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The present study has been designed for pharmacological validation of chronic social stress paradigm as a model of depressive symptoms in rats. For this, rats were subjected to 5 weeks of daily social defeat and in parallel treated for clinically relevant period of 4 weeks with antidepressant drugs citalopram and reboxetine and neuroleptic drug haloperidol. Anxiolytic diazepam was administered acutely at the end of the stress period. The effects of social stress and the treatments were investigated in behavioural paradigms such as sucrose preference, forced swim test, open field test and elevated plus maze. Four weeks of oral treatment with applied antidepressants ameliorated the adverse effects of social stress and normalized behaviours related to motivation and reward sensitivity. The treatment with haloperidol worsened the adverse effects of chronic social stress having effects similar to stress on reward and motivation related behaviours. Treatment with diazepam caused reduction of anxiety related behaviours as measured in elevated plus maze in control animals having no effects on socially stressed individuals. Neither sucrose preference nor performance in forced swim test was affected by diazepam treatment. Effectiveness and selectivity of antidepressant treatment in ameliorating socially induced behavioural disturbances proofs validity of chronic social stress as a model of depressive symptoms in rats.
Stress-induced structural and cellular alterations in the hippocampus can contribute to the pathophysiology of depression. The reversal of these alterations may be a mechanism by which antidepressants achieve their therapeutic effect. The aim of the present study was therefore to investigate the effect of tianeptine on stress-induced structural changes and alterations in cerebral metabolites. To this end, psychosocially stressed male tree shrews were treated with tianeptine. A combination of in vivo and postmortem methods was used to evaluate the antidepressant treatment on the preservation of neuronal plasticity. It was found that all stress-induced effects were prevented by the administration of tianeptine. It is concluded that these findings provide experimental evidence for recent theories that impairment of neuronal viability and neuroplasticity might be important causal factors in mood disorders, suggesting tianeptine as a potential stimulator of neural resilience.
Individuals with bipolar disorder (BD) are differentially affected by insulin resistance. Individuals without history of mental disorder with insulin resistance usually have high peripheral concentrations of phenylalanine (PHE) and tyrosine (TYR) together. Catecholamine dysfunction is described to be a state-dependend phenomen in patients suffering from BD. Catecholamines are synthesized from essential amino acids PHE and TYR which are biotransformed to dopamine and subsequently converted to nor/adrenaline. Amino acid dysregulation may be a possible mediator of insulin resistance in BD.
Peripheral PHE and TYR concentrations were investigated in euthymic adults with BD. Amino acid differences between normal and overweight individuals with BD were evaluated and outcomes were correlated with the measures of glucose homeostasis.
Mean plasma PHE to TYR ratio (PHE/TYR) was at the upper limit of the normal range in the whole sample. Enrolled subjects with PHE/TYR beyond the limits of normal exhibited the highest number of prior affective episodes. Sex-specific differences were noted as overweight BD females showed different profiles than normal-weight women. In the overweight females, PHE and TYR concentrations were significantly higher compared to normal-weight women. Significant correlations were noticed between PHE, TYR and PHE/TYR with insulin/Homeostasis Model of Assessment (HOMA)-IR in the whole sample and the subgroup of BD women.
These significant differences in gender, amino acid pathways and in correlations with immune marker as well as insulin function have not been reported previously. Taken together, increased levels of PHE in BD should be considered when adjudicating diabetes risk especially in women.
Bipolar Disorder is a devastating disease with a genetic heritability. An orchestra of around 500 gene variants is leading to vulnerability.
One interesting candidate gene group are the socalled CLOCK GENES. The molecular 24h clock has several CLOCK GENES and the last gene ARNTL encodes for an activator of MAOA transcription and leads therefore to changes in neurotransmitter levels.
Genotyping of 150 paricipants with Bipolar Disorder and 78 healthy controls with the Illumina GWAS chip Omniexpress 1.1. Hypothesis driven extraction of ARNTL SNPs with the software PLINK. Statistical analysis with Chi square test with SPSS.
Patients with Bipolar Disorder differ significantly in ARNTL genotypes compared to healthy controls. Details are presented during the poster session.
Circadian rhythms seem to play an important pathogenetic mechanism in Bipolar Disorder.
We generalize work by Bourgain and Kontorovich [On the local-global conjecture for integral Apollonian gaskets, Invent. Math. 196 (2014), 589–650] and Zhang [On the local-global principle for integral Apollonian 3-circle packings, J. Reine Angew. Math. 737, (2018), 71–110], proving an almost local-to-global property for the curvatures of certain circle packings, to a large class of Kleinian groups. Specifically, we associate in a natural way an infinite family of integral packings of circles to any Kleinian group
satisfying certain conditions, where
is an imaginary quadratic field, and show that the curvatures of the circles in any such packing satisfy an almost local-to-global principle. A key ingredient in the proof is that
possesses a spectral gap property, which we prove for any infinite-covolume, geometrically finite, Zariski dense Kleinian group in
containing a Zariski dense subgroup of
A number of laser facilities coming online all over the world promise the capability of high-power laser experiments with shot repetition rates between 1 and 10 Hz. Target availability and technical issues related to the interaction environment could become a bottleneck for the exploitation of such facilities. In this paper, we report on target needs for three different classes of experiments: dynamic compression physics, electron transport and isochoric heating, and laser-driven particle and radiation sources. We also review some of the most challenging issues in target fabrication and high repetition rate operation. Finally, we discuss current target supply strategies and future perspectives to establish a sustainable target provision infrastructure for advanced laser facilities.
Plant sterols (PS) lower LDL-cholesterol, an established risk factor for CHD. Endothelial dysfunction and low-grade inflammation are two important features in the development of atherosclerosis. Whether PS affect biomarkers of endothelial function and low-grade inflammation is not well studied. The aim of the present study was to investigate the effect of regular intake of PS on biomarkers of endothelial dysfunction and low-grade inflammation. In a double-blind, randomised, placebo-controlled, parallel-group study, which was primarily designed to investigate the effect of PS intake on vascular function (clinicaltrials.gov: NCT01803178), 240 hypercholesterolaemic but otherwise healthy men and women consumed a low-fat spread with added PS (3 g/d) or a placebo spread for 12 weeks. Endothelial dysfunction biomarkers (both vascular and intracellular adhesion molecules 1 and soluble endothelial-selectin) and low-grade inflammation biomarkers (C-reactive protein, serum amyloid A, IL-6, IL-8, TNF-α and soluble intercellular adhesion molecule-1) were measured using a multi-array detection system based on electrochemiluminescence technology. Biomarkers were combined using z-scores. Differences in changes from baseline between the PS and the placebo groups were assessed. The intake of PS did not significantly change the individual biomarkers of endothelial dysfunction and low-grade inflammation. The z-scores for endothelial dysfunction (−0·02; 95 % CI −0·15, 0·11) and low-grade inflammation (−0·04; 95 % CI −0·16, 0·07) were also not significantly changed after PS intake compared with placebo. In conclusion, biomarkers of endothelial dysfunction and low-grade inflammation were not affected by regular intake of 3 g/d PS for 12 weeks in hypercholesterolaemic men and women.
The glycaemic and insulin indices assess postprandial glycaemic and insulin response to foods, respectively, which may not reflect the long-term effects of diet on insulin response. We developed and evaluated the validity of four empirical indices to assess the insulinaemic potential of usual diets and lifestyles, using dietary, lifestyle and biomarker data from the Nurses’ Health Study (NHS, n 5812 for hyperinsulinaemia, n 3929 for insulin resistance). The four indices were as follows: the empirical dietary index for hyperinsulinaemia (EDIH) and the empirical lifestyle index for hyperinsulinaemia (ELIH); the empirical dietary index for insulin resistance (EDIR) and the empirical lifestyle index for insulin resistance (ELIR). We entered thirty-nine FFQ-derived food groups in stepwise linear regression models, and defined indices as patterns most predictive of fasting plasma C-peptide, for the hyperinsulinaemia pathway (EDIH and ELIH), and of theTAG:HDL-cholesterol ratio, for the insulin-resistance pathway (EDIR and ELIR). We evaluated the validity of indices in two independent samples from NHS-II and Health Professionals Follow-up Study (HPFS) using multivariable-adjusted linear regression analyses to calculate relative concentrations of biomarkers. The EDIH is comprised of eighteen food groups; thirteen were positively associated with C-peptide and five were inversely associated. The EDIR is comprised of eighteen food groups; ten were positively associated with TAG:HDL-cholesterol and eight were inversely associated. Lifestyle indices had fewer dietary components, and included BMI and physical activity as components. In the validation samples, all indices significantly predicted biomarker concentrations – for example, the relative concentrations of the corresponding biomarkers comparing extreme index quintiles in the HPFS were EDIH, 1·29 (95 % CI 1·22, 1·37); ELIH, 1·78 (95 % CI 1·68, 1·88); EDIR, 1·44 (95 % CI 1·34, 1·55); and ELIR, 2·03 (95 % CI 1·89, 2·19); all Ptrend<0·0001. The robust associations of these novel hypothesis-driven indices with insulin response biomarker concentrations suggest their usefulness in assessing the ability of whole diets and lifestyles to stimulate and/or sustain insulin secretion.
As physical activity may modify the effect of the apolipoprotein E (APOE) ε4 allele on the risk of dementia and Alzheimer's disease (AD) dementia, we tested for such a gene–environment interaction in a sample of general practice patients aged ⩾75 years.
Data were derived from follow-up waves I–IV of the longitudinal German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). The Kaplan–Meier survival method was used to estimate dementia- and AD-free survival times. Multivariable Cox regression was used to assess individual associations of APOE ε4 and physical activity with risk for dementia and AD, controlling for covariates. We tested for gene–environment interaction by calculating three indices of additive interaction.
Among the randomly selected sample of 6619 patients, 3327 (50.3%) individuals participated in the study at baseline and 2810 (42.5%) at follow-up I. Of the 2492 patients without dementia included at follow-up I, 278 developed dementia (184 AD) over the subsequent follow-up interval of 4.5 years. The presence of the APOE ε4 allele significantly increased and higher physical activity significantly decreased risk for dementia and AD. The co-presence of APOE ε4 with low physical activity was associated with higher risk for dementia and AD and shorter dementia- and AD-free survival time than the presence of APOE ε4 or low physical activity alone. Indices of interaction indicated no significant interaction between low physical activity and the APOE ε4 allele for general dementia risk, but a possible additive interaction for AD risk.
Physical activity even in late life may be effective in reducing conversion to dementia and AD or in delaying the onset of clinical manifestations. APOE ε4 carriers may particularly benefit from increasing physical activity with regard to their risk for AD.
Whether late-onset depression is a risk factor for or a prodrome of dementia remains unclear. We investigated the impact of depressive symptoms and early- v. late-onset depression on subsequent dementia in a cohort of elderly general-practitioner patients (n = 2663, mean age = 81.2 years).
Risk for subsequent dementia was estimated over three follow-ups (each 18 months apart) depending on history of depression, particularly age of depression onset, and current depressive symptoms using proportional hazard models. We also examined the additive prediction of incident dementia by depression beyond cognitive impairment.
An increase of dementia risk for higher age cut-offs of late-onset depression was found. In analyses controlling for age, sex, education, and apolipoprotein E4 genotype, we found that very late-onset depression (aged ⩾70 years) and current depressive symptoms separately predicted all-cause dementia. Combined very late-onset depression with current depressive symptoms was specifically predictive for later Alzheimer's disease (AD; adjusted hazard ratio 5.48, 95% confidence interval 2.41–12.46, p < 0.001). This association was still significant after controlling for cognitive measures, but further analyses suggested that it was mediated by subjective memory impairment with worries.
Depression might be a prodrome of AD but not of dementia of other aetiology as very late-onset depression in combination with current depressive symptoms, possibly emerging as a consequence of subjectively perceived worrisome cognitive deterioration, was most predictive. As depression parameters and subjective memory impairment predicted AD independently of objective cognition, clinicians should take this into account.