Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Background Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP–OX40 ligand (OX40L)–T cell axis and a TSLP–mast cell axis. ...Whether these pathways are active in human asthma is unknown. Objective We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways. Methods In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, TH 2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR. Results There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a TH 2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects. Conclusion TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and TH 2 inflammation.
Both common and rare genetic variants of laccase domain-containing 1 (
, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic ...arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of
, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and
colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A-producing CD4
T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying
variants.
Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the ...clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines interleukins (IL)-4, -5, and -13 can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.
Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three ...immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
Prior to the 1890s, dance coverage in North-American newspapers was infrequent and haphazard-a sub-species of music criticism or a titbit in the gossip column. Yet beginning in the early 1890s, with ...the emergence of modern dance on theatrical stages, dance reviewing became a regular feature within American dailies. Modern dance reviews from 1890 to 1920 show heterogeneous stylistic variances that provide retellings and evaluations of dances. Drawing on archival materials, this essay analyses the dance review as it was developing during the fin de siècle, outlining two major developments: first, the evolution of its stylistic expression from the feuilleton style, and second, the rise of its editorial significance within the overall newspaper during this period. Investigating the journalism responding to the work of Loïe Fuller, Isadora Duncan, and Maud Allan, this essay argues that these descriptive and critical writings on dance present nascent reviews, signalling also the development of what we now recognize as the dance review standard, which would become formally established in North-American presses by the 1930s.
Parallel transmit MRI at 7 T has increasingly been adopted in research projects and provides increased signal‐to‐noise ratios and novel contrasts. However, the interactions of fields in the body need ...to be carefully considered to ensure safe scanning. Recent advances in physically flexible body coils have allowed for high‐field abdominal imaging, but the effects of increased variability on energy deposition need further exploration. The aim of this study was to assess the impact of subject geometry, respiration phase and coil positioning on the specific absorption rate (SAR). Ten healthy subjects (body mass index BMI = 25 ± 5 kg m−2) were scanned (at 3 T) during exhale breath‐hold and images used to generate body models. Seven of these subjects were also scanned during inhale. Simplifications of the coil and body models were first explored, and then finite‐difference time‐domain simulations were run with a typical eight‐channel parallel transmit coil positioned over the abdomen. Simulations were used to generate 10 g averaged SAR (SAR10g) maps across 100,000 phase settings, and the worst‐case scenario 10 g averaged SAR (wocSAR10g) was identified using trigonometric maximisation. The average maximum SAR10g across the 10 subjects with 1 W input power per channel was 1.77 W kg−1. Hotspots were always close to the body surface near the muscle wall boundary. The wocSAR10g across the 10 subjects ranged from 2.3 to 3.2 W kg−1 and was inversely correlated to fat volume percentage (R = 8) and BMI (R = 0.6). The coefficient of variation values in SAR10g due to variations in subject geometry, respiration phase and realistic coil repositioning were 12%, 4% and 12%, respectively. This study found that the variability due to realistic coil repositioning was similar to the variability due to differing healthy subject geometries for abdominal imaging. This is important as it suggests that population‐based modelling is likely to be more useful than individual modelling in setting safe thresholds for abdominal imaging.
Abdominal 7 T MRI using eight‐channel parallel transmit coils introduce additional sources of variability in energy deposition due to their conformation to the body. The impact of a subject's geometry, respiration and small changes in coil position were assessed, showing minimal effects from respiration but safety relevant effects from realistic coil repositioning variability.
In 1892 American dancer Loïe Fuller (1862-1928) initiated a highly publicized copyright injunction to challenge an imitator of her work in court and safeguard ownership of her Serpentine Dance; it ...was a case she lost. Taking this copyright case as a starting-point, this article explores how the judge's ruling - that Fuller's work was non-narrative and, therefore, not eligible for copyright - lays the foundation for responses to Fuller's performances in popular media, which often reveal the spectator-reviewer at a loss for words when tasked with describing her dancing: modern dance is presented as an art form that is verbally inimitable. However, Fuller's imitators demonstrated otherwise: the multitude of live and filmic versions of Fuller's Serpentine Dance contextualize Fuller's movement style within popular visual culture, which hails Fuller as a popular culture icon of modernity - imitable and consumable for a myriad of women who figure their own identities through the vehicle of Fuller's dancing body. Ultimately, this contradiction reveals a crucial tension inherent in modern dance that was reinforced through both its criticism and popular reception.
IMPORTANCE: Child maltreatment is associated with serious negative physical, psychological, and behavioral consequences. OBJECTIVE: To review the evidence on primary care–feasible or referable ...interventions to prevent child maltreatment to inform the US Preventive Services Task Force. DATA SOURCES: PubMed, Cochrane Library, and trial registries through February 2, 2023; references, experts, and surveillance through December 6, 2023. STUDY SELECTION: English-language, randomized clinical trials of youth through age 18 years (or their caregivers) with no known exposure or signs or symptoms of current or past maltreatment. DATA EXTRACTION AND SYNTHESIS: Two reviewers assessed titles/abstracts, full-text articles, and study quality, and extracted data; when at least 3 similar studies were available, meta-analyses were conducted. MAIN OUTCOMES AND MEASURES: Directly measured reports of child abuse or neglect (reports to Child Protective Services or removal of the child from the home); proxy measures of abuse or neglect (injury, visits to the emergency department, hospitalization); behavioral, developmental, emotional, mental, or physical health and well-being; mortality; harms. RESULTS: Twenty-five trials (N = 14 355 participants) were included; 23 included home visits. Evidence from 11 studies (5311 participants) indicated no differences in likelihood of reports to Child Protective Services within 1 year of intervention completion (pooled odds ratio, 1.03 95% CI, 0.84-1.27). Five studies (3336 participants) found no differences in removal of the child from the home within 1 to 3 years of follow-up (pooled risk ratio, 1.06 95% CI, 0.37-2.99). The evidence suggested no benefit for emergency department visits in the short term (<2 years) and hospitalizations. The evidence was inconclusive for all other outcomes because of the limited number of trials on each outcome and imprecise results. Among 2 trials reporting harms, neither reported statistically significant differences. Contextual evidence indicated (1) widely varying practices when screening, identifying, and reporting child maltreatment to Child Protective Services, including variations by race or ethnicity; (2) widely varying accuracy of screening instruments; and (3) evidence that child maltreatment interventions may be associated with improvements in some social determinants of health. CONCLUSION AND RELEVANCE: The evidence base on interventions feasible in or referable from primary care settings to prevent child maltreatment suggested no benefit or insufficient evidence for direct or proxy measures of child maltreatment. Little information was available about possible harms. Contextual evidence pointed to the potential for bias or inaccuracy in screening, identification, and reporting of child maltreatment but also highlighted the importance of addressing social determinants when intervening to prevent child maltreatment.
IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Although IL-17A is the archetypal cytokine of T-helper 17 ...cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.
To identify the cellular source and the role of IL-17A in the early phase of lung injury.
Lung injury was induced in wild-type (C57BL/6) and IL-17 knockout (KO) mice with aerosolized LPS (100 μg) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing RORγt, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was performed by flow cytometry.
A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared with wild-type mice. The majority of RORγt(+) cells in the mouse lung were the recently identified group 3 innate lymphoid cells (ILC3s). Detailed characterization revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in recombinase-activating gene 2 KO mice, which lack T cells but retain innate lymphoid cells. No amelioration of pathology was observed in the recombinase-activating gene 2 KO mice.
IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3s. Modulation of the activity of pILC3s may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.
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