Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease

Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE ε4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD

The Ghrelin Signalling System Is Involved in the Consumption of Sweets

The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose- intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours

Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMonoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.Black Swan Research Initiative by the International Myeloma Foundation Icelandic Centre for Research European Research Council (ERC) University of Iceland Landspitali University Hospita

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Reward-related genes and alcohol dependence

Introduction: The rewarding properties of alcohol are mediated by the brain reward systems, specifically by the cholinergic-dopaminergic reward link, involving both nicotinic acetylcholine receptors (nAChRs) as well as the ghrelin signalling system. The susceptibility for developing alcohol dependence is influenced by genetic factors. Therefore, the aim of this thesis is to investigate the genes encoding nAChRs as well as ghrelin and its receptor (GHS-R1A) in human genetic association studies of alcohol dependence. Furthermore, various aspects of ghrelin signalling have been investigated in rats with different alcohol preference. Observations: In the genetic association studies it was shown that; (1) nAChR gene variants influence alcohol consumption and body weight in alcohol-dependent individuals; (2) genetic variants of the ghrelin signalling system influence the risk of developing alcohol dependence, even though the effect size is small, and these variants might also affect body weight. The animal studies in this thesis showed that; (3) GHS-R1A antagonism reduces alcohol intake in a genetic rat model of high alcohol consumption; (4) GHS-R1A gene expression is higher in high alcohol consuming rats than in low alcohol consuming ones in reward-related brain areas; (5) alcohol counteracts the reduction of plasma ghrelin levels over time. Conclusions: The data presented in this thesis suggest that genetic variations of reward-related genes may be involved in the pathogenesis of alcohol dependence, although not as major susceptibility genes. Rather, they contribute to increased vulnerability in the reward systems that, in combination with environmental factors, may lead to dependence

Non-use of Digital Health Meeting Services Among Swedish Elderly Living in the Countryside

Digital consultations in primary care have the advantage of offering equal healthcare for people residing in the countryside. While it is gaining acceptance among young- and middle-aged people, the elderly are reluctant to use it. The aim of this study was hence to identify reasons for non-use among elderly in the countryside and describe perceived possible challenges and opportunities with digital consultations. Semi-structured interviews were conducted with 13 persons over 65 years old residing in the Swedish countryside. There was a mistrust for services offered by private companies and their public funding, a lack of knowledge of available services, and a lack of perceived usefulness. Personal interaction and continuity was more important than time or travel conveniences, although these advantages were recognized. To prevent digital exclusion, caregivers need to offer information, encouragement, or tools for the elderly. Digital primary care also needs to offer familiarity, with continuity and personal connections

Non-use of Digital Health Meeting Services Among Swedish Elderly Living in the Countryside

Digital consultations in primary care have the advantage of offering equal healthcare for people residing in the countryside. While it is gaining acceptance among young- and middle-aged people, the elderly are reluctant to use it. The aim of this study was hence to identify reasons for non-use among elderly in the countryside and describe perceived possible challenges and opportunities with digital consultations. Semi-structured interviews were conducted with 13 persons over 65 years old residing in the Swedish countryside. There was a mistrust for services offered by private companies and their public funding, a lack of knowledge of available services, and a lack of perceived usefulness. Personal interaction and continuity was more important than time or travel conveniences, although these advantages were recognized. To prevent digital exclusion, caregivers need to offer information, encouragement, or tools for the elderly. Digital primary care also needs to offer familiarity, with continuity and personal connections

The perceptions of community members about school -community engagement with a high -achieving public high school

The purpose of this study was to explore the experiences of 12 community members who were engaged with a nationally recognized public high school and to describe their perceptions of their school engagement experience. Qualitative research procedure, specifically that of case study research, was used. Four themes emerged from the study; (1) the importance of education and school engagement in the community, as informants referred to an unwritten rule or perception about engagement that appeared to characterize the community—support the school and its programs, (2) school community engagement as a component of good parenting, as informants shared that engaging with the school was an important component to being a good parent, as was being involved with their students\u27 lives and activities, (3) the availability of engagement opportunities, as all 12 informants believed that if one wanted to engage with the school, opportunities were present, and (4) the importance of a welcoming climate projected by the school regarding engagement as informants felt welcomed and encouraged to become engaged with the high school

Non-use of Digital Health Consultations Among Swedish Elderly Living in the Countryside

Digital health consultations in primary care have the advantage of offering equal healthcare for people residing in the countryside. While it is gaining acceptance among young- and middle-aged people, the elderly are reluctant to use it. The aim of this study was hence to identify reasons for non-use among elderly in the countryside and describe perceived possible challenges and opportunities with digital health consultations. Semi-structured interviews were conducted with 13 persons over 65 years old residing in the Swedish countryside. There was a mistrust for services offered by private companies and their public funding, a lack of knowledge of available services, and a lack of perceived usefulness. Personal interaction and continuity was more important than time or travel conveniences, although these advantages were recognized. To prevent digital exclusion, caregivers need to offer information, encouragement, or tools for the elderly. Digital primary care also needs to offer familiarity, with continuity and personal connections