular ERP in a dose-dependent manner. Thus, H2O2 generation could contribute to ventricular arrhythmias, even in settings of sublethal and potentially reversible oxidative injury.

Animals↗
PubMed1991

Effects of varying the position of thyroid hormone response elements within the rat growth hormone promoter: implications for positive and negative regulation by 3,5,3'-triiodothyronine.

The thyroid hormone response element (T3RE) of the rat GH (rGH) promoter is located at -188 to -165 relative to the mRNA start site (TSS). Similar sites have been identified in other genes regulated by T3. We have investigated some of these T3REs in positions within the rGH promoter to assess the relative influences of DNA-binding site and position on positive and negative regulation by T3. Synthetic oligonucleotides were used with sequences from the rGH T3RE and proposed negative T3REs (nT3RE) from the rat and human alpha-subunit and rat beta TSH genes. The nT3REs were placed in the background of the wild-type rGH promoter in two positions, at -55 and down-stream of the TSS, with up- and down-mutations of the rGH T3RE. Rat GH T3RE elements were placed 700 basepairs up-stream of a basal rGH promoter and some also at the -55 and TSS positions. Constructions were tested in a transient transfection assay in rat pituitary tumor cells. Two copies of the rGHPAL (palindromic T3RE) placed 700 basepairs up-stream of the rGH promoter conferred 10-fold T3 induction. In the -55 position, the rGHPAL increased T3 induction compared to that in controls, whereas a fragment from the rat and human alpha-subunit gene in the same position reduced induction. Negative T3REs from rat beta TSH and human alpha-subunit reduced T3 induction 50% when placed at the TSS position of a rGH promoter containing an up-mutant T3RE. The T3REPAL placed at the same site increased T3 induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Spontaneous splenic rupture secondary to angiosarcoma.

Angiosarcoma of the spleen is a rare tumor with a very poor prognosis. Review of the world literature reveals only 57 reported cases of this neoplasm. Sixteen of these presented with an acute abdomen secondary to splenic rupture. Patients with this tumor have a mean survival time of 14.4 months after detection, and this decreases to 4.4 months after splenic rupture. The only rational treatment is splenectomy prior to splenic rupture. This paper describes another case presenting as spontaneous splenic rupture.

Adult↗
PubMed1989

Effects of flecainide on defibrillation thresholds in the anesthetized dog.

The effects of flecainide on defibrillation thresholds in 21 open chest, anesthetized dogs were studied. Defibrillation was accomplished using nontruncated exponential pulses delivered through two epicardial patches. Multiple shocks of varying energy were administered after 10 s of ventricular fibrillation in random order. The percent success was plotted against the energy delivered for each dog. A sigmoidal curve was fit to the data and the energy associated with 50% success (E50) calculated. Flecainide (n = 16) or saline solution (n = 5) was then infused and E50 again determined. Flecainide infusion produced mean (+/- standard error of the mean) plasma levels of 610 +/- 111 ng/ml. Defibrillation thresholds were obtainable in 10 of 16 dogs that received flecainide infusion. Flecainide infusion increased E50 by 75% (from 6.5 +/- 1.9 to 11.4 +/- 2.6 J) (P less than 0.05). Infusion of saline solution did not significantly affect defibrillation energy. Of 16 dogs that received flecainide infusion, 12 had one or more complications: 6 had ventricular fibrillation resistant to defibrillation, 6 developed severe hypotension after successful defibrillation and 5 had spontaneous ventricular fibrillation after successful defibrillation. These effects were not seen in any control dogs. Flecainide infusion significantly increases defibrillation threshold and has important adverse arrhythmic and hemodynamic effects in this experimental preparation.

Animals↗
PubMed1989

Errors in low flow oxygen delivery systems.

Accurate delivery of low flow oxygen is essential for the management of infants with chronic respiratory failure. Twenty-seven examples of one low flow oxygen meter were tested. Measured flows were found to differ greatly from indicated settings, particularly at 250 mL/min settings. Knowledge of such errors as well as improved quality control are essential for appropriate management of oxygen therapy.

Oxygen Inhalation Therapy↗