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Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging ((19)F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation. Here we investigated siponimod, a sphingosine 1-phosphate (S(1)P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo (19)F MR imaging of a disease modifying drug. METHODS: The (19)F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for (19)F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired (19)F MR spectra and images in vivo directly after administration, and in ex vivo tissues. RESULTS: The (19)F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue. Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver. Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs. In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum. No secondary (19)F signals were detected from metabolites. From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution. CONCLUSION: Siponimod can be imaged non-invasively using (19)F UTE MRI in the form administered to MS patients, without modification. This study lays the groundwork for more extensive preclinical and clinical investigations. With the necessary technical development, (19)F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology.

Extrahepatic cholangiocarcinomas, also called bile duct carcinomas, represent a special entity in gastrointestinal tumors, and histological specimens of the tumors are often difficult to obtain. A special feature of these tumors is the strong neovascularization, which can often be seen in the endoluminal endoscopic procedure called cholangioscopy, performed alone or in combination with laserscanning techniques. The additional analysis of microRNA expression profiles associated with inflammation and neovascularization in bile duct tumors or just the bile duct fluid of these patients could be of enormous additional importance. In particular, the dysregulation of microRNA in these cholangiocarcinomas (CCA) was previously reported to affect epigenetics (reported for miR-148, miR-152), inflammation (determined for miR-200, miR-125, and miR-605), and chemoresistance (miR-200b, 204) in patients with cholangiocarcinoma. More importantly, in the context of malignant neovascularization, well-defined microRNAs including miR-141, miR-181, miR-191, and miR-200b have been found to be dysregulated in cholangiocarcinoma and have been associated with an increased proliferation and vascularization in CCA. Thus, a panel of these microRNA molecules together with the clinical aspects of these tumors might facilitate tumor diagnosis and early treatment. To our knowledge, this is the first review that outlines the unique potential of combining macroscopic findings from cholangioscopy with microRNA expression.

According to the new legislation on organ donation in Germany, general practitioners (GPs) should regularly inform and educate their patients about organ donation from March 1, 2022. This is because of the persistently low organ donation rate in Germany. So far, there is a lack of information about the factors influencing the medical education of patients regarding organ donation provided by GPs.GPs were surveyed via a web-based questionnaire in November and December 2021. 215 data sets have been utilized.GPs see themselves in charge for educating people about organ donation (86%). However, most of them invest little time in educating patients. 75% of GPs think that there is no time available for educational talks in the daily routine and 80% perceive difficulties in raising the issue of organ donation due to social taboos. Only 24% of GPs are aware of the new legislation. Only half of the respondents feel sufficiently informed to provide information about organ donation. On average, GPs consider a reimbursement of about 40 euros to be appropriate.GPs have not dealt much with the topic of organ donation and need more comprehensive information for the education of patients. GPs require more time to accommodate education in everyday life. Younger citizens can only be reached by GPs to a limited extent. This group must be addressed by other means.Hintergrund: Laut des Gesetzes zur Stärkung der Entscheidungsbereitschaft bei der Organspende sollen Hausärzte in Deutschland ab 1. März 2022 ihre Patienten regelmäßig zur Organspende informieren und aufklären. Hintergrund sind die anhaltend niedrigen Organspendezahlen in Deutschland. Bislang ist jedoch wenig bekannt, welche Faktoren die Aufklärung durch Hausärzte beeinflussen.Es wurde eine bundesweite Online-Umfrage durchgeführt. Die Datenerhebung erfolgte im November und Dezember 2021. 215 Datensätze konnten ausgewertet werden.Ergebnisse: Hausärzte sehen sich in Verantwortung für die Aufklärung über Organspende (86%). Die meisten investieren bislang jedoch wenig Zeit in die Aufklärung von Patienten. 75% der Hausärzte geben an, im Alltag zu wenig Zeit für Aufklärungsgespräche zu haben und 80% sehen Schwierigkeiten bei der Thematisierung von Organspende durch gesellschaftliche Tabus. Die gesetzlichen Neuregelungen sind nur bei 24% der Hausärzte bekannt. Nur die Hälfte der Befragten hält sich für ausreichend informiert, um über Organspende aufzuklären. Hausärzte halten im Mittel eine Vergütung von knapp 40 Euro pro Aufklärungsgespräch für angemessen.Schlussfolgerungen: Hausärzte setzen sich bislang wenig mit dem Thema Organspende auseinander und benötigen umfassendere Informationen für die Aufklärung von Patienten. Zudem wird mehr Zeit benötigt, um der Aufklärung im Alltag gerecht zu werden. Jüngere Bürger können von Hausärzten jedoch nur eingeschränkt erreicht werden, diese Altersgruppe muss auf anderem Weg adressiert werden.Schlüsselwörter: Organspende, Transplantationsgesetz, Aufklärung, Hausarzt, OrganspendeausweisEingereicht am 17.1.2022 - Revision akzeptiert am 8.2.2022.

Dysregulation of noncoding microRNA molecules has been associated with immune cell activation in the context of Helicobacter pylori induced gastric inflammation as well as carcinogenesis, but also with downregulation of mismatch repair genes, and may interfere with immune checkpoint proteins that lead to the overexpression of antigens on gastric tumor cells. Numerous miR-molecules have been described as important tools and markers in gastric inflammation and cancer development -including miR-21, miR-143, miR-145, miR-201, and miR-335- all of which are downregulated in gastric tumors, and involved in cell cycle growth or tumor invasion. Among the many microRNAs involved in gastric inflammation, adenocarcinoma development and immune checkpoint regulation, miR-155 is notable in that its upregulation is considered a key marker of chronic gastric inflammation that predisposes a patient to gastric carcinogenesis. Among various other miRs, miR-155 is highly expressed in activated B and T cells and in monocytes/macrophages present in chronic gastric inflammation. Notably, miR-155 was shown to downregulate the expression of certain MMR genes, such as MLH1, MSH2, and MSH6. In tumor-infiltrating miR-155-deficient CD8+ T cells, antibodies against immune checkpoint proteins restored the expression of several derepressed miR-155 targets, suggesting that miR-155 may regulate overlapping pathways to promote antitumor immunity. It may thus be of high clinical impact that gastric pathologies mediated by miR-155 result from its overexpression. This suggests that it may be possible to therapeutically attenuate miR-155 levels for gastric cancer treatment and/or to prevent the progression of chronic gastric inflammation into cancer.

ZusammenfassungZysten im kleinen Becken sind eine seltene Erkrankung, die meist während einer Routinediagnostik als Zufallsbefund festgestellt werden. In der Literatur werden diese Zysten zum Teil kontrovers diskutiert und in Abhängigkeit von ihrer Lokalisation, ihres Zysteninhaltes und eventuell begleitender anatomischer Anomalien in verschiedene Typen unterschieden.Wir berichten in unserem Fall von einem 33-jährigen gesunden Patienten, der sich wegen einer großen retrovesikalen Zyste in unserer Klinik konsiliarisch vorstellte. Aufgrund von Unterbauchbeschwerden und Problemen bei der Defäkation war die Zyste im Ultraschall beim Hausarzt diagnostiziert worden. In der weiterführenden bildgebenden Diagnostik bestätigte sich eine retrovesikale Zyste unklarer Dignität, die retrospektiv als Müller-Gang-Zyste gewertet wurde. Aufgrund der Symptomatik und malignem Entartungspotential wurde die Indikation zur operativen Sanierung gestellt. Mit Hilfe des Operationsroboter konnte die als histologisch benigne beurteilte Zyste sicher und vollständig entfernt werden. Im Rahmen einer postoperativen Verlaufsuntersuchung zeigte sich sonographisch kein Anhalt für ein Rezidiv. Zudem gab der Patient an frei von Symptomen zu sein. Somit bestätigte sich die Roboter-assistierte Resektion als ein sicheres Verfahren zur Therapie von großen symptomatischen Müller-Gang-Zysten.

Cysts in the lesser pelvis are a rare disease and most often an incidental finding from routine diagnostic investigation. Published information is controversial. These cysts are distinguished by localisation, content of the cyst and accompanying anatomical anomalies. In this case, we report a 33 years old man who presented to our clinic due to a large retrovesical cyst. Because of lower abdominal pain and problems with defecation, the cyst was diagnosed by ultrasound. Further radiological diagnostic testing confirmed the presence of a retrovesical cyst of unknown malignancy, which was retrospectively evaluated as a Müllerian duct cyst. Due to symptoms and potential malignancy of the cyst, the decision was made to perform surgery. With the help of the operation robot, this benign cyst was safely and completely removed. In a follow-up, the patient presented free of symptoms and sonographically there was no sign of recurrence. Therefore robotic-assisted resection is a safe procedure to treat large symptomatic Müllerian duct cysts.Zysten im kleinen Becken sind eine seltene Erkrankung, die meist während einer Routinediagnostik als Zufallsbefund festgestellt werden. In der Literatur werden diese Zysten zum Teil kontrovers diskutiert und in Abhängigkeit von ihrer Lokalisation, ihres Zysteninhaltes und eventuell begleitender anatomischer Anomalien in verschiedene Typen unterschieden.Wir berichten in unserem Fall von einem 33-jährigen gesunden Patienten, der sich wegen einer großen retrovesikalen Zyste in unserer Klinik konsiliarisch vorstellte. Aufgrund von Unterbauchbeschwerden und Problemen bei der Defäkation war die Zyste im Ultraschall beim Hausarzt diagnostiziert worden. In der weiterführenden bildgebenden Diagnostik bestätigte sich eine retrovesikale Zyste unklarer Dignität, die retrospektiv als Müller-Gang-Zyste gewertet wurde. Aufgrund der Symptomatik und malignem Entartungspotential wurde die Indikation zur operativen Sanierung gestellt. Mit Hilfe des Operationsroboter konnte die als histologisch benigne beurteilte Zyste sicher und vollständig entfernt werden. Im Rahmen einer postoperativen Verlaufsuntersuchung zeigte sich sonographisch kein Anhalt für ein Rezidiv. Zudem gab der Patient an frei von Symptomen zu sein. Somit bestätigte sich die Roboter-assistierte Resektion als ein sicheres Verfahren zur Therapie von großen symptomatischen Müller-Gang-Zysten.

Objective Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of 19F MR that can be practically achieved when moving from 9.4 to 21.1 T. Materials and methods We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B0), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B0 with 2D-RARE and 2D-FLASH using 19F volume radiofrequency resonators together. T1 and T2 of PFCE were measured at both B0 strengths. Results Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of 19F T1 and T2 relaxation on B0 was demonstrated. High spatially resolved 19F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. Discussion Enhanced SNR and T1 shortening indicate the potential benefit of in vivo 19F MR at higher B0 to study inflammatory processes with greater detail. Electronic supplementary material The online version of this article (10.1007/s10334-018-0710-z) contains supplementary material, which is available to authorized users.

Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein–Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of these infections and the prediction of further cancer development could be clinically significant. To this end, microRNAs (miRNAs) could serve as promising new tools. MiRNAs are highly conserved noncoding RNAs that play an important role in gene silencing, mainly acting via translational repression and the degradation of mRNA targets. Recent reports demonstrate the downregulation of numerous miRNAs in GC, especially miR-22, miR-145, miR-206, miR-375, and miR-490, and these changes seem to promote cancer-cell invasion and tumor spreading. The dysregulation of miR-106b, miR-146a, miR-155, and the Let-7b/c complex seems to be of particular importance during H. pylori infection or gastric carcinogenesis. In contrast, many reports describe changes in host miRNA expression and outline the effects of bamHI-A region rightward transcript (BART) miRNA in EBV-infected tissue. The differential regulation of these miRNA, acting alone or in close interaction when both infections coexist, may therefore enable us to detect cancer earlier. In this review, we focus on the two different etiologies of gastric cancer and outline the molecular pathways through which H. pylori- or EBV-induced changes might synergistically act via miR-155 dysregulation to potentiate cancer risk. The three markers, namely, H. pylori presence, EBV infection, and miR-155 expression, may be checked in routine biopsies to evaluate the risk of developing gastric cancer.

Here we describe a simple and inexpensive protocol for preparing ex vivo rodent phantoms for use in MR imaging studies. The experimental animals are perfused and fixed with formaldehyde, and then wrapped with gauze and sealed with liquid latex. This yields a phantom that preserves all organs in situ, and which avoids the need to keep fixed animals and organs in containers that have dimensions very different from living animals. This is especially important for loading in MR detectors, and specifically the RF coils, they are usually used with. The phantom can be safely stored and conveniently reused, and can provide MR scientists with a realistic phantom with which to establish protocols in preparation for preclinical in vivo studies—for renal, brain, and body imaging. The phantom also serves as an ideal teaching tool, for trainees learning how to perform preclinical MRI investigations of the kidney and other target organs, while avoiding the need for handling living animals, and reducing the total number of animals required.This protocol chapter is part of the PARENCHIMA initiative “MRI Biomarkers for CKD” (CA16103), a community-driven Action of the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Kidney-associated pathologies would greatly benefit from noninvasive and robust methods that can objectively quantify changes in renal function. In the past years there has been a growing incentive to develop new applications for fluorine (19F) MRI in biomedical research to study functional changes during disease states. 19F MRI represents an instrumental tool for the quantification of exogenous 19F substances in vivo. One of the major benefits of 19F MRI is that fluorine in its organic form is absent in eukaryotic cells. Therefore, the introduction of exogenous 19F signals in vivo will yield background-free images, thus providing highly selective detection with absolute specificity in vivo. Here we introduce the concept of 19F MRI, describe existing challenges, especially those pertaining to signal sensitivity, and give an overview of preclinical applications to illustrate the utility and applicability of this technique for measuring renal function in animal models.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35–0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups—they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17–0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22–0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25–0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

The objective of this study was the design, implementation, evaluation and application of a compact wideband self-grounded bow-tie (SGBT) radiofrequency (RF) antenna building block that supports anatomical proton (H-1) MRI, fluorine (F-19) MRI, MR thermometry and broadband thermal intervention integrated in a whole-body 7.0 T system. Design considerations and optimizations were conducted with numerical electromagnetic field (EMF) simulations to facilitate a broadband thermal intervention frequency of the RF antenna building block. RF transmission (B-1(+)) field efficiency and specific absorption rate (SAR) were obtained in a phantom, and the thigh of human voxel models (Ella, Duke) for H-1 and F-19 MRI at 7.0 T. B-1(+) efficiency simulations were validated with actual flip-angle imaging measurements. The feasibility of thermal intervention was examined by temperature simulations (f = 300, 400 and 500 MHz) in a phantom. The RF heating intervention (P-in = 100 W, t = 120 seconds) was validated experimentally using the proton resonance shift method and fiberoptic probes for temperature monitoring. The applicability of the SGBT RF antenna building block for in vivo H-1 and F-19 MRI was demonstrated for the thigh and forearm of a healthy volunteer. The SGBT RF antenna building block facilitated F-19 and H-1 MRI at 7.0 T as well as broadband thermal intervention (234-561 MHz). For the thigh of the human voxel models, a B-1(+) efficiency >= 11.8 mu T/root kW was achieved at a depth of 50 mm. Temperature simulations and heating experiments in a phantom demonstrated a temperature increase Delta T >7 K at a depth of 10 mm. The compact SGBT antenna building block provides technology for the design of integrated high-density RF applicators and for the study of the role of temperature in (patho-) physiological processes by adding a thermal intervention dimension to an MRI device (Thermal MR).

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38.Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies.Dr Falk Pharma GmbH.

Radiofrequency ablation (RFA) is a new endoscopic palliation therapy for malignant biliary obstruction. The aim of this study was to compare the short-term effects of biliary drainage and adverse events of this technique with the standard of endoscopical treatment of hilar cholangiocarcinoma, photodynamic therapy (PDT).We retrospectively and since December 2012 prospectively investigated the efficacy and adverse events of RFA in patients with hilar cholangiocarcinoma in two tertiary referral centers between November 2011 and January 2013. The approach of the study was prospective, but because of the large amount of retrospectively included patients, the design of the study is overall retrospective. A group of 20 patients treated with PDT between April 2005 and May 2011 served as a historical control.Fourteen patients received 31 biliary RFAs and 20 patients received 36 PDTs. Within the RFA group, a significant decrease (p = 0.046) of the bilirubin level was seen 14 days after the first RFA (3.3 ± 3.9 (mg/dl) versus 2.3 ± 2.6 (mg/dl)). In the PDT group no significant decrease (p = 0.67) of the bilirubin level was obtained (4.1 ± 6.9 (mg/dl) versus 3.5 ± 5.3 (mg/dl)). In the PDT group (13/20, 65%) a significantly higher number of premature stent replacements (3 months) after the first intervention was noticed in comparison with the RFA group (four of 14, 29%) (p 0.01). Between the first and fifth procedure, post-interventional adverse events tend to occur more frequently in patients with PDT (eight of 20, 40%) than with RFA (three of 14, 21%) (p = 0.277).Looking at the short-term effects, we conclude that RFA may present a therapeutic alternative to PDT for palliative treatment of malignant biliary obstruction because of its simple feasibility and moderate adverse event rate. To provide a definitive evaluation of the long-term effects and of overall median survival, a controlled trial with PDT must follow.

Aims Apical rocking (ApRock) and septal flash (SF) are often observed phenomena in asynchronously contracting ventricles. We investigated the relationship of visually assessed ApRock and SF, reverse remodelling, and long-term survival in cardiac resynchronization therapy (CRT) candidates. Methods and results A total of 1060 patients eligible for CRT underwent echocardiographic examinations before and 12 ± 6 months after device implantation. Three blinded physicians were asked to visually assess the presence of ApRock and SF before device implantation and also their correction by CRT 12 ± 6 months post-implantation. Patients with a left ventricular (LV) end-systolic volume decrease of ≥15% during the first year of follow-up were regarded as responders. Patients were followed for a median period of 46 months (interquartile range: 27–65 months) for the occurrence of death of any cause. If corrected by CRT, visually assessed ApRock and SF were associated with reverse remodelling with a sensitivity of 84 and 79%, specificity of 79 and 74%, and accuracy of 82 and 77%, respectively. ApRock (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.30–0.53, P < 0.0001) and SF (HR 0.45 [CI 0.34–0.61], P < 0.001) were independently associated with lower all-cause mortality after CRT and had an incremental value over clinical variables and QRS width for identifying CRT responders. Both the absence of ApRock/SF and unsuccessful correction of ApRock/SF despite CRT were associated with a high risk for non-response and an unfavourable long-term survival. Conclusion A specific LV mechanical dyssynchrony pattern, characterized by ApRock and SF, is associated with a more favourable long-term survival after CRT. Both parameters are also indicators of an effective therapy. [10.1093/ehjci/jev324][1] [1]: /lookup/doi/10.1093/ehjci/jev324

To evaluate the accuracy of measurements of the velocities and timing of blood flow and of tissue motion, we tested four commercially available ultrasound systems. Pulsed wave, continuous wave and tissue Doppler recordings acquired across a range of angles of insonation were compared against a calibrated Doppler string phantom. Temporal delays were measured from the onset of the simulated electrocardiogram to the start of each Doppler signal. Across all modalities and angles, the mean errors of measurements of velocity using the four systems were 0.2%, 1.7%, 6.0% and 3.1%. The largest errors occurred using tissue Doppler at 5 cm/s (mean overestimation: 5.8%, range: +1.1%-12.5%). Mean delays in displaying the onset of flow were -3, 6, 11 and -16 ms. All differences between machines were statistically significant. The accuracy of high-end ultrasound systems for measuring velocities is better than in earlier reports, but the reporting of routine testing against standard phantoms should be mandatory.

This study examines the influence of the environmental factor temperature on theStudies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, TThe impact of temperature on the

OBJECTIVES The aim of this study was to compare the volumetric response and the long- term survival after cardiac resynchronization therapy (CRT) in patients with intrinsic left bundle branch block (LBBB) versus chronic right ventricular pacing (RVP) with respect to the presence of mechanical dyssynchrony (MD). BACKGROUND Chronic RVP induces an iatrogenic LBBB and asynchronous left ventricular contraction that is potentially reversible by upgrading to CRT. METHODS A total of 914 patients eligible for CRT (117 with conventional pacemakers and 797 with intrinsic LBBB) were included in the study. MD was visually assessed before CRT and was defined as the presence of either apical rocking and/or septal flash on baseline echocardiograms. Patients with a left ventricular end-systolic volume decrease of >= 15% during the follow-up were considered responders. Patients were followed for all-cause mortality during the median follow-up of 48 months (interquartile range: 29 to 66 months). RESULTS MDwas observed in 51% of patientswithRVP versus 77% in patients with intrinsic LBBB( p< 0.001). Patients with RVP and MD had a similar likelihood of volumetric response as did patients with intrinsic LBBB and MD (adjusted odds ratio: 0.71; 95% confidence interval: 0.33 to 1.53; p - 0.385). There was no significant difference in long-term survival between patients with RVP and intrinsic LBBB (adjusted hazard ratio: 1.101; 95% confidence interval: 0.658 to 1.842; p = 0.714). Patients with visual MD and either intrinsic LBBB or RVP had a more favorable survival than those without MD (p < 0.001). CONCLUSIONS The likelihood of volumetric response and a favorable long-term survival of patients with RVP was similar to those of patients with intrinsic LBBB and were mainly determined by the presence of MD and not by the nature of LBBB. (C) 2017 by the American College of Cardiology Foundation.

MicroRNAs (miRNAs) are ∼22-nt molecules exerting control of protein expression in cancer tissues. The current study determined the full spectrum of miRNA dysregulation in freshly isolated human colon or rectal cancer biopsies as well as in controls of healthy adjacent tissue (total of n = 100) using an Illumina sequencing technology. In this work, we aimed to identify miRNAs that may serve as future marker to discern between these two subtypes. DESeq2 analysis revealed 53 significantly dysregulated miRNAs in colon cancer, 67 miRNAs in rectal cancer, and 97 miRNAs in both at a Padj value < 0.05 and ≥ 10 read counts. 65% of miRNAs were upregulated in colon as well as rectal cancer. Highest significant dysregulation (Padj < 0.00001) was detected for hsa-miR-21-5p, -215-5p and -378a in both colon and rectal cancer. Among the group of miRNAs with Padj < 0.05 and more than 2-fold expression differences, hsa-miR-375 was detected in rectal cancer only, and hsa-miR-133a-3p only in colon cancer. Receiver operating characteristic (ROC) analysis confirmed highly distinct sensitivities for hsa-miR-375 to detect rectal cancer (area under the curve (AUC): 0.9), while hsa-miR-133a-3p (AUC: 0.89) had the highest sensitivity for detecting colon cancer. We conclude that hsa-miR-375 and hsa-miR-133a-3p may serve as new markers of rectal or colon cancer and should be further investigated to search for different etiologies of colorectal cancer.

Neuroinflammation can be monitored using fluorine-19 (19F)-containing nanoparticles and 19F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room temperature (RT) 19F radiofrequency (RF) coils and low spatial resolution 19F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new 19F transceive cryogenic quadrature RF probe ( 19 F-CRP) that provides the SNR necessary to acquire superior spatially-resolved 19F MRI. First we characterized the signal-transmission profile of the 19 F-CRP. The 19 F-CRP was then benchmarked against a RT 19F/1H RF coil. For SNR comparison we used reference compounds including 19F-nanoparticles and ex vivo brains from EAE mice administered with 19F-nanoparticles. The transmit/receive profile of the 19 F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 μm isotropic resolution with the 19 F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most 19F signals were undetectable using the RT coil. The 19 F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies.

Aims Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT. Methods and results In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 +/- 3 months postimplantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 +/- 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction >= 15%), and LV volume expansion (ESV increase >= 5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P

Hypertrophic Cardiomyopathy (HCM) confers a 4-5 %/year-risk for sudden cardiac death. Intramyocardial fibrosis (IF) is associated with this risk. The gold standard of IF visualization is cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE-CMR). In view of a number of CMR-limitations the hypothesis of this study was that late enhanced multi-slice computed tomography (leMDCT) enables demonstration of late enhancement (LE) indicating IF. In a prospective single-center validation study leMDCT research-scans were exclusively performed for IF-imaging in HCM-patients not including non-invasive coronary angiography during first-pass (64-slice; 80 kV; Iopromide, 150 mL, injected 7 min before scanning). Applying a 17-segment-polar-map short cardiac axis views (multiplanar reformations; 5 mm slice thickness) were analysed in order to exclude/detect, localize and measure LE practicing the manual quantification method if present. Finally, leMDCT and LGE-CMR data were unblinded for intermodal correlation. We included n = 24 patients consecutively (64.0 ± 14.5 years of age). LE was demonstrated by LGE-CMR in n = 14/24 patients (prevalence 58 %). Patient- and segment-based sensitivity in leMDCT was 100 and 68 %, respectively. In leMDCT tissue density of LE was 142 ± 51 versus 89.9 ± 19.3 HU in remote myocardium (p0.001). Signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) appeared to be 7.3 ± 3.3 and 2.3 ± 1, respectively. Sizing of LE-area gave 2.2 ± 1.4 cm(2) in leMDCT versus 2.9 ± 2.4 cm(2) in LGE-CMR (r = 0.93). Intra-/interobserver variability was assessed with an accuracy of 0.36 cm(2) (r = 0.91) and 0.47 cm(2) (r = 0.82), respectively. In consecutive HCM patients leMDCT can reliably detect intramyocardial fibrosis marked by LE. In view of a comparatively low SNR and CNR leMDCT may alternatively be applied in case of CMR contraindications.

Endoscopic therapy holds an important role in the management of benign biliary strictures. This study compares the long-term outcome of stenting therapy depending on the underlying cause of the stricture.In a retrospective cohort study, 228 patients with benign biliary strictures were identified using an endoscopic database, hospital charts, and cholangiograms between January 1992 and December 2008. Long-term follow-up was evaluated with cholangiograms, transabdominal ultrasound, laboratory parameters, and physical examination. The median follow-up period was 44.7 months.Endoscopic management showed best long-term results in patients with stone-associated biliary stricture. In this subgroup, endoscopic therapy could be successfully completed in 92% (71/77) of the patients. Patients with postoperative biliary stricture had good outcome in 83% (53/64) of cases. Idiopathic strictures presented a successful outcome in 58% (15/26). Biliary strictures caused by chronic pancreatitis had a significantly poorer outcome compared with strictures of other origin. Therapeutic success of endoscopic therapy could only be observed in 31% of patients (19/61).Long-term outcome of endoscopic therapy for benign strictures was significantly dependent on the underlying cause of the stricture. In particular, patients with biliary strictures due to chronic pancreatitis benefit least from endoscopic therapy, whereas patients with stone-associated strictures had the highest therapeutic success rate.

Pocket-size hand-held echocardiography (PHE) is low cost, portable, user friendly, and battery powered. Studies using PHE do not replace conventional echo studies and do not provide a complete diagnostic echocardiographic examination. PHE should be used for goal-oriented studies that include assessment of left ventricular (LV) cavity size, LV systolic function, detection of pericardial effusion, and haemodynamic compromise. Examinations using PHE have been demonstrated to be feasible and provide additional information to the physical examination. For potential users other than cardiology experts in echocardiography the accuracy of PHE data highly depends on training and competency. Emphasis must be placed on acquisition of good quality images and knowledge of pitfalls and limitations. The challenge is providing efficient training programmes to ensure competency in performing focused studies and have recognition of an appropriate threshold for seeking expert advice and full echo examination. PHE is a useful teaching tool and provides important complementary information for medical education.

To analyze whether left ventricular dyssynchrony (LVD) at baseline is predictive for long-term outcome in heart failure (CHF) patients with left ventricular (LV) dysfunction and conduction disturbances treated with cardiac resynchronization therapy (CRT).In 535 consecutive individuals with CHF scheduled for implantation of a CRT device, LVD was assessed by tissue Doppler imaging (TDI), defined as an electromechanical delay (EMD) difference of ≥40 ms in 2 opposed left ventricular wall regions (septal vs. lateral, anterior vs. inferior). All-cause mortality, heart transplantation, or assist device implantation was defined as combined primary end point. Secondary end points were measures of reverse LV remodeling and of symptomatic improvement.Mean follow-up was 68 ± 36 [range: 4-150] months. LVD at baseline was present in 308 patients (61%). Of these, 24% reached the combined primary endpoint in contrast to 58% of patients without LVD (p0.001). Furthermore, patients with LVD showed pronounced improvement of all secondary end point parameters. In our cohort LVD was an independent predictor for outcome (hazard ratio [95% CI]: 0.30 [0.21-0.42], p0.001).LVD at baseline as assessed by TDI is associated with a more pronounced clinical improvement and is a predictor for transplant-free long-term survival in CRT recipients.

We examined the prevalence of sleep-disordered breathing (SDB) in patients with severe aortic valve stenosis (AS) and the impact of transfemoral aortic valve implantation (TAVI) on SDB.79 patients underwent cardiorespiratory polygraphy (PG) before TAVI (CoreValve™), 62 of them a second PG after the procedure.Forty-nine (62 %) patients had obstructive sleep apnea (OSA), 25 (32 %) central sleep apnea (CSA), and 5 (6 %) presented without significant SDB (apnea-hypopnea index (AHI)5/h). Among the 62 patients evaluated before and after TAVI, 36 (58 %) had OSA, 22 (36 %) CSA, and 4 patients (7 %) no SDB. AHI was significantly higher in CSA patients than in OSA patients (34.5 ± 18.3 vs. 18.0 ± 12.6/h, p0.001). Successful TAVI had a significant impact on CSA but not on OSA: CSA patients with optimal TAVI results experienced a significant reduction in central respiratory events (AHI 39.6 ± 19.6-23.1 ± 16.0/h, p = 0.035), while no changes were detected in OSA patients (AHI 18.8 ± 13.0-20.25 ± 13.4/h, p = 0.376). In contrast, in patients who developed at least moderate periprosthetic aortic regurgitation (ARI), CSA increased significantly (AHI 26.3 ± 13.2-39.2 ± 18.4/h, p = 0.036), whereas no acute change was seen in patients with OSA (AHI 10.5 ± 7.8-12.5 ± 5.0/h, p = 0.5).OSA and CSA are prevalent in more than 90 % of patients undergoing TAVI for severe aortic valve stenosis. Successful TAVI had no significant impact on OSA but improved CSA. In case of an acute change from pressure overload (aortic stenosis) to acute volume overload (aortic regurgitation after TAVI), central, but not obstructive, sleep apnea deteriorated.

BackgroundLeft ventricular rotation is physiologically affected by acute changes in preload. We investigated the acute effect of preload changes in chronically underloaded and overloaded left ventricles in children with shunt lesions.MethodsA total of 15 patients with atrial septal defects (Group A: 7.4 ± 4.7 years, 11 females) and 14 patients with patent arterial ducts (Group B: 2.7 ± 3.1 years, 10 females) were investigated using 2D speckle-tracking echocardiography before and after interventional catheterisation. The rotational parameters of the patient group were compared with those of 29 matched healthy children (Group C).ResultsMaximal torsion (A: 2.45 ± 0.9°/cm versus C: 1.8 ± 0.8°/cm, p < 0.05), apical peak systolic rotation (A: 12.6 ± 5.7° versus C: 8.7 ± 3.5°, p < 0.05), and the peak diastolic torsion rate (A: −147 ± 48°/second versus C: −110 ± 31°/second, p < 0.05) were elevated in Group A and dropped immediately to normal values after intervention (maximal torsion 1.5 ± 1.1°/cm, p < 0.05, apical peak systolic rotation 7.2 ± 4.1°, p < 0.05, and peak diastolic torsion rate −106 ± 35°/second, p < 0.05). Patients in Group B had decreased maximal torsion (B: 1.8 ± 1.1°/cm versus C: 3.8 ± 1.4°/cm, p < 0.05) and apical peak systolic rotation (B: 8.3 ± 6.1° versus C: 13.9 ± 4.3°, p < 0.05). Defect closure was followed by an increase in maximal torsion (B: 2.7 ± 1.4°/cm, p < 0.05) and the peak diastolic torsion rate (B: −133 ± 66°/second versus −176 ± 84°/second, p < 0.05).ConclusionsPatients with chronically underloaded left ventricles compensate with an enhanced apical peak systolic rotation, maximal torsion, and quicker diastolic untwisting to facilitate diastolic filling. In patients with left ventricular dilatation by volume overload, the peak systolic apical rotation and the maximal torsion are decreased. After normalisation of the preload, they immediately return to normal and diastolic untwisting rebounds. These mechanisms are important for understanding the remodelling processes.

Cheyne-Stokes Respiration and Arrhythmias ObjectiveThis study aimed to investigate whether adequate treatment of Cheyne-Stokes respiration (CSR) reduces the risk of arrhythmic events in patients with chronic heart failure (CHF). MethodsA cohort of 403 registry patients with CHF (LVEF45%, NYHA-class2) and implanted cardioverter-defibrillator devices (ICD) was studied. They underwent overnight polygraphy, with 221 having mild or no CSR (apnea-hypopnea index [AHI] 15/h). Latter ones were offered therapy with adaptive servoventilation (ASV), which 96 patients accepted and 86 rejected. During follow-up (21 15 months) defibrillator therapies were recorded in addition to clinical and physiologic measures of heart failure severity. ResultsEvent-free survival from (a) appropriate cardioverter-defibrillator therapies and (b) appropriately monitored ventricular arrhythmias was shorter in the untreated CSR group compared to the treated CSR and the no CSR group. Stepwise Cox proportional hazard regression analysis showed untreated CSR (a: hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.46-2.72, P < 0.001; b: HR 2.19, 95%CI 1.42-3.37, P < 0.001), but not treated CSR (a: HR 1.06, 95%CI 0.74-1.50; P = 0.77; b: HR 1.21, 95%CI 0.75-1.93, P = 0.43) was an independent risk factor. The treated CSR group showed improvements in cardiac function and respiratory stability compared to the untreated CSR group. ConclusionThis study demonstrates a decrease of appropriate defibrillator therapies by ASV treated CSR in patients with CHF and ICD. A reduced exposure to hyperventilation, hypoxia, and improvement in indices of CHF severity and neurohumoral disarrangements are potential causative mechanisms.

Electromyostimulation (EMS) of thigh and gluteal muscles is a strategy to increase exercise capacity in patients with chronic heart failure (CHF). The aim of this non-randomised pilot study was to investigate the effects of different stimulation strategies in CHF patients using a newly developed stimulation suit also involving trunk and arm muscles [extended electromyostimulation (exEMS)] in comparison with EMS therapy limited to gluteal and leg muscles (limEMS). 60 individuals joined the EMS training programme. Stable CHF patients (NYHA class II–III) received either exEMS (22 patients, 15 males, mean age 59.95 ± 13.16 years) or limEMS (12 patients, 9 males, 62.75 ± 8.77 years). 26 participants served as healthy control group (CG) receiving exEMS. Training was performed for 10 weeks twice weekly for 20 min, and the level of daily activity remained unchanged. Effects on exercise capacity, oxygen uptake, left ventricular function (EF) and biomarkers were evaluated. There was a significant increase of oxygen uptake at aerobic threshold in all groups (exEMS: 13.7 ± 3.9–17.6 ± 5.1 ml/kg/min (+28.46 %, p

Until now, there is no consensus regarding the definition of a clinical response to cardiac resynchronization therapy (CRT) in patients with chronic heart failure (CHF) and systolic left ventricular (LV) dysfunction. The aim of this study was to evaluate if echocardiography is predictive for an objective improvement in exercise capacity during long-term follow-up of CRT.Each patient underwent echocardiography and spiroergometry both at baseline and at last follow-up. Left ventricular dyssynchrony (LVD) before CRT was defined by tissue Doppler imaging (TDI) as intra-LV delay ≥40 msec (septal-lateral or anterior-posterior). Clinical response to CRT was defined as increase of peakVO2 or as increase of maximal workload10% as compared to baseline.Mean follow-up was 69 ± 37 months. From the 238 consecutive patients included in the study, 141 (59%) were classified as clinical responders and 97 (41%) as nonresponders. Baseline data of responders and nonresponders were comparable. However, clinical responders showed more often LVD (64%) than nonresponders (42%, P = 0.004). On multivariate regression analysis, nonischemic origin of CHF (β-coefficient in the final model 0.1, P = 0.04) and LVD at baseline (β-coefficient in the final model 0.2, P 0.001) were independently associated with clinical response during long-term follow-up. Patients with LVD at baseline had significant more often an improvement of left ventricular ejection fraction10% (P = 0.02) and a reduction of left ventricular end-diastolic diameter (LVEDD)10% (P 0.01) than patients without LVD at baseline.LVD at baseline as assessed by a straightforward echocardiographic approach predicts the long-term clinical response to CRT and is associated with a more pronounced reverse LV remodeling.

Background The purpose of our study was to correlate the incidence of adequate implantable cardioverter-defibrillator (ICD) interventions in hypertrophic cardiomyopathy (HCM) patients with risk markers (RMs) for sudden cardiac death (SCD) plus myocardial fibrosis as detected by late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging. Methods In all, 87 patients with HCM underwent LGE-CMR imaging prior to ICD implantation, performed for secondary (n = 2; 2%) or primary SCD prophylaxis (n = 85; 98%). Fibrosis was graded with a 17-segment left ventricular model (0 = absent, 1=point-shaped, 2=limited to 1 left ventricular segment, 3=involving ≥ 2 segments). During follow-up, ICD memories were read out by a physician blinded to the individual patient data. Results The number of RMs per patient was 1.9 ± 0.8. Myocardial fibrosis was present in 78 patients (90%); 26 (30%) had a fibrosis score of 3. During follow-up (3.5 ± 2.6 [range, 0.2-11.4 years]), 15 patients had 50 appropriate ICD interventions. Episodes of atrial fibrillation were found in 28 patients. Fibrosis severity correlated with occurrence of ventricular tachycardia (Cramer's V, or φc = 0.4, P 0.001) and atrial fibrillation (φc = 0.6, P 0.001). On multivariate regression analysis, an independent association between myocardial fibrosis (s = 0.6, P 0.01) and sustained ventricular tachycardia was found. Conclusions In HCM patients treated with ICD implantation because of a high SCD risk by traditional RM assessment, a high rate of arrhythmic events was observed during long-term follow-up. In a cohort of patients with clinical markers for high risk of SCD, severity of myocardial fibrosis as detected by an easy LGE-CMR scoring system was associated with future arrhythmic events and appropriate ICD therapies.

Bei symptomatischen Patienten mit chronischen erworbenen Herzklappenfehlern kann eine Intervention indiziert sein, um Beschwerden und die Lebensqualitat zu verbessern. Interventionsziel bei asymptomatischen Patienten ist die Prognoseverbesserung durch Pravention typischer Komplikationen, insbesondere von Herzinsuffizienz und Arrhythmien. Leitliniengerecht ist es unerlasslich, Symptome zuverlassig zu erfassen und u. a. mithilfe der Spiroergometrie zu objektivieren. Bei zweifelsfrei asymptomatischen Patienten mit hamodynamisch fortgeschrittenen Klappenfehlern muss zudem gepruft werden, ob das Myokard an die chronische Druck- und/oder Volumenbelastung auch unter Belastungsbedingungen adaptiert ist (Kontraktilitatsreserve). Nach den klassischen Symptomen der diastolischen und systolischen Herzinsuffizienz zu fragen, ist dabei nicht ausreichend, da die Leitlinien ein abwartendes Vorgehen nur fur Patienten empfehlen, die frei von jedweder kausalen Symptomatik sind. Bei allen anderen Patienten ist grundsatzlich die Intervention indiziert. In Anbetracht des zunehmend alteren Patientenkollektivs mit Herzklappenfehlern – insbesondere mit degenerativer Aortenklappenstenose – gilt es zu berucksichtigen, dass der Lebensstil der Patienten oftmals durch die Vermeidung korperlicher Belastungen charakterisiert ist. Dementsprechend sind Fragen zur Belastungsintoleranz oft wenig hilfreich. Bei einer erschopften myokardialen Kontraktilitatsreserve ist eine Klappenintervention auch indiziert, wenn der Patient im Alltagsleben asymptomatisch ist.