Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1

Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson’s disease, Crohn’s disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identi ed. To investigate the signalling events through which LRRK2 acts to in uence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase

LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places

Associação entre líquen plano e infecção pelo vírus da hepatite C: um estudo prospectivo envolvendo 66 pacientes da clínica de dermatologia da Santa Casa de Misericórdia de São Paulo Association between lichen planus and hepatitis C virus infection: a prospective study with 66 patients of the dermatology department of the hospital Santa Casa de Misericórdia de São Paulo

FUNDAMENTOS: O líquen plano é dermatose inflamatória crônica de etiologia desconhecida. Sua associação com doença hepática, particularmente a hepatite C, é tema de diversos trabalhos em todo o mundo, desde 1990, quando a sorologia para detecção do vírus da hepatite C (VHC) se tornou disponível. OBJETIVOS: Este estudo visa avaliar uma possível relação causal entre a infecção pelo vírus C e o líquen plano. MÉTODOS: Tomaram-se por grupo de estudo 66 pacientes com líquen plano matriculados na Clínica de Dermatologia da Santa Casa de Misericórdia de São Paulo, no período de 2000 a 2003. O grupo comparativo foi constituído pelos doadores de sangue voluntários do Banco de Sangue da Santa Casa de Misericórdia de São Paulo, durante o período de outubro de 2001 a outubro de 2002. RESULTADOS: Dos 66 pacientes com líquen plano, cinco apresentaram sorologia positiva para VHC, representando 7,5% em comparação com 0,69% dos doadores de sangue. CONCLUSÕES: Esse resultado é compatível com muitos dados contidos na literatura médica mundial. Entretanto, são necessários novos estudos para o melhor conhecimento dessa controversa relação.<br>BACKGROUND: Lichen planus is a chronic inflammatory dermatosis of unknown etiology. Its association with liver diseases, particularly hepatitis C, has been widely approached since 1990, when serology for the detection of hepatitis C virus became available. OBJECTIVES: The objective of this study was to evaluate a possible causal relation between virus C infection and lichen planus. METHODS: Sixty-six patients with lichen planus seen at the Dermatology Department of Santa Casa de Misericórida de Sao Paulo from 2000 to 2003 were included in the study group. The control group comprised volunteer blood donors of the Blood Bank of Santa Casa de Misericórida de Sao Paulo, from October 2001 to October 2002. RESULTS: Five out of the 66 patients with lichen planus had a positive serology for HCV, representing 7.5% in comparison with 0.69% of the blood donors. CONCLUSIONS: Our findings are consistent with those reported in the medical literature. However, further studies are necessary to improve our knowledge on such a controversial relation