Will buffer zones around schools in agricultural areas be adequate to protect children from the potential adverse effects of pesticide exposure?

California has proposed limiting agricultural pesticide use within 0.4 km of schools and childcare facilities. However, the 0.4-km buffer may not be appropriate for all pesticides because of differing toxicities, fate, and application methods. Living near pesticide use has been associated with poorer birth outcomes, neurodevelopment, and respiratory function in children. More research about exposures in schools, childcare facilities, and homes is needed. Despite incomplete science, this regulation is an important step to reduce potential exposures to children. The most vulnerable exposure period may be in utero, and future regulations should also aim to reduce exposures to pregnant women

Effector Cells and Mechanisms in Chronic Spontaneous Urticaria

Background: Chronic spontaneous urticaria (CSU) is characterised by weals, angioedema, or both, which occur for six weeks or more. Itchy, red and raised weals in CSU are thought to occur as a result of skin mast cell activation, local vasodilatation and increased vascular permeability which are the cardinal features of the disease. Serum histamine-releasing activity and abnormal basophil function were implicated in the pathophysiology of CSU. We hypothesized that severe and/or persistent CSU may be associated with serum histamine releasing activity (HRA), abnormal basophil releasability, numbers and phenotype. Furthermore, serum HRA in CSU was hypothesized to be associated with higher local concentrations of pro-inflammatory mediators (histamine, tryptase) and IL-6 in the skin, local histamine release and, possibly, neutrophil infiltration in the dermis. To test this hypothesis, we carried out cutaneous microdialysis of autologous serum skin test (ASST) response, a prospective study of basophil-relate biomarkers in CSU and a retrospective histological study in CSU and urticarial vasculitis (UV). In cutaneous microdialysis study, 14 CSU patients and 13 healthy subjects were evaluated to determine the baseline levels of histamine, tryptase and cytokines and their changes in response to skin testing with PBS (pH = 7.4, 20μl), autologous serum (20μl) and codeine (0.3mM, 20μl). We demonstrated a slow low-grade local histamine release after intradermal injection of autologous serum in two HRA+ CSU patients. There was elevated dermal histamine (p=0.0193) but normal tryptase (p=0.1437) and IL-6 (p=0.1298) concentrations in CSU compared to healthy controls. Dermal histamine concentrations were correlated to clinical scores in CSU (r=0.602, p<0.05). The prospective observational study was carried out in 22 CSU patients at three time points over 6 months to elucidate the relationship between the biomarkers to disease severity and disease persistence. Laboratory assessments included serum-induced basophil HRA on healthy donor basophils, anti-IgE-induced basophil histamine release (BHR) from CSU patients, basophil flow cytometry. Baseline UAS7 correlated with serum HRA (r=0.58, p=0.0045), and anti-IgE-induced BHR (r=0.40, p=0.0666).HRA+CSU patients (n=8) had a more severe disease than HRA- CSU patients (n=14) (p=0.0152). Based on the ROC analysis for UAS7 at baseline, a cut-off value of 19 predicted persistence of CSU in our patient population with 63.16% accuracy (sensitivity of 60% and specificity of 66.67%). These results should, however, be interpreted with caution in view of a small sample size and the selected patient population from the secondary care dermatological setting. There was a persistent (n=3) versus transient (n=3) increase in serum HRA in CSU patients over time. Flow cytometric enumeration in CSU varied depending on choice of gating strategy for peripheral blood basophils (CCR3+CD123+ vs CCR3+CD63+ (p=0.0001), CD63+CD203c+ vs CCR3+CD123+ (p=0.0003), CD63+CD203c+ vs CCR3+CD63 (p=0.0001)). We then examined basophil variation using ImageStream® in healthy subjects. ImageStream® studies confirmed the difference in basophil percentages detected by CD63+CD203c+ and CCR3+CD63+ gating strategies (0.02% vs 0.4% of basophils) in peripheral blood from a healthy donor following Ficoll-Paque density gradient centrifugation. In the CD203c+ OR CD63+ Boolean gate, we identified a basophil subpopulation with surface alterations that comprised 17.7% cells in this gate in peripheral blood sample from a healthy donor. All basophils with surface alterations were CD63+cells, 93.75% of which were CCR3+cells and 0.78% of which were CD203c+cells in this healthy donor. In the retrospective study, we compared clinical and histological findings in CSU (n=33) and UV (n=43) patients for the presence of skin autoreactivity or serum HRA and eosinophils/neutrophil numbers per high power field (HPF). There were higher numbers of neutrophils/HPF in UV than CSU patients by haematoxylin and eosin (H&E) staining (p=0.0002) and immunohistochemical detection of myeloperoxidase (p=0.0001). Neutrophilic urticaria (more than 25 extravasated neutrophils per five HPF) was noted in 63.6% of CSU patients including two CSU patients with serum HRA. Conclusions: In CSU, disease severity is associated with higher dermal histamine concentrations, serum HRA and abnormal basophil releasability. In ASST+ patients, an intradermal injection of autologous serum resulted in local in vivo histamine release suggesting that the ASST response is a useful experimental model of spontaneous wealing in CSU. Whether in vivo local histamine release explains the ASST response in CSU patients needs to be established in future studies. Baseline UAS7 is associated with serum HRA and anti-IgE-induced BHR and may predict disease persistence in CSU patients. Basophil phenotypic variation was demonstrated by different gating strategies which may reflect in vivo basophil activation in CSU. Biological and technical factors may contribute to basophil variation in imaging flow cytometry. In the lesional skin biopsies, neutrophil counts/HPF, using H&E staining or immunohistochemistry, can be useful for the diagnosis of neutrophilic urticaria and to differentiate between CSU and UV

Toxicol Lett

DNA methylation may mediate inter-individual responses to chemical exposure and, thus, modify biomarker levels of exposure and effects. We analyzed inter-individual differences in inhalation and skin exposure to 1,6-hexamethylene diisocyanate (HDI) and urine biomarker 1,6-hexamethylene diamine (HDA) levels in 20 automotive spray-painters. Genome-wide 5-methyl cytosine (CpG) DNA methylation was assessed in each individual's peripheral blood mononuclear cells (PBMC) DNA using the Illumina 450K CpG array. Mediation analysis using linear regression models adjusted for age, ethnicity, and smoking was conducted to identify and assess the association between HDI exposure, CpG methylation, and urine HDA biomarker levels. We did not identify any CpGs common to HDI exposure and biomarker level suggesting that CpG methylation is a mediator that only partially explains the phenotype. Functional significance of genic- and intergenic-CpG methylation status was tested using protein-protein or protein-DNA interactions and gene-ontology enrichment to infer networks. Combined, the results suggest that methylation has the potential to affect HDI mass transport, permeation, and HDI metabolism. We demonstrate the potential use of PBMC methylation along with quantitative exposure and biomarker data to guide further investigation into the mediators of occupational exposure and biomarkers and its role in risk assessment.T42 OH008673/OH/NIOSH CDC HHS/United StatesR01 OH007598/OH/NIOSH CDC HHS/United StatesR21 OH010203/OH/NIOSH CDC HHS/United StatesR21-OH010203/OH/NIOSH CDC HHS/United StatesT42OH008673/ACL/ACL HHS/United StatesR01-OH007598/OH/NIOSH CDC HHS/United StatesP42 ES005948/ES/NIEHS NIH HHS/United StatesT42/CCT422952/PHS HHS/United StatesP30 ES010126/ES/NIEHS NIH HHS/United StatesT42/OH-008673/OH/NIOSH CDC HHS/United States2021-04-22T00:00:00Z25445006PMC8060918965

Celebrating Applied Sciences Reaches 20,000 Articles Milestone

To celebrate the publication of 20,000 articles in Applied Sciences, we launched this Special Issue “Celebrating Applied Sciences Reaching Its 20,000 Article Milestone: Feature Papers of the Applied Biosciences and Bioengineering Section”. We have invited well-known experts in different areas of interest covered in “Applied Biosciences and Bioengineering” to submit their original research papers and review articles of the highest quality in celebrating together with our readers on this special occasion. This Special Issue has collected more than 10 papers featuring important and recent developments or achievements in biosciences and bioengineering, with a special emphasis on recently discovered techniques or applications

TLR2 and TLR4 as Potential Biomarkers of Environmental Particulate Matter Exposed Human Myeloid Dendritic Cells

In many subjects who are genetically susceptible to asthma, exposure to environmental stimuli may exacerbate their condition. However, it is unknown how the expression and function of a family of pattern-recognition receptors called toll-like receptors (TLR) are affected by exposure to particulate pollution. TLRs serve a critical function in alerting the immune system of tissue damage or infection—the so-called “danger signals”. We are interested in the role that TLRs play in directing appropriate responses by innate immunity, particularly dendritic cells (DC), after exposing them to particulate pollution. Dendritic cells serve a pivotal role in directing host immunity. Thus, we hypothesized that alterations in TLR expression could be further explored as potential biomarkers of effect related to DC exposure to particulate pollution. We show some preliminary data that indicates that inhaled particulate pollution acts directly on DC by down-regulating TLR expression and altering the activation state of DC. While further studies are warranted, we suggest that alterations in TLR2 and TLR4 expression should be explored as potential biomarkers of DC exposure to environmental particulate pollution

Investigating problematic severe asthma in children : a translational approach

Children with problematic severe asthma (PA) have persistent symptoms and/or severe exacerbations despite treatment with high doses of currently available asthma medications. The term PA includes children who are difficult to treat due to unidentified exacerbating factors (e.g. allergens or environmental hazards, comorbidities, psychological and social issues, and/or poor adherence) and those lacking identifiable aggravating factors but, nonetheless, do not respond well to asthma therapy. Children with PA are a heterogeneous group of patients with varying clinical presentations, pulmonary function and patterns of inflammation. This thesis is based on the results of a Swedish nationwide cross-sectional study in which school aged children with PA (n=57) were compared to age matched peers with persistent, but controlled asthma (CA), (n=39). The major objectives were to identify distinguishing features of children suffering from PA, to differentiate between children who were difficult to treat and those who were severely resistant to therapy and to investigate novel and potentially clinical relevant biomarkers of PA. PA was defined by insufficient asthma control despite high doses of inhaled corticosteroids. The protocol included a detailed characterization of: history and clinical presentation; pulmonary function; bronchial hyperresponsiveness; inflammatory biomarkers in blood (including white blood cells, interleukin-5 and chitinases (chitotriosidase and the chitinase-like protein YKL-40)), urine (EPX) and exhaled air (FeNO); allergy (IgE antibodies, component resolved allergy diagnostics, basophil allergen threshold sensitivity (CD-sens)); morphology (computerized tomography of sinuses and lungs (in the PA group only)). The major distinguishing features of children with PA involve familial background (heredity, socioeconomic status), clinical presentation (comorbidities and triggering factors) and pathophysiological differences including degree of airway obstruction, bronchial hyperresponsiveness and inflammatory profile (IL-5, number of eosinophilic and neutrophilic cells in blood). Sixty percent of children with PA had therapy-resistant asthma, with the remainder being difficult to treat due to identified aggravating factors. Individual IgE-responses were similar between children with PA and CA. Children with PA were more often multi-sensitized to > 3 single lipocalin (nMus m 1, rEqu c 1, Fel d 4, rCan f 1, 2), kallikrein (rCan f 5) and secretoglobin (rFel d 1) allergens compared to children with CA. Cat-allergic children with PA had higher allergen sensitivity, as measured by CDsens, compared to cat-allergic peers with CA. Furthermore, CD-sens correlated with clinical markers of asthmatic disease, including asthma control and biomarkers of eosinophilic inflammation. YKL-40 levels and chitotriosidase activity were increased in the serum of children with PA, and YKL-40 specifically correlated with airway remodelling (as assessed by computerized tomography) and blood neutrophils in children severely resistant to asthma therapy. By employing a comprehensive and standardized clinical assessment we have discerned specific features of children with PA and identified children who are severely resistant to therapy. We have applied two novel methods of allergy diagnostics (Component resolved diagnostics and CD-sens) and found that these two methods provide relevant information when investigating children with PA. Finally, our findings confirm that YKL-40 is a potential biomarker of asthma severity and airway remodeling. A translational research approach is necessary when investigating associations between disease mechanisms and clinical presentation in complex diseases

The power and potential of BIOMAP to elucidate host-microbiome interplay in skin inflammatory diseases

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis.Peer reviewe

At the dawn of the transcriptomic medicine

Impact statement This review describes the impact of transcriptomics on experimental biology and its integration into medical practice. Transcriptomics is an essential part of modern biomedical research based on highly sophisticated and reliable technology. Transcriptomics can aid clinical practice and improve the precision of clinical diagnoses and decision-making by complementing existing clinical best practice. The power of which will be increased when combined with genomic variation from genome wide association studies and next generation sequencing. We are witnessing the implementation of RNA-based technologies in clinical practice that will eventually lead to the establishment of transcriptional medicine as a routine tool in diagnosis. Progress in genomic analytical technologies has improved our possibilities to obtain information regarding DNA, RNA, and their dynamic changes that occur over time or in response to specific challenges. This information describes the blueprint for cells, tissues, and organisms and has fundamental importance for all living organisms. This review focuses on the technological challenges to analyze the transcriptome and what is the impact of transcriptomics on precision medicine. The transcriptome is a term that covers all RNA present in cells and a substantial part of it will never be translated into protein but is nevertheless functional in determining cell phenotype. Recent developments in transcriptomics have challenged the fundamentals of the central dogma of biology by providing evidence of pervasive transcription of the genome. Such massive transcriptional activity is challenging the definition of a gene and especially the term “pseudogene” that has now been demonstrated in many examples to be both transcribed and translated. We also review the common sources of biomaterials for transcriptomics and justify the suitability of whole blood RNA as the current optimal analyte for clinical transcriptomics. At the end of the review, a brief overview of the clinical implications of transcriptomics in clinical trial design and clinical diagnosis is given. Finally, we introduce the transcriptome as a target for modern drug development as a tool for extending our capacity for precision medicine in multiple diseases

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn’s disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease

Health effects of occupational exposure to respirable crystalline silica

"Occupational exposures to respirable crystalline silica are associated with the development of silicosis, lung cancer, pulmonary tuberculosis, and airways diseases. These exposures may also be related to the development of autoimmune disorders, chronic renal disease, and other adverse health effects. Recent epidemiologic studies demonstrate that workers have a significant risk of developing chronic silicosis when they are exposed to respirable crystalline silica over a working lifetime at the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), the Mine Safety and Health Administration (MSHA) PEL, or the National Institute for Occupational Safety and Health (NIOSH) recommended exposure limit (REL). This NIOSH Hazard Review examines the health risks and diseases associated with occupational exposures to respirable crystalline silica, discusses important findings of recent epidemiologic studies, provides the reader with sources of more comprehensive information about health effects and experimental studies describes current sampling and analytical methods and their limitations for assessing occupational exposures to respirable crystalline silica, and suggests many areas for further research. Current sampling and analytical methods used to evaluate occupational exposure to respirable crystalline silica do not meet the accuracy criterion needed to quantify exposures at concentrations below the NIOSH REL of 0.05 mg/m3 as a time-weighted average (TWA) for up to a 10-hr workday during a 40-hr workweek. Until improved sampling and analytical methods are developed for respirable crystalline silica, NIOSH will continue to recommend an exposure limit of 0.05 mg/m3 to reduce the risk of developing silicosis, lung cancer, and other adverse health effects. NIOSH also recommends minimizing the risk of illness that remains for workers exposed at the REL by substituting less hazardous materials for crystalline silica when feasible, by using appropriate respiratory protection when source controls cannot keep exposures below the NIOSH REL, and by making medical examinations available to exposed workers." - NIOSHTIC-2"Faye L. Rice was the principal author. The analytical methods section was prepared by Rosa Key-Schwartz, Ph.D.; David Bartley, Ph.D; Paul Baron, Ph.D; and Paul Schlecht. Michael Gressel and Alan Echt contributed material on control technology." p. xvii"April 2002."Also available via the World Wide Web.Includes bibliographical references (p. 104-126)