Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary ...transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.
Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that ...mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non-CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HCO3- concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator-dependent alkalinization to abnormal CF ASL. In addition, we found that increasing Ca2+ concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing Ca2+ concentration, and/or altering electrostatic interactions in ASL might benefit early CF.
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting ...inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain. To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.
•3D printing is a growing field with a broad range of clinical applications.•Quality of application via 3D printing is reliant on workflow optimization.•Benchmarks for 3D printing application have ...been outlined nationally.
Three-dimensional (3D) printing has applications in many fields and has gained substantial traction in medicine as a modality to transform two-dimensional scans into three-dimensional renderings. Patient-specific 3D printed models have direct patient care uses in surgical and procedural specialties, allowing for increased precision and accuracy in developing treatment plans and guiding surgeries. Medical applications include surgical planning, surgical guides, patient and trainee education, and implant fabrication. 3D printing workflow for a laboratory or clinical service that produces anatomic models and guides includes optimizing imaging acquisition and post-processing, segmenting the imaging, and printing the model. Quality assurance considerations include supervising medical imaging expert radiologists' guidance and self-implementing in-house quality control programs. The purpose of this review is to provide a workflow and guide for starting or optimizing laboratories and clinical services that 3D-print anatomic models or guides for clinical use.
The purpose of this study was to describe the technique and outcomes of percutaneous thrombin injection into the superficial aspect of actively bleeding liver and kidney biopsy tracks identified with ...color Doppler ultrasound with the aim of hemorrhage termination. After percutaneous thrombin injection, 15/16 (94%) patients did not require further intervention. Ultrasound-guided thrombin injection into the superficial site of active bleeding is an effective technique for terminating bleeding in the immediate post-procedure period following kidney and liver biopsies and should be considered if active bleeding persists on color Doppler after ≥30 minutes of compression and observation.
Background: To report the evaluation of incentive spirometry (IS)-induced pressure changes in intra-abdominal drainage catheters and consider its use for maintaining catheter patency and enhancing ...drainage. Methods: Prospective study of patients with indwelling intra-abdominal drainage catheters for abdominal fluid collections who had their intra-abdominal pressures measured while performing incentive spirometry. Patients were instructed in the use of an incentive spirometer. Within a week after initial drainage, pressure changes with IS were evaluated three times at 1500 cc and three times at maximum inspiratory effort. Intra-abdominal pressure (IAP) was measured using a pressure monitor connected to the drainage catheter. Results: Twenty patients (men, 12; women, 8). Fluid collection locations were pelvis, Right-upper quadrant (RUQ), Left-upper quadrant (LUQ), Left-lower quadrant (LLQ), and Right-lower quadrant (RLQ). A total of 16 of 20 patients showed an elevation of IAP with IS. At 1500 cc, the pressure increased by an average of 41.24 mmH2O. At maximal inspiratory effort, the pressure increased by an average of 48.26 mmH2O. Pressure increase was greater in upper abdomen catheters. Four patients with lower abdominal and pelvic collections showed minimal pressure changes with IS. Conclusion: IS increases IAP and fluid flow through abdominal drainage catheters. Future studies are warranted to determine whether the use of IS enhances catheter performance and facilitates drainage via its effect on IAP.
Mucociliary transport (MCT) is an innate defense mechanism that removes particulates, noxious material, and microorganisms from the lung. Several airway diseases exhibit abnormal MCT, including ...asthma, chronic bronchitis, and cystic fibrosis. However, it remains uncertain whether MCT abnormalities contribute to the genesis of disease or whether they are secondary manifestations that may fuel disease progression. Limitations of current MCT assays and of current animal models of human disease have hindered progress in addressing these questions. Therefore, we developed an in vivo assay of MCT, and here we describe its use in newborn wild-type pigs. We studied pigs because they share many physiological, biochemical, and anatomical features with humans and can model several human diseases. We used X-ray multidetector-row–computed tomography to track movement of individual particles in the large airways of newborn pigs. Multidetector-row–computed tomography imaging provided high spatial and temporal resolution and registration of particle position to airway anatomy. We discovered that cilia orientation directs particles to the ventral tracheal surface. We also observed substantial heterogeneity in the rate of individual particle movement, and we speculate that variations in mucus properties may be responsible. The increased granularity of MCT data provided by this assay may provide an opportunity to better understand host defense mechanisms and the pathogenesis of airway disease.
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