Evaluation of a co-facilitated information and learning programme for service users: the EOLAS programme.

Background: The co-production and co-facilitation of recovery-focused education programmes is one way in which service users may be meaningfully involved as partners.

Objectives: To evaluate the impact of a clinician and peer co-facilitated information programme on service users' knowledge, confidence, recovery attitudes, advocacy and hope, and to explore their experience of the programme.

Methods: A sequential design was used involving a pre-post survey to assess changes in knowledge, confidence, advocacy, recovery attitudes and hope following programme participation.

Intensive monitoring for post-transplant diabetes mellitus and treatment with dipeptidyl peptidase-4 inhibitor therapy.

Aim: Current monitoring practices fail to diagnose patients with post-transplant hyperglycaemia and tend to delay initiation of treatment, which potentially results in adverse graft and morbidity outcomes. This real-world study set out to assess the impact on insulin resistance indices of a new clinical pathway for diagnosis and treatment of hyperglycaemia following renal transplantation.

Methods: A hundred and forty-seven adult renal transplant recipients, without pre-existing diabetes, from a single centre were included.

Outcomes of a co-facilitation skills training programme for mental health service users, family members, and clinicians: the EOLAS project.

Health policy is increasingly advocating for involvement of service users and family members in service development. In the present study, we evaluated the impact of a 4-day education programme in co-facilitation skills on clinician and peer (service users and family members) knowledge, confidence, and subsequent experience as co-facilitators. The programme was designed to train peers and clinicians as co-facilitators on a clinician and peer-led information programme for people experiencing mental health problems.

CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway.

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood.

NADPH oxidase activity of neutrophil specific granules: requirements for cytosolic components and evidence of assembly during cell activation.

Neutrophils and other phagocytic cells support host defense by ingesting microbes and destroying them with reactive oxygen species or oxygen independent mechanisms. Production of ROS is initiated by the phagocyte NADPH oxidase (phox), an enzyme system composed of several constituents. During activation of the cell cytosolic phox proteins (p47phox, p67phox, p40phox, and Rac2) translocate to the plasma membrane and specific granules fuse with the plasma membrane increasing the amount of flavocytochrome b(558).

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases.

Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in the FERM domain of Jak3 and investigated the functional consequences of these mutations. These mutations inhibited receptor binding and also abrogated kinase activity, suggesting interactions between the FERM and kinase domains.

Platelet P2 receptors: from curiosity to clinical targets.

Adenosine 5'-diphosphate (ADP) is a paracrine mediator that activates human blood platelets, causing them to become adhesive and thereby contributing to their role in hemostasis. The actions of ADP were initially thought to be mediated by a unique ADP receptor termed P2(T) found only on platelets and antagonized by ATP, but it appears that at least two P2Y receptor subtypes are involved, a P2Y(1) receptor linked in some way to control of intracellular-free calcium levels and another P2Y receptor linked via an inhibitory G protein to adenylate cyclase. In addition, the presence of excitatory P2X(1) receptors that mediate the influx of monovalent and divalent cations in response to both ADP and ATP has been demonstrated.

Neutrophils from patients after burn injury express a deficiency of the oxidase components p47-phox and p67-phox.

Infection is a major cause of morbidity and mortality in patients after thermal injury. This predisposition to infections is related, in part, to abnormal polymorphonuclear leukocyte (PMN) function and a diminished respiratory burst. To evaluate the biochemical basis for the defective respiratory burst after major burns, the status of the oxidase enzyme system and its components was investigated.

Platelets and neutrophils from healthy term neonates exhibit increased levels of immunoglobulins.

Immune-mediated thrombocytopenia and neutropenia are not uncommon problems in the newborn period. Such cytopenias have been associated with increased levels of IgG, IgM, or both, in the serum, documented by indirect assay, and/or on the cell surface, documented by direct assay, and decreased cell survival. However, interpretation of measurement of platelet- or neutrophil-associated antibodies is problematic due to the lack of data from healthy neonates.

(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923), a selective D2 dopamine receptor agonist demonstrates the presence of D2 dopamine receptors in the mouse vas deferens but not in the rat vas deferens.

Experiments were carried out using the D2 dopamine receptor-selective agonist (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923) in the rat and the mouse isolated vas deferens to determine whether these tissues contained inhibitory D2 receptors in addition to their inhibitory alpha-2 adrenoceptors. In the mouse vas deferens N-0923 and the alpha-2 adrenoceptor agonist clonidine inhibited the electrically evoked twitch responses. The actions of clonidine, but not of N-0923, were antagonized by the alpha-2 antagonist idazoxan (pKb = 7.

Flow cytometric analysis of residual white blood cell concentration and platelet activation antigens in double filtered platelet concentrates.

Reduction of contaminating leukocytes in platelet products by filtration has been shown to decrease the incidence of human leukocyte antigen (HLA) alloimmunization. Nonetheless, prevention is not complete when using current techniques, and a significant number of patients continue to exhibit clinical refractoriness and to produce alloantibodies. Interest in preventing HLA alloimmunization and other complications of white blood cell (WBC) contamination of transfused cellular products has resulted in ongoing efforts to increase the efficiency of leukodepletion filters.

Determinants of the atherogenic flux of low-density lipoprotein into arteries.

Evidence is provided that in anaesthetized rabbits the atherogenic uptake of low-density lipoprotein (LDL) by arterial walls is accelerated by norepinephrine at its physiological concentrations in rabbit and human blood. The principle of the experiments was to compare the uptake of intravenously injected, radioactively labelled LDL, methylated to prevent removal by high-affinity receptors, in the two carotid arteries of anaesthetized rabbits after infusing low concentrations of norepinephrine noradrenaline into one carotid and saline as control into the other, the volume rates of infusion being about 1% of the carotid blood flows. The results thus obtained may contribute towards an explanation for the accelerated atherosclerosis and the increased incidence of its clinical manifestation in conditions associated with elevated blood norepinephrine concentrations, including the episodic increases associated with stress and cigarette smoking as well as the more persistent increases caused by phaeochromocytoma.

Subtypes of P2-purinoceptors. Studies using analogues of ATP.

Studies using analogues of ATP have allowed a comparison of structure-activity relationships that has provided ample evidence for the existence of at least four subtypes of P2-purinoceptors responsive to adenine nucleotides. Competitive antagonists have defined clearly the P2T subtype, specific agonists are now available for the P2X and P2Y subtypes, and leads have been given for development of reversible specific antagonists for the P2X and P2Z subtypes. The availability especially of inhibitors of ectonucleotidases and of specific antagonists for each P2-purinoceptor subtype would enable the roles of endogenous extracellular nucleotides to be ascertained, as has already been shown for the interaction of platelets with the vasculature.

Evaluation of the binding to fixed platelets of agonists and antagonists of ADP-induced aggregation.

Steady state binding of eleven different ADP analogues to formaldehyde-fixed platelets has been determined in a competitive binding assay using 3H-ADP. The compounds tested were the inactive analogues L-ADP and L-ATP; the agonists 2-chloroadenosine 5'-diphosphate, adenosine 5'-O-(2-thiodiphosphate) and the diasteroisomeric pair Sp-adenosine 5'-(1-thiodiphosphate) (Sp-ADP-alpha-S) and Rp-adenosine 5'-(1-thiodiphosphate) (Rp-ADP-alpha-S); and the antagonists adenosine 5'-O-thiomonophosphate, 2-chloroadenosine 5'-O-thiomonophosphate, 2-choloroadenosine 5'-triphosphate, and the diastereoisomeric pair 5'-(1-thiotriphosphate) (Sp-ATP-alpha-S) and RP-adenosine 5'-(1-thiotriphosphate) (Rp-ATP-alpha-S). All compounds tested competed at the high affinity binding sites for ADP previously identified (Blood 1988; 71: 110-6) but in some cases competition could not be demonstrated at the low affinity sites because of the high nucleotide concentrations required.

Absence of P2-purinoceptors in hippocampal pathways.

1. Many apparent actions of adenosine 5'-triphosphate (ATP) are mediated by adenosine produced by enzymatic hydrolysis of the nucleotide. Previously described actions of ATP in the CNS have been partly due to this phenomenon.

Increased uptake of methylated low-density lipoprotein induced by noradrenaline in carotid arteries of anaesthetized rabbits.

Atherosclerosis is accelerated in hyperlipidaemias but, apart from the concentration of low-density lipoprotein (LDL) in the blood, very little is known about other influences on the disease process. We now provide evidence that in anaesthetized rabbits the atherogenic uptake of LDL by arterial walls is accelerated by noradrenaline at its physiological concentrations in rabbit and human blood. The principle of the experiments was to compare the uptake of intravenously injected, radioactively labelled LDL, methylated to prevent removal by high-affinity receptors, in the two carotid arteries of anaesthetized rabbits after infusing low concentrations of noradrenaline into one carotid and saline as control into the other, the volume rates of infusion being about 1% of the carotid blood flows.

Regulation of P2y-purinoceptor-mediated prostacyclin release from human endothelial cells by cytoplasmic calcium concentration.

1. ATP and ATP analogues induced prostacyclin (PGI2) secretion from human cultured umbilical vein endothelial cells. 2.

Evidence for the dependence of arterial haemostasis on ADP.

The possible involvement of adenosine diphosphate (ADP) in haemostatic platelet aggregation was investigated by determining the duration of primary haemorrhage as standardized bleeding times from punctures of small mesenteric arteries in anaesthetized rats. The bleeding times were highly significantly increased by infusing into the mesenteric arterial blood flowing towards the punctures either the nucleotide-dephosphorylating enzyme apyrase or the ADP-receptor antagonists ATP, adenosine 5'-(beta,gamma-methylene)triphosphonate (AMP-PCP) or 2-methylthioadenosine 5'-(beta,gamma-methylene)triphosphonate (2-MeS-AMP-PCP). The increases in bleeding times could not be accounted for by local vasodilator effects of the agents.

Characterisation of the ATP4- receptor that mediates permeabilisation of rat mast cells.

ATP (as the tetrabasic acid, ATP4-) applied externally to rat mast cells causes the formation of lesions which permit influx and efflux of low molecular weight, normally impermeant aqueous solutes. To monitor membrane permeabilisation we have used two fluorescent dyes, ethidium which stains the nucleus, and TMA-DPH which stains the cytosolic surfaces of intracellular membranes following entry into the cells Permeabilisation by ATP is not affected by the metabolic status of the cells, and is maintained at temperatures as low as 8 degrees C. We have tested the ability of 30 structural analogues of ATP to effect mast cell permeabilisation.

The structure-activity relationships of ectonucleotidases and of excitatory P2-purinoceptors: evidence that dephosphorylation of ATP analogues reduces pharmacological potency.

The dephosphorylation of adenine nucleotides and their analogues by ectonucleotidases on the guinea-pig urinary bladder was studied using HPLC. The rate of dephosphorylation of each analogue was compared with its pharmacological potency at causing contraction. ATP, ADP and AMP were rapidly dephosphorylated, and substitution on the purine ring did not affect the rate of breakdown.

Pharmacological effects of isopolar phosphonate analogues of ATP on P2-purinoceptors in guinea-pig taenia coli and urinary bladder.

Isopolar methylene phosphonate analogues of adenosine triphosphate (ATP) were synthesized and tested on the guinea-pig isolated taenia coli (where ATP causes relaxation) and urinary bladder (where ATP causes contraction), to see if restoration of the electronegativity of the methylene linkage would enhance pharmacological potency. The compounds used were the dichloromethylene and difluoromethylene analogues of adenosine 5'-(beta,gamma-methylene)triphosphonate (AMP-PCP), L-adenosine 5'-(beta,gamma-methylene)triphosphonate (L-AMP-PCP) and 2-methylthioadenosine 5'-(beta,gamma-methylene)-triphosphonate (2-methylthio-AMP-PCP). The order of potency of the analogues depended on the tissue, and was independent of the nature of the purine or ribose moieties.

Characteristics of the P2 purinoceptor that mediates prostacyclin production by pig aortic endothelial cells.

Release of prostacyclin was studied by superfusing small columns containing cells cultured on microcarrier beads. Transient dose-dependent stimulation of prostacyclin release by up to 500-fold was induced by adenosine 5'-triphosphate (ATP; 0.5-50 microM).