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Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients., (© 2020 by The American Society of Hematology.)

Study Objectives: The purpose of this study was to evaluate the short-term repeatability of the Epworth Sleepiness Scale (ESS) in patients with suspected obstructive sleep apnea and to determine whether transitory sleepiness of the patient influenced ESS results., Methods: Adult participants with suspected obstructive sleep apnea taking part in a study on the diagnostic accuracy of repeated sleep studies were eligible. For assessment of repeatability, the agreement between 2 sequential ESS scores obtained within 1 day (same-day group) or on different days within 1 week (same-week group) was evaluated. By analyzing the within-day repeatability, a possible influence of situational sleepiness on ESS results was assessed. By comparing correlations of sequential scores between both groups, a potential influence of test day-specific sleepiness on ESS results was evaluated. Data were analyzed using Bland-Altman plots, intraclass correlation coefficients, standard error of measurement analysis, and relative amounts of ESS discrepancies beyond 2, 3, 5, and 7 points., Results: Forty participants (mean age, 47.7 ± 15.4 years; 67.5% men) were included in this study, with 20 in each group. Bland-Altman analysis demonstrated considerable variability of repeated scores (mean ± 1.96 × SD = 1.93 [-3.81 to 7.66]). Discrepancies of at least 3 points between sequential ESS scores were found in 48% of all participants. Comparison of ESS repeatability between both groups showed no evidence for a difference., Conclusions: A clinically relevant variability in ESS scores was found, even when repeated on the same day, possibly because of situational sleepiness influencing ESS results. Changes in ESS in response to interventions should be interpreted with caution because of its low test-retest reliability., (© 2020 American Academy of Sleep Medicine.)

Skeletal muscle dysfunction, functional exercise capacity impairment and reduced physical activity are characteristic features in patients with chronic obstructive pulmonary disease (COPD). Assessments addressing muscle strength of the upper limb, such as measurement of handgrip strength (HGS), are rarely performed and reported. We aimed to analyze the course of HGS and possible predictors of changes in HGS over time in COPD. Yearly assessments of various disease markers were performed for a follow-up of up to seven years in a cohort of COPD patients to assess the longitudinal disease process. Data of 194 patients with at least one follow-up measurement were analyzed. HGS decreased significantly by B = -0.86 (95% CI -1.09/-0.62, p  < 0.001) over time. The multivariate mixed effects model showed an independent association between greater annual declines in HGS and lower numbers of steps per day by B  = 0.11 (95% CI 0.03/0.18, p  = 0.006) and an enhanced change in COPD Assessment Test scores by B = -0.01 (95% CI -0.01/-0.00, p  = 0.034). No evidence for an independent association between annual decline in HGS and FEV 1 % pred. by B = -0.01 (95% CI -0.03/0.01, p  = 0.297) was shown. Patients who died during follow-up did not exhibit greater declines in HGS compared to survivors ( p  = 0.884). Although HGS significantly decreased over time, no pathophysiological link with COPD disease progression could be demonstrated. Previous cross-sectional associations between HGS and mortality could not be confirmed in this longitudinal setting. Our data suggests that repeated monitoring of HGS in clinical settings seems not to be helpful to predict COPD specific disease progression.

Recent trial results support catheter-based renal denervation (RDN) for treatment of hypertension, while the exact mechanisms causing blood pressure to fall remain incompletely understood. Cardiac magnetic resonance imaging was used to assess the effects of RDN on cardiac function in patients with hypertension undergoing RDN and compared with sham treatment. Cardiac magnetic resonance imaging was used to assess stroke volume index, cardiac index, heart rate, systemic vascular resistance index, and stroke work index from aortic flow measurements. Patients with resistant hypertension from a randomized, sham-controlled RDN trial underwent cardiac magnetic resonance imaging before RDN and at follow-up (randomized cohort). Results were then validated in a cohort of patients with resistant hypertension undergoing RDN and cardiac magnetic resonance imaging (validation cohort). In total, 162 patients were included 52 patients in the randomized trial (27 shams) and 110 patients in the validation cohort. In the randomized cohort, stroke volume index was reduced by 4.7±9.8 mL/m 2 in the RDN cohort and remained unchanged in the sham cohort ( P =0.008 for between-group comparison), while cardiac index and stroke work index tended to be reduced in RDN patients but not in sham patients (-0.10±5.9 versus 0.17±0.51 L/min per m 2 and -7.1±12.5 versus -1.4±10.4 g/m 2 , P =0.08 for both). In contrast, systemic vascular resistance index and heart rate remained unchanged after RDN. In the validation cohort, reduction of stroke volume index was confirmed, and cardiac index and stroke work index were also reduced significantly, whereas systemic vascular resistance index and heart rate remained unchanged at follow-up. In this study of patients with resistant hypertension, RDN resulted in a reduction of stroke volume when compared with sham.

We demonstrate mass production compatible fabrication of polymer-based micro Fresnel lenses by injection compression molding. The extremely robust titanium-molding tool is structured with high precision by focused ion beam milling. In order to achieve optimal shape accuracy in the titanium we use an iterative design optimization. The inverse Fresnel lens structured into the titanium is transferred to polymers by injection compression molding, enabling rapid mass replication. We show that the optical performance of the molded diffractive Fresnel lenses is in good agreement with simulations, rendering our approach suitable for applications that require compact and high-quality optical elements in large numbers.

Die aktuellen Leitlinien empfehlen, unkomplizierte Patientinnen und Patienten mit Verdacht auf obstruktive Schlafapnoe (OSA) mittels einer einzigen Schlafuntersuchung zu diagnostizieren. Eine kürzlich veröffentlichte Meta-Analyse konnte hingegen eine ausgeprägte intra-individuelle Variabilität respiratorischer Parameter von Nacht zu Nacht zeigen. Wir präsentieren den Fall eines 76-jährigen Patienten mit Verdacht auf OSA, der innerhalb von 13 Wochen sechs Schlafuntersuchungen unterzogen wurde. Hierbei präsentierte sich eine relevante Variabilität des AHI zwischen 1,1 und 43,1/h. Es konnten keine relevanten Unterschiede betreffend Gewicht, Alkoholkonsum, Medikation und Begleiterkrankungen zwischen den Schlafuntersuchungen festgestellt werden. Aufgrund fehlender subjektiver Wirksamkeit wurde die CPAP-Therapie nach einem Jahr gestoppt. Die ausgeprägte Nacht-zu-Nacht-Variabilität respiratorischer Parameter stellt eine akkurate OSA-Diagnostik mittels einer einzelnen Schlafuntersuchung in Frage.

Background: Right ventricular (RV) function is prognostically relevant in heart failure with preserved ejection fraction (HFpEF) but data on profound assessment of RV and right atrial (RA) interaction in HFpEF are lacking. The current study characterizes RV and RA interaction using invasive pressure-volume-loop analysis and cardiac magnetic resonance imaging (CMR) data., Methods and Results: We performed CMR and myocardial feature-tracking in 24 HFpEF patients and 12 patients without HFpEF. Invasive pressure-volume-loops were obtained to evaluate systolic and diastolic RV properties. RV early filling was determined from CMR RV volume-time curves. RV systolic function was slightly increased in HFpEF (RV EF 68 ± 8 vs. 60 ± 9%, p = 0.01), while no differences in RV stroke volume were found (45 ± 7 vs 42 ± 9 ml/m 2 , p = 0.32). RV early filling was decreased in HFpEF (21 ± 11 vs. 40 ± 11% of RV filling volume, p < 0.01) and RV early filling was the strongest predictor for VO 2max even after inclusion of invasively derived RV stiffness and relaxation constant (Beta 0.63, p < 0.01). RA conduit-function was lower in HFpEF (RA conduit-strain - 11 ± 5 vs. - 16 ± 4%, p < 0.01) while RA booster-pump-function was increased (RA active-strain - 18 ± 6 vs. - 12 ± 6%, p = 0.01) as a compensation. RV filling was associated with RA conduit-function (r = - 0.55, p < 0.01) but not with invasively derived RV relaxation constant., Conclusion: In compensated HFpEF patients RV early filling was impaired and compensated by increased RA booster pump function, while RV systolic function was preserved. Impaired RV diastology and RA-RV interaction were linked to impaired exercise tolerance and RA-RV-coupling seems to be independent of RV relaxation, suggestive of an independent pathophysiological contribution of RA dysfunction in HFpEF., Clinical-Trial-Registration: NCT02459626 (www.clinicaltrials.gov).

Background: The pathogenesis and etiology of thoracic aortic aneurysms (TAA) are largely unknown. Preliminary data from patients with aortic dissection and abdominal aneurysms suggest a causal link of obstructive sleep apnea (OSA) on aortic disease., Objectives: The aim of the study was to assess the prevalence of OSA in patients with TAA compared to a matched control group., Method: In this prospective parallel-cohort study, we 2-to-1 matched 208 patients with verified TAA (at the aortic sinus and/or ascending aorta) to 104 controls without TAA according to sex, age, height, weight, and left ventricular ejection fraction. All participants underwent an ultrasound of the thoracic aorta and a level III respiratory polygraphy. OSA was defined as apnea-hypopnea index ≥5/h. The prevalence of OSA was compared with conditional logistic regression and controlling for the matching variables., Results: A total of 312 patients (mean age 65 ± 11 years, 82% male, mean body mass index 27 ± 4 kg/m2) were successfully 2-to-1 matched in the final model. Prevalence of OSA was significantly higher in the TAA-group when compared to the matched control group (63 vs. 47%; odds ratio 1.87 [95% CI 1.05-3.34]; p = 0.03). When applying a higher apnea-hypopnea index threshold (≥15/h), the odds ratio increased to 3.25 (95% CI 1.65-6.42; p < 0.001). The median apnea-hypopnea index was higher in patients with TAA (9.2/h [3.3-20.0] vs. 4.5/h [2.2-11.1], p < 0.001)., Conclusions: Patients with TAA have a higher prevalence of OSA when compared to the general population. Since OSA is effectively treatable and might contribute to the pathogenesis of TAA, further longitudinal trials are needed to assess the association between OSA and TAA., (© 2019 S. Karger AG, Basel.)

BackgroundThe establishment of a timely and correct diagnosis in heart failure-like myocarditis remains one of the most challenging in clinical cardiology.PurposeTo assess the diagnostic potential of texture analysis in heart failure-like myocarditis with comparison to endomyocardial biopsy (EMB) as the reference standard.Materials and MethodsSeventy-one study participants from the Magnetic Resonance Imaging in Myocarditis (MyoRacer) trial (ClinicalTrials.gov registration no. NCT02177630) with clinical suspicion for myocarditis and symptoms of heart failure were prospectively included (from August 2012 to May 2015) in the study. Participants underwent biventricular EMB and cardiac MRI at 1.5 T, including native T1 and T2 mapping and standard Lake Louise criteria. Texture analysis was applied on T1 and T2 maps by using an open-source software. Stepwise dimension reduction was performed for selecting features enabling the diagnosis of myocarditis. Diagnostic performance was assessed from the area under the curve (AUC) from receiver operating characteristic analyses with 10-fold cross validation.ResultsIn participants with acute heart failure-like myocarditis ( n = 31; mean age, 47 years ± 17; 10 women), the texture feature GrayLevelNonUniformity from T2 maps (T2&#95;GLNU) showed diagnostic performance similar to that of mean myocardial T2 time (AUC, 0.69 for both). The combination of mean T2 time and T2&#95;GLNU had the highest AUC (0.76; 95% confidence interval [CI]: 0.43, 0.95), with sensitivity of 81% (25 of 31) and specificity of 71% (22 of 31). In patients with chronic heart failure-like myocarditis ( n = 40; mean age, 48 years ± 13; 12 women), the histogram feature T2&#95;kurtosis demonstrated superior diagnostic performance compared to that of all other single parameters (AUC, 0.81; 95% CI: 0.66, 0.96). The combination of the two texture features, T2&#95;kurtosis and the GrayLevelNonUniformity from T1, had the highest diagnostic performance (AUC, 0.85; 95% CI: 0.57, 0.90; sensitivity, 90% [36 of 40]; and specificity, 72% [29 of 40]).ConclusionIn this proof-of-concept study, texture analysis applied on cardiac MRI T1 and T2 mapping delivers quantitative imaging parameters for the diagnosis of acute or chronic heart failure-like myocarditis and might be superior to Lake Louise criteria or averaged myocardial T1 or T2 values.© RSNA, 2019 Online supplemental material is available for this article. See also the editorial by de Roos in this issue.

Objectives: This study sought to examine the impact of chronic right ventricular (RV) volume overload and implications of tricuspid regurgitation (TR) reduction on biventricular function., Background: Severe TR is a major determinant of adverse outcomes in advanced heart failure patients. The understanding of TR pathophysiology and implications of correction is still limited. Transcatheter tricuspid edge-to-edge repair (TTVR) is a new treatment option in patients at high surgical risk and provides a unique pathophysiological model without confounding effects of cardiac surgery., Methods: Twenty-nine patients (78 ± 4 years of age) with severe isolated TR and high surgical risk underwent TTVR using the MitraClip system, and of these 18 underwent repeated cardiac magnetic resonance. Clinical follow-up was realized at 1 and 6 months after the intervention., Results: TR fraction was reduced from 41% to 21% (p < 0.01) without increase in RV afterload (p = 0.52) and RV end-diastolic volume (p < 0.01), and RV stroke volume decreased (p = 0.03), whereas RV effective forward flow increased (p = 0.03). Left ventricular (LV) filling improved with an increase in LV end-diastolic volume (p = 0.01) and LV stroke volume (p = 0.02), leading to an augmentation of cardiac indices (2.2 ± 0.6 l/min/m 2 vs. 2.7 ± 0.6 l/min/m 2 ; p < 0.01) with similar results at 6 months follow-up. After TTVR, New York Heart Association functional class significantly improved (p < 0.01), peripheral edema decreased (p = 0.01), and 6-min walk distance increased by 20% and 22% after 1 and 6 months, respectively (p < 0.01)., Conclusions: TTVR reduces chronic RV volume overload without increase in RV afterload, improves RV performance and LV filling, and enhances cardiac output. These changes translate into symptomatic and functional improvement. These implications for biventricular physiology and clinical status are maintained at 6 months follow-up., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with isolated systolic hypertension (ISH) are thought to show a diminished blood pressure (BP)-lowering effect after renal sympathetic denervation (RDN). This conclusion is mostly derived from unipolar radiofrequency catheter ablation studies. Limited data for newer RDN technologies exist. We used data from the RADIOSOUND-HTN (Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension) comparing 3 different RDN approaches to investigate a possible interaction between ISH and RDN response. One hundred twenty patients were stratified by having ISH or combined systolic-diastolic hypertension (CH). Of these, 39 underwent radiofrequency ablation of the renal main arteries, 39 combined radiofrequency ablation of the main and branch arteries, and 42 were treated with ultrasound-based ablation of the main renal artery. Patients with ISH (n=61) were older and had lower systolic and diastolic BP on ambulatory measurement (ambulatory BP measurement) at baseline in comparison to CH (n=59). At 3 months, patients with ISH showed a less pronounced BP-lowering effect of RDN as compared to patients with CH (daytime average -5.9±11.8 versus -13.3±11.7 mm Hg, P=0.001). This difference was significant for radiofrequency ablation of the renal main arteries and ultrasound-based ablation of the main renal artery treatment but did not reach significance in the radiofrequency ablation of the main and branch arteries group. After adjustment for baseline BP values and age, there was no significant difference in BP reduction between ISH and CH. Using unadjusted BP values, RDN seems to be more effective in CH than in ISH. However, adjusting for baseline BP values revealed similar BP reduction in ISH and CH patients, irrespective of the RDN treatment used. The value of ISH as predictor for successful RDN might have been overestimated in the past. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02920034.

Polymer optics have gained increasing importance in recent years. With advancing requirements for the optical components, the fabrication process remains a challenge. In particular, the fabrication of the mold inserts for the replication process is crucial for obtaining high-quality optical components. This review focuses on fabrication technologies for optical mold inserts. Thereby, two main types of technologies can be distinguished: fabrication methods to create mold inserts with optical surface quality and methods to create optical microstructures. Since optical mold inserts usually require outstanding form accuracies and surface qualities, a focus is placed on these factors. This review aims to give an overview of available methods as well as support the selection process when a fabrication technology is needed for a defined application. Furthermore, references are given to detailed descriptions of each technology if a deeper understanding of the processes is required., Competing Interests: The authors declare no conflict of interest

Background: Only 2 small placebo-controlled trials on peanut oral immunotherapy (OIT) have been published., Objective: We examined the efficacy, safety, immunologic parameters, quality of life (QOL), and burden of treatment (BOT) of low-dose peanut OIT in a multicenter, double-blind, randomized placebo-controlled trial., Methods: A total of 62 children aged 3 to 17 years with IgE-mediated, challenge-proven peanut allergy were randomized (1:1) to receive peanut OIT with a maintenance dose of 125 to 250 mg peanut protein or placebo. The primary outcome was the proportion of children tolerating 300 mg or more peanut protein at oral food challenge (OFC) after 16 months of OIT. We measured the occurrence of adverse events (AEs), immunologic changes, and QOL before and after OIT and BOT during OIT., Results: Twenty-three of 31 (74.2%) children of the active group tolerated at least 300 mg peanut protein at final OFC compared with 5 of 31 (16.1%) in the placebo group (P < .001). Thirteen of 31 (41.9%) children of the active versus 1 of 31 (3.2%) of the placebo group tolerated the highest dose of 4.5 g peanut protein at final OFC (P < .001). There was no significant difference between the groups in the occurrence of AE-related dropouts or in the number, severity, and treatment of objective AEs. In the peanut-OIT group, we noted a significant reduction in peanut-specific IL-4, IL-5, IL-10, and IL-2 production by PBMCs compared with the placebo group, as well as a significant increase in peanut-specific IgG 4 levels and a significant improvement in QOL; 86% of children evaluated the BOT positively., Discussion: Low-dose OIT is a promising, effective, and safe treatment option for peanut-allergic children, leading to improvement in QOL, a low BOT, and immunologic changes showing tolerance development., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies., Methods: Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound-based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months., Results: Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg ( P<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (-13.2±13.7 versus -6.5±10.3 mm Hg; mean difference, -6.7 mm Hg; global P=0.038 by ANOVA, adjusted P=0.043), no significant difference was found between the radiofrequency ablation groups (-8.3±11.7 mm Hg for additional side branch ablation; mean difference, -1.8 mm Hg; adjusted P>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global P=0.77)., Conclusions: In patients with resistant hypertension, endovascular ultrasound-based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02920034.

The Dispase autolysis-inducing protein (DAIP) is produced by Streptomyces mobaraensis to disarm neutral metalloproteases by decomposition. The absence of a catalytic protease domain led to the assumption that the seven-bladed β-propeller protein DAIP causes structural modifications, thereby triggering autolysis. Determination of protein complexes consisting of DAIP and thermolysin or DAIP and a nonfunctional E138A bacillolysin variant supported this postulation. Protein twisting was indicated by DAIP-mediated inhibition of thermolysin while bacillolysin underwent immediate autolysis under the same conditions. Interestingly, an increase in SYPRO orange fluorescence allowed tracking of the fast degradation process. Similarly rapid autolysis of thermolysin mediated by DAIP was only observed upon the addition of amphiphilic compounds, which probably amplify the induced structural changes. DAIP further caused degradation of FITC-labeled E138A bacillolysin by trypsin, as monitored by a linear decrease in fluorescence polarization. The kinetic model, calculated from the obtained data, suggested a three-step mechanism defined by (a) fast DAIP-metalloprotease complex formation, (b) slower DAIP-mediated protein twisting, and (c) fragmentation. These results were substantiated by crystallized DAIP attached to a C-terminal helix fragment of thermolysin. Structural superposition of the complex with thermolysin is indicative of a conformational change upon binding to DAIP. Importantly, the majority of metalloproteases, also including homologs from various pathogens, are highly conserved at the autolysis-prone peptide bonds, suggesting their susceptibility to DAIP-mediated decomposition, which may offer opportunities for pharmaceutical applications. DATABASES: The atomic coordinates and structure factors (PDB ID: 6FHP) have been deposited in the Protein Data Bank (http://www.pdb.org/). ENZYMES: Aureolysin, EC 3.4.24.29; bacillolysin (Dispase, Gentlyase), EC 3.4.24.28; lasB (elastase), EC 3.4.24.4; subtilisin, EC 3.4.21.62; thermolysin, EC 3.4.24.27; transglutaminase, EC 2.3.2.13; trypsin, EC 3.4.21.4; vibriolysin (hemagglutinin(HA)/protease), EC 3.4.24.25., (© 2018 Federation of European Biochemical Societies.)

Purpose To assess the diagnostic potential of texture analysis applied to T1 and T2 maps obtained with cardiac MRI for the diagnosis of acute infarctlike myocarditis. Materials and Methods This prospective study from August 2012 to May 2015 included 39 participants (overall mean age ± standard deviation, 34.7 years ± 12.2 [range, 18-63 years]; mean age of women, 46.1 years ± 10.8 [range, 24-63 years]; mean age of men, 29.8 years ± 9.2 [range, 18-56 years]) from the Magnetic Resonance Imaging in Myocarditis (MyoRacer) trial with clinical suspicion of acute myocarditis and infarctlike presentation. Participants underwent biventricular endomyocardial biopsy, cardiac catheterization, and cardiac MRI at 1.5 T, in which native T1 and T2 mapping as well as Lake Louise criteria (LLC) were assessed. Texture analysis was applied on T1 and T2 maps by using a freely available software package. Stepwise dimension reduction and texture feature selection was performed for selecting features enabling the diagnosis of myocarditis by using endomyocardial biopsy as the reference standard. Results Endomyocardial biopsy confirmed the diagnosis of acute myocarditis in 26 patients, whereas 13 participants had no signs of acute inflammation. Mean T1 and T2 values and LLC showed a low diagnostic performance, with area under the curve in receiver operating curve analyses as follows: 0.65 (95% confidence interval [CI]: 0.45, 0.85) for T1, 0.67 (95% CI: 0.49, 0.85) for T2, and 0.62 (95% CI: 0.42, 0.79) for LLC. Combining the texture features T2 run-length nonuniformity and gray-level nonuniformity resulted in higher diagnostic performance with an area under the curve of 0.88 (95% CI: 0.73, 1.00) (P < .001) and a sensitivity and specificity of 89% [95% CI: 81%, 93%] and 92% [95% CI: 77%, 93%], respectively. Conclusion Texture analysis of T2 maps shows high sensitivity and specificity for the diagnosis of acute infarctlike myocarditis. © RSNA, 2018 Online supplemental material is available for this article.

A case highlighting the importance of nitrate administration, as routinely performed during coronary arteriography.

Background: Most trials regarding catheter-based renal sympathetic denervation (RDN) describe a proportion of patients without blood pressure response. Recently, we were able to show arterial stiffness, measured by invasive pulse wave velocity (IPWV), seems to be an excellent predictor for blood pressure response. However, given the invasiveness, IPWV is less suitable as a selection criterion for patients undergoing RDN. Consequently, we aimed to investigate the value of cardiac magnetic resonance (CMR) based measures of arterial stiffness in predicting the outcome of RDN compared to IPWV as reference., Methods: Patients underwent CMR prior to RDN to assess ascending aortic distensibility (AAD), total arterial compliance (TAC), and systemic vascular resistance (SVR). In a second step, central aortic blood pressure was estimated from ascending aortic area change and flow sequences and used to re-calculate total arterial compliance (cTAC). Additionally, IPWV was acquired., Results: Thirty-two patients (24 responders and 8 non-responders) were available for analysis. AAD, TAC and cTAC were higher in responders, IPWV was higher in non-responders. SVR was not different between the groups. Patients with AAD, cTAC or TAC above median and IPWV below median had significantly better BP response. Receiver operating characteristic (ROC) curves predicting blood pressure response for IPWV, AAD, cTAC and TAC revealed areas under the curve of 0.849, 0.828, 0.776 and 0.753 (p = 0.004, 0.006, 0.021 and 0.035)., Conclusions: Beyond IPWV, AAD, cTAC and TAC appear as useful outcome predictors for RDN in patients with hypertension. CMR-derived markers of arterial stiffness might serve as non-invasive selection criteria for RDN.

Our understanding of the patterns of plant diversity in tropical forests and their responses to fragmentation are mostly based on tree surveys. But are these patterns and responses representative of other plant life-forms? We sampled trees, lianas, herbs, and ferns in a fragmented tropical forest landscape in South-west China. We compared community types generated by clustering presence-absence data for the non-tree life-forms with those generated for trees. We tested how well measures of tree diversity, density and composition, predicted cognate indices in other life-forms. We compared fragmentation responses, with respect to the three measures, of all four life-forms. Presence-absence data from all life-forms generated three community clusters, with only small differences between classifications, suggesting that tree data identified community types representative of all vascular plant life-forms. Tree species diversity and density indices poorly predicted cognate indices of lianas and ferns, but represented herbs well. However, the slopes of these relationships differed substantially between community types. All life-forms responded to fragmentation variables but their responses did not consistently match with responses of trees. Plot-level tree data can identify vegetation community types, but is poorly representative of the richness and density of other life-forms, and poorly represents forest fragmentation responses for the entire plant community.

In this work, a polymer microlens array (MLA) for a hyperspectral imaging (HSI) system is produced by means of ultraprecision milling (UP-milling) and injection compression molding. Due to the large number of over 12,000 microlenses on less than 2 cm², the fabrication process is challenging and requires full process control. The study evaluates the process chain and optimizes the single process steps to achieve high quality polymer MLAs. Furthermore, design elements like mounting features are included to facilitate the integration into the final HSI system. The mold insert was produced using ultraprecision milling with a diamond cutting tool. The machining time was optimized to avoid temperature drifts and enable high accuracy. Therefore, single immersions of the diamond tool at a defined angle was used to fabricate each microlens. The MLAs were replicated using injection compression molding. For this process, an injection compression molding tool with moveable frame plate was designed and fabricated. The structured mold insert was used to generate the compression movement, resulting in a homogeneous pressure distribution. The characterization of the MLAs showed high form accuracy of the microlenses and the mounting features. The functionality of the molded optical part could be demonstrated in an HIS system by focusing light spectrums onto a CCD image sensor.

Background: Renal sympathetic denervation (RDN) as treatment for hypertension shows highly variable results. Although some patients do not show any blood pressure (BP) change and in most patients a BP reduction of at least 5 mmHg can be found, some show a reduction at least 20 mmHg. We sought to identify predictors for such a profound BP response., Methods: Profound BP response was defined as drop of at least 20 mmHg in daytime systolic ambulatory BP measurement (ABPM) 3 months after catheter-based RDN. Three different denervation devices were used for RDN, and pulse wave velocity was determined invasively in a subgroup of patients., Results: One hundred and ninety consecutive patients were included in this analysis. Profound BP response was found in 33 patients. Patients with profound BP response were younger (P = 0.04), presented with higher baseline ABPM values (P < 0.001), were treated with ultrasound-based RDN and received more often a combined treatment with two different diuretics (P = 0.005 for both). After 3 months, a treatment target of daytime BP less than 135 mmHg could be achieved more frequently in patients with profound BP response (61 vs. 17%, P < 0.001). Age, use of ultrasound RDN, combined diuretic therapy and baseline BP independently predicted pronounced BP reduction. A second multivariate logistic regression model including pulse wave velocity if available identified baseline BP, pulse wave velocity and use of ultrasound denervation as independent predictors for profound BP response., Conclusion: Younger vascular age, higher baseline BP, treatment with ultrasound RDN and combined diuretic therapy were found as predictors for a pronounced BP reduction following RDN, improving BP control at follow-up.

Objectives: The present study aimed to test the clinical benefit of combined transcatheter mitral plus tricuspid valve edge-to-edge repair (TMTVR) as compared with transcatheter mitral valve edge-to-edge repair (TMVR) alone in patients with both significant mitral (MR) and tricuspid regurgitation (TR) at high surgical risk., Background: A growing number of patients with severe MR at increased surgical risk are treated by transcatheter techniques. Evidence suggests that residual TR remains a predictor of adverse outcome in these patients., Methods: Sixty-one patients (mean age 79.5 ± 8.4 years, EuroSCORE II 8.6 ± 5.9%) underwent TMTVR (n = 27) or TMVR (n = 34). Echocardiographic and cardiac magnetic resonance imaging was performed before and after the procedure., Results: Reduction of MR was similar in patients undergoing TMTVR and TMVR. Effective regurgitant orifice area of TR was reduced from 0.51 to 0.29 cm 2 in patients with TMTVR (p < 0.01), but remained unchanged after TMVR. On cardiac magnetic resonance imaging, only patients in the TMTVR group exhibited improved effective right and left ventricular stroke volume, and increased cardiac index (2.1 vs. 2.5 l/min/m 2 ; p < 0.01). TMTVR led to superior improvement in New York Heart Association functional class, NT-proBNP levels, and 6-min walking distance as compared with TMVR. After up to 18 months of follow-up, patients with TMTVR experienced fewer hospitalizations for heart failure when compared with patients with TMVR (p = 0.02), whereas rates of death were comparable between both groups of patients., Conclusions: TMTVR appears superior to TMVR in terms of cardiac output and functional improvement early after the intervention, and improves clinical outcome up to 18 months of follow-up., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although systolic right ventricular (RV) dysfunction has been shown to be a potent predictor for adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF), RV functional abnormalities in the course of the syndrome are not well characterized. We, therefore, sought to assess load-independent and load-dependent systolic and diastolic characteristics of RV function in stable outpatients with HFpEF., Methods and Results: We invasively obtained RV and left ventricular pressure-volume loops in 24 HFpEF patients and 9 patients without heart failure symptoms with a conductance catheter during basal conditions and handgrip exercise. Transient preload reduction was used to extrapolate the RV end-systolic elastance and diastolic stiffness constant. HFpEF patients and controls showed similar left ventricular and RV dimensions and ejection fractions with elevated left ventricular filling pressures. In HFpEF patients, invasively determined load-independent RV contractility ( P =0.04) and load-independent passive RV stiffness constant β ( P <0.01) were elevated. Although RV relaxation and cardiac output were similar at baseline, HFpEF patients demonstrated a blunted increase in cardiac output under exercise ( P =0.01) associated with prolonged RV relaxation ( P =0.01), decrease in stroke volume ( P <0.01), higher RV-filling pressures ( P <0.01), and a marked increase in the end-diastolic pressure-volume relationship ( P <0.01)., Conclusions: In compensated stages of the HFpEF syndrome, systolic RV function is preserved, but diastolic abnormalities with intrinsic RV stiffness and prolonged RV relaxation are already present. Impaired diastolic RV reserve contributes to a blunted increase in cardiac output during exertion. Because impairments in diastolic function seem to be a biventricular phenomenon, RV diastolic dysfunction warrants further consideration when characterizing HFpEF patients., Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02459626., (© 2018 American Heart Association, Inc.)

Introduction: The effectiveness of renal sympathetic denervation (RDN) as a treatment for therapy-resistant hypertension has been doubted as the Simplicity-HTN-3 trial was unable to show any treatment benefit over sham procedure. This might partly be explained by a high procedural variability in treatment with radiofrequency-based catheters. Recently, newer systems for RDN, like ultrasound-based devices, have been introduced into practice. To date however, data on their effectiveness for the treatment of resistant hypertension are scarce. We sought to evaluate the safety and effectiveness of an ultrasound-based, balloon-irrigated RDN catheter in a larger single-center cohort., Methods: Patients with therapy-resistant hypertension [average blood pressure (BP) >135 mmHg SBP or >90 mmHg DBP in ambulatory BP measurement despite at least three antihypertensive drugs, including at least one diuretic] underwent ultrasound-based RDN. Treatment effect was assessed by comparing BP values at baseline and 3 months after the procedure. Patients underwent renal artery duplex sonography or MRI before and after RDN to exclude renal artery stenosis., Results: Fifty consecutive patients underwent ultrasound-based RDN, of which 25 had undergone an unsuccessful radiofrequency RDN before. Mean SBP change at 3 months was -9.7 ± 12.6/-10.6 ± 13.7/-8.2 ± 15.2 mmHg (ambulatory 24-h mean/daytime/night, P < 0.001 for all) and DBP changed by -5.1 ± 7.4/-5.8 ± 7.8/-3.9 ± 10.3 mmHg (P ≤ 0.001/<0.001/0.01). No new renal artery stenosis could be detected after RDN., Conclusion: Ultrasound-based RDN seems to be well tolerated and effective for the treatment of patients with therapy-resistant hypertension.

Diphtheria toxin kills human cells because it delivers its enzyme domain DTA into their cytosol where it inhibits protein synthesis. After receptor-mediated uptake of the toxin, DTA translocates from acidic endosomes into the cytosol, which might be assisted by host cell factors. Here we investigated the role of Hsp90 and its co-chaperones during the uptake of native diphtheria toxin into human cells and identified the components of the Hsp90 machinery including Hsp90, Hsp70, Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding partners. Moreover, pharmacological inhibition of the chaperone activity of Hsp90 and Hsp70 and of the peptidyl-prolyl cis/trans isomerase (PPIase) activity of Cyps and FKBPs protected cells from intoxication with diphtheria toxin and inhibited the pH-dependent trans-membrane transport of DTA into the cytosol. In conclusion, these host cell factors facilitate toxin uptake into human cells, which might lead to development of novel therapeutic strategies against diphtheria.

Background: Although left atrial (LA) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), its functional implications beyond the reflection of left ventricular (LV) pathology are not well understood. The aim of this study was to further characterize LA function in HFpEF patients., Methods and Results: We performed cardiac magnetic resonance myocardial feature tracking in 22 patients with HFpEF and 12 patients without HFpEF. LA reservoir strain, LA conduit strain, and LA booster pump strain were quantified. Peak oxygen uptake (VO2max) was determined. Invasive pressure-volume loops were obtained to evaluate LV diastolic properties. LV early filling was determined from LV volume-time curves as derived from cardiac magnetic resonance. LA reservoir and conduit strain were significantly lower in HFpEF (LA reservoir strain, 22±7% versus 29±6%, P =0.04; LA conduit strain, -9±5% versus -15±4%, P <0.01). Patients with HFpEF showed lower oxygen uptake (17±6 versus 29±8 mL/(kg min); P <0.01). Strain measurement for LA conduit function was strongly associated with VO2max ( r =0.80; P <0.01). On multivariable regression analysis, LA conduit strain emerged as strongest predictor for VO2max even after inclusion of LV stiffness and relaxation time (β=0.80; P <0.01). LA conduit strain correlated with the volume of early ventricular filling ( r =0.67; P <0.01), but not LV stiffness constant β (-0.34; P =0.051) or relaxation constant τ ( r =-0.33; P =0.06)., Conclusions: Cardiac magnetic resonance myocardial feature tracking-derived conduit strain is significantly impaired in HFpEF and associated with exercise intolerance. Impaired conduit function is associated with impaired early ventricular filling, as potential mechanism leading to impaired oxygen uptake. Our results propose that impaired LA conduit function represents a distinct feature of HFpEF, independent of LV stiffness and relaxation., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02459626., (© 2017 American Heart Association, Inc.)

Background: Galectin (Gal)-3 is a β-galactoside-binding lectin and currently intensely studied as a biomarker in heart failure. Gal-3 also exerts proinflammatory effects, at least in extracardiac tissues. Objective of this study was to characterize the relationship of plasma and myocardial Gal-3 levels with cardiac fibrosis and inflammation in patients with nonischemic dilated cardiomyopathy and inflammatory cardiomyopathy (iCMP)., Methods and Results: Endomyocardial biopsies and blood samples were obtained from patients with newly diagnosed cardiomyopathy and clinical suspicion of myocarditis. According to histopathologic findings, patients were classified as having dilated cardiomyopathy (n=40) or iCMP (n=75). Cardiac fibrosis was assessed histologically on endomyocardial biopsy sections. In patients with iCMP, myocardial Gal-3 expression significantly correlated with inflammatory cell count on endomyocardial biopsy ( r =0.56; P <0.05). In contrast, an inverse association was observed between myocardial Gal-3 expression and cardiac fibrosis in patients with iCMP ( r =-0.59; P <0.05). In patients with dilated cardiomyopathy, myocardial Gal-3 expression correlated with cardiac fibrosis on left ventricular biopsy ( P =0.63; P <0.01). Of note, in both groups, plasma Gal-3 levels did not correlate with myocardial Gal-3 levels or left ventricular fibrosis, whereas a positive correlation between plasma Gal-3 levels and inflammatory cell count on endomyocardial biopsy was observed in patients with iCMP., Conclusions: The present study suggests that myocardial Gal-3 can be considered as a possible marker for both cardiac inflammation and fibrosis, depending on the pathogenesis of heart failure. However, circulating concentrations of Gal-3 do not seem to reflect endomyocardial Gal-3 levels or cardiac fibrosis., (© 2017 American Heart Association, Inc.)

Background: Optimal patient characterization in heart failure with preserved ejection fraction (HFpEF) is essential to tailor successful treatment strategies. Cardiac magnetic resonance (CMR)-derived T1 mapping can noninvasively quantify diffuse myocardial fibrosis as extracellular volume fraction (ECV)., Objectives: This study aimed to elucidate the diagnostic performance of T1 mapping in HFpEF by examining the relationship between ECV and invasively measured parameters of diastolic function. It also investigated the potential of ECV to differentiate among pathomechanisms in HFpEF., Methods: We performed T1 mapping in 24 patients with HFpEF and 12 patients without heart failure symptoms. Pressure-volume loops were obtained with a conductance catheter during basal conditions and handgrip exercise. Transient pre-load reduction was used to extrapolate the diastolic stiffness constant., Results: Patients with HFpEF showed higher ECV (p < 0.01), elevated load-independent passive left ventricular (LV) stiffness constant (beta) (p < 0.001), and a longer time constant of active LV relaxation (p = 0.02). ECV correlated highly with beta (r = 0.75; p < 0.001). Within the HFpEF cohort, patients with ECV greater than the median showed a higher beta (p = 0.05), whereas ECV below the median identified patients with prolonged active LV relaxation (p = 0.01) and a marked hypertensive reaction to exercise due to pathologic arterial elastance (p = 0.04). On multiple linear regression analyses, ECV independently predicted intrinsic LV stiffness (β = 0.75; p < 0.01)., Conclusions: Diffuse myocardial fibrosis, assessed by CMR-derived T1 mapping, independently predicts invasively measured LV stiffness in HFpEF. Additionally, ECV helps to noninvasively distinguish the role of passive stiffness and hypertensive exercise response with impaired active relaxation. (Left Ventricular Stiffness vs. Fibrosis Quantification by T1 Mapping in Heart Failure With Preserved Ejection Fraction [STIFFMAP]; NCT02459626)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Stress echocardiography (SE) is a powerful functional imaging technique to assess cardiac performance under work conditions. The main indication is the detection of myocardial ischemia due to coronary artery disease (CAD), however it can also be used in patients with structural heart disease (e. g. valvular disease, hypertrophic obstructive cardiomyopathy). Dynamic or pharmacological (dobutamine / adenosine) modalities are available to induce cardiac stress, basically depending on the clinical problem and the patient's ability to exercise. Exercise on a treadmill or a semi-supine bicycle is the most physiological way to induce stress. Dobutamine stimulation is useful in patients who are unable to exercise and for detection of viable myocardium in hypo- or akinetic segments. Adenosin-induced hyperaemia causes steal effects in myocardial segments with significant CAD. Main limitations of SE are the need for an appropriate acoustic window and the user-dependent variability with regard to the interpretation of the results., (© Georg Thieme Verlag KG Stuttgart · New York.)

Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme component CDTa into mammalian target cells. CDTb binds to its receptor on the cell surface, CDTa assembles and CDTb/CDTa complexes are internalised. In acidic endosomes, CDTb mediates the delivery of CDTa into the cytosol, most likely by forming a translocation pore in endosomal membranes. We demonstrate that a seven-fold symmetrical positively charged β-cyclodextrin derivative, per-6-S-(3-aminomethyl)benzylthio-β-cyclodextrin, which was developed earlier as a potent inhibitor of the translocation pores of related binary toxins of Bacillus anthracis, Clostridium botulinum and Clostridium perfringens, protects cells from intoxication with CDT. The pore blocker did not interfere with the CDTa-catalyzed ADP-ribosylation of actin or toxin binding to Vero cells but inhibited the pH-dependent membrane translocation of CDTa into the cytosol. In conclusion, the cationic β-cyclodextrin could serve as the lead compound in a development of novel pharmacological strategies against the CDT-producing strains of C. difficile.

Lianas are an important component of tropical forests, and may reach their highest densities in disturbed areas. However, information on seed and germination characteristics is scarce. Twenty Amazon liana species were screened for their germination characteristics, including light dependence, tolerance of desiccation and of alternating temperatures; these characteristics are considered important for the germination success in areas with relatively open canopies. Between 31-1,420 seeds per species were available, as 15 species seeds came from one mother plant. We studied seed biometry and conducted germination trials with fresh seeds (12 h light daily, or dark) and desiccated seeds at 25 °C. Germination at alternating temperatures (20/30 °C, 15/35 °C) was analyzed for nine species. Of the 20 species, eight species with the largest seeds had desiccation sensitive seeds; this is the first record for species of four genera and one family, where only desiccation tolerant seeds are otherwise recorded. Light-dependent germination was found in three species (0.01-0.015 g) and is the first record for two; however, results were based on seeds from one plant per species. Alternating temperatures of 15/35 °C decreased final germination of four out of nine species, and response to 20/30 °C cycles varied compared to constant 25 °C. Seed and germination characteristics of the species ranged from pioneer to climax traits indicating that establishment of lianas from seeds may be confined to species specific niches.

In glomerulonephritis, the migration of inflammatory cells into the glomerulus is an important step in disease initiation and progression. The viral receptor Toll-like receptor 3 (TLR3) is known to play a role in virus-associated glomerulonephritis. Based on this knowledge, this study aimed to define the effects of the TLR3 ligand polyriboinosinic:polyribocytidylic acid (poly(I:C)) on the expression of adhesion molecules and macrophage colony-stimulating factor (M-CSF) on resident glomerular cells. Experiments in MCs demonstrated that the activation of viral receptors by poly(I:C) leads to a time- and dose-dependent induction of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and M-CSF at both the mRNA and protein levels; these results were confirmed by incubating MCs with HCV RNA. As shown in knockdown experiments, this effect is specifically mediated by TLR3. The prestimulation of MCs with proinflammatory cytokines increases the effects of poly(I:C), except for its induction of VCAM-1. Tumor-necrosis factor (TNF)-α, likewise, induces ICAM-1, VCAM-1 and M-CSF, and amplifies the mesangial response to poly(I:C). These results were confirmed by incubating MCs with HCV RNA. We thus provide evidence that human MCs represent a potential target of the leukocytes and monocytes that infiltrate the glomerulus in viral disease-associated GN, highlighting the possibility that MCs may act as resident antigen-presenting cells.

To characterize the auditory manifestations of patients diagnosed with Pelizaeus-Merzbacher Disease (PMD), a rare X-linked disorder of myelin classically characterized by nystagmus, spastic quadriparesis, ataxia, and cognitive delay in early childhood or progressive disease in adulthood. A prospective case study of 5 pediatric and 3 adult patients diagnosed with PMD who demonstrate varying degrees of abnormal auditory function. These patients underwent comprehensive audiological evaluations (audiometry, tympanometry, otoacoustic emissions), auditory processing tests (Dichotic Listening, Frequency Pattern Test, Duration Pattern Test), and electrophysiological measures (Auditory Brainstem Response). Abnormal electrophysiological findings with normal cochlear function were found in all test subjects. Further testing completed on adult subjects revealed further central auditory dysfunction via auditory processing tests. All the adult test subjects had abnormal results on auditory processing tests including significant left ear deficits on dichotic digits and poor duration pattern test scores. Auditory processing test results indicated strong right ear advantages for all adult PMD test subjects in Dichotic Digit testing. The degree of audiological central dysfunction findings was more severe in subjects with greater symptoms of the disease. Our findings indicate the need for a full audiological test battery on all patients with Pelizaeus-Merzbacher disease and other severe neurological disorders.

Background: Viral infections are a major problem worldwide. Many of these infections are frequently complicated by a virus-associated glomerulonephritis. In glomerulonephritis, progression of renal failure is mainly attributed to the development of extensive glomerular and interstitial fibrosis. Advanced glomerular disease is characterized by the accumulation of extracellular matrix components in the mesangial matrix and glomerular basement membrane. These matrix components are metabolized by matrix metalloproteinases (MMPs) as well as tissue inhibitors of metalloproteinase (TIMPs)., Methods: The expression of MMP2, MMP9 and TIMP-1 in human mesangial cells in culture was analysed by RT-PCR., Results: Mesangial cells express the viral receptors toll-like receptor 3 and RIG-I. Activation of these viral receptors by viral RNA exemplified by poly (I:C) RNA leads to a time- and dose-dependent expression of MMP9 without affecting the expression of MMP2 and TIMP-1. To show the specific effect of viral receptors, knockdown experiments with siRNA specific for TLR3 and RIG-I were performed., Conclusion: This novel finding of the functional expression of these viral sensors on glomerular fibrosis may indicate a novel link between viral infections and glomerular inflammation and indicates a pathophysiologic role of viral receptors in these processes.

Viral inflammation and infection of mesothelial cells (MC) are a major problem in several organ systems including pleura, pericardium and peritoneum. Toll-like receptors (TLRs) are an essential part of the innate immune system for early recognition of pathogen-associated molecular patterns. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. MC exhibit an expression of TLR3, RIG-I and MDA5. Poly (I:C) RNA stimulation resulted in an up-regulation of proinflammatory cytokines and chemokines as well as type I interferons. This novel finding of functional expression of viral sensors on human MC may indicate a novel link between viral infections and mesothelial inflammation and indicates a pathophysiologic role of viral receptors in these processes.

Vascular endothelial growth factor (VEGF) plays a key role in formation of pleural effusions and in tumorigenesis and progression of malignant mesothelioma. Mesothelial cells (MC) express the viral receptors Toll-like receptor 3 (TLR3), RIG-I and MDA5. Activation of these receptors by viral RNA exemplified by poly(I:C) RNA leads to a time- and dose-dependent increase of mesothelial VEGF synthesis. To show the specific effect of viral receptors knockdown experiments with siRNA for TLR3, RIG-I and MDA5 were performed. This finding of viral induced mesothelial VEGF synthesis may indicate a novel link between viral infections and formation of pleural effusions and progression of malignant mesothelioma.

Background/aims: Viral infections are a major problem worldwide and many of them are complicated by virally induced glomerulonephritides. Progression of kidney disease to renal failure is mainly attributed to the development of renal fibrosis characterized by the accumulation of extracellular matrix components in the mesangial cell compartment and the glomerular basement membrane. Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) are major regulators of plasmin generation and play an important role in generation and degradation of glomerular extracellular matrix components. Viral receptors expressed by mesangial cells (MC) are known to be key mediators in immune-mediated glomerulonephritis. We investigated the effect of stimulation of the viral receptors toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I) on the expression of PAI-1 and t-PA., Methods: Expression of PAI-1 and t-PA in immortalized human MC stimulated with polyriboinosinic:polyribocytidylic acid [poly(I:C)] RNA and cytokines were analyzed by real-time RT-PCR and ELISA., Results: Incubation of MC with poly(I:C) RNA to activate the viral receptors TLR3 and RIG-I upregulates the expression of PAI-1 and t-PA. Knockdown of viral receptors with specific siRNA abolishes the induction of PAI-1 and t-PA., Conclusion: For the first time a link between the activation of viral receptors on MC and potentially causative agents in the development of glomerulosclerosis and tubulointerstitial fibrosis is shown. The progression of inflammatory processes to glomerulosclerosis can be postulated to be directly enhanced by viral infection., (Copyright 2009 S. Karger AG, Basel.)

Hepatitis C virus (HCV) infection is frequently complicated by glomerulonephritis with immune complexes containing viral RNA. We examined the potential influence of Toll-like receptors (TLRs), specifically TLR3 recognition of viral dsRNA exemplified by polyriboinosinic:polyribocytidylic acid [poly(I:C) RNA]. Normal human kidney stained positive for TLR3 on mesangial cells (MCs), vascular smooth muscle cells, and collecting duct epithelium. Cultured MCs have low TLR3 mRNA levels with predominant intracellular protein localization, which was increased by tumor necrosis factor-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, and the TLR3 ligand poly(I:C) RNA. Poly(I:C) RNA stimulation of MCs increased mRNA and protein synthesis of IL-6, IL-1beta, M-CSF, IL-8/CXCL8, RANTES/CCL5, MCP-1/CCL2, and ICAM-I; it also increased anti-proliferative and proapoptotic effects, the latter of which was decreased by inhibiting caspase-8. In microdissected glomeruli of normal and non-HCV membranoproliferative glomerulonephritis biopsies, TLR3 mRNA expression was low. In contrast TLR3 mRNA expression was significantly increased in hepatitis C-positive glomerulonephritis and was associated with enhanced mRNA for RANTES/CCL5 and MCP-1/CCL2. We hypothesize that immune complexes containing viral RNA activate mesangial TLR3 during HCV infection, thereby contributing to chemokine/cytokine release and effecting proliferation and apoptosis. Thus, TLR3 expression on renal cells, and especially MCs, may establish a link between viral infections and glomerular diseases.

Palatability of parasitic plants may be influenced by their host species, because the parasites take up nutrients and secondary compounds from the hosts. If parasitic plants acquired the full spectrum of secondary compounds from their host, one would expect a correlation between host and parasite palatability. We examined the palatability of leaves of the root-hemiparasite Melampyrum arvense grown with different host plants and the palatability of these host plants for two generalist herbivores, the caterpillar of Spodoptera littoralis and the slug Arion lusitanicus. We used 19 species of host plants from 11 families that are known to contain a wide spectrum of anti-herbivore compounds. Growth of M. arvense was strongly influenced by the host species. The palatability of the individual host species for the two herbivores differed strongly. Both A. lusitanicus and S. littoralis discriminated also between hemiparasites grown with different host plants. There was no correlation between the palatability of a host species and that of the parasites grown on that host, i.e., hemiparasites grown on palatable host species were not more palatable than those grown on unpalatable hosts. We suggest an interacting pattern of specific effects of chemical anti-herbivore defences and indirect effects of the hosts on herbivores through effects on growth and tissue quality of the parasites.

Soy isoflavones display estrogenic activity in humans and animals, and thus are referred to as phytoestrogens. This study was performed to observe the effects of the soy isoflavones genistein, daidzein, and glycitein on cell cultures of rat skeletal muscles. [3H]Thymidine incorporation was used to determine cell proliferation, while protein synthesis and degradation were determined by tracking radiolabeled leucine. For the proliferation studies, insulin, estradiol, genistein, daidzein, or glycitein was supplemented at 0, 0.04, 0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, or 20 microM, respectively, or in combinations with final concentrations of 0, 0.1, 1, or 10 microM. Genistein reacted most similarly to estradiol, inhibiting proliferation at > or = 1 microM (P < .001). A combination of phytoestrogens resulted in significant inhibition of cell proliferation, but not to the extent observed with genistein alone. For the protein synthesis and degradation experiments, treatments of 0.1 microM dexamethasone or 1 microM concentrations of insulin, genistein, daidzein, or glycitein were used. Phytoestrogens did not inhibit or stimulate protein degradation or synthesis (P > .05). A one-tailed univariate analysis of variance revealed a trend (P < or = .1) in protein stimulation with genistein and glycitein treatments. These results suggest that the tyrosine kinase inhibiting activity of genistein may be affecting phosphorylation of the mitosis-promoting factor, preventing the advancement of the mitotic cell cycle. In addition, at higher total combined concentrations, daidzein and glycitein may be able to outcompete genistein for receptor sites. These results suggest that soy isoflavones in the diet may potentially modulate normal growth and development in humans and animals that ingest soy-based products.

In Pseudomonas aeruginosa, virulence determinants and biofilm formation are coordinated via a hierarchical quorum sensing cascade, which involves the transcriptional regulators LasR and RhlR and their cognate homoserine lactone activators C12-HSL [N-(3-oxododecanoyl)-L-homoserine lactone] and c4-hsl (n-butanoyl-L-homoserine lactone), which are produced by LasI and RhlI, respectively. The exoenzyme S regulon of P. aeruginosa, comprises genes for a type III secretion system and for four anti-host effector proteins (ExoS, T, U and Y), which are translocated into host cells. It is a reasonable assumption that this ExoS regulon should be downregulated in the biofilm growth state and thus should also be under the regulatory control of the Las/Rhl system. Therefore, an exoS'-gfp reporter construct was used, and the influence of the Las and Rhl quorum sensing systems and the effect of the stationary-phase sigma factor RpoS on regulation of the exoS gene was examined. Evidence is provided for downregulation of exoS during biofilm formation of P. aeruginosa PAO1. The rhlI mutant PDO100 and rhlR mutant PDO111, but not the lasI mutant PDO-JP1, showed approximately twofold upregulation of the exoS'-gfp reporter in comparison to PAO1. Upregulation of exoS'-gfp in the PDO100 mutant could be repressed to normal level by adding C4-HSL autoinducer, indicating a negative regulatory effect of RhlR/C4-HSL on exoS expression. As RhlR/C4-HSL is also involved in regulation of RpoS, the P. aeruginosa rpoS mutant SS24 was examined and the exoS'-gfp reporter was found to be fivefold upregulated in comparison to PAO1. For the first time evidence is reported for a regulatory cascade linking RhlR/RhlI and RpoS with the expression of the anti-host effector ExoS, part of the exoenzyme S regulon. Moreover, these data suggest that the exoenzyme S regulon may be downregulated in P. aeruginosa biofilms.

Purpose: The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model., Methods: All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining., Results: No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA., Conclusions: Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

Purpose: Racemic valnoctamide (VCD) is a central nervous system-active drug commercially available in Europe. VCD possesses two chiral centers and, therefore, it exists as a mixture of four stereoisomers. The purpose of this study was to evaluate the anticonvulsant activity of two VCD stereoisomers in comparison with VCD (racemate), valpromide (VPD), and valproic acid (VPA) and to study their pharmacokinetic-pharmacodynamic relationships., Methods: The ability of racemic VCD, (2S,3S)-VCD, (2R,3S)-VCD and VPD to block partial seizures was studied in the 6Hz psychomotor seizure model in mice and in the hippocampal kindled rat. The ability of (2S,3S)-VCD and (2R,3S)-VCD to prevent generalized seizures was evaluated in the maximum electroshock (MES) and subcutaneous metrazole (sc Met) seizure tests. The PK of (2S,3S)-VCD, (2R,3S)-VCD, and VPD was studied in the mice utilized in the 6Hz model., Results: All of the tested compounds were effective in the models tested. No significant difference in ED50 values was observed but the plasma and brain EC50 values of (2R,3S)-VCD in the 6Hz model at 32 mA stimulation were 2-fold higher than the EC50 values of (2S,3S)-VCD. An excellent pharmacokinetic-pharmacodynamic correlation was found between the plasma and brain concentrations of the VCD stereoisomers and their anticonvulsant effect in mice. Stereoselectivity was observed in clearance, volume of distribution, and in brain-to-plasma AUC ratio at a dose of 25 mg/kg, but the difference disappeared at higher doses as the clearance of the stereoisomers decreased and their half-life increased. For (2R,3S)-VCD the brain-to-plasma AUC ratio doubled at the tested dose range, while it remained constant for (2S,3S)-VCD., Conclusions: Racemic VCD, VPD, (2R,3S)-VCD, and (2S,3S)-VCD are effective anticonvulsants in animal models of partial seizures and are more potent than VPA. The more favorable brain penetration of (2S,3S)-VCD and its lower EC50 value in the 6Hz test provides one advantage over (2R,3S)-VCD as a new antiepileptic drug.

Purpose: The new antiepileptic drug, levetiracetam (LEV, ucb LO59), is a chiral molecule with one asymmetric carbon atom whose anticonvulsant activity is highly enantioselective. The purpose of this study was to evaluate and compare the pharmacokinetics (PK) of LEV [(S)-alpha-ethyl-2-oxo-pyrrolidine acetamide] and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide (REV) after i.v. administration to dogs. This is the first time that the pharmacokinetics of both enantiomers has been evaluated., Methods: Optically pure LEV and REV were synthesized, and 20 mg/kg of individual enantiomers was administered intravenously to six dogs. Plasma and urine samples were collected until 24 h, and the concentrations of LEV and REV were determined by an enantioselective assay. The levels of 2-pyrrolidone-N-butyric acid, an acid metabolite of LEV and REV, were determined by high-performance liquid chromatography (HPLC). The data were used for PK analysis of LEV and REV., Results: LEV and REV had similar mean +/- SD values for clearance; 1.5 +/- 0.3 ml/min/kg and volume of distribution; 0.5 +/- 0.1 L/kg. The half-life (t1/2) and mean residence time (MRT) of REV (t1/2, 4.3 +/- 0.8 h, and MRT, 6.0 +/- 1.1 h) were, however, significantly longer than those of LEV (t1/2, 3.6 +/- 0.8 h, and MRT, 5.0 +/- 1.2 h). The renal clearance and fraction excreted unchanged for LEV and REV were significantly different., Conclusions: In addition to the enantioselective pharmacodynamics, alpha-ethyl-2-oxo-pyrrolidine acetamide has enantioselective PK. The enantioselectivity was observed in renal clearance. Because REV has more favorable PK in dogs than LEV, the higher antiepileptic potency of LEV is more likely due to intrinsic pharmacodynamic activity rather than to enantioselective PK.

A 2-yr study was conducted to evaluate the interactions of castration, feeding length, and dietary CP on growth and carcass characteristics of male cattle (bulls and steers) that vary in expression of muscular hypertrophy. Crossbred cows were bred by AI to Hereford, Limousin, or Piedmontese bulls, which represented genotypes with normal, moderate, and hypermuscularity, respectively, but with similar mature weights. Male calves (131 in yr 1 and 120 in yr 2) were placed in pens with individual electronic feeding gates. Calves were fed growing diets until they reached 386 kg BW and then were individually switched to finishing diets for 90 or 132 d. Interactions were observed among sire breed, gender, and feeding length on carcass composition. Bulls were more efficient than steers in producing live weight gain. Length of finishing period accounted for a larger source of variation than gender for weight characteristics, whereas gender was the larger source of variation for carcass composition. Concentration or degradability of dietary CP influenced rate of gain from weaning to 386 kg. Interactions resulting from varying management on carcass characteristics among calves of different sire breeds indicate that unique strategies may be beneficial for the production of meat from these breeds.