Recent exposure to ultrafine particles in school children alters miR-222 expression in the extracellular fraction of saliva

Background: Ultrafine particles (< 100 nm) are ubiquitous present in the air and may contribute to adverse cardiovascular effects. Exposure to air pollutants can alter miRNA expression, which can affect downstream signaling pathways. miRNAs are present both in the intracellular and extracellular environment. In adults, miR-222 and miR-146a were identified as associated with particulate matter exposure. However, there is little evidence of molecular effects of ambient air pollution in children. This study examined whether exposure to fine and ultrafine particulate matter (PM) is associated with changes in the extracellular content of miR-222 and miR-146a of children. Methods: Saliva was collected from 80 children at two different time points, circa 11 weeks apart and stabilized for RNA preservation. The extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We regressed the extracellular miRNA expression against recent exposure to ultrafine and fine particles measured at the school site using mixed models, while accounting for sex, age, BMI, passive smoking, maternal education, hours of television use, time of the day and day of the week. Results: Exposure to ultrafine particles (UFP) at the school site was positively associated with miR-222 expression in the extracellular fraction in saliva. For each IQR increase in particles in the class room (+8504 particles/cm(3)) or playground (+ 28776 particles/cm(3)), miR-222 was, respectively 23.5 % (95 % CI: 3.5 %-41.1 %; p = 0.021) or 29.9 % (95 % CI: 10.6 %-49.1 %; p = 0.0027) higher. No associations were found between miR-146a and recent exposure to fine and ultrafine particles. Conclusions: Our results suggest a possible epigenetic mechanism via which cells respond rapidly to small particles, as exemplified by miR-222 changes in the extracellular fraction of saliva

Children’s screen time alters the expression of saliva extracellular miR-222 and miR-146a

An imbalance between energy uptake and energy expenditure is the most important reason for increasing trends in obesity starting from early in life. Extracellular miRNAs are expressed in all bodily fluids and their expression is influenced by a broad range of stimuli. We examined whether screen time, physical activity and BMI are associated with children's salivary extracellular miR-222 and miR-146a expression. In 80 children the extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We studied the association between children's salivary extracellular miRNA expression and screen time, physical activity and BMI using mixed models, while accounting for potential confounders. We found that higher screen time was positively associated with salivary extracellular miR-222 and miR-146a levels. On average, one hour more screen time use per week was associated with a 3.44% higher miR-222 (95% CI: 1.34 to 5.58; p = 0.002) and 1.84% higher miR-146a (95% CI: -0.04 to 3.75; p = 0.055) level in saliva. BMI and physical activity of the child were not significantly associated with either miR-222 or miR-146a. A sedentary behaviour, represented by screen time use in children, is associated with discernible changes in salivary expression of miR-146a and or miR-222. These miRNA targets may emerge attractive candidates to explore the role of these exposures in developmental processes of children's health

Training specialists to write appropriate reply letters to general practitioners about patients with medically unexplained physical symptoms; A cluster-randomized trial.

Objective: To evaluate effects of a communication training for specialists on the quality of their reply letters to general practitioners (GPs) about patients with medically unexplained physical symptoms (MUPS). Methods: Before randomization, specialists included ≤3 MUPS patients in a multi-center cluster-randomized trial. In 14 h of MUPS-specific communication training, 2.5 h focused on reply letters. Letters were discussed with regard to reporting and answering GPs' referral questions and patients' questions, and to reporting findings, explaining MUPS with perpetuating factors and giving advice. After the training, all doctors again included ≤3 MUPS patients. Reply letters to GPs were assessed for quality and blindly rated on a digital scale. Results: We recruited 478 MUPS patients and 123 specialists; 80% of the doctors wrote ≥1 reply letters, 285 letters were assessed. Trained doctors reported (61% versus 37%, OR=2.55, F(1281)=6.60, pgroup*time=.01) and answered (63% versus 33%, OR=3.31, F(1281)=5.36, pgroup*time=.02) patients' questions more frequently than untrained doctors. Conclusion: Training improves reply letters with regard to patients' questions, but not with regard to the following: GPs' referral questions, somatic findings, additional testing, explaining, and advice. Practice implications: Training specialists to write appropriate reply letters needs more focus on explanation and advice

Real-world palbociclib effectiveness in patients with metastatic breast cancer: Focus on neutropenia-related treatment modification strategies and clinical outcomes

INTRODUCTION: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes. MATERIALS AND METHODS: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not. RESULTS: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90). CONCLUSION: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Cord blood leptin and insulin levels in association with mitochondrial DNA content

Abstract Background The developmental origins of health and disease theory states that a disturbance in the early life environment can contribute to disease risk in later life. Leptin and insulin are anorectic hormones involved in energy homeostasis and are crucial for foetal growth. Disturbances in the levels of these hormones contribute to obesity and diabetes. In adults, altered mitochondrial function is an important hallmark of metabolic disorders, including obesity and diabetes. However, the mitochondrial effects of early life metabolic variation are unexplored. We investigated whether there is an association between metabolic hormones and mitochondrial DNA (mtDNA) content in early life. Methods The study included 236 newborns from the FLEHS III birth cohort, Flanders (Belgium). Relative mtDNA content of cord blood leukocytes was determined using quantitative PCR. Cord blood levels of leptin and insulin were determined using immunoassays. We studied the association between these metabolic hormones and mtDNA content using multiple linear regression models, while accounting for covariates and potential confounders. Results Leptin and insulin levels were positively associated with cord blood mtDNA content. mtDNA content was respectively 4.49% (95% CI 1.15–7.93; p = 0.008) and 1.60% (95% CI 0.31–2.91; p = 0.02) higher for a interquartile range increase of respectively cord blood leptin and insulin levels. In a sensitivity analysis, we observed that insulin and leptin were independently associated to mtDNA content and that insulin was stronger associated to mtDNA content in boys than in girls. Conclusion Neonatal metabolic hormones were associated with cord blood mtDNA content, which suggests that in early life the variation of mtDNA content might accommodate or reflect changes in the metabolic status

Recent exposure to ultrafine particles in school children alters miR-222 expression in the extracellular fraction of saliva

Ultrafine particles (<100 nm) are ubiquitous present in the air and may contribute to adverse cardiovascular effects. Exposure to air pollutants can alter miRNA expression, which can affect downstream signaling pathways. miRNAs are present both in the intracellular and extracellular environment. In adults, miR-222 and miR-146a were identified as associated with particulate matter exposure. However, there is little evidence of molecular effects of ambient air pollution in children. This study examined whether exposure to fine and ultrafine particulate matter (PM) is associated with changes in the extracellular content of miR-222 and miR-146a of children.status: publishe

Neonatal exposure to environmental pollutants and placental mitochondrial DNA content : a multi-pollutant approach

Background: Placental mitochondrial DNA (mtDNA) content can be indicative of oxidative damage to the placenta during fetal development and is responsive to external stressors. In utero exposure to environmental pollutants that may influence placental mtDNA needs further exploration. Objectives: We evaluated if placental mtDNA content is altered by environmental pollution in newborns and identified pollutants independently associated to alterations in placental mtDNA content. Methods: mtDNA content was measured in placental tissue of 233 newborns. Four perfluoroalkyl compounds and nine organochlorine compounds were quantified in cord blood plasma samples and six toxic metals in whole cord blood. We first applied a LASSO (least absolute shrinkage and selection operator) penalized regression model to identify independent associations between environmental pollutants and placental mtDNA content, without penalization of several covariates. Then adjusted estimates were obtained using an ordinary least squares (OLS) regression model evaluating the pollutants' association with placental mtDNA content, adjusted for several covariates. Results: Based on LASSO penalized regression, oxychlordane, p,p'-dichlorodiphenyldichloroethylene, beta-hexachlorocyclohexane, perfluorononanoic acid, arsenic, cadmium and thallium were identified to be independently associated with placental mtDNA content. The OLS model showed a higher placental mtDNA content of 2.71% (95% CI: 0.3 to 5.2%; p = 0.03) and 1.41% (0.1 to 2.8%, p = 0.04) for a 25% concentration increase of respectively cord blood beta-hexachlorocyclohexane and arsenic. For a 25% concentration increase of cord blood thallium, a 4.88% lower placental mtDNA content (95% CI: -9.1 to -0.5%, p = 0.03) was observed. Conclusion: In a multi-pollutant approach, low fetal exposure levels of environmental organic and inorganic pollutants might compromise placental mitochondrial function as exemplified in this study by alterations in mtDNA content

Neonatal exposure to environmental pollutants and placental mitochondrial DNA content : a multi-pollutant approach

Background: Placental mitochondrial DNA (mtDNA) content can be indicative of oxidative damage to the placenta during fetal development and is responsive to external stressors. In utero exposure to environmental pollutants that may influence placental mtDNA needs further exploration. Objectives: We evaluated if placental mtDNA content is altered by environmental pollution in newborns and identified pollutants independently associated to alterations in placental mtDNA content. Methods: mtDNA content was measured in placental tissue of 233 newborns. Four perfluoroalkyl compounds and nine organochlorine compounds were quantified in cord blood plasma samples and six toxic metals in whole cord blood. We first applied a LASSO (least absolute shrinkage and selection operator) penalized regression model to identify independent associations between environmental pollutants and placental mtDNA content, without penalization of several covariates. Then adjusted estimates were obtained using an ordinary least squares (OLS) regression model evaluating the pollutants' association with placental mtDNA content, adjusted for several covariates. Results: Based on LASSO penalized regression, oxychlordane, p,p'-dichlorodiphenyldichloroethylene, beta-hexachlorocyclohexane, perfluorononanoic acid, arsenic, cadmium and thallium were identified to be independently associated with placental mtDNA content. The OLS model showed a higher placental mtDNA content of 2.71% (95% CI: 0.3 to 5.2%; p = 0.03) and 1.41% (0.1 to 2.8%, p = 0.04) for a 25% concentration increase of respectively cord blood beta-hexachlorocyclohexane and arsenic. For a 25% concentration increase of cord blood thallium, a 4.88% lower placental mtDNA content (95% CI: -9.1 to -0.5%, p = 0.03) was observed. Conclusion: In a multi-pollutant approach, low fetal exposure levels of environmental organic and inorganic pollutants might compromise placental mitochondrial function as exemplified in this study by alterations in mtDNA content