MODELING THE DYNAMICS OF AIRWAY CONSTRICTION: EFFECTS OF AGONIST TRANSPORT AND BINDING

Recent advances have revealed that during exogenous airway challenge, airway diameters can not be adequately predicted by their initial diameters. Furthermore, airway diameters can also vary greatly in time on scales shorter than a breath. In order to better understand these phenomena, we developed a multiscale model which allows us to simulate aerosol challenge in the airways during ventilation. The model incorporates agonist-receptor binding kinetics to govern the temporal response of airway smooth muscle (ASM) contraction on individual airway segments, which together with airway wall mechanics, determines local airway caliber. Global agonist transport and deposition is coupled with pressure-driven flow, linking local airway constrictions with global flow dynamics. During the course of challenge, airway constriction alters the flow pattern, redistributing agonist to less constricted regions. This results in a negative feedback which may be a protective property of the normal lung. As a consequence, repetitive challenge can cause spatial constriction patterns to evolve in time, resulting in a loss of predictability of airway diameters. Additionally, the model offers new insight into several phenomena including the intra- and inter-breath dynamics of airway constriction throughout the tree structure.

Fractals for physicians

There is increasing interest in the study of fractals in medicine. In this review, we provide an overview of fractals, of techniques available to describe fractals in physiological data, and we propose some reasons why a physician might benefit from an understanding of fractals and fractal analysis, with an emphasis on paediatric respiratory medicine where possible. Among these reasons are the ubiquity of fractal organisation in nature and in the body, and how changes in this organisation over the lifespan provide insight into development and senescence. Fractal properties have also been shown to be altered in disease and even to predict the risk of worsening of disease. Finally, implications of a fractal organisation include robustness to errors during development, ability to adapt to surroundings, and the restoration of such organisation as targets for intervention and treatment.

Variability of lung function predicts loss of asthma control following withdrawal of inhaled corticosteroid treatment

BACKGROUND One aspect of a multidimensional approach to understanding asthma as a complex dynamic disease is to study how lung function varies with time. Variability measures of lung function have been shown to predict response to beta(2)-agonist treatment. An investigation was conducted to determine whether mean, coefficient of variation (CV) or autocorrelation, a measure of short-term memory, of peak expiratory flow (PEF) could predict loss of asthma control following withdrawal of regular inhaled corticosteroid (ICS) treatment, using data from a previous study. METHODS 87 adult patients with mild to moderate asthma who had been taking ICS at a constant dose for at least 6 months were monitored for 2-4 weeks. ICS was then withdrawn and monitoring continued until loss of control occurred as per predefined criteria. Twice-daily PEF was recorded during monitoring. Associations between loss of control and mean, CV and autocorrelation of morning PEF within 2 weeks pre- and post-ICS withdrawal were assessed using Cox regression analysis. Predictive utility was assessed using receiver operator characteristics. RESULTS 53 out of 87 patients had sufficient PEF data over the required analysis period. The mean (389 vs 370 l/min, p<0.0001) and CV (4.5% vs 5.6%, p=0.007) but not autocorrelation of PEF changed significantly from prewithdrawal to postwithdrawal in subjects who subsequently lost control, and were unaltered in those who did not. These changes were related to time to loss of control. CV was the most consistent predictor, with similar sensitivity and sensitivity to exhaled nitric oxide. CONCLUSION A simple, easy to obtain variability measure of daily lung function such as the CV may predict loss of asthma control within the first 2 weeks of ICS withdrawal.

Reproducibility and validity of video screen measurements of gait in children with spastic cerebral palsy

PURPOSE: To determine the reproducibility and validity of video screen measurement (VSM) of sagittal plane joint angles during gait. METHODS: 17 children with spastic cerebral palsy walked on a 10m walkway. Videos were recorded and 3d-instrumented gait analysis was performed. Two investigators measured six sagittal joint/segment angles (shank, ankle, knee, hip, pelvis, and trunk) using a custom-made software package. The intra- and interrater reproducibility were expressed by the intraclass correlation coefficient (ICC), standard error of measurements (SEM) and smallest detectable difference (SDD). The agreement between VSM and 3d joint angles was illustrated by Bland-Altman plots and limits of agreement (LoA). RESULTS: Regarding the intrarater reproducibility of VSM, the ICC ranged from 0.99 (shank) to 0.58 (trunk), the SEM from 0.81 degrees (shank) to 5.97 degrees (trunk) and the SDD from 1.80 degrees (shank) to 16.55 degrees (trunk). Regarding the interrater reproducibility, the ICC ranged from 0.99 (shank) to 0.48 (trunk), the SEM from 0.70 degrees (shank) to 6.78 degrees (trunk) and the SDD from 1.95 degrees (shank) to 18.8 degrees (trunk). The LoA between VSM and 3d data ranged from 0.4+/-13.4 degrees (knee extension stance) to 12.0+/-14.6 degrees (ankle dorsiflexion swing). CONCLUSION: When performed by the same observer, VSM mostly allows the detection of relevant changes after an intervention. However, VSM angles differ from 3d-IGA and do not reflect the real sagittal joint position, probably due to the additional movements in the other planes.

Preoperative MRI findings and functional outcome after selective dorsal rhizotomy in children with bilateral spasticity

PURPOSE: To identify MRI characteristics that may predict the functional effect of selective dorsal rhizotomy (SDR) in children with bilateral spastic paresis. METHODS: We performed SDR in a group of 36 patients. The gross motor functioning measure-66 (GMFM-66) was applied before and after SDR. Available cerebral MRIs were retrospectively classified into three diagnostic groups: periventricular leucomalacia (PVL; n = 10), hydrocephalus (n = 2), and normal (n = 6). In patients with PVL, we scored the severity of the MR abnormalities. We compared the changes in the GMFM-66 after SDR in the diagnostic groups. In patients with PVL, we correlated the severity of the MR abnormalities with the changes in the GMFM-66. RESULTS: The mean follow-up period was 5 years and 4 months (range, 1 year and 1 month to 9 years). The best improvement in gross motor function was observed in patients with normal MRI, and the slightest improvement was observed in patients with hydrocephalus. The severity of the PVL did correlate with the GMFM-66 score before SDR but not with the functional effect of SDR. CONCLUSION: We conclude that with respect to gross motor skills, the improvements after SDR are good in patients with no MRI abnormalities. In the patients with hydrocephalus, the improvements after SDR were insignificant. In patients with PVL, the improvements were intermediate and did not correlate with the degree of PVL.

Expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases

BACKGROUND: Inflammatory lung diseases are a major morbidity factor in children. Therefore, novel strategies for early detection of inflammatory lung diseases are of high interest. Bacterial lipopolysaccharide (LPS) is recognized via Toll-like receptors and CD14. CD14 exists as a soluble (sCD14) and membrane-associated (mCD14) protein, present on the surface of leukocytes. Previous studies suggest sCD14 as potential marker for inflammatory diseases, but their potential role in pediatric lung diseases remained elusive. Therefore, we examined the expression, regulation and significance of sCD14 and mCD14 in pediatric lung diseases. METHODS: sCD14 levels were quantified in serum and bronchoalveolar lavage fluid (BALF) of children with infective (pneumonia, cystic fibrosis, CF) and non-infective (asthma) inflammatory lung diseases and healthy control subjects by ELISA. Membrane CD14 expression levels on monocytes in peripheral blood and on alveolar macrophages in BALF were quantified by flow cytometry. In vitro studies were performed to investigate which factors regulate sCD14 release and mCD14 expression. RESULTS: sCD14 serum levels were specifically increased in serum of children with pneumonia compared to CF, asthma and control subjects. In vitro, CpG induced the release of sCD14 levels in a protease-independent manner, whereas LPS-mediated mCD14 shedding was prevented by serine protease inhibition. CONCLUSIONS: This study demonstrates for the first time the expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases and suggests sCD14 as potential marker for pneumonia in children.

Bone images from dual-energy subtraction chest radiography in the detection of rib fractures

To assess the sensitivity and image quality of chest radiography (CXR) with or without dual-energy subtracted (ES) bone images in the detection of rib fractures.

Hematopoietic stem cell transplantation in Switzerland: a comprehensive quality control report on centre effect

QUESTIONS UNDER STUDY / PRINCIPLES: Interest groups advocate centre-specific outcome data as a useful tool for patients in choosing a hospital for their treatment and for decision-making by politicians and the insurance industry. Haematopoietic stem cell transplantation (HSCT) requires significant infrastructure and represents a cost-intensive procedure. It therefore qualifies as a prime target for such a policy. METHODS: We made use of the comprehensive database of the Swiss Blood Stem Cells Transplant Group (SBST) to evaluate potential use of mortality rates. Nine institutions reported a total of 4717 HSCT - 1427 allogeneic (30.3%), 3290 autologous (69.7%) - in 3808 patients between the years 1997 and 2008. Data were analysed for survival- and transplantation-related mortality (TRM) at day 100 and at 5 years. RESULTS: The data showed marked and significant differences between centres in unadjusted analyses. These differences were absent or marginal when the results were adjusted for disease, year of transplant and the EBMT risk score (a score incorporating patient age, disease stage, time interval between diagnosis and transplantation, and, for allogeneic transplants, donor type and donor-recipient gender combination) in a multivariable analysis. CONCLUSIONS: These data indicate comparable quality among centres in Switzerland. They show that comparison of crude centre-specific outcome data without adjustment for the patient mix may be misleading. Mandatory data collection and systematic review of all cases within a comprehensive quality management system might, in contrast, serve as a model to ascertain the quality of other cost-intensive therapies in Switzerland.

TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF-kappaB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.

ABCA4 and ROM1: Implications for modification of the PRPH2-associated macular dystrophy phenotype

To identify the causative mutation leading to autosomal dominant macular dystrophy, cone dystrophy, and cone-rod dystrophy in a five-generation family and to explain the high intrafamilial phenotypic variation by identifying possible modifier genes.

Posaconazole salvage treatment in paediatric patients: a multicentre survey

While a paediatric dosage has not been defined, posaconazole is occasionally being used in children. We conducted a multicentre retrospective survey and identified 15 patients (median age 10 years [range 3.6-17.5]) who received posaconazole salvage therapy for proven (9 patients) or probable (6 patients) invasive fungal infections. Posaconazole was administered for a median of 32 days (range 4-262) at a median dosage of 21 mg/kg (range 4.8-33.3). None of the patients discontinued therapy due to adverse events, which were mostly mild and observed in 11 patients. Complete or partial responses were observed in 4/7 patients with zygomycosis, 3/4 patients with invasive mould infection, 1/2 patients with invasive aspergillosis and 1/2 patients with chronic disseminated candidiasis. We conclude from the data that posaconazole displays favourable safety and tolerance and may be useful for management of individual paediatric patients with invasive infections.

The worldwide fight against doping: from the beginning to the World Anti-Doping Agency

This article describes the worldwide endeavor to combat doping in sports. It describes the historical reasons the movement began and outlines the current status of this effort by international sports groups, governments, and the World Anti-Doping Agency. The purposes, strengths, and limitations of the various entities are illustrated; and recommendations for improvements are made.

Effects of exposure to physical factors on homeopathic preparations as determined by ultraviolet light spectroscopy

Clinical trials have reported statistically significant and clinically relevant effects of homeopathic preparations. We applied ultraviolet (UV) spectroscopy to investigate the physical properties of homeopathic preparations and to contribute to an understanding of the not-yet-identified mode of action. In previous investigations, homeopathic preparations had significantly lower UV light transmissions than controls. The aim of this study was to explore the possible effects of external factors (UV light and temperature) on the homeopathic preparations. Homeopathic centesimal (c) dilutions, 1c to 30c, of copper sulfate (CuSO(4)), decimal dilutions of sulfur (S(8)), 1x to 30x, and controls (succussed potentization medium) were prepared, randomized, and blinded. UV transmission was measured at six different time points after preparation (from 4 to 256 days). In addition, one series of samples was exposed to UV light of a sterilization lamp for 12 h, one was incubated at 37 degrees Celsius for 24 h, and one was heated to 90 degrees Celsius for 15 min. UV light transmission values from 190 or 220 nm to 340 nm were measured several times and averaged. After each exposure, UV transmission of the homeopathic preparations of CuSO(4) was significantly reduced compared to the controls, particularly after heating to 37 degrees Celsius. Overall, the nonexposed CuSO(4) preparations did not show significantly lower UV transmission compared to controls; however, the pooled subgroup of measurements at days 26, 33, and 110 yielded significant differences. UV light transmission for S(8) preparations did not show any differences compared to controls. Our conclusion is that exposure to external factors, incubation at 37 degrees Celsius in particular, increases the difference in light transmission of homeopathic CuSO(4) preparations compared to controls.