Quantification of perfusion abnormalities using dynamic contrast-enhanced magnetic resonance imaging in muco-obstructive lung diseases

Pulmonary perfusion is regionally impaired in muco-obstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) due to the destruction of the alveolar-capillary bed and hypoxic pulmonary vasoconstriction in response to alveolar hypoxia. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an established technique for assessing regional perfusion abnormalities by exploiting contrast enhancement in the lung parenchyma during the first pass of an intravenously injected contrast agent bolus. Typically, perfusion abnormalities are assessed in clinical studies by visual scoring or by quantifying pulmonary blood flow (PBF) and pulmonary blood volume (PBV). Automated quantification can help to address inter-reader variability issues with human reader, facilitate detailed perfusion analyses and is time efficient. However, currently used absolute quantification of PBF and PBV is highly variable. For this reason, an algorithm was developed to quantify the extent of pulmonary perfusion in percent (QDP) using unsupervised clustering algorithms, which leads to an intrinsic normalisation and can reduce variability compared to absolute perfusion quantification. The aims of this work were to develop a robust algorithm for quantifying QDP, to investigate the midterm reproducibility of QDP, and to validate QDP using MRI perfusion scoring, quantitative computed tomography (CT) parameters, and pulmonary function testing (PFT) parameters. Furthermore, the performance of QDP was compared to the performance of PBF and PBV. The development of QDP and its technical and clinical validation were performed using data from two studies, which utilise DCE-MRI. First, the algorithm was developed using data of 83 COPD subjects from the ‘COSYCONET’ COPD cohort by comparing different unsupervised clustering approaches including Otsu´s method, k-means clustering, and 80th percentile threshold. Second, the reproducibility of QDP was investigated using data from a study of 15 CF and 20 COPD patients who underwent DCE-MRI at baseline and one month later (reproducibility study). According to the indicator dilution theory, impulse response function maps were calculated from DCE-MRI data, which formed the basis for the quantification of QDP, PBF and PBV. Overall, QDP based on Otsu´s method showed the highest agreement with the MRI perfusion score, quantitative CT parameters and PFT parameters in the COSYCONET study and was therefore selected for further evaluations. QDP correlated moderately with the MRI perfusion score in CF (r=0.46, p<0.05) and moderately to strongly in COPD (r=0.66 and r=0.72, p<0.001) in both studies. PBF and PBV correlated poorly with the MRI perfusion score in CF (r=-0.29, p=0.132 and r=-0.35, p=0.067, respectively) and moderately in COPD (r=-0.49 to -0.57, p<0.001). QDP correlated strongly with the CT parameter for emphysema (r=0.74, p<0.001) and weakly with the CT parameter for functional small airway disease (r=0.35, p<0.001) in COPD. The extent of perfusion defects from DCE-MRI corresponded to extent of abnormal lung (emphysema+functional small airway disease) from CT, with a mean difference of 6.03±16.94. QDP correlated moderately with PFT parameters in both studies and patient groups, with one exception in the reproducibility study where no correlation was observed in the COPD group. The use of unsupervised clustering approaches increased the reproducibility (±1.96SD related to the median) of QDP (CF: ±38%, COPD: ±37%) compared to PBF(CF: ±89%, COPD: ±55%) and PBV(CF: ±55%, COPD: ±51%) and reduced outliers. These results demonstrate that the quantification of pulmonary perfusion using unsupervised clustering approaches in combination with the mathematical models of the indicator dilution theory improves the reproducibility and the correlations with visual MRI perfusion scoring, quantitative CT parameters and PFT parameters. QDP based on Otsu´s method showed high agreement with the MRI perfusion score, suggesting that in future clinical studies pulmonary perfusion can be assessed objectively by computer algorithms replacing the time-consuming visual scoring. Concordance between the extent of QDP from MRI and the extent of abnormal lung from CT indicates that pulmonary perfusion abnormalities themselves may contribute to, or at least precede, the development of irreversible emphysema. The findings of both studies show that QDP is clinically meaningful in muco-obstructive lung diseases as it is significantly associated with the MRI perfusion score, quantitative CT parameters, and PFT parameters

Reaktivität von Serotonin-Transmitterrezeptoren des Subkommissuralorgans bei Goldhamstern im Tag-Nacht-Rhythmus

In der vorliegenden Arbeit wurde der tageszeitkorrelierte Serotonin-Gehalt des SCO, sowie die Expression der 5-HT1A- und 5-HT2A-Rezeptoren und die Synthese- bzw. Sekretionsleistung des SCO bei Goldhamstern untersucht. Serotonin entfaltet im SCO des Goldhamsters eine inhibitorische Wirkung und hemmt die Sezernierungsrate von Glykoproteinen, die den RF formen. Dies bestätigt die Tatsache, dass mit steigender Rezeptorausprägung die Immunreaktivität für AFRU abnimmt. Ob Serotonin beim Hamster auch auf die Synthese von Glykoproteinen wirkt, muss nachfolgend geklärt werden, da in unserem Versuchsaufbau lediglich die Glykoprotein-Sezernierung untersucht wurde. Aussagen bezüglich der Auswirkung von Serotonin auf die Synthese und Sezernierung von löslichen Komponenten des SCO konnten bei dem von uns verwendeten Versuchsaufbau nicht gemacht werden. Deren mögliche Funktionen bleiben noch fraglich und eröffnen neue Optionen. Geklärt ist nun auch die quantitative Relation von 5-HT1A- und 5-HT2A-Rezeptoren im SCO. Es sind deutlich mehr 5-HT1A-Rezeptoren exprimiert. Dies lässt darauf schließen, dass Serotonin im SCO einen entscheidenden Einfluss auf die Glykoprotein-Synthese oder -Sekretion hat. Die tageszeitkorrelierte Rezeptorausprägung muss diskutiert werden. Sie ist tageszeitkorreliert relativ konstant, fraglich bleibt jedoch, wieso die Rezeptorausprägung im zweiten Abschnitt der Tiefschlafphase der Tiere abnimmt, obwohl hier der serotonerge Input weiterhin hoch sein müsste, um in der Aktivitätsphase wieder abzunehmen. Wahrscheinlich ist die Erklärung hierfür in den Expressionsmechanismen der G-Protein-gekoppelten Rezeptoren selbst zu finden. Welche Proteine die geschwindigkeitsbestimmenden Faktoren der 5-HT1A- und 5-HT2A-Rezeptorexpression sind, bleibt zu klären und auch ob sich der Verdacht bestätigt, dass die 5-HT1A-Rezeptorausprägung deutlich schneller voran geht als die der 5-HT2A-Rezeptoren und damit mehr 5-HT1A--Rezeptoren zur Prezeption von Serotonin zur Verfügung stehen. Mit dieser tageszeitkorrelierten Ausprägung schützt sich das SCO unter Umständen vor einer völligen Entleerung der Glykoprotein-Speicher unter erheblichem Serotonin-Einfluss während der Schlafphase. Dieser Aspekt und dessen mögliche Folgen müssen weiter untersucht werden. Weiterhin bleibt fraglich, wie die relative Konstanz in der Glykoprotein-Ausschüttung am Tag und in der Nacht etabliert werden kann, da die Serotonin-Ausschüttung der Raphe-Kerne am SCO nachweislich einer periodischen Rhythmik unterworfen ist. Neben dem Nucleus raphe dorsalis und dem Nucleus raphe medianus ist der Einfluss weiterer Aktivitätszentren auf das SCO denkbar. Auch eine Co-Stimulation der ependymalen und hypendymalen SCO-Zellen mit anderen Transmitterklassen ist möglich und teilweise auch bewiesen. Beide genannten Aspekte könnten Teil eines Feedback-Mechanismus sein, der das SCO vor vollständiger Entspeicherung schützt.In the present investigation, the diurnal cycle of the serotonin-content and its related 5-HT1A- and 5-HT2A-receptors were studied in the SCO of the golden hamster. In summary serotonin expresses inhibitory actions on the secretionrate of SCO-glycoproteins which form the RF. This proves that increasing receptorexpression is related with decreased immunreactivity for AFRU. It has to be clarified wether serotonin influences also the synthesis of SCO-glycoproteins, because the present experimental setup was restricted to the analysis of the secretion rate. Statements regarding the influence of serotonin on soluble components cannot be given. However the quantitative relation of 5-HT1A- und 5-HT2A-receptors in the SCO is deciphered. Markedly more 5-HT1A-receptors are suggestive of a serotoninfunction in glycoprotein synthesis and secretion. The diurnal receptorexpression is a matter of debate. During the daynightcycle, the receptor expression is relatively constant, questionable is the drop of the receptorexpression during the last phase of the deep-sleep period, although the strong serotonergic input is maintained. An explanation for this pattern can be propably found in the expressionmechanism of the G-protein related receptors. It has to be discussed which protein is determining the rate of the 5-HT1A- and 5-HT2A-receptorexpression and wether the 5-HT1A-receptorexpression precedes faster than that of 5-HT1A-receptors. With its diurnal receptorexpression, the SCO possibly protects its glycoproteinstorage during strong serotonergic input. It is not known how the relative constancy in the glycoproteinsecretion during day vs. night can be explained, although the serotoninrelease originating from the raphe nuclei shows periodic rhythms. It may be based on the influence on the SCO by other centers of activity different from the Nucleus raphe dorsalis and raphe medianus. Costimulation of the ependymal and hypendymal cells of the SCO via other transmitters is possible and in some cases it was even demonstrated. Both aspects could be part of a feedbackmechanism which serves the glycoproteinstorage within the SCO

Table_1_GOLD stage-specific phenotyping of emphysema and airway disease using quantitative computed tomography.docx

BackgroundIn chronic obstructive pulmonary disease (COPD) abnormal lung function is related to emphysema and airway obstruction, but their relative contribution in each GOLD-stage is not fully understood. In this study, we used quantitative computed tomography (QCT) parameters for phenotyping of emphysema and airway abnormalities, and to investigate the relative contribution of QCT emphysema and airway parameters to airflow limitation specifically in each GOLD stage.MethodsNon-contrast computed tomography (CT) of 492 patients with COPD former GOLD 0 COPD and COPD stages GOLD 1–4 were evaluated using fully automated software for quantitative CT. Total lung volume (TLV), emphysema index (EI), mean lung density (MLD), and airway wall thickness (WT), total diameter (TD), lumen area (LA), and wall percentage (WP) were calculated for the entire lung, as well as for all lung lobes separately. Results from the 3rd-8th airway generation were aggregated (WT3-8, TD3-8, LA3-8, WP3-8). All subjects underwent whole-body plethysmography (FEV1%pred, VC, RV, TLC).ResultsEI was higher with increasing GOLD stages with 1.0 ± 1.8% in GOLD 0, 4.5 ± 9.9% in GOLD 1, 19.4 ± 15.8% in GOLD 2, 32.7 ± 13.4% in GOLD 3 and 41.4 ± 10.0% in GOLD 4 subjects (p 3-8 showed no essential differences between GOLD 0 and GOLD 1, tended to be higher in GOLD 2 with 52.4 ± 7.2%, and was lower in GOLD 4 with 50.6 ± 5.9% (p = 0.010 – p = 0.960). In the upper lobes WP3–8 showed no significant differences between the GOLD stages (p = 0.824), while in the lower lobes the lowest WP3-8 was found in GOLD 0/1 with 49.9 ± 6.5%, while higher values were detected in GOLD 2 with 51.9 ± 6.4% and in GOLD 3/4 with 51.0 ± 6.0% (p 3–8 (p ConclusionQCT parameters showed a significant increase of emphysema from GOLD 0–4 COPD. Airway changes showed a different spatial pattern with higher values of relative wall thickness in the lower lobes until GOLD 2 and subsequent lower values in GOLD3/4, whereas there were no significant differences in the upper lobes. Both, EI and WP5-8 are independently correlated with lung function decline.</p

Optimizing airway wall segmentation and quantification by reducing the influence of adjacent vessels and intravascular contrast material with a modified integral-based algorithm in quantitative computed tomography.

IntroductionQuantitative analysis of multi-detector computed tomography (MDCT) plays an increasingly important role in assessing airway disease. Depending on the algorithms used, airway dimensions may be over- or underestimated, primarily if contrast material was used. Therefore, we tested a modified integral-based method (IBM) to address this problem.MethodsTemporally resolved cine-MDCT was performed in seven ventilated pigs in breath-hold during iodinated contrast material (CM) infusion over 60s. Identical slices in non-enhanced (NE), pulmonary-arterial (PA), systemic-arterial (SA), and venous phase (VE) were subjected to an in-house software using a standard and a modified IBM. Total diameter (TD), lumen area (LA), wall area (WA), and wall thickness (WT) were measured for ten extra- and six intrapulmonary airways.ResultsThe modified IBM significantly reduced TD by 7.6%, LA by 12.7%, WA by 9.7%, and WT by 3.9% compared to standard IBM on non-enhanced CT (pConclusionsThe modified IBM can optimize airway wall segmentation and reduce the influence of CM on quantitative CT. This allows a more precise measurement as well as potentially the comparison of enhanced with non-enhanced scans in inflammatory airway disease

The value of chest magnetic resonance imaging compared to chest radiographs with and without additional lung ultrasound in children with complicated pneumonia.

INTRODUCTION:In children with pneumonia, chest x-ray (CXR) is typically the first imaging modality used for diagnostic work-up. Repeated CXR or computed tomography (CT) are often necessary if complications such as abscesses or empyema arise, thus increasing radiation exposure. The aim of this retrospective study was to evaluate the potential of radiation-free chest magnetic resonance imaging (MRI) to detect complications at baseline and follow-up, compared to CXR with and without additional lung ultrasound (LUS). METHODS:Paired MRI and CXR scans were retrospectively reviewed by two blinded readers for presence and severity of pulmonary abscess, consolidation, bronchial wall thickening, mucus plugging and pleural effusion/empyema using a chest MRI scoring system. The scores for MRI and CXR were compared at baseline and follow-up. Furthermore, the MRI scores at baseline with and without contrast media were evaluated. RESULTS:33 pediatric patients (6.3±4.6 years), who had 33 paired MRI and CXR scans at baseline and 12 at follow-up were included. MRI detected significantly more lung abscess formations with a prevalence of 72.7% compared to 27.3% by CXR at baseline (p = 0.001), whereas CXR+LUS was nearly as good as MRI. MRI also showed a higher sensitivity in detecting empyema (p = 0.003). At follow-up, MRI also showed a slightly better sensitivity regarding residual abscesses. The overall severity of disease was rated higher on MRI. Contrast material did not improve detection of abscesses or empyema by MRI. CONCLUSION:CXR and LUS seem to be sufficient in most cases. In cases where LUS cannot be realized or the combination of CXR+LUS might be not sufficient, MRI, as a radiation free modality, should be preferred to CT. Furthermore, the admission of contrast media is not mandatory in this context

Mesopolysaccharides: The extracellular surface layer of visceral organs.

The mesothelium is a dynamic and specialized tissue layer that covers the somatic cavities (pleural, peritoneal, and pericardial) as well as the surface of the visceral organs such as the lung, heart, liver, bowel and tunica vaginalis testis. The potential therapeutic manipulation of visceral organs has been complicated by the carbohydrate surface layer-here, called the mesopolysaccharide (MPS)-that coats the outer layer of the mesothelium. The traditional understanding of MPS structure has relied upon fixation techniques known to degrade carbohydrates. The recent development of carbohydrate-preserving fixation for high resolution imaging techniques has provided an opportunity to re-examine the structure of both the MPS and the visceral mesothelium. In this report, we used high pressure freezing (HPF) as well as serial section transmission electron microscopy to redefine the structure of the MPS expressed on the murine lung, heart and liver surface. Tissue preserved by HPF and examined by transmission electron microscopy demonstrated a pleural MPS layer 13.01±1.1 um deep-a 100-fold increase in depth compared to previously reported data obtained with conventional fixation techniques. At the base of the MPS were microvilli 1.1±0.35 um long and 42±5 nm in diameter. Morphological evidence suggested that the MPS was anchored to the mesothelium by microvilli. In addition, membrane pits 97±17 nm in diameter were observed in the apical mesothelial membrane. The spatial proximity and surface density (29±4.5%) of the pits suggested an active process linked to the structural maintenance of the MPS. The striking magnitude and complex structure of the MPS indicates that it is an important consideration in studies of the visceral mesothelium