Antimony Compounds Associate with Atopic Dermatitis and Influence Models of Itch and Dysbiosis.

Compared to the myriad of known triggers for rhinitis and asthma, environmental exposure research for atopic dermatitis (AD) is not well established. We recently reported that an untargeted search of U.S. Environmental Protection Agency (EPA) databases versus AD rates by United States (U.S.) postal codes revealed that isocyanates, such as toluene diisocyanate (TDI), are the pollutant class with the strongest spatiotemporal and epidemiologic association with AD. We further demonstrated that (di)isocyanates disrupt ceramide-family lipid production in commensal bacteria and activate the thermo-itch host receptor TRPA1. In this report, we reanalyzed regions of the U.S. with low levels of diisocyanate pollution to assess if a different chemical class may contribute. We identified antimony compounds as the top associated pollutant in such regions. Exposure to antimony compounds would be expected from brake dust in high-traffic areas, smelting plants, bottled water, and dust from aerosolized soil. Like TDI, antimony inhibited ceramide-family lipid production in Roseomonas mucosa and activated TRPA1 in human neurons. While further epidemiologic research will be needed to directly evaluate antimony exposure with surrounding AD prevalence and severity, these data suggest that compounds which are epidemiologically associated with AD, inhibit commensal lipid production, and activate TRPA1 may be causally related to AD pathogenesis.

Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1.

We recently used EPA databases to identify that isocyanates, most notably toluene diisocyanate (TDI), were the pollutant class with the strongest spatiotemporal and epidemiologic association with atopic dermatitis (AD). Our findings demonstrated that isocyanates like TDI disrupted lipid homeostasis and modeled benefit in commensal bacteria like Roseomonas mucosa through disrupting nitrogen fixation. However, TDI has also been established to activate transient receptor potential ankyrin 1 (TRPA1) in mice and thus could directly contribute to AD through induction of itch, rash, and psychological stress. Using cell culture and mouse models, we now demonstrate that TDI induced skin inflammation in mice as well as calcium influx in human neurons; each of these findings were dependent on TRPA1. Furthermore, TRPA1 blockade synergized with R. mucosa treatment in mice to improve TDI-independent models of AD. Finally, we show that the cellular effects of TRPA1 are related to shifting the balance of the tyrosine metabolites epinephrine and dopamine. This work provides added insight into the potential role, and therapeutic potential, or TRPA1 in the pathogenesis of AD.

Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria.

Atopic dermatitis (AD) is a chronic inflammatory skin condition increasing in industrial nations at a pace that suggests environmental drivers. We hypothesize that the dysbiosis associated with AD may signal microbial adaptations to modern pollutants. Having previously modeled the benefits of health-associated Roseomonas mucosa, we now show that R. mucosa fixes nitrogen in the production of protective glycerolipids and their ceramide by-products. Screening EPA databases against the clinical visit rates identified diisocyanates as the strongest predictor of AD. Diisocyanates disrupted the production of beneficial lipids and therapeutic modeling for isolates of R. mucosa as well as commensal Staphylococcus. Last, while topical R. mucosa failed to meet commercial end points in a placebo-controlled trial, the subgroup who completed the full protocol demonstrated sustained, clinically modest, but statistically significant clinical improvements that differed by study site diisocyanate levels. Therefore, diisocyanates show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis.

Management of Subacute Thyroiditis - A Systematic Review of Current Treatment Protocols.

Purpose: This systematic review endeavors to find an effective treatment protocol for subacute thyroiditis (SAT) to minimize side effects, recurrence and long-term hypothyroidism. Materials and Methods: We analyzed available original studies on treatment protocols for SAT. A thorough literature search was performed on the following online databases PubMed, Cochrane library nd Google Scholar using appropriate keywords for choosing relevant articles. Two reviewers assessed the methodological quality of selected articles independently using a critical appraisal instrument. The results were analyzed and synthesized qualitatively using the level of evidence method. Results: The literature search retrieved a total of 460 publications after abstract screening; out of which 36 articles met the inclusion criteria. After full text screening, 23 articles were further excluded as they were focusing on aspects of SAT other than management, the remaining 15 articles were investigated for both reliability and validity. Thirteen studies provided low-quality evidence, and two randomized control trials (RCT) provided a high quality of evidence. Steroid therapy was found to be the most effective for moderate to severe SAT and provided relief from acute symptoms but was found to not be a risk factor for recurrence. Low initial doses of steroid (15 mg) were preferred over high initial dosage (30-40 mg). Furthermore, a look into the mode of steroid delivery (RCT) revealed that intrathyroidal steroid therapy can potentially become a safer and faster mode of therapy. The duration of tapering was found to be of significance as a short tapering period was linked with greater recurrence rates. Conclusion: Low initial doses of steroid along with an extended tapering period may help lower recurrence rates; also, intrathyroidal steroid injections are potentially a better alternative to oral prednisone (PSN) with regard to safety and speed of action. However, the evidence is of moderate quality and further investigation is required.

Impact of Skin Tissue Collection Method on Downstream MALDI-Imaging.

MALDI imaging is a novel technique with which to study the pathophysiologies of diseases. Advancements in the field of metabolomics and lipidomics have been instrumental in mapping the signaling pathways involved in various diseases, such as cancer and neurodegenerative diseases (Parkinson's). MALDI imaging is flexible and can handle many sample types. Researchers primarily use either formalin-fixed paraffin-embedded (FFPE) or fresh frozen tissue samples to answer their scientific questions. FFPE samples allow for easy long-term storage, but the requirement for extensive sample processing may limit the ability to provide a clear picture of metabolite distribution in biological tissue. Frozen samples require less handling, but present logistical challenges for collection and storage. A few studies, mostly focused on cancer cell lines, have directly compared the results of MALDI imaging using these two tissue fixation approaches. Herein, we directly compared FFPE and fresh frozen sample preparation for murine skin samples, and performed detailed pathway analysis to understand how differences in processing impact MALDI results from otherwise identical tissues. Our results indicate that FFPE and fresh frozen methods differ significantly in the putative identified metabolite content and distribution. The fixation methods shared only 2037 metabolites in positive mode and only 4079 metabolites in negative ion mode. However, both fixation approaches allowed for downstream fluorescent staining, which may save time and resources for samples that are clinically precious. This work represents a direct comparison of the impacts of the two main tissue processing methods on subsequent MALDI-MSI. While our results are similar to previous work in cancer tissue, they provide novel insights for those using MALDI-MSI in skin.

Delivery room interventions to prevent bronchopulmonary dysplasia in preterm infants: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: As gestational age decreases, incidence of bronchopulmonary dysplasia (BPD) and chronic lung disease increases. There are many interventions used in the delivery room to prevent acute lung injury and consequently BPD in these patients. The availability of different treatment options often poses a practical challenge to the practicing neonatologist when it comes to making an evidence-based choice as the multitude of pairwise systematic reviews including Cochrane reviews that are currently available only provide a narrow perspective through head-to-head comparisons. METHODS AND ANALYSIS: We will conduct a systematic review of all randomised controlled trials evaluating delivery room interventions within the first golden hour after birth for prevention of BPD. The primary outcome includes BPD. Secondary outcomes include death at 36 weeks of postmenstrual age or before discharge; severe intraventricular haemorrhage (grade 3 or 4 based on the Papile criteria); any air leak syndromes (including pneumothorax or pulmonary interstitial emphysema); retinopathy of prematurity (any stage) and neurodevelopmental impairment at 18-24 months. We will search from their inception to August 2018, the following databases: Medline, EMBASE and Cochrane Central Register of Controlled Trials as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information and assess the risk of bias and the confidence in the estimate (with Grading of Recommendations Assessment, Development and Evaluation approach). This review will use Bayesian network meta-analysis approach which allows the comparison of the multiple delivery room interventions for prevention of BPD. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, effectiveness and safety of delivery room interventions for prevention of BPD. ETHICS AND DISSEMINATION: The proposed protocol is a network meta-analysis, which has been registered on PROSPERO International prospective register of systematic reviews (CRD42018078648). The results will provide an evidence-based guide to choosing the right sequence of early postnatal interventions that will be associated with the least likelihood of inducing lung injury and BPD in preterm infants. Furthermore, we will identify knowledge gaps and will encourage further research for other therapeutic options. Therefore, its results will be disseminated through peer-reviewed publications and conference presentations. Due to the nature of the design, no ethics approval is necessary.