TNF-alpha antagonists: monoclonal antibodies, soluble receptors, thalidomide and other novel approaches.

Tumour necrosis factor-alpha (TNF-alpha) is a pleiotropic molecule produced in response to a variety of stimuli during normal host defence. At low levels, TNF-alpha confers protection against infectious agents, tumours and tissue damage, and plays a role in the development of humoral immunity. However, overproduction of TNF-alpha has been implicated in the pathogenesis of a wide variety of conditions, including autoimmunity, malignancy, inflammatory and immunopathological diseases.

Folate-based inhibitors of thymidylate synthase: synthesis and antitumor activity of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).

In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala.

Comparison of IL-2- and IL-4-transfected B16-F10 cells with a novel oil-microemulsion adjuvant for B16-F10 whole cell tumour vaccine.

The use of whole cell tumour vaccines in the treatment of malignant melanoma has given mixed results. Cytokine-transfected tumour cells as vaccine have shown efficacy in animal models but need to be compared with other means of enhancing a systemic anti-tumour immune response. A new generation of immunological adjuvants claimed to be more effective than the conventional adjuvants is now available for assessment.

First year RNs' actual and self-rated pharmacology knowledge.

A questionnaire survey was conducted of first year registered nurses whose postal details were recorded on the Victorian Nursing Council's 1994 mailing list. The nurses were asked to self-rate their knowledge of five categories of pharmacology and to answer questions that tested their knowledge of the same categories. The survey also obtained data related to aspects of the nurses' pharmacology education.

Are prostaglandins major mediators in perennial allergic rhinitis?

Certain prostaglandins acting as inflammatory mediators have been implicated in the aetiology of perennial allergic rhinitis (PAR). Inhibition of prostaglandin synthesis in the nasal mucosa might therefore influence the symptoms associated with PAR. A randomised, doubleblind, placebo-controlled cross-over trial using 0.

Interleukin-10-induced HIV-1 expression is mediated by induction of both membrane-bound tumour necrosis factor (TNF)-alpha and TNF receptor type 1 in a promonocytic cell line.

Objective: To investigate whether the upregulatory effect of interleukin (IL)-10 on HIV expression in a model of latent HIV infection is mediated by induction of endogenous tumour necrosis factor (TNF)-alpha and TNF receptors (TNFR).

Design: The latently HIV-infected promonocytic cell line U1 was examined, because in this in vitro model IL-10 has been shown to synergize with multiple cytokines, including TNF-alpha, in enhancing HIV production.

Methods: Membrane-bound TNF-alpha, TNFR-1 and TNFR-2 surface expression were determined by flow cytometry.

Abnormal cytokine profiles in patients with idiopathic dilated cardiomyopathy and their asymptomatic relatives.

Objectives: Immunological abnormalities in idiopathic dilated cardiomyopathy (DCM) include an increase in soluble interleukin (IL)-2 receptor, disease specific cardiac autoantibodies, an HLA-DR4 association, and familial aggregation of disease; however, cytokine profiles have not been defined. Serum concentrations of IL-2, IL-4, IL-10, and IL-12 were measured in patients with DCM (WHO criteria), relatives with asymptomatic left ventricular enlargement (LVE), patients with ischaemic heart failure (IHD), and healthy controls.

Design: Serum from 20 individuals from each of the four groups was assayed for cytokine concentrations by a commercial enzyme linked immunosorbent assay.

The functional affinity and specificity of autoantibodies in animal models of anti-glomerular basement membrane disease.

We studied characteristics of the anti-glomerular basement membrane (GBM) antibody response in three animal models of Goodpasture's disease: treatment of Brown Norway (BN) rats with the polyclonal activator mercuric chloride (HgCl2), and immunization of BN and Wistar Kyoto (WKY) rats with rat GBM. Serial serum samples were obtained over the time course of the models, and anti-GBM antibodies eluted from the kidneys. Functional affinity of the anti-GBM antibodies was measured in a solid-phase ELISA incorporating the mild chaotropic agent diethylamine.

Anti-phospholipid antibodies in the mercuric chloride treated brown Norway rat.

Anti-phospholipid antibodies (aPL), in the form of anti-cardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC), are found in a number of disorders, including systemic lupus erythematosus. Autoimmune aPL are associated with clinical manifestations that may include vascular thrombosis, recurrent fetal loss, thrombocytopenia, livedo reticularis and neurological abnormalities. aPL found in the context of infections such as syphilis are not usually associated with clinical complications.

Serial functional affinity of autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (GBM) disease is caused by an autoantibody directed against an epitope on the alpha 3 chain of type IV collagen. Animal models demonstrate that the higher the affinity of such antibodies, the greater the degree of glomerular injury. Affinity maturation (the process whereby somatic mutation followed by antigen selection leads to an increase in affinity of antibody) might therefore be of pathogenic significance if it occurs in human anti-GBM disease.

Antimitochondrial autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (GBM) disease is characterized by the production of an autoantibody with very restricted specificity, with no evidence of polyclonal B cell activation. It was therefore surprising to find that in a solid-phase ELISA a proportion of anti-GBM sera showed significant binding to pyruvate dehydrogenase (PDH), a reactivity usually associated with the antimitochondrial autoantibodies (AMA) found in primary biliary cirrhosis (PBC). The specificity of this reactivity was confirmed by inhibition and competition experiments.

The use of proprietary medicines by patients presenting with peptic ulcer haemorrhage.

1. Medication, social and symptom histories were compared in patients with severe haemorrhage from a peptic ulcer (n = 71) and matched control subjects. Self-medication with proprietary agents was catalogued in addition to therapy prescribed by general medical practitioners.

Lack of heart rate variation between morning and afternoon exercise testing in coronary artery disease patients.

The purpose of this study was to investigate cardiovascular [heart rate (HR), blood pressures, rate-pressure product (RPP)], physiological (oxygen uptake), and metabolic (blood plasma lactic acid concentration) responses during symptom-limited graded exercise testing (SL-GXT) during early morning and late afternoon hours in an unmedicated, regularly exercising, coronary artery disease population. Subjects, males ages 41-71 yr (n = 11), underwent SL-GXT via cycle ergometry at 8:30 A.M.

Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors.

Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.

Use of paramagnetic chelated metal derivatives of polysaccharides and spin-labeled polysaccharides as contrast agents in magnetic resonance imaging.

Soluble and insoluble polysaccharides were derivatized with diethylenetriaminepentaacetic acid (DTPA) and/or spin-labeled with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Polysaccharides derivatized with DTPA were prepared via cyanogen bromide activation, coupling to a diamine linker, and to DTPA anhydride. Spin-labeled polysaccharides were also prepared via cyanogen bromide activation.

Issues in the evaluation of a community psychogeriatric service.

The need for evaluation of community psychogeriatric programs is stressed. The results of the evaluation of an outpatient service, with a liaison component, based in a community general hospital are presented. The use of treatment outcome scales, user satisfaction surveys, and a study of cost effectiveness are discussed.

Effects of hypoxia upon contractions evoked in isolated rabbit pulmonary artery by potassium and noradrenaline.

1. Comparisons have been made between rabbit thoracic aorta and main pulmonary artery of the effects of hypoxia upon contractions evoked by noradrenaline (NA) and KCl (K+). 2.

Differential effects of hypoxia upon contractions evoked by potassium and noradrenaline in rabbit arteries in vitro.

1. A study has been made on isolated sections of rabbit femoral, renal and saphenous arteries of the effects of graded hypoxia (reducing bath PO2 from 110 mmHg, normoxia, to 55, 23 and 6 mmHg) upon contractile responses evoked by noradrenaline (NA) and KCl to 80% of maximum. 2.

The effects of verapamil upon noradrenaline-induced contraction of the rat isolated aorta following acute and prolonged alterations in PO2.

1. Noradrenaline (NA;ED90) caused a contraction of the rat aorta which could be separated into two components, a rapid response mediated by release of intracellular Ca2+ and a more slowly developing contraction which relied principally upon Ca2+ influx. 2.

Characterization and in vivo distribution of 99mTc- and 111In-labelled magnetite.

Magnetite (Fe3O4) particles 0.1-0.5 microns in diameter doped with either 99mTc or 111In have been prepared and characterized by electron microscopy and Mössbauer spectroscopy.

A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein.

1. The actions of the chemically distinct calcium entry blockers, verapamil (Ver), diltiazem (Dlz) and flunarizine (Flu) have been compared in rat isolated aorta and portal vein. 2.

Water-maze learning and effects of cholinergic drugs in mouse strains with high and low hippocampal pyramidal cell counts.

Morphological differences have been found in inbred strains of mice in the number and volume of pyramidal cells in Ammon's horn of the hippocampus. Among the mouse strains surveyed, NZB/BINJ (NZB) and C57BL/10J (B10) are most divergent in both total volume and total number of neurons. These genetically derived differences were exploited to determine hippocampal involvement in the acquisition of a spatial water maze.

An investigation of the actions of diltiazem on rat aorta exposed to acute hypoxia followed by re-oxygenation.

1 The effects of diltiazem and removal of extracellular Ca2+ were examined on contractions, of the rat isolated aorta, to noradrenaline (NA) and high K+, during exposure to oxygenated conditions and hypoxia followed by re-oxygenation. 2 Exposure to hypoxia caused a similar reduction of contractile responses to NA and KCl, while re-oxygenation restored contractile activity. 3 Ca2+-free conditions abolished responses to KCl but a transient response to NA remained which was resistant to hypoxia.

Amnesia-reversal activity of a series of cyclic imides.

A series of dihydro-1H-pyrrolizine-3,5(2H,6H)-diones were synthesized and evaluated for their ability to reverse electroconvulsive shock (ECS) induced amnesia in mice. Among the structure-activity relationships explored were the effects of ring size, the presence of heteroatoms (sulfur) in the ring system, and the introduction of alkyl substituents. The optimal ring size for the bicyclic system was 5.