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33P Medical Research Society 11 H Y P E R S E C m I O N OF LUTEINISING HORMONE (LH) IN THE POLYCYSTIC OVARY SYNDROME (PC0S)A.H. B A L M , DEPT. ENWCRINOLOGY. UIDDLESEX HOSPITAL, LONDON. WlN E M . Hypersecretion of LH, a feature of the PCOS. is' associated with an increased risk of infertility and miscarriage. It appears to be due to abnormal, non-steroidal, ovarian-pituitary feedback. Women receiving superovulation treatment have an attenuated mid-cycle LH surge and are thought to secrete an excess of an ovarian LH-inhibitory factor, which appears to be nonsteroidal, and has been termed "gonadotrophin surge attenuating factor", although it has yet to be isolated. Our hypothesis is that women who hypersecrete LH are deficient in this putative factor. A novel, in-vitro, rat pituicyte culture system was developed as a bioassay for LH and FSH inhibitory activity in human follicular fluid. The following observations were made: 1. Rat pituicytes autonomously secreted FSH in serum-free medium over a period of up to 12 days. LH was only secreted after stimulation by gonadotrophin-releasing hormone (GnRH). 2. Recombinant human inhibin inhibited basal FSH secretion and GnRH-stimulated FSH and LH secretion. The time course for inhibition of FSH was 4 hours, whilst inhibition of LH was not seen until 16 hours in culture. 3. Human follicular fluid contained FSH and LH inhibitory bioactivity, which remained after the removal of steroids, but was lost when inhibin was removed. The time course for these effects was similar to that of inhibin. This suggested 'that the putative LH-inhibitory factor, may infact be either inhibin or a member of the inhibin family. The findings are consistent with the notion that a non-steroidal ovarian factor may influence pituitary LH secretion. The experiments, however, were not able to demonst rate the presence of an LH-inhi bi tory factor distinct from inhibin. 12 ENDOTHELlALCELL ACTIVATION IN INFLAMMATORYREACTIONS J R BRADLEY oepartment ol Medicine. Addenbrodte's Hospbl. Cambrdge c82 200 Vascular endolhelil cells (EC) respond to products d adwaled leucocytes by undwgoinga rmmber ol l u n c l i l Changes *h endow them m(h the CapacllY lo pomote inllammatory r e a e l i . For example. cytokines such as TNF. IL-1 and interterons cause cytoskelecalchanges which increase vascular permeability. and the synthesis and eapreslon ol surlace glycoproteim which enable EC to interact wilh leukocytes. I have lound that sub-injurious concentrations of hydrogen peroxlde cause reversible EC relraclin and selectively increase steady state mRNA and surface e m i o n . ol i n t d l u l a r adhesm molecule-1 (ICAM-1) and MHC class 1. This abiliy d hydrogen peroxide to mimic some eltects 01 cytokiner rakes lhe possWii that c y l o k i i gene induction may be medlaled by a lree-cadical dependent pathway. In suppoll d this TNF and 1L-l-induclw)nof the Iramcriplbn lactor NFKB. of mRNA encoding endothelil leucocyle adhesion nukuIe-1 (ELAM-1). ICAM-1 and vascular cell adheson molecule-1 (VCAM-1).and ol sutace ercpressbn d there molecules. can be in part inhailed by the antioxidant Kace(yl-L-cysteine. m e r . hydrogen peroxide does mt aclvale NFrB in EC. Furthemnre.co-trealm ol EC with hydrogen peroxideihbils TNFinduced oene expression at 4h. an Meet which is associsted with reversible inhaiton ol spaatk Iialj-TNF binding lo EC sutlace receptors These results suggast that hydmgen pem& c a n acIhrale vascular endolhelium. but that the elfects. and the s i g n a l i mechanisms imohred. dilter lrom those d cytokines I have investigated lutther the signalling pathways involved in cytokine aclivation 01 EC Binding 01 cylokine to EC sullace receplors is IoUowed by lnternalisatlon of the receptorcyldrine conplex. Ihave found that expasure d &I$ to phamawbglcalinhibnm , d reeepla-medialed endocytoda such as hypertonicly. cytoplasm acdlicalion. metabolic lnhbnbn by phenylarsine oxide. and primary amines. each inhibits intemalitbn ol TNF. and each inhibiis TNF-inducedsurface expressm 01 ELAM1. Remarkably. aU lrealmenls exeepl phenyiarsineox&. which irreversw inhiMs EC prolein synthesis. selectively inhibii the response to TNF compared to the . response 10 PMA. a d w that Induces EUM-1 through a pathway that bvpasss surface receptors Primary amnes. Whtch can be used lor up In 72h under physlokgcat culture conditions. inhibit TNF induction 01 C A M 1 and VCAM t expresston. as well as IL-1-inducedincreases in ELAMI CAM-I and VCAM-1 Primary annnes ako inhbt TNF-. IFN+ and IFN-~ned~aled induction d class I MHC molecules and IFN7-md1atedinducton d class II MHC molecules Levels 01 mRNA encoding cylokine-inducible molecules are also selectively reduced by primary amines These results suggest that gene induction by inflammatory cytokines may involve receptor-mediated endocylosis Colleclively these data suggest that anli-oxidanls and primary amnes may provlde two polenlially rloucl therapies Whch d l l y the intlammalory capaclty ot EC 13 IDENTIFICATION OF TRANSCRIPTION FACTORS INVOLVED IN HUMAN CARDIAC GENE EXPRESSION N BRAND, P BHAVSAR, N EABHADE, M YACOUB and P BARTON Molecular Biology Group, Department of Cardiothoracic Surgery, National Heart and Lung Institute. London SW3 6LY, UK We are studying how cardiac gene expression may be regulated in two ways; by dissecting at the molecular level the promoter for the human cardiac Troponin I gene (TnIc), expressed solely in cardiac muscle and cloned in our laboratory (Vallins er al (1990) FEBS Letts m:57-61; Barton ef 01, in press), and by cloning transcription factors (TFs) from cardiac muscle and analysing their function. Using reverse transcriptaselpolymerasechain reaction techniques (RTlPCR) we have isolated cDNA clones for six potential TFs expressed in human heart which are related in sequence to the mammalian testis-determining factor These facton, named SOX for =-box. are expressed in both adult atrial and ventricular muscle, and also fetal heart (Denny ef al(1992) NAR a:2887). We are currently charactensing one clone, SOXS. which appears to be expressed only in muscle, including cardiac, skeletal and vascular smooth muscles. Further, using RTlPCR we have been unable to identify from cardiac muscle facton which are analogous to the MyoD family of TFs expressed in skeletal muscle. A n atrial muscle cDNA library was screened w i t h oligonucleotide probes specific for conserved regions within zinc finger TFs. Several cDNA sequences related to the Drosophila gap gene kruppel were isolated. including an Spllike sequence and at least two sequences which may represent alternatively spliced products of the gene encoding the human homologue of the mouse gene mkr5. Additionally we have cloned a novel kruppel-related cDNA called PLZF (for . RomyelocyticLeukaemia Zinc Anger) in collaboration with Dr. Arthur Zelent, Leukaemia Research Fund Centre, London. -PLZF was initially identified from a single case of acute promyelocytic leukaemia in which a t(1 I ; 17) translocation involving the PLZF and relinoic acid receptor-a loci results in the expression of novel reciprocal transcripts encoding chimaeric TFs (Chen er ul, EMBO 1.. in press). The function of PLZF in cardiac muscle is currently being examined. m. ' 14 , THE ROLE OF THE EXTRA-CELLULAR MATRIX IN THE MIGRATION AND LOCALISATION OF THE HAIRY CELLS (HCs) OF HAIRY-CELL LEUKAEMIA (HCL) ].BURTHEM P.K.BAKER J.C.CAWLEY Department of Haanatology. Royal Livapool University Hospital. Prescot Street. Liverpool L7 8XP. England. t The tissue distribution of the malignant HCs in HCL is very distinctive and includes invasion of splenic red pulp, hepatic sinusoids and bone