Mucus hypersecretion contributes to the morbidity and mortality of smoking-related lung diseases, especially chronic obstructive pulmonary disease (COPD), which starts in the small airways. Despite progress in animal studies, the genes and their expression pattern involved in mucus production and secretion in human airway epithelium are not well understood. We hypothesized that comparison of the transcriptomes of the small airway epithelium of individuals that express high vs low levels of MUC5AC, the major macromolecular component of airway mucus, could be used as a probe to identify the genes related to human small airway mucus production/secretion. Flexible bronchoscopy and brushing were used to obtain small airway epithelium (10th to 12th order bronchi) from healthy nonsmokers (n=60) and healthy smokers (n=72). Affymetrix HG-U133 plus 2.0 microarrays were used to assess gene expression. Massive parallel sequencing (RNA-Seq) was used to verify gene expression of small airway epithelium from 5 nonsmokers and 6 smokers. MUC5AC expression varied 31-fold among the healthy nonsmokers. Genome-wide comparison between healthy nonsmokers (n = 60) grouped as "high MUC5AC expressors" vs "low MUC5AC expressors" identified 528 genes significantly up-regulated and 15 genes significantly down-regulated in the high vs low expressors. This strategy identified both mucus production and secretion related genes under control of a network composed of multiple transcription factors. Based on the literature, genes in the up-regulated list were used to identify a 73 "MUC5AC-associated core gene" list with 9 categories: mucus component; mucus-producing cell differentiation-related transcription factor; mucus-producing cell differentiation-related pathway or mediator; post-translational modification of mucin; vesicle transport; endoplasmic reticulum stress-related; secretory granule-associated; mucus secretion-related regulator and mucus hypersecretory-related ion channel. As a validation cohort, we assessed the MUC5AC-associated core gene list in the small airway epithelium of an independent set of healthy smokers (n = 72). There was up-regulation of MUC5AC in the small airway epithelium of smokers (2.3-fold, p < 10-8) associated with a coordinated up-regulation of MUC5AC-associated core gene expression pattern in the small airway epithelium of smokers (p < 0.01). Deep sequencing confirmed these observations. The identification of the genes associated with increased airway mucin production in humans should be useful in understanding the pathogenesis of airway mucus hypersecretion and identifying therapeutic targets. Mucus hypersecretion contributes to the morbidity and mortality of smoking-related lung diseases, especially chronic obstructive pulmonary disease (COPD), which starts in the small airways. Little is known about the gene networks associated with the synthesis and secretion of mucins in the human small airway epithelium. Taking advantage of the knowledge that MUC5AC is a major mucin secreted by the small airway epithelium, the expression of MUC5AC in small airway epithelium is highly regulated at the transcriptional level and our observation that healthy nonsmokers have variable numbers of MUC5AC+ secretory cells in the human small airway epithelium, we compared genome-wide gene expression of the small airway epithelium of high vs low MUC5AC expressors from 60 nonsmokers to identify the genes associated with MUC5AC expression. This novel strategy enabled identification of a 73 "MUC5AC-associated core gene" list with 9 categories, which control a series of processes from mucin biosynthesis to mucus secretion. The coordinated gene expression pattern of MUC5AC-associated core genes were corroborated in an independent cohort of 72 healthy smokers. Deep sequencing of small airway epithelium RNA confirmed these observations. This finding will be useful in identifying therapeutic targets to treat small airway mucus hypersecretion.
Aortic paravalvular leak (PVL) is a known complication of TAVR. PVL closure using vascular occluder devices can be used, particularly in cases with annular calcification preventing adequate seal; however, delivery of equipment can be challenging in TAVR patients due to interaction with the valve stent. We describe a novel antegrade closure approach to treat transcatheter aortic PVL.
Introduction: Big data techniques offer a novel opportunity to characterize individuals with extreme phenotypes. In this context, we aimed to describe the prevalence of classical Fredrickson-Levy dyslipidemia phenotypes at the extremes of HDL-C levels in a cross-sectional big data study. Methods: We examined 848,801 U.S. adults and children from the Very Large Database of Lipids 1.0 who were referred for lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th to 99th to 99.9th, and >99.9th). We examined the prevalence of Fredrickson-Levy dyslipidemia phenotypes (I, IIa, IIb, III, IV and V) within these categories. We identified those who did not meet criteria for any classical dyslipidemia phenotype as the continuum group. Results: Type I and V were mostly present at extremely low HDL-C levels. Type IIa was more prevalent in high vs. low HDL-C levels. Type III was 2-fold more prevalent in extremely low vs. high HDL-C levels. Type IV was the most prevalent classical dyslipidemia phenotype in our population, and was the most frequent at low HDL-C percentiles. About 50% of the extremely low and 90% of the extremely high HDL-C levels were classified into the continuum group. Conclusion: In our cross-sectional big data analysis, there was a significantly higher prevalence of most classical dyslipidemia phenotypes at extremely low HDL-C compared with extremely high HDL-C levels. Only types I and V were more prevalent in extreme groups than general population. To some extent, very low HDL-C levels may be determined by inheritable, highly atherogenic dyslipidemias.
Visual expertise refers to advanced visual skills demonstrated when performing domain-specific visual tasks. Prior research has emphasized the fact that medical experts rely on such perceptual pattern-recognition skills when interpreting medical images, particularly in the field of electrocardiogram (ECG) interpretation. Analyzing and modeling cardiology practitioners' visual behavior across different levels of expertise in the health care sector is crucial. Namely, understanding such acquirable visual skills may help train less experienced clinicians to interpret ECGs accurately.This study aims to quantify and analyze through the use of eye-tracking technology differences in the visual behavior and methodological practices for different expertise levels of cardiology practitioners such as medical students, cardiology nurses, technicians, fellows, and consultants when interpreting several types of ECGs.A total of 63 participants with different levels of clinical expertise took part in an eye-tracking study that consisted of interpreting 10 ECGs with different cardiac abnormalities. A counterbalanced within-subjects design was used with one independent variable consisting of the expertise level of the cardiology practitioners and two dependent variables of eye-tracking metrics (fixations count and fixation revisitations). The eye movements data revealed by specific visual behaviors were analyzed according to the accuracy of interpretation and the frequency with which interpreters visited different parts/leads on a standard 12-lead ECG. In addition, the median and SD in the IQR for the fixations count and the mean and SD for the ECG lead revisitations were calculated.Accuracy of interpretation ranged between 98% among consultants, 87% among fellows, 70% among technicians, 63% among nurses, and finally 52% among medical students. The results of the eye fixations count, and eye fixation revisitations indicate that the less experienced cardiology practitioners need to interpret several ECG leads more carefully before making any decision. However, more experienced cardiology practitioners rely on their skills to recognize the visual signal patterns of different cardiac abnormalities, providing an accurate ECG interpretation.The results show that visual expertise for ECG interpretation is linked to the practitioner's role within the health care system and the number of years of practical experience interpreting ECGs. Cardiology practitioners focus on different ECG leads and different waveform abnormalities according to their role in the health care sector and their expertise levels.
Current research on valvular heart repair has focused on tissue-engineered heart valves (TEHV) because of its potential to grow similarly to native heart valves. Decellularized xenografts are a promising solution; however, host recellularization remains challenging. In this study, decellularized porcine aortic valves were implanted into the right ventricular outflow tract (RVOT) of sheep to investigate recellularization potential. Porcine aortic valves, decellularized with sodium dodecyl sulfate (SDS), were sterilized by supercritical carbon dioxide (scCO2) and implanted into the RVOT of five juvenile polypay sheep for 5 months (n = 5). During implantation, functionality of the valves was assessed by serial echocardiography, blood tests, and right heart pulmonary artery catheterization measurements. The explanted valves were characterized through gross examination, mechanical characterization, and immunohistochemical analysis including cell viability, phenotype, proliferation, and extracellular matrix generation. Gross examination of the valve cusps demonstrated the absence of thrombosis. Bacterial and fungal stains were negative for pathogenic microbes. Immunohistochemical analysis showed the presence of myofibroblast-like cell infiltration with formation of new collagen fibrils and the existence of an endothelial layer at the surface of the explant. Analysis of cell phenotype and morphology showed no lymphoplasmacytic infiltration. Tensile mechanical testing of valve cusps revealed an increase in stiffness while strength was maintained during implantation. The increased tensile stiffness confirms the recellularization of the cusps by collagen synthesizing cells. The current study demonstrated the feasibility of the trans-species implantation of a non-fixed decellularized porcine aortic valve into the RVOT of sheep. The implantation resulted in recellularization of the valve with sufficient hemodynamic function for the 5-month study. Thus, the study supports a potential role for use of a TEHV for the treatment of valve disease in humans.
