Neurobiological basis of the nicotine withdrawal reaction : an experimental analysis

The mesolimbocortical dopamine (DA) system is pivotal for the mediation of the reinforcing effects of many dependence-producing drugs. It consists of cell bodies in the ventral tegmental area (VTA) that project to e.g. the nucleus accumbens (NAC), the central nucleus of amygdala (CNA) and the medial prefrontal cortex. In experimental animals, nicotine increases DA output in the NAC, exerts a locomotor stimulatory effect and is readily self-administered. These effects of systemic nicotine appear largely mediated via nicotinic receptors (nAChRs) in the VTA. Moreover, recently the a7 nAChR subtype has been implicated in some of the acute effects of nicotine. The effects of nicotine withdrawal on behavior and mesolimbocortical dopaminergic neurotransmission in rats have remained largely unknown. Therefore, utilizing behavioral methods, in vivo microdialysis, intracerebral drug injections and immunohistochemistry, we explored in detail the effects of nicotine withdrawal on these parameters. Rats were, by means of subcutaneously implanted minipumps, treated chronically with a dose of nicotine that yielded plasma levels similar to those encountered in heavy smokers. A somatic nicotine abstinence reaction was induced through removal of the infusion pump or through administration of a nAChR antagonist, acting either centrally and peripherally or peripherally only. Administration of nicotine or of a peripherally acting nAChR agonist both reversed the withdrawal reaction. Systemic administration of the nAChR antagonist mecamylamine significantly reduced DA output in the NAC selectively in the nicotine-treated group. The somatic withdrawal signs and the reduction in NAC DA appeared not to be specifically or causally related. Also intrategmental injection of mecamylamine elicited a reduction in accumbal DA output, somatic withdrawal signs as well as hypolocomotion, whereas intraaccumbal administration of mecamylamine failed to elicit any changes in NAC DA output or in somatic signs. Similarly, intrategmental application of an a7 nAChR antagonist resulted in a decreased NAC DA output and a reduction in locomotor activity. Finally, nicotine withdrawal precipitated by a systemic injection of mecamylamine both attenuated DA output and activated c?fos in the CNA. These results demonstrate a significant contribution of peripheral nAChRs to the nicotine withdrawal reaction and predict that drugs stimulating selectively peripheral nAChRs may have some usefulness in smoking cessation. The withdrawal-induced reduction in NAC DA, if it occurs also in man, may have bearing on clinical symptoms such as depression and dysphoria that are often encountered in association with smoking cessation. In addition, the clinical efficacy of bupropion in smoking cessation programmes may largely be due to its ability to restore a compromised mesolimbic DA function. Specifically, nAChRs at the level of the VTA rather than in the NAC seem to contribute to the behavioral and biochemical consequences of nicotine withdrawal precipitated with systemic mecamylamine, and a role for a7 nAChRs within the VTA is indicated in this regard. The withdrawal-induced selective activation of c-fos in the CNA may have bearing on anxiety and distress, symptoms that in animals can be elicited from this brain region and frequently occur in nicotine abstinent humans

ENT COBRA (Consortium for Brachytherapy Data Analysis): Interdisciplinary standardized data collection system for head and neck patients treated with interventional radiotherapy (brachytherapy)

Purpose: Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection. Material and methods: GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group. Results: Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of "brokers", data can be extracted directly from the single center's storage systems through a connection with "structured query language database" (SQL-DB), Microsoft Access®, FileMaker Pro®, or Microsoft Excel®. The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of "on-purpose data projection". The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called "distributed learning" approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared. Conclusions: Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the center's own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.This study makes use of data generated by the UK10K Consortium, derived from samples from the ALSPAC and TwinsUK data sets. A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Funding for UK10K was provided by the Wellcome Trust under award WT091310. The research of N.S. is supported by the Wellcome Trust (grants WT098051 and WT091310), the European Union Framework Programme 7 (EPIGENESYS grant 257082 and BLUEPRINT grant HEALTH-F5-2011-282510) and the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or NHSBT. P.L.A. was supported by NHLBI R21 HL121422-02. A full list of grant support and acknowledgements can be found in the Supplementary Note and ref. 14