New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials.

Context: There has been little systematic attempt to validate current pharmacologic treatment algorithms and guidelines for severe personality disorder. Objective: We evaluated studies on the effectiveness of psychoactive drugs on specific symptom domains for borderline and/or schizotypal personality disorder. Data sources: The literature was searched for placebo-controlled randomized clinical trials (PC-RCTs) on the effectiveness of psychopharmacologic drugs in personality disorder patients. The PubMed, PsychINFO, PiCarta, Cochrane, and Web of Science databases were searched using the search terms borderline personality, schizotypal personality, personality disorder, cluster A, cluster B, treatment, drug, pharmacotherapy, antipsychotic, antidepressant, mood stabilizer, effect, outcome, review, and meta-analysis for studies published between 1980 and December 2007, and references were identified from bibliographies from articles and books. Study selection: Placebo-controlled randomized clinical trials on the efficacy of antipsychotics, antidepressants, and mood stabilizers regarding cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety; anger, and mood lability) were selected in patients with well defined borderline and/or schizotypal personality disorder. Studies whose primary emphasis was on the treatment of Axis I disorders were excluded. Meta-analyses were conducted using 21 retrieved studies. Results: Antipsychotics have a moderate effect on cognitive-perceptual symptoms (5 PC-RCTs; standardized mean difference [SMD] = 0.56) and a moderate to large effect on anger (4 PC-RCTs; SMD = 0.69). Antidepressants have no significant effect on impulsive-behavioral dyscontrol and depressed mood. They have a small but significant effect on anxiety (5 PC-RCTs; SMD = 0.30) and anger (4 PC-RCTs; SMD = 0.34). Mood stabilizers have a very large effect on impulsive-behavioral dyscontrol (6 PC-RCTs; SMD = 1.51) and anger (7 PC-RCTs; SMD = 1.33), a large effect on anxiety (3 PC-RCTs; SMD = 0.80), but a moderate effect on depressed mood (5 PC-RCTs; SMD = 0.55). Mood lability as an outcome measure was seldomly assessed. Mood stabilizers have a more pronounced effect on global functioning (3 PC-RCTs; SMD = 0.79) than have antipsychotics (5 PC-RCTs; SMD = 0.37). The effect of antidepressants on global functioning is negligible. Conclusions: Drug therapy tailored to well-defined symptom domains can have a beneficial effect on patients with severe personality disorder. The findings from this study raise questions on current pharmacologic algorithms. J Clin Psychiatry 2010,71(1):14-25 (C) Copyright 2010 Physicians Postgraduate Press, In

Direct measurements of biogenic dimethylsulphide fluxes from the oceans : a synthesis

Author Posting. © National Research Council Canada, 2004. This article is posted here by permission of National Research Council Canada for personal use, not for redistribution. The definitive version was published in Canadian Journal of Fisheries and Aquatic Sciences 61 (2004): 836-844, doi:10.1139/F04-047.This paper provides a brief overview of the state-of-the-art of techniques that are currently used for field measurements of trace gas fluxes and the subsequent derivation of gas transfer rates over the oceans. Special attention is given to the relaxed eddy accumulation (REA) and gradient flux (GF) techniques, which rely on empirical functions thus far mainly validated over land. The universality of these functions and their application at sea have not yet been fully evaluated. New experiments have shown that the emission of dimethylsulphide (DMS) can be measured by the REA and GF techniques. Moreover, these measurements have provided parameterizations of gas exchange rates that are within the range of relationships between wind speed and gas transfer that have recently been derived from eddy correlation (EC) and deliberate tracer measurements. Using DMS as a model, gas is potentially a powerful approach to intercalibrate the REA, GF, and EC techniques, test their applicability in the marine environment, and investigate processes that determine trace gas exchange across the ocean surface