Ventilator-induced lung injury results in oxidative stress response and mitochondrial swelling in a mouse model

© 2022. The Author(s).BACKGROUND: Mechanical ventilation is a life-saving therapy for critically ill patients, providing rest to the respiratory muscles and facilitating gas exchange in the lungs. Ventilator-induced lung injury (VILI) is an unfortunate side effect of mechanical ventilation that may lead to serious consequences for the patient and increase mortality. The four main injury mechanisms associated with VILI are: baro/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; oxygen toxicity due to use of high ratio of oxygen in inspired air, causing formation of free radicals; and biotrauma, the resulting biological response to tissue injury, that leads to a cascade of events due to excessive inflammatory reactions and may cause multi-organ failure. An often-overlooked part of the inflammatory reaction is oxidative stress. In this research, a mouse model of VILI was set up with three tidal volume settings (10, 20 and 30 mL/kg) at atmospheric oxygen level. Airway pressures and heart rate were monitored and bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken. RESULTS: We show a correlation between increased inflammation and barrier failure, and higher tidal volumes, evidenced by increased IL-6 expression, high concentration of proteins in BALF along with changes in expression of adhesion molecules. Furthermore, swelling of mitochondria in alveolar type II cells was seen indicating their dysfunction and senescence-like state. RNA sequencing data present clear increases in inflammation, mitochondrial biogenesis and oxidative stress as tidal volume is increased, supported by degradation of Keap1, a redox-regulated substrate adaptor protein. CONCLUSIONS: Oxidative stress seems to be a more prominent mechanism of VILI than previously considered, indicating that possible treatment methods against VILI might be identified by impeding oxidative pathways.Peer reviewe

Adolescent well-being amid the COVID-19 pandemic: Are girls struggling more than boys?

Background: Differential effects of the coronavirus SARS-CoV-2 (COVID-19) pandemic and associated public restrictions on adolescent girls and boys are emerging but have not been elucidated. This study examined gender differences across broad indicators of adolescent well-being during the COVID-19 pandemic in Iceland, and explored potential explanations for these differences. Methods: In total, 523 youth (56.5% girls) born in Iceland in 2004 completed measures on mental health problems (depressive symptoms, anger and suicide attempts) and measures designed for this study to assess broad indicators of adolescent well-being (e.g., day-to-day life, academic performance, family and peer relationships, and mental and physical health) and behavioral changes during the COVID-19 pandemic. Mental health problems during the pandemic were compared to expected scores based on nationwide ratings of same-aged peers in 2018. Results: Although both boys and girls appeared affected, girls reported a greater negative impact across all the broad indicators of well-being and behavioral change during COVID-19 than boys, and their depressive symptoms were above and beyond the expected nationwide scores (t(1514) = 4.80, p < .001, Cohen's d = 0.315). Higher depressive symptoms were associated with increased passive social media use and decreased connecting with family members via telephone or social media among girls, and decreased sleeping and increased online gaming alone among boys. Concern about others contracting COVID-19, changes in daily and school routines, and not seeing friends in person were among the primary contributors to poor mental health identified by youth, particularly girls. Conclusions: Adolescents were broadly negatively affected by the COVID-19 pandemic and accompanying restrictions; however, this negative impact was more pronounced in girls. The findings suggest that a steady routine and remaining socially connected may help youth cope with the uncertainty and social restrictions associated with a pandemic. Moreover, healthcare providers, teachers, and other professionals should pay close attention to depressive symptoms among girls during a pandemic

A multi-level developmental approach towards understanding adolescent mental health and behaviour: rationale, design and methods of the LIFECOURSE study in Iceland

Purpose: Identifying and understanding modifiable risk and protective factors that can inform early detection and intervention to prevent adolescent emotional problems and harmful behaviours is among the most pressing modern-day public health challenges. This paper describes the rationale, objectives, methods, and anticipated outcomes of the LIFECOURSE study, a multi-level, bio-psychosocial prospective study designed to advance our understanding of factors that shape adolescent mental health and behaviour. Methods: Conducted by the Icelandic Centre for Social Research and Analysis at Reykjavik University, LIFECOURSE is a longitudinal population-based developmental study of Icelandic adolescents born in 2004. The study utilizes a comprehensive multi-informant assessment of individual, societal and biological factors measured across the lifespan. Data assembly and collection were conducted from 2016-2020 and utilize both retrospective and prospective data sources: (a) retrospective registry data assembled from seven national databases, (b) prospectively collected social surveys and (c) biomarker samples. Results: Of the 3914 eligible adolescents, 60.8% (n = 2378) provided informed parental consent and student assent to participate in the study, with approximately half of the participants being female (n = 1175, 49.4%) and the majority being born in the capital area (n = 1455; 61.2%). The coverage of available data from the national databases and participation in the social surveys ranged from 81.7 to 100%. Conclusions: Major gaps remain in our knowledge of how individual, societal and biological factors across the lifespan-from early life to adolescence-interact and shape the risk for emotional problems and harmful behaviours during adolescence. The LIFECOURSE study was designed to address this knowledge gap

Depressive symptoms, mental wellbeing, and substance use among adolescents before and during the COVID-19 pandemic in Iceland: a longitudinal, population-based study

Background: Adolescence represents a crucial developmental period in shaping mental health trajectories. In this study, we investigated the effect of the COVID-19 pandemic on mental health and substance use during this sensitive developmental stage. Methods: In this longitudinal, population-based study, surveys were administered to a nationwide sample of 13-18-year-olds in Iceland in October or February in 2016 and 2018, and in October, 2020 (during the COVID-19 pandemic). The surveys assessed depressive symptoms with the Symptom Checklist-90, mental wellbeing with the Short Warwick Edinburgh Mental Wellbeing Scale, and the frequency of cigarette smoking, e-cigarette use, and alcohol intoxication. Demographic data were collected, which included language spoken at home although not ethnicity data. We used mixed effects models to study the effect of gender, age, and survey year on trends in mental health outcomes. Findings: 59 701 survey responses were included; response rates ranged from 63% to 86%. An increase in depressive symptoms (β 0·57, 95% CI 0·53 to 0·60) and worsened mental wellbeing (β -0·46, 95% CI -0·49 to -0·42) were observed across all age groups during the pandemic compared with same-aged peers before COVID-19. These outcomes were significantly worse in adolescent girls compared with boys (β 4·16, 95% CI 4·05 to 4·28, and β -1·13, 95% CI -1·23 to -1·03, respectively). Cigarette smoking (OR 2·61, 95% CI 2·59 to 2·66), e-cigarette use (OR 2·61, 95% CI 2·59 to 2·64), and alcohol intoxication (OR 2·59, 95% CI 2·56 to 2·64) declined among 15-18-year-olds during COVID-19, with no similar gender differences. Interpretation: Our results suggest that COVID-19 has significantly impaired adolescent mental health. However, the decrease observed in substance use during the pandemic might be an unintended benefit of isolation, and might serve as a protective factor against future substance use disorders and dependence. Population-level prevention efforts, especially for girls, are warranted

Dietary habits in adolescence and midlife and risk of breast cancer in older women

Publisher's version (útgefin grein)Recent studies indicate that lifestyle factors in early life affect breast cancer risk. We therefore explored the association of high consumption of meat, milk, and whole grain products in adolescence and midlife, on breast cancer risk. We used data from the population based AGES-Reykjavik cohort (2002–2006), where 3,326 women with a mean age of 77 years (SD 6.0) participated. For food items and principal component derived dietary patterns we used Cox proportional models to calculate multivariate hazard ratios (HR) with 95% confidence intervals (95% CI). During a mean follow-up of 8.8 years, 97 women were diagnosed with breast cancer. For both adolescence and midlife, daily consumption of rye bread was positively associated with breast cancer (HR 1.7, 95% CI 1.1–2.6 and HR 1.8, 95% CI 1.1–2.9, respectively). In contrast, persistent high consumption of oatmeal was negatively associated with breast cancer (0.4, 95% CI 0.2–0.9). No association was found for other food items or dietary patterns that included rye bread. High rye bread consumption in adolescence and midlife may increase risk of late-life breast cancer whilst persistent consumption of oatmeal may reduce the risk.The AGES-Reykjavik Study was funded by NIH contract N01-AG-12100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association and the Icelandic Parliament. This work was supported by the The Icelandic Centre for Research, RANNIS grant number: 152495051, (http://en.rannis.is/) (A. Haraldsdottir) and the Public Health Fund of the Icelandic Directorate of Health (A. Haraldsdottir). The funding agencies (National Institute on Aging, Icelandic Heart Association and Icelandic Parlament,) for the AGES-Reykjavik Study, RANNIS, or Directorate of Health had no role in the design, analysis or writing of this article.Peer Reviewe

Azithromycin induces epidermal differentiation and multivesicular bodies in airway epithelia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBACKGROUND: Azithromycin (Azm) is a macrolide recognized for its disease-modifying effects and reduction in exacerbation of chronic airway diseases. It is not clear whether the beneficial effects of Azm are due to its anti-microbial activity or other pharmacological actions. We have shown that Azm affects the integrity of the bronchial epithelial barrier measured by increased transepithelial electrical resistance. To better understand these effects of Azm on bronchial epithelia we have investigated global changes in gene expression. METHODS: VA10 bronchial epithelial cells were treated with Azm and cultivated in air-liquid interface conditions for up to 22 days. RNA was isolated at days 4, 10 and 22 and analyzed using high-throughput RNA sequencing. qPCR and immunostaining were used to confirm key findings from bioinformatic analyses. Detailed assessment of cellular changes was done using microscopy, followed by characterization of the lipidomic profiles of the multivesicular bodies present. RESULTS: Bioinformatic analysis revealed that after 10 days of treatment genes encoding effectors of sterol and cholesterol metabolism were prominent. Interestingly, expression of genes associated with epidermal barrier differentiation, KRT1, CRNN, SPINK5 and DSG1, increased significantly at day 22. Together with immunostaining, these results suggest an epidermal differentiation pattern. We also found that Azm induced the formation of multivesicular and lamellar bodies in two different airway epithelial cell lines. Lipidomic analysis revealed that Azm was entrapped in multivesicular bodies linked to different types of lipids, most notably palmitate and stearate. Furthermore, targeted analysis of lipid species showed accumulation of phosphatidylcholines, as well as ceramide derivatives. CONCLUSIONS: Taken together, we demonstrate how Azm might confer its barrier enhancing effects, via activation of epidermal characteristics and changes to intracellular lipid dynamics. These effects of Azm could explain the unexpected clinical benefit observed during Azm-treatment of patients with various lung diseases affecting barrier function.Icelandic Research Council EpiEndo Pharmaceuticals, Reykjavik, Icelan

Dietary patterns in adolescence and risk of colorectal cancer: a population-based study.

To access publisher's full text version of this article click on the hyperlink belowPurpose: To study whether dietary patterns in adolescence are associated with risk of colorectal cancer (CRC). Methods: Food frequency data were obtained from the AGES-Reykjavik study, conducted between 2002 and 2006, which included 5,078 (58% women) participants with mean age of 77 (± 5.8) years. Principal component analysis was used to identify dietary patterns. Participants were followed through linkage to the Icelandic Cancer Registry. Multivariable Cox models were used to calculate hazard ratios (HR) of CRC and 95% confidence interval (CI) by dietary patterns. Results: During the follow-up period (mean 8.2 years), 136 participants (75 women and 61 men) were diagnosed with CRC. The main dietary pattern in adolescence was characterized by high intake of traditional food items consumed in the earlier half of the twentieth century, namely, salted or smoked meat and fish, milk, offal, rye bread, and oatmeal. Compared to the lowest tertile, the middle tertile of this pattern was associated with increased risk of CRC (HR 1.63, 95% CI 1.04-2.57), while the highest tertile was not statistically associated with CRC (HR 1.48, 95% CI 0.93-2.37), except among women (HR 2.06, 95% CI 1.11-3.84). Conclusion: These data suggest that strong adherence to a traditional Icelandic diet in adolescence might increase the risk of CRC, particularly among women. More research is need on the association between food items and dietary patterns of relevance to CRC at different points in the life cycle. Keywords: Adolescent; Colorectal cancer; Dietary pattern; Epidemiology; Factor analysis.United States Department of Health & Human Services National Institutes of Health (NIH) - USA Appeared in source as:NIH United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) Appeared in source as:Intramural Research Program of the National Institute on Aging United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Eye Institute (NEI) Icelandic Heart Association Icelandic Parliament University of Iceland Research Fund United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA

Correction: Dietary habits in adolescence and midlife and risk of breast cancer in older women.

[This corrects the article DOI: 10.1371/journal.pone.0198017.]

ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.

To access publisher's full text version of this article click on the hyperlink belowThe tumor microenvironment is increasingly recognized as key player in cancer progression. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Here, we sought out to analyze epithelial-endothelial cross talk in the breast using isogenic non-tumorigenic vs. tumorigenic breast epithelial cell lines and primary ECs. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Targeting this interaction may provide a novel possibility to improve cancer treatment.Landspitali University Hospital Science Fund University of Iceland Research Fund Icelandic Science and Technology Polic

Dietary habits among participants through different time periods.

<p>Dietary habits among participants through different time periods.</p