Stress, a matter of balance

Modern society is a dynamic plot pervaded by cultural, social, emotional, and biological experiences, some of which ultimately endanger our lifestyle and affect our physiology and behaviour. For health and survival, adequate regulatory control of the HPA stress axis is required. Over the years, chronic stress has been frequently implicated in altered brain function. Current evidence shows that the habituation of HPA axis response is more complex than previously thought. The adaptive reduction of repeated stress-induced responses seems to involve complex crosstalk between negative feedback mechanisms induced by the release of GCs under repeated stress, response habituation processes produced by repetitive exposure to the stress stimulus, and likely more complex learning and memory encoding information regarding previous stressful events. We directed our research towards two major problems that currently impede advances in modeling HPA habituation in mice and mechanisms leading to it. By doing so, we contribute to a better understanding of normal behavior and mechanisms. Here, we show that glucocorticoid receptors in the hypothalamic paraventricular nucleus in CRF neurons are essential for HPA axis habituation. When re-exposed to the same stressor, glucocorticoid receptors led to essential cellular modulation and dampened HPA axis activation by increasing inhibitory tone onto CRF neurons. The current research study provides a new set of data that confidently positions the GR-CRF system as a crucial player in the executive function following repeated stress exposure, thus offering a molecular mechanism through which this effect occurs. Hence, it shows a possible pharmacological target that could support the production of active measures to mitigate the deleterious effects of repeated stress exposure

Expression and glucocorticoid-dependent regulation of the stress-inducible protein DRR1 in the mouse adult brain

Identifying molecular targets that are able to buffer the consequences of stress and therefore restore brain homeostasis is essential to develop treatments for stress-related disorders. Down-regulated in renal cell carcinoma 1 (DRR1) is a unique stress-induced protein in the brain and has been recently proposed to modulate stress resilience. Interestingly, DRR1 shows a prominent expression in the limbic system of the adult mouse. Here, we analyzed the neuroanatomical and cellular expression patterns of DRR1 in the adult mouse brain using in situ hybridization, immunofluorescence and Western blot. Abundant expression of DRR1 mRNA and protein was confirmed in the adult mouse brain with pronounced differences between distinct brain regions. The strongest DRR1 signal was detected in the neocortex, the CA3 region of the hippocampus, the lateral septum and the cerebellum. DRR1 was also present in circumventricular organs and its connecting regions. Additionally, DRR1 was present in non-neuronal tissues like the choroid plexus and ependyma. Within cells, DRR1 protein was distributed in a punctate pattern in several subcellular compartments including cytosol, nucleus as well as some pre- and postsynaptic specializations. Glucocorticoid receptor activation (dexamethasone 10\ua0mg/kg s.c.) induced DRR1 expression throughout the brain, with particularly strong induction in white matter and fiber tracts and in membrane-rich structures. This specific expression pattern and stress modulation of DRR1 point to a role of DRR1 in regulating how cells sense and integrate signals from the environment and thus in restoring brain homeostasis after stressful challenges

MR Volumetry of Lung Nodules: A Pilot Study.

Introduction: Computed tomography (CT) is currently the reference modality for the detection and follow-up of pulmonary nodules. While 2D measurements are commonly used in clinical practice to assess growth, increasingly 3D volume measurements are being recommended. The goal of this pilot study was to evaluate preliminarily the capabilities of 3D MRI using ultra-short echo time for lung nodule volumetry, as it would provide a radiation-free modality for this task. Material and Methods: Artificial nodules were manufactured out of Agar and measured using an ultra-short echo time MRI sequence. CT data were also acquired as a reference. Image segmentation was carried out using an algorithm based on signal intensity thresholding (SIT). For comparison purposes, we also performed manual slice by slice segmentation. Volumes obtained with MRI and CT were compared. Finally, the volumetry of a lung nodule was evaluated in one human subject in comparison with CT. Results: Using the SIT technique, minimal bias was observed between CT and MRI across the entire range of volumes (2%) with limits of agreement below 14%. Comparison of manually segmented MRI and CT resulted in a larger bias (8%) and wider limits of agreement (-23% to 40%). In vivo, nodule volume differed of <16% between modalities with the SIT technique. Conclusion: This pilot study showed very good concordance between CT and UTE-MRI to quantify lung nodule volumes, in both a phantom and human setting. Our results enhance the potential of MRI to quantify pulmonary nodule volume with similar performance to CT

Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD:a cohort study

Background: Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD Methods: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia. Results: Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05–22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58–0.85), self-reported heart failure (OR 6.92, 95%CI 1.56–30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17–6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38–7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up. Conclusions: Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia. Trial registration COPDGene is registered at ClinicalTrials.gov: NCT00608764 (Registration Date: January 28, 2008) Electronic supplementary material The online version of this article (doi:10.1186/s12890-016-0331-0) contains supplementary material, which is available to authorized users

Delineation of molecular pathway activities of the chronic antidepressant treatment response suggests important roles for glutamatergic and ubiquitin–proteasome systems

The aim of this study was to identify molecular pathways related to antidepressant response. We administered paroxetine to the DBA/2J mice for 28 days. Following the treatment, the mice were grouped into responders or non-responders depending on the time they spent immobile in the forced swim test. Hippocampal metabolomics and proteomics analyses revealed that chronic paroxetine treatment affects glutamate-related metabolite and protein levels differentially in the two groups. We found significant differences in the expression of N-methyl-d-aspartate receptor and neuronal nitric oxide synthase proteins between the two groups, without any significant alterations in the respective transcript levels. In addition, we found that chronic paroxetine treatment altered the levels of proteins associated with the ubiquitin–proteasome system (UPS). The soluble guanylate cyclase-β1, proteasome subunit α type-2 and ubiquitination levels were also affected in peripheral blood mononuclear cells from antidepressant responder and non-responder patients suffering from major depressive disorder. We submit that the glutamatergic system and UPS have a crucial role in the antidepressant treatment response in both mice and humans

Eur Radiol

OBJECTIVES: The study aimed to validate automated quantification of high and low signal intensity volumes using ultrashort echo-time MRI, with CT and pulmonary function test (PFT) as references, to assess the severity of structural alterations in cystic fibrosis (CF). METHODS: This prospective study was performed in a single center between May 2015 and September 2017. Participants with CF completed clinical examination, CT, MRI, and PFT the same day during routine clinical follow-up (M0), and then 1 year after (M12) except for CT. Using MRI, percentage high (%MR-HSV), low (%MR-LSV), and total abnormal (%MR-TSV) signal intensity volumes were recorded, as well as their corresponding attenuation values using CT (%CT-HAV, %CT-LAV, %CT-TAV, respectively). Automated quantifications and visual Bhalla score were evaluated independently by two observers. Correlations were assessed using the Spearman test, comparisons using the Mann-Whitney test, and reproducibility using the intraclass correlation coefficient (ICC). RESULTS: A total of 30 participants were enrolled (median age 27 years, 18 men). At M0, there was a good correlation between %MR-HSV and %CT-HAV (ρ = 0.70; p \textbackslashtextless 0.001) and %MR-LSV and %CT-LAV (ρ = 0.60; p \textbackslashtextless 0.001). Automated MR metrics correlated to PFTs and Bhalla score (p \textbackslashtextless 0.05) while %MR-TSV was significantly different between CF with and without respiratory exacerbation (p = 0.01) at both M0 and M12. The variation of %MR-HSV correlated to the variation of FEV1% at PFT (ρ = - 0.49; p = 0.008). Reproducibility was almost perfect (ICCs \textbackslashtextgreater 0.95). CONCLUSIONS: Automated quantification of abnormal signal intensity volumes relates to CF severity and allows reproducible cross-sectional and longitudinal assessment. TRIAL REGISTRATION: Clinical trial identifier: NCT02449785 KEY POINTS: • Cross-sectionally, the automated quantifications of high and low signal intensity volumes at UTE correlated to the quantification of high and low attenuation using CT as reference. • Longitudinally, the variation of high signal intensity volume at UTE correlated to the variation of pulmonary function test and was significantly reduced in CF with an improvement in exacerbation status. • Automated quantification of abnormal signal intensity volumes are objective and reproducible tools to assess structural alterations in CF and follow-up longitudinally, for both research and clinical purposes

The clinical use of lung MRI in cystic fibrosis: what, now, how?

International audienceTo assess airway and lung parenchymal damage noninvasively in cystic fibrosis (CF), chest MRI has been historically out of the scope of routine clinical imaging because of technical difficulties such as low proton density and respiratory and cardiac motion. However, technological breakthroughs have emerged that dramatically improve lung MRI quality (including signal-to-noise ratio, resolution, speed, and contrast). At the same time, novel treatments have changed the landscape of CF clinical care. In this contemporary context, there is now consensus that lung MRI can be used clinically to assess CF in a radiation-free manner and to enable quantification of lung disease severity. MRI can now achieve three-dimensional, high-resolution morphologic imaging, and beyond this morphologic information, MRI may offer the ability to sensitively differentiate active inflammation vs scarring tissue. MRI could also characterize various forms of inflammation for early guidance of treatment. Moreover, functional information from MRI can be used to assess regional, small-airway disease with sensitivity to detect small changes even in patients with mild CF. Finally, automated quantification methods have emerged to support conventional visual analyses for more objective and reproducible assessment of disease severity. This article aims to review the most recent developments of lung MRI, with a focus on practical application and clinical value in CF, and the perspectives on how these modern techniques may converge and impact patient care soon

SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system

Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety-and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission

An adverse early life environment can enhance stress resilience in adulthood

Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress