Physiological,pharmacological and toxicological considerations of drug-induced structural cardiac injury

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.     

Geographic variation of epilepsy for older Americans: How close to the geographic variation of stroke?

Purpose: Given the strong association of stroke and epilepsy in older persons, and the existence of a Stroke Belt in the United States, we hypothesized that geographic variation in epilepsy prevalence would follow geographic patterns similar to stroke. Methods: We used a 2005 5% random sample of Medicare beneficiaries 65 and older in 48 U.S. contiguous states. Epilepsy was identified from claims for physician visits, hospitalizations, and outpatient procedures. Prevalence was obtained by state and county. Logistic regressions determined the independent association of the likelihood of epilepsy (prevalent or new case) and residence in Stroke Belt states, controlling for residence in highest epilepsy prevalence states, demographics (race, age, gender), comorbid conditions, cerebrovascular disease, dementia, and county characteristics. Key Findings: Of 1,212,015 beneficiaries, 11.9 per 1,000 had prevalent and 2.9 new cases of epilepsy. Nine of 11 Stroke Belt states were among the 20 states with the highest epilepsy prevalence. Counties in the 10 highest epilepsy prevalence states were more likely to be large urban counties with a higher number of neurologists or neurosurgeons per capita. The higher likelihood of prevalent epilepsy cases associated with Stroke Belt residence was explained by beneficiaries’ race; that associated with residence in high epilepsy prevalence states was not. The likelihood of new epilepsy cases was negatively associated with Stroke Belt residence when controlling for covariates. Significance: The geographic variation in epilepsy prevalence is not explained by variations in known risk factors. Further research should investigate why eastern U.S. states have higher frequency of epilepsy.     

Social Adjustment of Women With and Without a Substance-Abusing Partner

Little normative information is available about the psychosocial functioning of women who have a substance-abusing intimate partner. This study examined whether the social adjustment of women who indicate that they have a substance-abusing partner (n=69) is compromised relative to that of women who indicate that their partner does not abuse substances (n=68). Women with a substance-abusing partner reported compromised social adjustment relative to a comparison sample both overall and in five of six life domains (work, social/leisure, primary relationship, parental, family). Results suggest the potential benefit of expanding the focus of research and treatment to include effects and outcomes for these women and to influence treatment-related policy.     

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemia-reperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b⁺ cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis. The CD11b⁺/Ly6C^high population associated with the onset of renal injury and increase in proinflammatory cytokines, whereas the CD11b⁺/Ly6C^intermediate population peaked during kidney repair. The CD11b⁺/Ly6C^low population emerged with developing renal fibrosis. Principal component and hierarchical cluster analyses identified gene signatures unique to each population. The CD11b⁺/Ly6C^intermediate population had a distinct phenotype of wound healing, confirmed by results of studies inhibiting the macrophage colony-stimulating factor 1 receptor,whereas the CD11b⁺/Ly6C^low population had a profibrotic phenotype. All populations, including the CD11b⁺/Ly6C^high population, carried differential inflammatory signatures. The expression of M2-specific markers was detected in both the CD11b⁺/Ly6C^intermediate and CD11b⁺/Ly6C^low populations, suggesting these in vivo populations do not fit into the traditional classifications defined by in vitro systems. Results of this study in a renal ischemia-reperfusion injury model allow phenotype and function to be assigned to CD11b⁺/Ly6C⁺ monocyte/macrophage populations in the pathophysiology of disease after AKI.     

Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405^EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.     

Factor V Quebec revisited

Factor V Quebec has been described as a bleeding disorder that exhibits an autosomal dominant inheritance pattern and presents severe bleeding after trauma. Two members of a fourth-generation (IV.13 and IV.15) Canadian family have been studied in detail and are the subject of this report. Their clinical presentations and histories have been described previously (Tracy et al: J Clin Invest 74:1221, 1984). Persistent abnormalities include mild thrombocytopenia and defective platelet factor V. Plasma factor V is present at near normal concentration and is fully functional. Thus, the bleeding diathesis appears to reflect the absence of platelet factor V activity. The recent report (Hayward et al: Blood 84:110a, 1994 [suppl, abstr]) of multimerin deficiency in these individuals led us to reevaluate these patients. Western blot analyses of platelet lysates developed with a variety of monoclonal antibodies show that the alpha-granule proteins, fibrinogen, von Willebrand factor, factor V and osteonectin are decreased in concentration and significantly degraded in the platelets of these patients. Thrombospondin, while not degraded, is substantially decreased. In contrast, platelet factor 4 and beta-thromboglobulin do not appear to be affected. These observations suggest that the alpha- granules are correctly assembled but the contents are subsequently subjected to proteolytic degradation. The results indicate that factor V Quebec disorder is probably associated with a generalized defect that leads to degradation of most proteins of the alpha-granules.