ABSTRACT
Although beta blockers have had significant impact in the treatment of portal hypertension, the question of how long they should be continued for prevention of variceal hemorrhage remains unknown. Prospective studies on beta blockers to prevent variceal hemorrhage lack long-term follow-up, and indefinite administration of beta blockers for primary prevention of variceal bleeding has become standard practice. The aim of this study was to determine the outcomes of patients in whom beta blocker therapy was discontinued. Patients completing a prospective, randomized, double-blind, placebo-controlled trial of propranolol for the primary prevention of variceal hemorrhage were tapered off of propranolol and placebo and followed prospectively for subsequent events. Of the 49 patients in the follow-up study (25 former propranolol, 24 former placebo), 9 experienced variceal hemorrhage (6 former propranolol, 3 former placebo). Following withdrawal of propranolol, the freedom from variceal bleeding was not significantly different between these 2 groups of patients, suggesting that the protective effect of propranolol against variceal hemorrhage, noted previously, was no longer present. Seventeen patients died (12 former propranolol, 5 former placebo) during the follow-up study. Cumulative survival was longer in the placebo group. These trends for EVH and survival were opposite to those observed in the original study population while patients were taking medication. When propranolol is withdrawn, the risk of variceal hemorrhage returns to what would be expected in an untreated population. Patients who discontinue beta blockers experience increased mortality compared with an untreated population. These observations support the current practice of indefinite prophylactic therapy.
Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Esophageal and Gastric Varices/drug therapy , Gastrointestinal Hemorrhage/prevention & control , Propranolol/administration & dosage , Adrenergic beta-Antagonists/therapeutic use , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Propranolol/therapeutic use , Prospective Studies , Survival AnalysisSubject(s)
Hepatitis C, Chronic/diagnosis , Hyperbilirubinemia/etiology , Liver Transplantation/physiology , Postoperative Complications , Esophageal and Gastric Varices/surgery , Granulocyte Colony-Stimulating Factor/therapeutic use , Hepacivirus/growth & development , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/physiopathology , Humans , Interferon-alpha/therapeutic use , Liver Function Tests , Liver Transplantation/pathology , Male , Middle Aged , Recurrence , Transplantation, Homologous , Virus ActivationABSTRACT
Thyroid hormone is required for basal and estrogen-induced expression of anterior pituitary galanin. Steady-state anterior pituitary galanin mRNA levels decreased 6-fold in hypothyroid rats after 3 weeks of treatment. Similarly, hypothyroidism resulted in a 2.6-fold decrease in estrogen induction of galanin gene expression. The effect of thyroid hormone on anterior pituitary galanin gene expression appears to be exerted, at least in part, at the pituitary itself. Transient expression assays in GH3 cells suggest the involvement of transcriptional mechanisms in the regulation of galanin gene expression by thyroid hormone. A region between -41 and -132 bp upstream of the transcriptional start site confers thyroid hormone responsiveness to the galanin gene. Gel-mobility shift assays show specific binding of 'SPI-like' proteins in GH3 nuclear extracts to this region of the galanin gene. This binding was greatly enhanced by thyroid hormone.
Subject(s)
Estradiol/pharmacology , Galanin/biosynthesis , Gene Expression Regulation , Hypothyroidism/metabolism , Pituitary Gland, Anterior/metabolism , Thyroxine/pharmacology , Transcription, Genetic , Triiodothyronine/pharmacology , Animals , Base Sequence , Cell Line , Cells, Cultured , Gene Expression Regulation/drug effects , Genes, Reporter , Hypothyroidism/chemically induced , Male , Molecular Sequence Data , Pituitary Gland, Anterior/drug effects , Propylthiouracil , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/biosynthesis , Regulatory Sequences, Nucleic Acid , TransfectionABSTRACT
Growth factors coordinately regulate a variety of different genes to stimulate cellular proliferation. In the stomach, gastrin, epidermal growth factor (EGF), and transforming growth factor-alpha all mediate gastric mucosal homeostasis by promoting cell renewal. We have previously shown that EGF and phorbol esters stimulate the human gastrin promoter through a novel GC-rich DNA element 5'-(68)GGGGCGGGGTGGGGGG-53 called gERE (gastrin EGF response element). In this report, we show that three factors bind to this element, the transcription factor Sp1 and two fast migrating complexes designated gastrin EGF response proteins (gERP 1 and 2). To understand how these factors bind and confer EGF responsiveness, mutations of gERE were tested in vitro for protein binding and in vivo for promoter activation. Both gel shift assays and UV cross-linking studies revealed that the factors bind to overlapping domains, Sp1 to the 5' half-site and gERP 1 and 2 to the 3' half-site. Placing either the 5' or 3' mutations upstream of a minimal gastrin promoter abolished EGF induction. Therefore both the 5' and 3' domains were required to confer EGF induction. Collectively, these results demonstrate that complex interactions between Sp1 and other factors binding to overlapping gERE half-sites confer EGF responsiveness to the gastrin promoter.
