Biomedical subjects
S Hawley
Publications and source records attributed to S Hawley.
Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.
This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P <.001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (>/=2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B.
Regulation of lipid metabolism by the AMP-activated protein kinase.
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Differential nuclear expression of enhancer A DNA-binding proteins in human first trimester trophoblast cells.
In order to investigate the possible molecular regulatory mechanisms that repress classical HLA class I and stimulate nonclassical HLA-G and E-class I gene transcription in human trophoblast cells, we searched for the nuclear expression of the enhancer A DNA-binding proteins of the KBF1/NF-KB/rel family. Using both purified extravillous cytotrophoblast and villous syncytiotrophoblast from first trimester human placenta, it appeared that members of this family were present in the cytotrophoblast and absent in the syncytiotrophoblast. First, using the double stranded enhancer A DNA nucleotidic sequence that contains the palindromic KB site, known to be the binding site of the p50 subunits of KBF1-NF-KB and c-rel factors, we demonstrated, by band-shift assay, that binding activity, inhibited by addition of anti-p50 polyclonal serum, was present in cytotrophoblast as well as control maternal decidual cells, embryonic fibroblasts, and the trophoblast-derived JAR cell line. In contrast, this DNA-protein complex was undetectable in syncytiotrophoblast nuclear extracts. The specificity of this protein-DNA complex was further demonstrated by its disappearance upon competition with an excess of cold homologous nucleotidic competitor. Other nucleoprotein complexes were also detected in all nuclear extracts, including syncytiotrophoblast, that were competed out by an excess of cold enhancer A competitor DNA but were not affected by the addition of anti-p50 or anti-NF-KB sera, suggesting the presence of additional enhancer A-binding factors different from the KBF1/NF-KB/rel family. Second, using a Western immunoblot analysis, a doublet around 85 kDa was specifically stained by the same anti-p50 serum in cytotrophoblast, maternal decidual cells, embryonic fibroblasts, and the JAR nuclear extracts whereas no signal was obtained in syncytiotrophoblast. Finally, immunofluorescence cell staining using the same anti-p50 serum showed a positive staining in both cytoplasm and nucleus of cytotrophoblast and its absence in syncytiotrophoblast. We hypothesize that this enhancer A DNA-binding factor might represent the c-rel trans-acting factor, related to p50/KBF1/NF-KB proteins, and we discuss its possible relevance to the HLA class I transcription in human tissues.
Human extravillous trophoblast MHC class I expression is resistant to regulation by interferon-alpha.
We have shown that MHC Class I antigen expression by first trimester human extravillous trophoblast cells is resistant to upregulation by IFN-alpha while embryonic fibroblasts of the same gestational age are responsive. This is in contrast to our previous finding that IFN-gamma increases both Class I mRNA and surface expression in these trophoblast cells. It would appear that human trophoblast has differential susceptibility to the effects of the two classes of IFN.
Tolerability of enteric-coated sulphasalazine in rheumatoid arthritis: results of a co-operating clinics study.
One thousand three hundred and eighty-two patients with rheumatoid arthritis requiring second-line therapy at 108 centres were entered into an open 6-months prospective tolerability study of enteric-coated sulphasalazine 2 g/day (Salazopyrin EN-tabs). Clinical and laboratory variables were measured, any adverse reactions and the reasons for withdrawal of medication were recorded. The outcome of therapy was known in 87.5% of patients entered of whom 65% continued with sulphasalazine beyond the 6-month study period. 3.2% withdrew for reasons unrelated to treatment, 5% for lack of effect and 26.8% due to an adverse event; gastrointestinal/central nervous 66.6%, rash 15.4%, haematological 5.1%, hepatic 4.7% and miscellaneous 8.1%. 1.2% of patients experienced potentially serious reactions: anaphylactic, haematological and hepatic. The majority of adverse events occurred early and were reversible upon cessation of medication. No clear relationship between withdrawal due to an adverse event attributed to sulphasalazine and the nature of the concomitant non-steroidal anti-inflammatory drug was identified.
Effect of government and commercial warnings on reducing prescription misuse: the case of propoxyphene.
We analyzed trends in prescribing and overdose deaths related to propoxyphene (e.g., Darvon) before and after a 1978-80 informational campaign carried out by the US Food and Drug Administration and the drug's manufacturer through mailed warnings, face-to-face education of prescribers, press releases, and labeling changes. The goals included a reduction in propoxyphene use with alcohol or other CNS depressants, reduced prescribing of refills, and cessation of prescribing for patients at risk of abuse and misuse (suicide). We conducted time-series analyses of nationwide propoxyphene use data 1974-83 and analyzed data on drug overdose death rates covering a combined population of about 83 million. Segmented regression methods were used to determine if the informational program was associated with changes in trends of prescribing or overdose deaths. Comparison drug series were analyzed to control for other secular trends in prescribing. Nationwide propoxyphene use during the warnings continued a pre-existing decline of about 8 per cent per year, but this decline halted after the warnings. The no-refill recommendation had no impact on refill rates. The risk of overdose death per propoxyphene prescription filled has remained about constant since 1979. Sharper declines in misuse of such drugs will require stronger, more sustained regulatory or educational measures.
Brief communication: human pregnancy sera from sequential stages of gestation are increasingly inhibitory to the growth of trophoblast cells in culture.
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Evaluation of a monoclonal antibody, BC-1, which identifies an antigen expressed on the surface membrane of human extravillous trophoblast.
This paper describes a new Mab BC-1 which is directed at a cell surface antigen expressed by extravillous cytotrophoblast and not by villous cytotrophoblast, so it is useful for distinguishing between the two populations. The antigen recognised by BC-1 is trypsin-resistant, which allows it to be used for flow cytometric analysis of living trophoblast isolated by enzymic disaggregation. However, BC-1 is not trophoblast-specific but cross-reacts with some other tissues, in particular endothelial cells and peripheral blood monocytes. The nature of this antigen has not been established.