38 research outputs found
Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals
No full textFamilial longevity is marked by lower diurnal salivary cortisol levels: the leiden longevity study
No full textBackground
Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity.
Methods
Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors.
Results
Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28).
Conclusion
Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed.On behalf of the Leiden Longevity Study grou
A systematic review of randomised controlled trials of interventions promoting effective condom use.
No full textBACKGROUND: Effective condom use can prevent sexually transmitted infections (STIs) and unwanted pregnancy. We conducted a systematic review and methodological appraisal of randomised controlled trials (RCTs) of interventions to promote effective condom use. METHODS: We searched for all RCTs of interventions to promote effective condom use using the Cochrane Infectious Diseases Group's trials register (Oct 2006), CENTRAL (Issue 4, 2006), MEDLINE (1966 to Oct 2006), EMBASE (1974 to Oct 2006), LILACS (1982 to Oct 2006), IBSS (1951 to Oct 2006) and Psychinfo (1996 to Oct 2006). We extracted data on allocation sequence, allocation concealment, blinding, loss to follow-up and measures of effect. Effect estimates were calculated. RESULTS: We identified 139 trials. Seven out of ten trials reported reductions in 'any STI' with five statistically significant results. Three out of four trials reported reductions in pregnancy, although none was statistically significant. Only four trials met all the quality criteria. Trials reported a median of 11 (IQR 7-17) outcome measures. Few trials used the same outcome measure. Altogether, 10 trials (7%) used the outcome 'any STI', 4 (3%) self-reported pregnancy and 22 (16%) used 'condom use at last sex'. CONCLUSIONS: The results are generally consistent with modest benefits but there is considerable potential for bias due to poor trial quality. Because of the low proportion of trials using the same outcome the potential for bias from selective reporting of outcomes is considerable. Despite the public health importance of increasing condom use there is little reliable evidence on the effectiveness of condom promotion interventions
Mapping Developmental Precursors of Cyber-Aggression: Trajectories of Risk Predict Perpetration and Victimization
No full textTechnologically mediated contexts are social arenas in which adolescents can be both perpetrators and victims of aggression. Yet, there remains little understanding of the developmental etiology of cyber aggression, itself, as experienced by either perpetrators or victims. The current study examines 3-year latent within-person trajectories of known correlates of cyber-aggression: problem behavior, (low) self-esteem, and depressed mood, in a large and diverse sample of youth (N = 1,364; 54.6 % female; 12–14 years old at T1). Findings demonstrate that developmental increases in problem behavior across grades 8–10 predict both cyber-perpetration and victimization in grade 11. Developmental decreases in self-esteem also predicted both grade 11 perpetration and victimization. Finally, early depressed mood predicted both perpetration and victimization later on, regardless of developmental change in depressed mood in the interim. Our results reveal a clear link between risky developmental trajectories across the early high school years and later cyber-aggression and imply that mitigating trajectories of risk early on may lead to decreases in cyber-aggression at a later date
Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis
No full textThe circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD
Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and Age of Onset in Schizophrenia: A Combined Analysis of Independent Samples
No full textMethylenetetrahydrofolate reductase (MTHFR) is involved in the one-carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T-allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta-analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia
Neuroepigenetic signatures of age and sex in the living human brain
No full textAge- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior
Brain structural alterations, genetic risk variants and the onset of psychosis
No full textOne of the central motivations behind research of the at-risk mental state is to prevent or delay potential transition to psychosis and further progression to schizophrenia, by studying the early signs and symptoms without potential confounding effects of disease progression and medication. And although the pathophysiological mechanism is still poorly understood, it is known that there is a large genetic heritability where a combination of different genetic variants sets a predisposition. Therefore, the identification of markers that characterise all states of the disease, namely schizophrenia, first-episode of psychosis and the at-risk mental state, are a main goal. A very robust marker is hippocampal volume reduction in schizophrenia, first- episode of psychosis and the at-risk mental state.
In this thesis, I will present research for a deeper characterisation of the hippocampus in schizophrenia, first-episode of psychosis and the at-risk mental state and the association to genetic risk variants. First, we we found no association of the brain- derived neurotrophic factor rs6265 polymorphism with the hippocampal volumes neither in the original analysis of large cohort of young healthy individuals nor a meta-analysis with 5298 healthy subjects in total. Moreover, we detected differences between the applied hippocampal measuring techniques, i.e. manual or automated segmentation. Second, a meta-analysis of the same association but in 18 independent neuropsychiatric patient cohorts including schizophrenia revealed again no association. Also, we showed similar hippocampal reductions for Val/Val homozygote and Met-carrier patients compared to healthy controls. Third, group- related comparison of subcortical volumes revealed hippocampal and thalamic reductions in at-risk mental state individuals compared to healthy controls. Moreover, we found comparable medium effect sizes for both structures assessed with two different statistical methods. Fourth, in a cohort of at-risk mental state individuals and first-episode of psychosis patients we found a negative association between the hippocampal volumes and a polygenic schizophrenia-related risk score. Furthermore, a higher polygenic schizophrenia-related risk score was significantly associated with a higher probability of an individual being assigned to the first-episode of psychosis group compared to the total at-risk mental state group.
These studies aid a better understanding of hippocampal volume reduction and genetic variants associated with schizophrenia, first-episode of psychosis and the at- risk mental state
Investigação da ação antidepressiva e neuroprotetora do ácido fólico
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em BioquímicaÁcido fólico é essencial para o funcionamento do sistema nervoso central, uma vez que desempenha um importante papel na neuroplasticidade e manutenção da integridade neuronal. O ácido fólico apresenta muitas propriedades importantes, como neuroprotetora, antidepressiva e cognitiva. O presente trabalho realizado através de estudos in vivo e in vitro avaliou os efeitos tipo-antidepressivo (teste do nado forçado, TNF, ou estresse agudo de contenção), cognitivo (TRO, teste do reconhecimento de objeto) e neuroprotetor (protocolos de morte celular induzidas por dexametasona ou glutamato) do ácido fólico. Os resultados dos estudos in vivo mostram que uma dose sub-ativa de ácido fólico (10 mg/Kg, p.o.) combinada com doses sub-ativas de inibidores da GSK-3? (glicogênio sintase cinase-3?) (AR-A014418 ou lítio), agonista PPAR? (receptor ativado por proliferador peroxissomal-?) (rosiglitazona) ou inibidores de canais de potássio (K+) (glibenclamida, caribdotoxina ou apamina), produziram um efeito tipo-antidepressivo sinérgico no TNF em camundongos. Por outro lado, o pré-tratamento dos animais com um inibidor da PI3K (fosfoinositol 3-cinase) (LY294002), um agonista PPAR? (GW-9662) ou um ativador de canais de K+ (cromacalim) reverteu o efeito tipo-antidepressivo de uma dose ativa de ácido fólico (50 mg/Kg, p.o.). Além disso, outro estudo in vivo mostrou que o ácido fólico (50 mg/kg, p.o.) administrado 1 h antes do estresse de contenção foi capaz de proteger contra o aumento do tempo de imobilidade induzido pelo estresse no TNF, mas não foi efetivo contra o prejuízo de memória no TRO. Adicionalmente, o estresse agudo de contenção promoveu aumento dos níveis de substâncias reativas ao ácido tiobarbitúrico (TBARS) e das atividades da catalase (CAT), glutationa peroxidase (GPx) e glutationa redutase (GR) no córtex cerebral e hipocampo, e aumento da atividade da superóxido dismutase (SOD) somente no hipocampo. O tratamento com ácido fólico restaurou a atividade da SOD, CAT, GR e GPx e reduziu os níveis de TBARS no hipocampo. Contudo, glutationa (GSH), um antioxidante não-enzimático não foi alterada pelo estresse, nem mesmo pelo ácido fólico. Além disso, um estudo in vitro mostrou que o pré-tratamento com ácido fólico (10-300 µM) reduziu a toxicidade induzida por dexametasona (1mM), de maneira concentração-dependente, em linhagem de células neuroblastoma humano SH-SY5Y. Este efeito neuroprotetor foi revertido por um inibidor da PI3K/Akt (LY294002), proteína cinase dependente de Ca2+/calmodulina II (CaMKII, KN-93) e proteína cinase A (PKA, H-89), mas não pelo inibidor da proteína cinase ativada por mitógeno/cinase regulada por sinal extracelular (MEK 1/2, PD98059) e proteína cinase C (PKC, queleritrina).Um adicional estudo in vitro, também mostrou que o tratamento de fatias hipocampais de ratos com ácido fólico (100 µM) reduziu significativamente a morte celular e a liberação de D-[3H]aspartato induzidos pelo glutamato (1mM), os quais foram abolidos pela presença de LY294002. Além disso, as fatias hipocampais incubadas por 30 minutos com ácido fólico per se induziu fosforilação da GSK-3?. Adicionalmente, ácido fólico na presença de glutamato (decorridos 6 h de incubação das fatias em meio, depois da retirada do glutamato), induziu fosforilação da GSK-3? e expressão da ?-catenina. O ácido fólico também reverteu o aumento da expressão da iNOS (óxido nítrico sintase induzida) promovido por glutamato. Estes resultados em conjunto, indicam que o efeito tipo-antidepressivo do ácido fólico no TNF pode ser dependente da modulação da via PI3K/Akt/GSK-3?, inibição de canais de K+ e ativação do receptor PPAR?, bem como, desempenhar um específico perfil antidepressivo, pelo menos em parte, devido ao seu papel antioxidante. Além disso, o efeito neuroprotetor do ácido fólico contra os estímulos tóxicos, dexametasona ou glutamato, pode ser dependente PI3K/GSK-3?/?-catenina e iNOS, respectivamenteFolate is essential for the functioning of the nervous system, since it plays an important role in neuroplasticity and in the maintenance of neuronal integrity. Many roles for folic acid have been reported, including neuroprotective, antidepressant and cognitive properties. The present work using an in vivo and in vitro approach evaluated the antidepressant-like (forced swimming test, FST or acute restraint stress), cognitive (ORT, object recognition test) and neuroprotective (dexamethasone or glutamate-induced cell death protocols) effects of folic acid. The results from in vivo studies showed that a sub-effective dose of folic acid (10 mg/Kg, p.o.) combined with sub-effective doses of GSK-3? (glycogen synthase kinase-3?) inhibitors (AR-A014418 or lithium), PPAR? (peroxisome proliferator-activated receptor-?) agonist (rosiglitazone) or potassium (K+) channel inhibitors (glibenclamide, charibdotoxin or apamin), elicited synergistic antidepressant-like effect in the mouse FST, while the pre-treatment of animals with a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), a PPAR? antagonist (GW-9662) or a K+channel opener (cromakalim) reversed the antidepressant-like effect of an active dose of folic acid (50 mg/Kg, p.o.). Moreover, another in vivo study showed that folic acid (50 mg/kg, p.o.) administred 1 h before restraint stress was able to protect against the stress-induced depressive-like effect in the FST, but not the memory impairment in the ORT. Moreover, acute restraint stress increased thiobarbituric acid reactive substances (TBARS) levels and catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities in the cerebral cortex and hippocampus, and superoxide dismutase (SOD) activity in the hippocampus. Folic acid treatment restored the activity of SOD, CAT, GR and GPx and reduced TBARS levels in the hippocampus. Glutatione (GSH), a non-enzymatic antioxidant was not altered by stress and/or folic acid administration. Additionaly, an in vitro study found that folic acid pretreatment (10-300 µM) reduced dexamethasone (1mM)-induced toxicity in a concentration dependent manner in SH-SY5Y neuroblastoma cell line. This neuroprotective effect was reversed by the PI3K/Akt (LY294002), calcium/calmodulin-dependent protein kinase II (CaMKII, KN-93) and protein kinase A (PKA, H-89) inhibitors, but not the mitogen-activated protein/extracellular signal-regulated kinase (MEK 1/2, PD98059) and protein kinase C (PKC, Chelerythrine) inhibitors. A further in vitro study, also showed that the treatment of hippocampal slices with folic acid (100 µM) significantly reduced glutamate (1mM)-induced cell death and D-[3H]aspartate release, which were abolished by LY294002. Moreover, hippocampal slices incubated with folic acid per se for 30 minutes induced GSK-3? phosphorylation. Furthermore, folic acid in presence of glutamate insult, in hippocampal slices maintained for an additional period of 6 h in fresh culture medium without glutamate and/or folic acid, induced phosphorylation of GSK-3? and ?-catenin expression. In addition, folic acid was able to reverse the increase on iNOS expression induced by glutamate. Altogether, these results indicate that the antidepressant-like effect of folic acid in the FST might be dependent on the modulation of PI3K/Akt/GSK-3? pathway, inhibition of K+ channels and activation of PPAR?. In addition, the antidepressant activity of folic acid in the restraint stress paradigm may be at least partly due to its antioxidant role. Moreover, the neuroprotective effect of folic acid against the toxic insults, dexametasone or glutamate, might be dependent on signaling pathway that involves PI3K/Akt, CaMKII and PKA or PI3K/GSK-3?/?-catenin and iNOS, respectivel
LD Score regression distinguishes confounding from polygenicity in genome-wide association studies
No full textBoth polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size
