675 research outputs found
Development of a complex intervention to improve participation of nursing home residents with joint contractures: a mixed-method study
Joint contractures in nursing home residents limit the capacity to perform daily activities and restrict social participation. The purpose of this study was to develop a complex intervention to improve participation in nursing home residents with joint contractures
Genome Wide Meta-analysis Highlights the Role of Genetic Variation in RARRES2 in the Regulation of Circulating Serum Chemerin.
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0Ć10?8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8Ć10?14, beta = ?0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations
Das Tumormikromilieu bei SpeicheldrĆ¼senkarzinomen ā mƶgliche Konsequenzen fĆ¼r neue Therapiekonzepte
Hintergrund
SpeicheldrĆ¼senkarzinome (āsalivary gland carcinomasā, SGC) sind seltene Tumoren, die aufgrund ihrer histologischen Vielfalt und den in AbhƤngigkeit vom Subtyp unterschiedlichen KrankheitsverlƤufen eine Herausforderung fĆ¼r Diagnostik und Therapie darstellen. Ćber die Zusammensetzung des Tumormikromilieus (TME) bei SGC ist bislang wenig bekannt. Ein umfassenderes VerstƤndnis der relevanten molekularen VerƤnderungen und immunologischen Prozesse des Tumors sowie des umgebenden Stromas kƶnnte dazu beitragen, die therapeutische Effizienz ā beispielsweise durch eine adjuvante Immunmodulation ā zu verbessern.
Methoden
In diesem Manuskript wurden Ergebnisse aus Studien zusammengefasst, die sich mit der Zusammensetzung des TME bei SGC beschƤftigen.
Ergebnisse
Das Immunzellinfiltrat der verschiedenen TumorentitƤten ist unterschiedlich. Bei einem Drittel der SGC wurde eine Expression des OberflƤchenzellrezeptors LAG3 (ālymphocyte activation gene 3ā) auf tumorinfiltrierenden Lymphozyten beobachtet. LAG3 inhibiert ā Ƥhnlich wie CTLAā4 (ācytotoxic Tālymphocyte antigen 4ā) und PDā1 (āprogrammed cell death 1 proteinā) ā die zellulƤre Proliferation, Aktivierung und Homƶostase von antitumoral wirksamen TāZellen. Hƶhere Expressionen sind dabei insbesondere bei den prognostisch ungĆ¼nstigeren EntitƤten wie den Speichelgangkarzinomen und Adenokarzinomen NOS (ānot otherwise specifiedā) zu beobachten.
Schlussfolgerungen
LAG3 ist insbesondere bei aggressiven EntitƤten und fortgeschrittenen Tumoren nachzuweisen. Folglich kƶnnte eine Therapie mit LAG3-Inhibitoren eine Therapie bei fortgeschrittenen und metastasierten SGC unterstĆ¼tzen
A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz
The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.
Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex
Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes
Pemphigus vulgaris (PV) is an autoimmune disease characterized by binding of IgG autoantibodies to epidermal keratinocyte desmosomes. IgG autoantibodies obtained from a patient with mucocutaneous PV reacted with plakoglobin (Plkg) in addition to desmoglein-3 (Dsg3) and Dsg1. Immunofluorescence analysis confirmed that IgG autoantibodies, unlike antibodies from a healthy volunteer, caused disruption of cell-cell contacts in HaCaT keratinocytes. Moreover, apoptosis was enhanced in cells treated with autoantibodies compared to those treated with normal antibodies. The apoptotic process induced by IgG autoantibodies was characterized by caspase-3 activation, Bcl-2 depletion and Bax expression. The present report demonstrates that PV IgG autoantibodies promote apoptosis in HaCaT keratinocytes
Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study
Background:
Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.
Methods:
We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10ā195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106ā353 patients with established coronary heart disease and 19ā332 deaths in 22 studies or cohorts.
Findings:
The median follow-up was 9Ā·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1Ā·44, 95% CI 1Ā·14ā1Ā·83) and the presence of either LPA SNP (1Ā·88, 1Ā·40ā2Ā·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0Ā·95, 0Ā·81ā1Ā·11 and either LPA SNP 1Ā·10, 0Ā·92ā1Ā·31) or cardiovascular mortality (0Ā·99, 0Ā·81ā1Ā·2 and 1Ā·13, 0Ā·90ā1Ā·40, respectively) or in the validation studies.
Interpretation:
In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
Funding:
Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fĆ¼r Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny
Structure and Function of the Hair Cell Ribbon Synapse
Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse ā the electron-dense synaptic ribbon or synaptic body ā has been recognized for decades, dissection of the synapseās molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years
Growing old at home ā A randomized controlled trial to investigate the effectiveness and cost-effectiveness of preventive home visits to reduce nursing home admissions: study protocol [NCT00644826]
<p>Abstract</p> <p>Background</p> <p>Regarding demographic changes in Germany it can be assumed that the number of elderly and the resulting need for long term care is increasing in the near future. It is not only an individual's interest but also of public concern to avoid a nursing home admission. Current evidence indicates that preventive home visits can be an effective way to reduce the admission rate in this way making it possible for elderly people to stay longer at home than without home visits. As the effectiveness and cost-effectiveness of preventive home visits strongly depends on existing services in the social and health system existing international results cannot be merely transferred to Germany. Therefore it is necessary to investigate the effectiveness and cost-effectiveness of such an intervention in Germany by a randomized controlled trial.</p> <p>Methods</p> <p>The trial is designed as a prospective multi-center randomized controlled trial in the cities of Halle and Leipzig. The trial includes an intervention and a control group. The control group receives usual care. The intervention group receives three additional home visits by non-physician health professionals (1) geriatric assessment, (2) consultation, (3) booster session.</p> <p>The nursing home admission rate after 18 months will be defined as the primary outcome. An absolute risk reduction from a 20% in the control-group to a 7% admission rate in the intervention group including an assumed drop out rate of 30% resulted in a required sample size of N = 320 (n = 160 vs. n = 160).</p> <p>Parallel to the clinical outcome measurement the intervention will be evaluated economically. The economic evaluation will be performed from a society perspective.</p> <p>Discussion</p> <p>To the authors' knowledge for the first time a trial will investigate the effectiveness and cost-effectiveness of preventive home visits for people aged 80 and over in Germany using the design of a randomized controlled trial. Thus, the trial will contribute to the existing evidence on preventive home visits especially in Germany.</p
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