Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal

Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.Determination of the biological consequences of ultradian cortisol pulsatility.A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function

Enriching for correct prediction of biological processes using a combination of diverse classifiers

<p>Abstract</p> <p>Background</p> <p>Machine learning models (classifiers) for classifying genes to biological processes each have their own unique characteristics in what genes can be classified and to what biological processes. No single learning model is qualitatively superior to any other model and overall precision for each model tends to be low. The classification results for each classifier can be complementary and synergistic suggesting the benefit of a combination of algorithms, but often the prediction probability outputs of various learning models are neither comparable nor compatible for combining. A means to compare outputs regardless of the model and data used and combine the results into an improved comprehensive model is needed.</p> <p>Results</p> <p>Gene expression patterns from NCI's panel of 60 cell lines were used to train a Random Forest, a Support Vector Machine and a Neural Network model, plus two over-sampled models for classifying genes to biological processes. Each model produced unique characteristics in the classification results. We introduce the Precision Index measure (PIN) from the maximum posterior probability that allows assessing, comparing and combining multiple classifiers. The class specific precision measure (PIC) is introduced and used to select a subset of predictions across all classes and all classifiers with high precision. We developed a single classifier that combines the PINs from these five models in prediction and found that the PIN Combined Classifier (PINCom) significantly increased the number of correctly predicted genes over any single classifier. The PINCom applied to test genes that were not used in training also showed substantial improvement over any single model.</p> <p>Conclusions</p> <p>This paper introduces novel and effective ways of assessing predictions by their precision and recall plus a method that combines several machine learning models and capitalizes on synergy and complementation in class selection, resulting in higher precision and recall. Different machine learning models yielded incongruent results each of which were successfully combined into one superior model using the PIN measure we developed. Validation of the boosted predictions for gene functions showed the genes to be accurately predicted.</p

Are mental health and binge drinking associated in Dutch adolescents? Cross-sectional public health study

<p>Abstract</p> <p>Background</p> <p>Depression and anxiety disorders have a high disease burden and as many as 15% of young people report mental health problems. Binge drinking, which is a particularly harmful way of consuming alcohol, is common among secondary school students. The aim of this study was to examine the association between binge drinking and self-reported mental health in boys and girls aged 12 to 18 years.</p> <p>Findings</p> <p>This cross-sectional analysis was performed on data collected by the Community Health Service (GGD) Brabant Zuidoost, the Netherlands, in 2007. In this Youth Survey, 10 090 randomly selected adolescents aged 12 tot 18 years were each sent a letter, a questionnaire, and a user name and log-in code for if they preferred to complete the Internet version of the questionnaire. Mental health was assessed using the Mental Health Inventory (MHI-5), a short 5-item questionnaire to detect feelings of depression and anxiety. Participants were asked about current alcohol consumption, their relationship with their parents, drug use, and sociodemographic data.</p> <p>Corrected for confounders, binge drinking and mental health problems were associated in the 12 to 15 year old girls (OR 2.43; 95% CI 1.86-3.17, p = 0.000) and boys (OR 1.64, 95% CI 1.19-2.27, p = 0.003). The majority of the 16 to 18 year old adolescents had been binge drinking in the previous 4 weeks (69.6% boys and 56.8% girls). In this age group, boys with mental health problems were less likely to be classified as binge drinkers than were boys without mental health problems (OR 0.63, 95% CI 0.45-0.87, p = 0.005). No such association between binge drinking and mental health was found in girls of this age.</p> <p>Conclusion</p> <p>Girls and boys aged 12-15 years were classified as binge drinkers significantly more often when they reported poor mental health. Because binge drinking damages the brain, especially at a young age, it is important that health professionals are alert to possible binge drinking when young adolescents report mental health problems and should ask their patients about their drinking behaviour. Likewise, if youngsters under 16 present with binge drinking, they should be asked whether they are anxious or depressed.</p

Co-localization and regulation of basic fibroblast growth factor and arginine vasopressin in neuroendocrine cells of the rat and human brain

<p>Abstract</p> <p>Background</p> <p>Adult rat hypothalamo-pituitary axis and choroid plexus are rich in basic fibroblast growth factor (FGF2) which likely has a role in fluid homeostasis. Towards this end, we characterized the distribution and modulation of FGF2 in the human and rat central nervous system. To ascertain a functional link between arginine vasopressin (AVP) and FGF2, a rat model of chronic dehydration was used to test the hypothesis that FGF2 expression, like that of AVP, is altered by perturbed fluid balance.</p> <p>Methods</p> <p>Immunohistochemistry and confocal microscopy were used to examine the distribution of FGF2 and AVP neuropeptides in the normal human brain. In order to assess effects of chronic dehydration, Sprague-Dawley rats were water deprived for 3 days. AVP neuropeptide expression and changes in FGF2 distribution in the brain, neural lobe of the pituitary and kidney were assessed by immunohistochemistry, and western blotting (FGF2 isoforms).</p> <p>Results</p> <p>In human hypothalamus, FGF2 and AVP were co-localized in the cytoplasm of supraoptic and paraventricular magnocellular neurons and axonal processes. Immunoreactive FGF2 was associated with small granular structures distributed throughout neuronal cytoplasm. Neurohypophysial FGF2 immunostaining was found in axonal processes, pituicytes and Herring bodies. Following chronic dehydration in rats, there was substantially-enhanced FGF2 staining in basement membranes underlying blood vessels, pituicytes and other glia. This accompanied remodeling of extracellular matrix. Western blot data revealed that dehydration increased expression of the hypothalamic FGF2 isoforms of ca. 18, 23 and 24 kDa. In lateral ventricle choroid plexus of dehydrated rats, FGF2 expression was augmented in the epithelium (Ab773 as immunomarker) but reduced interstitially (Ab106 immunostaining).</p> <p>Conclusions</p> <p>Dehydration altered FGF2 expression patterns in AVP-containing magnocellular neurons and neurohypophysis, as well as in choroid plexus epithelium. This supports the involvement of centrally-synthesized FGF2, putatively coupled to that of AVP, in homeostatic mechanisms that regulate fluid balance.</p

A systematic review of longitudinal studies on the association between depression and smoking in adolescents

<p>Abstract</p> <p>Background</p> <p>It is well-established that smoking and depression are associated in adolescents, but the temporal ordering of the association is subject to debate.</p> <p>Methods</p> <p>Longitudinal studies in English language which reported the onset of smoking on depression in non clinical populations (age 13-19) published between January 1990 and July 2008 were selected from PubMed, OVID, and PsychInfo databases. Study characteristics were extracted. Meta-analytic pooling procedures with random effects were used.</p> <p>Results</p> <p>Fifteen studies were retained for analysis. The pooled estimate for smoking predicting depression in 6 studies was 1.73 (95% CI: 1.32, 2.40; p < 0.001). The pooled estimate for depression predicting smoking in 12 studies was 1.41 (95% CI: 1.21, 1.63; p < 0.001). Studies that used clinical measures of depression were more likely to report a bidirectional effect, with a stronger effect of depression predicting smoking.</p> <p>Conclusion</p> <p>Evidence from longitudinal studies suggests that the association between smoking and depression is bidirectional. To better estimate these effects, future research should consider the potential utility of: (a) shorter intervals between surveys with longer follow-up time, (b) more accurate measurement of depression, and (c) adequate control of confounding.</p

Selected sociodemographic factors and related differences in patterns of alcohol use among university students in Slovakia

Background: Alcohol use and misuse and their relation to sociodemograhic factors are well studied among university students in Western European countries and the USA, but less is known about students in Eastern Europe. The historical past as communistic countries might have affected the social life among these populations, which is again one of the main factors determining the alcohol consumption among university students. The aim of our study was to assess the association of selected sociodemographic factors with different patterns of alcohol use among university students in Slovakia. Methods: A sample of 813 young adults (mean age 21.1 years, 63.8% females; response rate of 71%) from four universities in Kosice answered questions about their sociodemographic background and about alcohol use. To obtain a detailed picture of different aspects, alcohol use was measured by four variables: frequency of alcohol use, heavy episodic drinking, frequency of drunkenness and problem drinking. Four separate logistic regression models were used to assess the association between sociodemographic and alcohol-related variables. To assess the potentially different effects in both genders, all two-way interactions with gender were tested. Results: While 41% of the students drank alcohol once a week or more often, 77% reported heavy episodic drinking and 49% had been drunk more than once in the last month. Problem drinking existed in 23.3% of the sample. Gender was consistently associated with all four alcohol-related variables, with males being at higher risk. A higher study year was associated only with lower levels of heavy episodic drinking, but displayed no association with the other studied variables. Living with parents during the semester was consistently associated with less frequent heavy episodic drinking, drunkenness episodes, and problem drinking while having an intimate relationship was associated with less problem drinking only. Conclusions: Our findings for the university students from Slovakia are in line with previous studies in Western Europe. Additionally, it appears that frequent alcohol use, excessive alcohol use (heavy episodic drinking and drunkenness) and problem drinking among university students represent a continuum and are influenced by the same sociodemographic factors

Adolescent Binge Drinking Leads to Changes in Alcohol Drinking, Anxiety, and Amygdalar Corticotropin Releasing Factor Cells in Adulthood in Male Rats

Heavy episodic drinking early in adolescence is associated with increased risk of addiction and other stress-related disorders later in life. This suggests that adolescent alcohol abuse is an early marker of innate vulnerability and/or binge exposure impacts the developing brain to increase vulnerability to these disorders in adulthood. Animal models are ideal for clarifying the relationship between adolescent and adult alcohol abuse, but we show that methods of involuntary alcohol exposure are not effective. We describe an operant model that uses multiple bouts of intermittent access to sweetened alcohol to elicit voluntary binge alcohol drinking early in adolescence (∼postnatal days 28–42) in genetically heterogeneous male Wistar rats. We next examined the effects of adolescent binge drinking on alcohol drinking and anxiety-like behavior in dependent and non-dependent adult rats, and counted corticotropin-releasing factor (CRF) cell in the lateral portion of the central amygdala (CeA), a region that contributes to regulation of anxiety- and alcohol-related behaviors. Adolescent binge drinking did not alter alcohol drinking under baseline drinking conditions in adulthood. However, alcohol-dependent and non-dependent adult rats with a history of adolescent alcohol binge drinking did exhibit increased alcohol drinking when access to alcohol was intermittent. Adult rats that binged alcohol during adolescence exhibited increased exploration on the open arms of the elevated plus maze (possibly indicating either decreased anxiety or increased impulsivity), an effect that was reversed by a history of alcohol dependence during adulthood. Finally, CRF cell counts were reduced in the lateral CeA of rats with adolescent alcohol binge history, suggesting semi-permanent changes in the limbic stress peptide system with this treatment. These data suggest that voluntary binge drinking during early adolescence produces long-lasting neural and behavioral effects with implications for anxiety and alcohol use disorders

Transcriptomic analysis supports similar functional roles for the two thymuses of the tammar wallaby

Background: The thymus plays a critical role in the development and maturation of T-cells. Humans have a single thoracic thymus and presence of a second thymus is considered an anomaly. However, many vertebrates have multiple thymuses. The tammar wallaby has two thymuses: a thoracic thymus (typically found in all mammals) and a dominant cervical thymus. Researchers have known about the presence of the two wallaby thymuses since the 1800s, but no genome-wide research has been carried out into possible functional differences between the two thymic tissues. Here, we used pyrosequencing to compare the transcriptomes of a cervical and thoracic thymus from a single 178 day old tammar wallaby.Results: We show that both the tammar thoracic and the cervical thymuses displayed gene expression profiles consistent with roles in T-cell development. Both thymuses expressed genes that mediate distinct phases of T-cells differentiation, including the initial commitment of blood stem cells to the T-lineage, the generation of T-cell receptor diversity and development of thymic epithelial cells. Crucial immune genes, such as chemokines were also present. Comparable patterns of expression of non-coding RNAs were seen. 67 genes differentially expressed between the two thymuses were detected, and the possible significance of these results are discussed.Conclusion: This is the first study comparing the transcriptomes of two thymuses from a single individual. Our finding supports that both thymuses are functionally equivalent and drive T-cell development. These results are an important first step in the understanding of the genetic processes that govern marsupial immunity, and also allow us to begin to trace the evolution of the mammalian immune system