Biomedical subjects
Publications and source records attributed to D Picard.
The percutaneous transjugular intrahepatic portacaval stent shunt is a nonsurgical approach to portosystemic shunting. The case of a large defect seen on a radiocolloid liver--spleen scan is attributed to a hepatic infarct related to the shunting procedure.
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This report describes the prevalence of non-cavitated and cavitated carious lesions in 911 randomly selected children in grades one through three on the Island of Montreal, Quebec, Canada. The criteria for diagnosis were developed for a longitudinal epidemiological study of restorative treatment decisions by dentists practising under a provincial dental insurance program for children. The intra- and inter-examiner reliability correlation coefficients of the two examiners were excellent (Kappa > or = 0.80). The most frequent carious lesion found in the examined children were non-cavitated carious lesions (incipient) within 1.5 of the gingival line on smooth tooth surfaces, and stained or non-cavitated carious lesions on pits and fissures. Out of 911 children in the study, 19.6% had sealants. Children whose parents completed a university education had a significantly lower prevalence of non-cavitated and cavitated carious lesions and fillings, and a significantly higher mean number of sealants than children whose parents had only primary school education. Education status of the parents was a significant risk marker of children with high caries experience and these children had a significantly higher mean number of non-cavitated carious lesions. This study has found that non-cavitated carious lesions are significantly more prevalent than cavitated carious lesions in children.
A 28-yr-old male with Rotor's disease was studied with 99mTc-mebrofenin. The scintigraphic pattern was that of a slow liver uptake with unimpaired excretion and persistent visualization of the cardiac blood pool, kidneys and urinary tract up to 6 hr. The gallbladder was visualized at 55 min postinjection.
The protooncogene c-fos has been implicated in the control of proliferation and transformation of fibroblasts, and its protein product is an essential component of transcription factor AP1. The important target genes and, hence, the molecular mechanism of Fos function are, however, still unknown, partly due to the lack of a tightly regulated Fos-induction system. Here we show that different activities of the Fos protein can be controlled hormonally by fusing the mouse c-Fos protein to the ligand-binding domain of either the rat glucocorticoid or the human estrogen receptor. These fusion proteins stimulate AP1-dependent transcription and repress endogenous fos mRNA synthesis in a strictly hormone-dependent manner. Expression of these chimeric proteins in rat fibroblasts results in fast, reversible, and tightly controlled transformation in response to hormone. A Fos-estrogen receptor expressing cell line was used to isolate Fos-responsive genes by subtractive cDNA cloning. Run-on analysis of one of these genes showed that its transcription is rapidly and directly regulated by the hormone-activated Fos-estrogen receptor protein, demonstrating the potential of this induction system for identifying Fos target genes.
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Signalling by steroid hormones is mediated by receptor proteins that bind hormonal ligands and regulate the transcription of specific genes. The heat-shock protein hsp90 seems to associate selectively with unliganded receptors (aporeceptors), but it has not been determined whether this interaction affects receptor function in vivo. To address the role of hsp90, we have taken advantage of the capacity of mammalian steroid receptors to function in yeast. We constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type. At low levels of hsp90, aporeceptors seem to be mostly hsp90-free, yet fail to enhance transcription; on hormone addition, the receptors are activated but with markedly reduced efficiency. Thus hsp90 does not inhibit receptor function solely by steric interference; rather, hsp90 seems to facilitate the subsequent response of the aporeceptor to the hormonal signal. This is the first biological evidence that hsp90 acts in the signal transduction pathway for steroid receptors.
We have developed a vector system for inducible gene expression in both fission yeast (Schizosaccharomyces pombe) and budding yeast (Saccharomyces cerevisiae). The autonomously replicating expression vector contains multiple glucocorticoid response elements, rendering a linked promoter inducible 20-70-fold by glucocorticoid hormones in the presence of the mammalian glucocorticoid receptor. A polylinker with several unique cloning sites allows insertion of cDNAs of interest. Glucocorticoids are gratuitous signalling molecules in yeast, exerting little or no effect on the expression of genes other than those fused to the regulated promoter.
The glucocorticoid receptor accumulates in nuclei only in the presence of bound hormone, whereas the estrogen receptor has been reported to be constitutively nuclear. To investigate this distinction, we compared the nuclear localization domains of the two receptors and the capacity of their respective hormone-binding regions to regulate nuclear localization activity. As with the glucocorticoid receptor, we showed that the human estrogen receptor contained a nuclear localization signal between the DNA-binding and hormone-binding regions (amino acids 256-303); however, in contrast to the glucocorticoid receptor, the estrogen receptor lacked a second nuclear localization domain within the hormone-binding region. Moreover, the hormone-binding domain of the unliganded estrogen receptor failed to regulate nuclear localization signals, although it efficiently regulated other receptor functions. We conclude that the two receptors employ a common mechanism for signal transduction involving a novel "inactivation" function, but that they differ in their control of nuclear localization. Thus, despite the strong relatedness of the estrogen and glucocorticoid receptors in structure and activity, certain differences in their properties could have important functional implications.
Patients with ascites are known to have complications such as pleural effusions and hernias. Special diagnostic procedures are occasionally necessary to determine the nature of the abnormality and to determine the corrective medico-surgical approach. The two cases described illustrate the usefulness of intraperitoneal as well as intrapleural injection of a radionuclide in diagnosing the leakage of ascitic fluid.
The Tc-99m HMPAO brain imaging confirmed marked hypoperfusion secondary to anomalous cerebral venous drainage of the Sturge-Weber syndrome. Until now, this had been a hypothesis suggested by results obtained from conventional brain scans and cerebral arteriography.
We examined the usefulness of technetium-99m-phytate (99mTc-phytate) hepatic scintigraphy in the evaluation of hepatic function, and the assessment of prognosis in patients with cirrhosis. Ninety-four patients with biopsy-documented cirrhosis had, at the time of entry into the study, a scintigraphy with 99mTc-phytate complexed with calcium in vivo. Extrahepatic uptake (EHU) of 99mTc-phytate on scintigraphy was graded from 0 (absent EHU) to 5 (important EHU) according to the relative distribution of the radiotracer between the liver, the spleen and the bone marrow. The severity of liver disease was also assessed according to the index of Child and Turcotte as modified by Pugh et al. Mean follow-up was 2 yr. EHU was correlated to the Pugh score (r = 0.73) and to survival. Survival at 2 yr was 97% for an EHU equal or inferior to 2.5, 62% for grades 3-4.5, and 31% for grade 5. In conclusion, hepatic imaging with 99mTc-phytate, in addition to its diagnostic value, also contains valuable prognostic information in patients with cirrhosis.
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The human proto-oncogene myc encodes a nuclear phosphoprotein whose primary biochemical function is still unknown. To facilitate further study of that function, we have created conditional alleles of myc by fusing the hormone-binding domain of the human oestrogen receptor gene to the 5' or the 3' end of human myc. The two chimaeric genes, designated mycer and ermyc, encode proteins that bind oestrogen with high affinity. Expression of one of the genes, mycer, transforms a rat fibroblast cell line in a tightly oestrogen-dependent manner. Transformation is dependent on the presence of a functional myc gene in the chimaera and is reversible upon removal of the hormone. The chimaeric genes will be useful tools to study the mechanisms by which Myc affects cellular phenotype. Recently, chimaeras between the adenovirus E1A protein and the hormone binding domain of the rat glucocorticoid receptor were shown to activate transcription in a manner characteristic for E1A, but in a hormone regulated manner. We therefore asked whether the same strategy could be applied to the product of myc.
Numerous studies on somatic cell hybrids have shown that expression of tissue-specific functions can be suppressed as a consequence of fusion with cells that do not express the given functions. We have further investigated this phenomenon, using as a model system the regulation of expression of kappa light chain genes in intraspecific hybrids between mouse myeloma cells and mouse fibroblasts. Hybrids containing only one genome equivalent from each parent cell (1s:1s) were isolated by fluorescence-activated cell sorting from within 10 h after fusion, and they were grown for no more than 16 days thereafter in order to ensure maximum integrity of the genomic constitution. Here we report that in hybrid cells, kappa gene transcription was specifically turned off as demonstrated by nuclear run-on assays performed on 16-day-old proliferating hybrids. Furthermore, a mechanism affecting mRNA stability may also contribute, at least initially, to the rapid depletion of cytoplasmic kappa transcripts, observed during the first few hours after fusion. Suppression was dominant and could not be overridden by increasing the relative myeloma ploidy at either the heterokaryon or the synkaryon stage. Nor could suppression be relieved by treating hybrids with cycloheximide.
The glucocorticoid receptor is a signal transducer that interacts both with the signal and with the genes it regulates. We showed previously that nuclear localization of the receptor requires hormone binding. We have now constructed recombinant receptors that relieve hormonal control of nuclear localization, and we demonstrate that the DNA binding/transcriptional regulatory functions of the receptor are also regulated directly by hormone. Surprisingly, regulation by the steroid binding domain appears to be relatively independent of protein structure. For example, regulation is maintained when the steroid binding region is repositioned from the C-terminus to the N-terminus of the receptor. Furthermore, the activity of an unrelated protein, the adenovirus E1A gene product, becomes hormone regulated upon fusion to the steroid binding domain. We speculate that the inhibitory effect of the unliganded steroid binding domain may be mediated by heat shock protein hsp90, which binds selectively to the unliganded receptor.
The glucocorticoid receptor regulates transcriptional initiation upon binding to its cognate hormone. A series of fusion genes was constructed to examine the mechanism of hormone-regulated transcriptional enhancement. The DNA binding domain of the bacterial LexA repressor was fused to receptor derivatives lacking the region that is necessary and sufficient for specific DNA binding and transcriptional enhancement at glucocorticoid response elements (GRE's). The resultant hybrid proteins activated transcription from promoters linked to the lex operator. Enhancement still required hormone binding by the hybrid receptor regardless of the exact positioning of the LexA binding domain within the protein. Thus, the unliganded hormone binding domain of the receptor acts as a strong but reversible inhibitor of receptor activity in a manner that is independent of the means by which the receptor recognizes DNA. The results also show directly that the receptor contains at least one "enhancement domain" other than that overlapping the GRE binding region; the second domain, enh2, occupies a region near the receptor amino terminus.