The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Emotion Processing, Reappraisal, and Craving in Alcohol Use Disorder Patients and Healthy Controls: A Functional Magnetic Resonance Imaging Study

Impaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive–motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815

Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2

Rift Valley fever in Kruger National Park : do buffalo play a role in the inter-epidemic circulation of virus?

Rift Valley fever (RVF) is a zoonotic mosquito-borne virus disease of livestock and wild ruminants that has been identified as a risk for international spread. Typically, the disease occurs in geographically limited outbreaks associated with high rainfall events and can cause massive losses of livestock. It is unclear how RVF virus persists during inter-epidemic periods but cryptic cycling of the virus in wildlife populations may play a role. We investigated the role that free-living African buffalo (Syncerus caffer caffer) might play in inter-epidemic circulation of the virus and looked for geographic, age and sex patterns of Rift Valley fever virus (RVFV) infection in African buffalo. Buffalo serum samples were collected (n = 1615) in Kruger National Park (KNP), South Africa, during a period of 1996–2007 and tested for antibodies to RVF. We found that older animals were more likely to be seropositive for anti- RVFV antibody than younger animals, but sex was not correlated with the likelihood of being anti-RVFV antibody positive. We also found geographic variation within KNP; herds in the south were more likely to have acquired anti-RVFV antibody than herds farther north – which could be driven by host or vector ecology. In all years of the study between 1996 and 2007, we found young buffalo (under 2 years of age) that were seropositive for anti-RVFV antibody, with prevalence ranging between 0 and 27% each year, indicating probable circulation. In addition, we also conducted a 4-year longitudinal study on 227 initially RVFV seronegative buffalo to look for evidence of seroconversion outside known RVF outbreaks within our study period (2008–2012). In the longitudinal study, we found five individuals that seroconverted from anti-RVFV antibody negative to anti-RVFV antibody positive, outside of any detected outbreak. Overall, our results provide evidence of longterm undetected circulation of RVFV in the buffalo population.This work was supported in part by a National Science Foundation Ecology of Infectious Diseases Grant (NSF DEB-1102493/EF-0723928 and EF-0723918). Brianna Beechler is supported by a Morris Animal Foundation Fellowship.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1865-16822016-02-27hj201

A 19-SNP coronary heart disease gene score profile in subjects with type 2 diabetes: the coronary heart disease risk in type 2 diabetes (CoRDia study) study baseline characteristics

Background The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits. Methods Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox’s Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185). Results Overall, 10-year CHD risk ranged from 2–72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plus risk group (n = 66) (p = 0.80) and a sample of UK healthy men (n = 1360). The GS was also associated with LDL-cholesterol (p = 0.05) and family history (p = 0.03) in a sample of UK healthy men (n = 1360). Conclusions CHD risk is high in this group of T2D subjects. The risk array is an accurate genotyping assay, and is suitable for estimating an individual’s genetic CHD risk. Trial registration This study has been registered at ClinicalTrials.gov; registration identifier NCT0189178

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A?42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A?42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A?42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC?2 pathway as drug-target

The complete sequence of the Acacia ligulata chloroplast genome reveals a highly divergent clpP1 gene

Legumes are a highly diverse angiosperm family that include many agriculturally important species. To date, 21 complete chloroplast genomes have been sequenced from legume crops confined to the Papilionoideae subfamily. Here we report the first chloroplast genome from the Mimosoideae, Acacia ligulata, and compare it to the previously sequenced legume genomes. The A. ligulata chloroplast genome is 158,724 bp in size, comprising inverted repeats of 25,925 bp and single-copy regions of 88,576 bp and 18,298 bp. Acacia ligulata lacks the inversion present in many of the Papilionoideae, but is not otherwise significantly different in terms of gene and repeat content. The key feature is its highly divergent clpP1 gene, normally considered essential in chloroplast genomes. In A. ligulata, although transcribed and spliced, it probably encodes a catalytically inactive protein. This study provides a significant resource for further genetic research into Acacia and the Mimosoideae. The divergent clpP1 gene suggests that Acacia will provide an interesting source of information on the evolution and functional diversity of the chloroplast Clp protease comple