Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.     

Attachment styles and sleep measures in a community-based sample of older adults

BackgroundMeasures of attachment style are often used to appraise social and emotional health. In developmental literature, the concept of attachment is used to explain relationships between children and their adult caregivers. While both attachment styles and sleep patterns are conceived as developmentally organized systems, very few studies have explored the link between the two. The present study examined whether attachment styles and sleep measures are associated among older adults.MethodsRelationships between attachment styles (i.e., secure, fearful, preoccupied, and dismissive) and subjective sleep measures were assessed utilizing data from 70 older participants (mean age: 68 ± 6 years; Blacks: 59% and Whites: 41%) in a community-based study assessing subjective health characteristics. After obtaining informed consent, each participant provided demographic and socioeconomic data, as well as relevant medical and subjective data.ResultsIndependent of participants’ demographic and subjective factors, significant correlations were found between the preoccupied attachment dimension and sleep measures. Specifically, individuals scoring high on the preoccupied attachment dimension were more likely to report daytime napping (r_p = 0.31, p < 0.01) and to use sleep-inducing medications (r_p = 0.37, p < 0.05). No significant correlations were found among sleep measures and the secure, dismissive, and fearful dimensions.ConclusionsImportant relations have been observed between specific attachment styles and subjective sleep factors in our data. Although only one-dimension (preoccupied) demonstrated statistical significance, a trend was observed, suggesting possible associations between the secure attachment style dimension and subjective sleep measures. Future studies are needed to broaden our understanding of the relationship between attachment styles and sleep patterns.     

Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats

Background and purpose:

Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease.

Experimental approach:

Obese male rats were treated with irbesartan (30 mg·kg⁻¹·day⁻¹, incorporated into chow) from 12 to 25 weeks of age.

Key results:

Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels (∼50%). Fasting plasma triglycerides were marginally reduced (∼25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%).

Conclusions and implications:

Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.     

Tumour necrosis factor in neonatal listeriosis: a case report

A newborn with fatal neonatal listeriosis developed septic shock, neutropenia, thrombocytopenia and profound hypoxaemia due to severe pulmonary hypertension. Tumour necrosis factor , interleukin-1- and interferon- serum concentrations were markedly elevated, suggesting the participation of these cytokines in the aetiopathogenesis of shock induced by Listeria monocytogenes in the neonate.Abbreviations IFN- interferon- - IFN- interferon- - IL-1 interleukin-1 - MPA monocytosis producing agent - TNF- tumour necrosis factor