The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, ...idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.
Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants ...in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF.
Finite element simulations employing an idealized network of alveoli (155) show that the stiffening of a single central alveolus, or a cluster of alveoli, without reducing Va intensifies septal wall ...strain in the remaining patent alveoli. Because the morphology of pulmonary fibrosis is characterized by alveolar collapse, where Va approaches zero, we have included finite element simulations of an idealized alveolar network that is based on a previously published model (157) and described in the online supplement (Figure E2). ...although the alveoli adjacent to the collapsed region in Figures 2D and 2E have areas 15% and 33% smaller, respectively, than those of the far-field alveoli, it is the strain on the alveolar septa, not the Va, that causes overdistention-induced damage. Because the tethering-induced strains in these adjacent septa at FRC are greater than septal strains predicted at TLC in the open lung, it is likely that the basement membrane is distended and that the increased length is not due solely to the unfolding of septal pleats (158). Above that point, however, further expansion stretches the basement membrane and increases strain. ...the physiological and psychological benefits of regular exercise, together with the fact that the pathophysiology described is currently an untested hypothesis that lacks even a single study demonstrating proof of concept, lead us to conclude that making any recommendation regarding limiting the frequency or intensity of exercise is premature.
comb-p is a command-line tool and a python library that manipulates BED files of possibly irregularly spaced P-values and (1) calculates auto-correlation, (2) combines adjacent P-values, (3) performs ...false discovery adjustment, (4) finds regions of enrichment (i.e. series of adjacent low P-values) and (5) assigns significance to those regions. In addition, tools are provided for visualization and assessment. We provide validation and example uses on bisulfite-seq with P-values from Fisher's exact test, tiled methylation probes using a linear model and Dam-ID for chromatin binding using moderated t-statistics. Because the library accepts input in a simple, standardized format and is unaffected by the origin of the P-values, it can be used for a wide variety of applications.
comb-p is maintained under the BSD license. The documentation and implementation are available at https://github.com/brentp/combined-pvalues.
bpederse@gmail.com
A polymorphism on the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) but not with systemic sclerosis (SSc) with interstitial lung disease (ILD). We genotyped ...the MUC5B promoter in the first 142 patients of the French national prospective cohort of IPF, in 981 French patients with SSc (346 ILD), 598 Italian patients with SSc (207 ILD), 1383 French controls and 494 Italian controls. A meta-analysis was performed including all American data available. The T risk allele was present in 41.9% of the IPF patients, 10.8% of the controls (P = 2 × 10(-44)), OR 6.3 4.6-8.7 for heterozygous patients and OR 21.7 10.4-45.3 for homozygous patients. Prevalence of the T allele was not modified according to age, gender, smoking in IPF patients. However, none of the black patients with IPF presented the T allele. The prevalence of the T risk allele was similar between French (10%) and Italian (12%) cohorts of SSc whatever the presence of an ILD (11.1% and 13.5%, respectively). Meta-analysis confirmed the similarity between French, Italian and American cohorts of IPF or SSc-ILD. This study confirms 1) an association between the T allele risk and IPF, 2) an absence of association with SSc-ILD, suggesting different pathophysiology.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the preferred surgical treatment for refractory or complicated ulcerative colitis (UC) and familial ...adenomatous polyposis (FAP). Pouchitis is the most common complication of this procedure and can occur in about 50% of patients. Treatment of pouchitis depends on the phenotype of disease. Pouchitis can be classified as acute, chronic/refractory, or secondary pouchitis, which includes pouchitis occurring due to Crohn's disease (CD). CD of the pouch is becoming an increasingly recognized problem, and management is challenging. This article reviews the literature and offers treatment recommendations regarding management of pouchitis and CD of the pouch.
Asthma is heritable, influenced by the environment, and modified by in utero exposures and aging; all of these features are also common to epigenetic regulation. Furthermore, the transcription ...factors that are involved in the development of mature T cells that are critical to the TH 2 immune phenotype in asthmatic patients are regulated by epigenetic mechanisms. Epigenetic marks (DNA methylation, modifications of histone tails, and noncoding RNAs) work in concert with other components of the cellular regulatory machinery to control the spatial and temporal levels of expressed genes. Technology to measure epigenetic marks on a genomic scale and comprehensive approaches to data analysis have recently emerged and continue to improve. Alterations in epigenetic marks have been associated with exposures relevant to asthma, particularly air pollution and tobacco smoke, as well as asthma phenotypes, in a few population-based studies. On the other hand, animal studies have begun to decipher the role of epigenetic regulation of gene expression associated with the development of allergic airway disease. Epigenetic mechanisms represent a promising line of inquiry that might, in part, explain the inheritance and immunobiology of asthma.
Abstract
Background
Fistulas may arise as a relevant complication of Crohn’s disease (CD). Despite their clinical significance and the substantial burden imposed on patients, limited data are ...available on the epidemiology of fistulizing CD in the United States.
Methods
A systematic literature review was conducted to identify data published between 1970 and 2017 on the epidemiology of fistulas in patients with CD, with the aim to estimate the number of prevalent cases in the United States. Retrieved titles and abstracts were screened by 2 independent researchers for inclusion criteria (US population-based studies reporting data on the epidemiology of fistulizing CD). To validate the literature-based estimate, data from a US claims database (Truven Health MarketScan database) were analyzed. This database has broad geographic coverage, with health care data for >60 million patients during the period of the analysis.
Results
The literature search retrieved 7 articles for full-text review, and only 1 met the criteria for inclusion. This study described the cumulative incidence of fistulas in a CD population from Minnesota over 20 years. From the reported data, the estimated number of prevalent cases with fistulizing CD in the United States was ~76,600 in 2017 (~52,900 anal, ~7400 rectovaginal, ~2300 enterocutaneous, and ~14,100 internal). Analysis from the US health care database resulted in an estimated number of ~75,700 patients, confirming the robustness of the original estimate from the literature.
Conclusions
Based on 2 separate analyses, the estimated number of patients with fistulizing CD in the United States is ~77,000 patients.
This article describes a literature review and population-based database search that estimate the number of patients with fistulizing Crohn’s Disease (CD) in the United States to be ~77,000. The data indicates that fistulizing CD is an orphan condition.
We report the autopsy pathology findings of a 21-week stillborn fetus with congenital mpox syndrome that occurred in the Democratic Republic of the Congo in 2008. The fetus acquired mpox from the ...mother after intrauterine transplacental monkeypox virus transmission. We confirmed monkeypox virus infection in the mother, fetus, and placenta by using a monkeypox virus-specific quantitative PCR. Subtyping of the virus was not performed, but the mother and fetus were almost certainly infected with the clade I variant that was endemic in the Democratic Republic of the Congo at the time. Risk for intrauterine infection appears to differ between virus clades, but clinicians should be aware of potential for intrauterine monkeypox virus transmission among pregnant persons during ongoing and future mpox outbreaks.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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