Compliance, hysteresis, and collapsibility of human small airways

We tested the hypothesis that airway wall dimensions are important determinants for the mechanical properties of airways. Lung tissue was obtained from 31 smokers with different degrees of chronic obstructive pulmonary disease (COPD) who were operated on for a solitary lung lesion. Segments of small airways (n = 35) were mounted on cannulas in an organ bath and inflated and deflated cyclically between +15 and -15 cm H(2)O. For each airway this was done at baseline, after methacholine, and after isoprenaline. Specific compliance (sCdyn), specific hysteresis (seta), and pressure at which the airways collapsed (Pcol) were calculated from each recording. Airway wall dimensions were measured morphometrically. Lung function parameters of airflow obstruction were correlated to sCdyn, seta, and Pcol. At baseline, after methacholine, and after isoprenaline sCdyn was 0.059, 0.052, and 0. 085 cm H(2)O(-)(1), seta was 13.5, 12.9, and 7.1%, and Pcol was -3.4, -3.5, and -1.9 cm H(2)O, respectively. Differences between sCdyn, seta, and Pcol after methacholine and after isoprenaline were highly significant (p < 0.001). Of all dimensions studied, smooth muscle area, but not total wall ar

Experimental validation of geosmin uptake in rainbow trout, Oncorhynchus mykiss (Waldbaum) suggests biotransformation

The bioconcentration of waterborne geosmin in rainbow trout, Oncorhynchus mykiss (Waldbaum) was assessed. Fifty rainbow trout with a mean (SD) weight of 226.6 (29.0) g and lipid content of 6.2 (0.6) % (w/w) were exposed to geosmin in static water for 0, 2, 4, 6, 8, 12, 24, 36, 48 and 120 hr, with one tank containing five fish for eac h exposure period. Geosmin concentrations were measured in fish tissue and water samples collected over time. With time the geosmin concentration in the fish increased and decreased in the water. However, the total absolute amount of geosmin in the system declined over time which could be explained by induction of biotransformation. This is in accordance with the decreasing lipid normalized geosmin levels in the liver compared with the liver-free carcass. Geosmin distribution within rainbow trout clearly is not exclusively governed by the lipid content of tissues. In vivo geosmin bioconcentration in rainbow trout is slower and the body burden reached is lower than the generally accepted theoretical model predicts

Focus on focus: Lack of coherence between systemic and microvascular indices of oedema formation

Background: Fluid therapy remains a cornerstone of therapy in shock states. However, fluid overloading ultimately results in oedema formation which is related to excess morbidity and mortality. Handheld microscopes are now frequently used to study the sublingual microcirculation. As a corollary, these devices measure focal distance, or surface to capillary distance. Physiologically, this could represent a microvascular index of oedema formation and could have the potential to guide fluid therapy. This potential tool should be investigated, especially given the frequently reported lack of coherence between systemic and microvascular parameters in the critically ill. Therefore, we set out to assess the correlation between microvascular focal distance and systemic indices of oedema formation, specifically fluid balance and weight gain. Methods: Following ex vivo testing of focal distance measurement reliability, we conducted a prospective observational cohort study in patients admitted to the intensive care unit of our university teaching hospital. We determined surface to capillary distance using sidestream dark field (SDF) and incident dark field (IDF) imaging by assessing the focal distance point or object distance range at which a sharp recording could be made. Measurements were performed in post-cardiac surgery patients and in patients following emergency admission at two time points separated by at least several hours. Data on fluid balance, weight and weight gain were collected simultaneously. Results: Sixty patients were included. The focal setting, focus point for SDF and the object distance range for IDF did not differ significantly between time points. Focus was not correlated with difference in fluid balance or weight gain. Conclusions: There is a lack of coherence between surface to capillary distance as determined by SDF or IDF imaging and fluid balance or weight gain. Thus, focal distance as a microvascular index of oedema formation cannot currently be used as a proxy for systemic indices of oedema formation. However, given the lack of coherence, further research should determine whether focal distance may provide better guidance for fluid therapy than traditional markers of overzealous fluid administration

Association between early cumulative fluid balance and successful liberation from invasive ventilation in COVID-19 ARDS patients - insights from the PRoVENT-COVID study:a national, multicenter, observational cohort analysis

BACKGROUND: Increasing evidence indicates the potential benefits of restricted fluid management in critically ill patients. Evidence lacks on the optimal fluid management strategy for invasively ventilated COVID-19 patients. We hypothesized that the cumulative fluid balance would affect the successful liberation of invasive ventilation in COVID-19 patients with acute respiratory distress syndrome (ARDS). METHODS: We analyzed data from the multicenter observational 'PRactice of VENTilation in COVID-19 patients' study. Patients with confirmed COVID-19 and ARDS who required invasive ventilation during the first 3 months of the international outbreak (March 1, 2020, to June 2020) across 22 hospitals in the Netherlands were included. The primary outcome was successful liberation of invasive ventilation, modeled as a function of day 3 cumulative fluid balance using Cox proportional hazards models, using the crude and the adjusted association. Sensitivity analyses without missing data and modeling ARDS severity were performed. RESULTS: Among 650 patients, three groups were identified. Patients in the higher, intermediate, and lower groups had a median cumulative fluid balance of 1.98 L (1.27-7.72 L), 0.78 L (0.26-1.27 L), and - 0.35 L (- 6.52-0.26 L), respectively. Higher day 3 cumulative fluid balance was significantly associated with a lower probability of successful ventilation liberation (adjusted hazard ratio 0.86, 95% CI 0.77-0.95, P = 0.0047). Sensitivity analyses showed similar results. CONCLUSIONS: In a cohort of invasively ventilated patients with COVID-19 and ARDS, a higher cumulative fluid balance was associated with a longer ventilation duration, indicating that restricted fluid management in these patients may be beneficial. Trial registration Clinicaltrials.gov ( NCT04346342 ); Date of registration: April 15, 2020

Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale

Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration

KidneyNetwork:Using kidney-derived gene expression data to predict and prioritize novel genes involved in kidney disease

Abstract: Genetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the disorder as potentially pathogenic variants can reside in genes that are not yet known to be involved in kidney disease. We have developed KidneyNetwork, that utilizes tissue-specific expression to inform candidate gene prioritization specifically for kidney diseases. KidneyNetwork is a novel method constructed by integrating a kidney RNA-sequencing co-expression network of 878 samples with a multi-tissue network of 31,499 samples. It uses expression patterns and established gene-phenotype associations to predict which genes could be related to what (disease) phenotypes in an unbiased manner. We applied KidneyNetwork to rare variants in exome sequencing data from 13 kidney disease patients without a genetic diagnosis to prioritize candidate genes. KidneyNetwork can accurately predict kidney-specific gene functions and (kidney disease) phenotypes for disease-associated genes. The intersection of prioritized genes with genes carrying rare variants in a patient with kidney and liver cysts identified ALG6 as plausible candidate gene. We strengthen this plausibility by identifying ALG6 variants in several cystic kidney and liver disease cases without alternative genetic explanation. We present KidneyNetwork, a publicly available kidney-specific co-expression network with optimized gene-phenotype predictions for kidney disease phenotypes. We designed an easy-to-use online interface that allows clinicians and researchers to use gene expression and co-regulation data and gene-phenotype connections to accelerate advances in hereditary kidney disease diagnosis and research. Translational statement: Genetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the patient’s disorder. Potentially pathogenic variants can reside in genes not yet known to be involved in kidney disease, making it difficult to interpret the relevance of these variants. This reveals a clear need for methods to predict the phenotypic consequences of genetic variation in an unbiased manner. Here we describe KidneyNetwork, a tool that utilizes tissue-specific expression to predict kidney-specific gene functions. Applying KidneyNetwork to a group of undiagnosed cases identified ALG6 as a candidate gene in cystic kidney and liver disease. In summary, KidneyNetwork can aid the interpretation of genetic variants and can therefore be of value in translational nephrogenetics and help improve the diagnostic yield in kidney disease patients.</p