Estimating health care cost savings from an educational intervention to prevent bleeding-related complications: the outcomes impact analysis model.

INTRODUCTION: Investments in continuing medical education (CME) exceed $2 billion annually, but few studies report the economic impact of CME activities. Analysis of patient-level economic outcomes data is often not feasible. Accordingly, we developed a model to illustrate estimation of the potential economic impact associated with CME activity outcomes. METHODS: Outcomes impact analysis demonstrated how costs averted from a CME symposium that promoted prevention of bleeding-related complications (BRC) and reoperation for bleeding (RFB) in cardiac and thoracic operations could be estimated. Model parameter estimates were from published studies of costs associated with BRC and RFB. Operative volume estimates came from the Society of Thoracic Surgeons workforce data. The base case predicted 3 in 10 participants preventing one BRC or RFB in 2% or 1.5% of annual operations, respectively. Probabilistic sensitivity analysis (PSA) evaluated the effect of parameter uncertainty. RESULTS: 92% of participants (n = 133) self-reported commitment to change, a validated measure of behavior change. For BRC, estimates for costs averted were $1,502,769 (95% confidence interval [CI], $869,860-$2,359,068) for cardiac operations and $2,715,246 (95% CI, $1,590,308-$4,217,092) for thoracic operations. For RFB, the savings estimates were $2,233,988 (95% CI, $1,223,901-$3,648,719). DISCUSSION: Our economic model demonstrates that application of CME-related learning to prevent bleeding complications may yield substantial cost savings. Model prediction of averted costs associated with CME allows estimation of the economic impact on outcomes in the absence of patient-level outcomes data related to CME activities.

CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence.

Although a number of first- and second-generation antipsychotics are available, achieving optimal therapeutic response for patients with schizophrenia can be challenging. The presence of polymorphic alleles for cytochrome P (CYP) 450 may result in lack of expression, altered levels of expression, or altered function of CYP450 enzymes. CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels. Consequently, standard dosing may result in drug plasma concentrations that are subtherapeutic or toxic in some patients. Patient CYP450 genotype testing can predict altered pharmacokinetics, and is currently available and relatively inexpensive. Evidence-based guidelines provide dose recommendations for some antipsychotics. To date few studies have demonstrated a significant association with genotype-guided antipsychotic use and clinical efficacy. However, many studies have been small, retrospective or cohort designs, and many have not been adequately powered. Numerous studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia.

An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages.

MIP-1beta/CCL4 is a principal regulator of macrophage migration and signals through CCR5. Several protein kinases are linked to CCR5 in macrophages including the src kinase Lyn, PI3K, focal adhesion related kinase Pyk2, and members of the MAPK family, but whether and how these kinases regulate macrophage chemotaxis are not known. To define the role of these signaling molecules, we examined the functions and interactions of endogenous proteins in primary human macrophages. Using siRNA gene silencing and pharmacologic inhibition, we show that chemotaxis in response to CCR5 stimulation by MIP-1beta requires activation of Pyk2, PI3K p85, and Lyn, as well as MAPK ERK. MIP-1beta activation of CCR5 triggered translocation of Pyk2 and PI3K p85 from the cytoplasm to colocalize with Lyn at the plasma membrane with formation of a multimolecular complex. We show further that arrestins were recruited into the complex, and arrestin down-regulation impaired complex formation and macrophage chemotaxis toward MIP-1beta. Together, these results identify a novel mechanism of chemokine receptor regulation of chemotaxis and suggest that arrestins may serve as scaffolding proteins linking CCR5 to multiple downstream signaling molecules in a biologically important primary human cell type.

Signaling mechanism of HIV-1 gp120 and virion-induced IL-1beta release in primary human macrophages.

HIV-1 envelope glycoprotein gp120 induces, independently of infection, the release of proinflammatory cytokines, including IL-1beta from macrophages, that are implicated in the pathogenesis of HIV-associated dementia. However, the signal transduction pathways involved have not been fully defined. Previously, our laboratory reported that soluble gp120 activates multiple protein kinases in primary human monocyte-derived macrophages, including the Src family kinase Lyn, PI3K, and the focal adhesion-related proline-rich tyrosine kinase Pyk2. In this study we showed that gp120 induces IL-1beta release from macrophages in a time- and concentration-dependent manner through binding to the chemokine receptor CCR5 and coupling to G(i)alpha protein. Using pharmacological inhibitors and small interfering RNA gene knockdown, we demonstrated that concomitant activation of Lyn, Pyk2, and class IA PI3K are required for gp120-induced IL-1beta production. By coimmunoprecipitation and immunofluorescence confocal microscopy, we showed that CCR5 activation by gp120 triggered the assembly of a signaling complex involving endogenous Lyn, PI3K, and Pyk2 and is associated with PI3K and Pyk2 translocation from the cytoplasm to the membrane where they colocalized with Lyn. Finally, we demonstrated that virion-associated gp120 induced similar response, as structurally intact whole virions also triggered IL-1beta release and re-localization of PI3K and Pyk2. This study identifies a novel signaling mechanism for HIV-1-induced IL-1beta production by primary human macrophages that may be involved in the neuropathogenesis of HIV-associated dementia.

Functional coupling of the Galpha(olf) variant XLGalpha(olf) with the human adenosine A2A receptor.

A recently identified novel Galphaolf variant, XLGalphaolf, is shown to functionally couple to the human adenosine A2A receptor (A2AR). In Sf9 cells expressing A2AR, beta1, and gamma2, co-expression of XLGalphaolf increased NECA-induced [35S]GTPgammaS binding from approximately 130% to 300% of basal levels. Pharmacological characteristics of A2AR ligands on these cells were evaluated by using [3H]ZM241385- and [35S]GTPgammaS- binding assays. The rank order of the equilibrium binding constants (Kd or Ki) of adenosine receptor ligands were [3H]ZM241385 approximately CGS15943 < MRS1220 < < CV1808 approximately NECA < CGS21680 approximately adenosine < IBMECA < HEMADO approximately CPA approximately CCPA. The rank order of EC50 values for agonists were CV1808 approximately NECA < adenosine approximately CGS26180 < IBMECA < HEMADO approximately CPA approximately CCPA. This pharmacology is consistent with the literature for A2AR and suggests that Sf9 cells co-expressing A2AR, beta1, gamma2, and XLGalphaolf could serve as a heterologous expression system for A2AR drug screening.

The Src kinase Lyn is required for CCR5 signaling in response to MIP-1beta and R5 HIV-1 gp120 in human macrophages.

CCR5 is a receptor for several beta chemokines and the entry coreceptor used by macrophage-tropic (R5) strains of HIV-1. In addition to supporting viral entry, CCR5 ligation by the HIV-1 envelope glycoprotein 120 (gp120) can activate intracellular signals in macrophages and trigger inflammatory mediator release. Using a combination of in vitro kinase assay, Western blotting for phospho-specific proteins, pharmacologic inhibition, CCR5 knockout (CCR5Delta32) cells, and kinase-specific blocking peptide, we show for the first time that signaling through CCR5 in primary human macrophages is linked to the Src kinase Lyn. Stimulation of human monocyte-derived macrophages with either HIV-1 gp120 or MIP-1beta results in the CCR5-mediated activation of Lyn and the concomitant Lyn-dependent activation of the mitogen-activated protein (MAP) kinase ERK-1/2. Furthermore, activation of the CCR5/Lyn/ERK-1/2 pathway is responsible for gp120-triggered production of TNF-alpha by macrophages, which is believed to contribute to HIV-1 pathogenesis. Thus, Lyn kinase may play an important role both in normal CCR5 function in macrophages and in AIDS pathogenesis in syndromes such as AIDS dementia where HIV-1 gp120 contributes to inappropriate macrophage activation, mediator production, and secondary injury.