Biomedical subjects
Publications and source records attributed to F Clarke.
Flumazenil is a competitive benzodiazepine antagonist. It is indicated for reversal of excess benzodiazepine sedation under certain circumstances, including the reversal of overdosage effects when it is felt best to avoid ventilation, such as in the very old or the very young. We report a case where the use of flumazenil was associated with complete heart block in an elderly patient.
Lipoxygenase metabolites have been found to be active in the rosette inhibition assay by inducing increased rosette inhibition titres. Leukotrienes B4, C4, D4 and E4 were identified as possessing this activity. The cycloxygenase products, prostaglandins E2, D2 and F2 alpha had no such activity; however, prostaglandin E2 and to a lesser degree prostaglandin D2 could counteract the activity of the leukotrienes in this assay. The identified leukotrienes are the first characterised molecules known to display activity in the assay. In this respect they mimic the action of early pregnancy serum, an action ascribed to a so called 'early pregnancy factor'.
Following on from previous work reported in this journal, a practical system has been developed for in situ fibre reinforcement of bone cement in the hip joint prosthesis. A fibre preform is inserted during the operation, surrounding the metal stem of the prosthesis, forming a composite with the cement. Tests performed on full-scale models of the joint show improvements in fatigue life by more than an order of magnitude when a preform of metal fibres is used; this significantly delays the onset of cement cracking and stem loosening. Initial results reported previously suggest that other fibre materials such as carbon may give even greater improvements. Clinical trials have begun, using a form of the metal mesh.
Binding of triose-phosphate isomerase (D-glyceraldehyde-3-phosphate ketol-isomerase, EC 5.3.1.1) to muscle myofibrils depends upon the concurrent binding of either fructose-bisphosphate aldolase (EC 4.1.2.13), glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) or both of these enzymes together. Thus triose-phosphate isomerase does not bind directly to myofibrils but to glycolytic enzymes already bound to the myofibril. This was established using 125I-labelled enzymes, which are required to provide the necessary sensitivity for the measurement of the complex multiphasic adsorption isotherms. In the presence of aldolase, the most stable stoichiometric relationship is two aldolase bound per triose-phosphate isomerase. The results show that not all sites of aldolase or glyceraldehyde-3-phosphate dehydrogenase binding are available for triose-phosphate isomerase binding. Nevertheless, the results suggest the formation under particular circumstances of a minicomplex spanning the catalysis of fructose 1,6-bisphosphate to 3-phosphoglycerate. Such a complex could provide the physical basis of metabolic channeling in which metabolic intermediates are not released from the complex.
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Further biochemical characterisations of the 20 kd and 67 kd EPF active polypeptides from pregnant ewes' sera are described. Both polypeptides are shown to possess compact, disulphide linked domains which are almost totally resistant to proteolytic attack without prior reduction. In contrast to previous reports on the influence of ammonium sulphate on the expression of EPF activity, neither the biochemical nor the activity characteristics of either polypeptide is changed by ammonium sulphate fractionation. In addition, direct comparative studies have been performed which clearly distinguish the EPF active polypeptides from the known ovine hormones, prolactin, placental lactogen and growth hormone.
A series of monoclonal antibodies to human glomerular antigens was prepared by immunisation of a mouse with isolated whole glomeruli, followed by boosting with particulate glomerular basement membrane and fusion of murine spleen cells with the NSI-myeloma line. Hybridoma supernatants were screened jointly by a radioimmunoassay involving binding to isolated glomeruli, and by a 4-layer immunoperoxidase technique applied to polyester wax-embedded sections. Seven monoclonal antibodies with different specificities (PHM7-PHM13) were established and repeatedly cloned. Each antibody displayed a distinctive distribution within the glomerulus, including different patterns of staining of mesangial cells, mesangial matrix and glomerular basement membrane, in addition to extra-glomerular basement membranes and extracellular matrix. All antibodies also stained cellular outgrowths of isolated glomeruli cultured in vitro, and showed additive binding to cultured cells by radioimmunoassay. Physical characterization using absorptions with purified substrates, plus specific chemical and enzymatic digestions, indicated that PHM12 is directed against type IV collagen. PHM13 is directed against fibronectin as shown by absorption with purified fibronectin and immunoprecipitation of a 220 000 MW glycoprotein. The remaining 5 monoclonal antibodies, which react with carbohydrate (PHM7) or protein (PHM8-PHM11) determinants, were shown to be nonreactive with type IV collagen, fibronectin or other known glomerular components including sialic acid, laminin, amyloid P-component or various glycosaminoglycans. These monoclonal antibodies therefore appear to define a new series of human glomerular antigens, or possibly closely related antigenic determinants, which are synthesized by glomerular cells and incorporated into the mesangium and glomerular basement membrane. These antibodies, by providing markers for at least 2 antigens known to be important in glomerular cell-matrix interactions, should prove useful in research into the mechanisms involved in renal pathology.
A four-step procedure is described for the isolation of the polypeptides which are responsible for a major portion of the EPF activity present in pregnant ewes' sera between 3-8 weeks gestation. The procedure utilises large-scale molecular size fractionation on hollow fibres in combination with conventional ion-exchange chromatography and HPLC gel permeation. It yields two homogeneous active fractions. One contains a single polypeptide of molecular weight approximately 20K, the other a 67K polypeptide. When compared on either a weight or molar basis the 20K polypeptide was at least an order of magnitude more active in the rosette inhibition test than the 67K polypeptide. The 20K polypeptide appears to represent the major form of RIT active material (EPF) present in pregnancy sera at this stage of gestation in the ewe.
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Four black and three whilte families have a male-to-female transexual member surgically reassigned more than 5 years ag. The black families were more open than the white in declaring the reassignment within the family and community. Thereby they relieved themselves and the transexual member of a need for deception, defiance, or defensiveness, and they were less scheming and manipulative. Without the anxiety of concealment, they could feel more positive about sex reassignment as a form of rehabilitation. A formal public declaration of sex reassignment, analogous to a declared change of citizenship, would be advantageous in transexual rehabilitation.
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