Mode-of-action of the PROPELLA concept in fulminant myocarditis.

AIMS: Haemodynamic load induces cardiac remodelling via mechano-transduction pathways, which can further trigger inflammatory responses. We hypothesized that particularly in an inflammatory disorder such as myocarditis, a therapeutic strategy is required which, in addition to providing adequate circulatory support, unloads the left ventricle, decreases cardiac wall stress, and mitigates inflammatory responses. METHODS AND RESULTS: Axial flow pumps such as the Impella systems comply with these requirements. Here, we report a potential mode-of-action of prolonged Impella support (PROPELLA concept) in fulminant myocarditis, including a decrease in cardiac immune cell presence, and integrin α1, α5, α6, α10 and ß6 expression during unloading. CONCLUSION: PROPELLA may provide benefits beyond its primary function of mechanical circulatory support in the form of additional disease-altering effects, which may contribute to enhanced myocardial recovery/remission in patients with chronic fulminant myocarditis.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports.

BACKGROUND: Recent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients' therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status. CASE PRESENTATION: We present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization. CONCLUSIONS: Our case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a »-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.

The potential of spatial information in human biomonitoring by example of two German environmental epidemiology studies.

This study aimed at statistically investigating the association between the internal exposure of children and young adults to uranium (U) and epidemiologically relevant external determinants of exposure. The investigation was performed with data from two studies within the framework of the German health-related environmental monitoring program: The German Environmental Survey for Children (GerES IV) conducted by the Federal Environment Agency (Umweltbundesamt) with data on 1,780 children 3-14 years of age and their home environment and the German Environmental Specimen Bank (ESB, section: human specimens) with data on 2,253 students 20-29 years of age. Both studies provided data on the U levels in human urine for all probands. GerES IV furthermore provided an extensive environmental and demographic database on, e.g., U levels in drinking water. The data from GerES IV and ESB were linked by GIS to spatially relevant exposure information, including background values of U in stream sediments and in upper and lower soils, U levels in mosses and particulate matter in the lower atmosphere, precipitation and elevation as well as forest density. Bivariate correlation analysis and two decision tree models showed moderate but significant associations between U in human urine and U levels in drinking water, stream sediments and upper and lower soils. Future investigations considering additional epidemiologically relevant data sets may differentiate the results. Furthermore, the sample design of future environmental epidemiology studies should take the spatial evaluation of the data into greater account.

The "TIDE"-Algorithm for the Weaning of Patients With Cardiogenic Shock and Temporarily Mechanical Left Ventricular Support With Impella Devices. A Cardiovascular Physiology-Based Approach.

Objectives: Mechanical circulatory support (MCS) is often required to stabilize therapy-refractory cardiogenic shock patients. Left ventricular (LV) unloading by mechanical ventricular support (MVS) via percutaneous devices, such as with Impella® axial pumps, alone or in combination with extracorporeal life support (ECLS, ECMELLA approach), has emerged as a potential clinical breakthrough in the field. While the weaning from MCS is essentially based on the evaluation of circulatory stability of patients, weaning from MVS holds a higher complexity, being dependent on bi-ventricular function and its adaption to load. As a result of this, weaning from MVS is mostly performed in the absence of established algorithms. MVS via Impella is applied in several cardiogenic shock etiologies, such as acute myocardial infarction (support over days) or acute fulminant myocarditis (prolonged support over weeks, PROPELLA). The time point of weaning from Impella in these cohorts of patients remains unclear. We here propose a novel cardiovascular physiology-based weaning algorithm for MVS. Methods: The proposed algorithm is based on the experience gathered at our center undergoing an Impella weaning between 2017 and 2020. Before undertaking a weaning process, patients must had been ECMO-free, afebrile, and euvolemic, with hemodynamic stability guaranteed in the absence of any inotropic support. The algorithm consists of 4 steps according to the acronym TIDE: (i) Transthoracic echocardiography under full Impella-unloading; (ii) Impella rate reduction in single 8-24 h-steps according to patients hemodynamics (blood pressure, heart rate, and ScVO2), including a daily echocardiographic assessment at minimal flow (P2); (iii) Dobutamine stress-echocardiography; (iv) Right heart catheterization at rest and during Exercise-testing via handgrip. We here present clinical and hemodynamic data (including LV conductance data) from paradigmatic weaning protocols of awake patients admitted to our intensive care unit with cardiogenic shock. We discuss the clinical consequences of the TIDE algorithm, leading to either a bridge-to-recovery, or to a bridge-to-permanent LV assist device (LVAD) and/or transplantation. With this protocol we were able to wean 74.2% of the investigated patients successfully. 25.8% showed a permanent weaning failure and became LVAD candidates. Conclusions: The proposed novel cardiovascular physiology-based weaning algorithm is based on the characterization of the extent and sustainment of LV unloading reached during hospitalization in patients with cardiogenic shock undergoing MVS with Impella in our center. Prospective studies are needed to validate the algorithm.

Solving conical diffraction grating problems with integral equations.

Off-plane scattering of time-harmonic plane waves by a plane diffraction grating with arbitrary conductivity and general surface profile is considered in a rigorous electromagnetic formulation. Integral equations for conical diffraction are obtained involving, besides the boundary integrals of the single and double layer potentials, singular integrals, the tangential derivative of single-layer potentials. We derive an explicit formula for the calculation of the absorption in conical diffraction. Some rules that are expedient for the numerical implementation of the theory are presented. The efficiencies and polarization angles compared with those obtained by Lifeng Li for transmission and reflection gratings are in a good agreement. The code developed and tested is found to be accurate and efficient for solving off-plane diffraction problems including high-conductive gratings, surfaces with edges, real profiles, and gratings working at short wavelengths.

Case Report First-in-Man Method Description: Left Ventricular Unloading With iVAC2L During Veno-Arterial Extracorporeal Membrane Oxygenation: From Veno-Arterial Extracorporeal Membrane Oxygenation to ECMELLA to EC-iVAC®.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used in bi-ventricular failure with cardiogenic shock to maintain systemic perfusion. Nonetheless, it tends to increase left ventricular (LV) afterload and myocardial oxygen demand. In order to mitigate these negative effects on the myocardium, an Impella CP® (3.5 L/min Cardiac Output) can be used in conjunction with V-A ECMO (ECMELLA approach). We implemented this strategy in a patient with severe acute myocarditis complicated by cardiogenic shock. Due to a hemolysis crisis, Impella CP® had to be substituted with PulseCath iVAC2L®, which applies pulsatile flow to unload the LV. A subsequent improvement in LV systolic function was noted, with increased LV ejection fraction (LVEF), LV end-diastolic diameter (LVEDD) reduction, and a reduction in plasma free hemoglobin. This case documents the efficacy of iVAC2L in replacing Impella CP as a LV vent during V-A ECMO, with less hemolysis.

The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders.

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling>[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.

Striking observations during emergency catecholamine treatment of cardiac syncope in a patient with initially unrecognized takotsubo cardiomyopathy.

A case is presented of initially unrecognized takotsubo cardiomyopathy with a dramatic clinical course after emergency catecholamine treatment for circulatory support during stress-induced cardiac syncope followed by complete recovery of cardiac function after catecholamine withdrawal and starting beta-blocker therapy. Echocardiography including 2D-strain imaging suggested that the left ventricle (LV) wall motion abnormality was mainly the consequence of geometry-induced regional differences in wall stress (progressively amplified by catecholamines), which might be another possible pathophysiological mechanism involved in the development of LV dysfunction in takotsubo cardiomyopathy. This case also suggests that in emergency, before coronary angiography is possible, echocardiography can be helpful for initial therapeutic decisions, especially to avoid emergency inotropic therapy in such patients.

Mechanical Unloading by Fulminant Myocarditis: LV-IMPELLA, ECMELLA, BI-PELLA, and PROPELLA Concepts.

Mechanical circulatory support (MCS) is often required to stabilize patients with acute fulminant myocarditis with cardiogenic shock. This review gives an overview of the successful use of left-sided Impella in the setting of fulminant myocarditis and cardiogenic shock as the sole means of MCS as well as in combination with right ventricular (RV) support devices including extracorporeal life support (ECLS) (ECMELLA) or an Impella RP (BI-PELLA). It further provides evidence from endomyocardial biopsies that in addition to giving adequate support, LV unloading by Impella exhibits disease-modifying effects important for myocardial recovery (i.e., bridge-to-recovery) achieved by this newly termed "prolonged Impella" (PROPELLA) concept in which LV-IMPELLA 5.0, implanted via an axillary approach, provides support in awake, mobilized patients for several weeks. Finally, this review addresses the question of how to define the appropriate time point for weaning strategies and for changing or discontinuing unloading in fulminant myocarditis.

Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1).

C57BL/6 (B6) mice develop glucose intolerance with age, whereas C3H/He (C3H) mice do not. In this study, we examined whether this differential glucose homeostasis was associated with differences of proteolytic activation of pancreatic prohormones. Radioimmunoassays showed comparable levels of fasting plasma insulin between the two strains but a significantly lower glucagon level in B6 mice. Pulse-chase analysis of glucagon biosynthesis in isolated pancreatic islets revealed that proglucagon was less efficiently processed in B6 mice. Because proprotein convertase (PC)2 and its 7B2 helper protein are required for this processing, we quantified islet mRNA levels by RT-PCR and protein levels by immunoblotting. The levels of proPC2 mRNA were similar between the two strains, but B6 protein extracts contained less of the mature PC2. In contrast, 7B2 mRNA and protein levels were both significantly lower in B6 pancreas. Sequencing of the 7B2 gene promoter and cDNA in the two strains revealed seven single nucleotide polymorphisms and one dinucleotide insertion/deletion in the cDNA as well as a single nucleotide polymorphism and two insertions/deletions in the promoter. Differential expression of 7B2 may contribute to the difference between B6 and C3H mice not only in glucagon production and secretion but also in glucose tolerance.

Nitrogen accumulation in forests. Exposure monitoring by mosses.

At present, there is still little information on nitrogen (N) accumulation in forests contrasting with the crucial importance of N in forest ecosystems. This work analyzes the N bioaccumulation in mosses from forested areas from Lower Saxony and North Rhine-Westphalia (two of 16 federal states of Germany), the Weser Ems Region (part of Lower Saxony), and the Euro Region Nissa (covering the Czech Republic, Germany, Poland). The studies involved samples collected from 190 sites between 1998 and 2005. Different spatial scales and regional differences in land use were chosen to assess the factors affecting N bioaccumulation in forested areas. A continuous reduction of N bioaccumulation was found from Lower Saxony (a region where agriculture is most predominant) to North Rhine-Westphalia (mostly urban). The Weser Ems Region (an agricultural region) showed a higher N concentration in mosses than the Euroregion Nissa (a former industrial region). Statistical analyses performed at the different spatial scales revealed that the areas showing greater agricultural and livestock spatial densities favor N bioaccumulation in mosses. N concentration in mosses was moderately correlated with the N concentration in the leaves and needles of the surrounding trees. No significant relationships were found regarding the crown density of forest trees or N deposition estimations from a combination of atmospheric models and deposition measurements.

Analysis of climate change affecting German forests by combination of meteorological and phenological data within a GIS environment.

The regional assessment of global change effects on plant phenology usually relies on local observations that need to be up-scaled. Therefore, methodological difficulties mostly related to data spatial resolution and congruency arise while performing broader-scale evaluations. Geostatiscs could be a useful tool to solve this type of problem, provided that a database with adequate spatial and temporal resolution is available. An assessment of variations in air temperature and plant phenology was carried out at the country level by using two German datasets regarding spring phenological phases of 15 plant species and air temperature. The data were collected from 1961-2002 at 1,279 and 675 sites, respectively. The annual mean air temperature in Germany was found to rise from 8.3 degrees C in the 1961-1990 period to 9.1 degrees C in the 1991-2002 term. The overall 15-species mean for the start of spring was found to be 6 days earlier in the latter period. The geostatistical analysis of the data revealed the suitability of Syringa vulgaris to be used as an indicator species to detect phenological changes in German forests. Moreover, their spatial patterns were found to be related to altitude and latitude. Therefore, geostatistics proved to be a useful tool to overcome some of the methodological problems related to the regional assessments of global change impacts on terrestrial ecosystems.

Clonidine effects on pain evoked SII activity in humans.

We investigated pain evoked activity in the human secondary sensory cortex (SII) following clonidine administration in six healthy volunteers using multi-channel magnetoencephalography (MEG). Pain was elicited by electrical shocks applied intracutaneously to the fingertip. Subjects rated pain intensity and perceptions of tiredness and passiveness by numerical ranking scales. Each subject underwent two investigations, one week apart from each other, with clonidine doses of 1.5 or 3.0microg/kg, administered intravenously in a random order and double-blinded. We applied a total number of seven blocks, each consisting of 60 painful stimuli, with one adaptation block, one pre-medication block, four post-medication blocks and one recovery block at the end of the session. MEG data were analysed by dipole reconstruction using CURRY(R) (Neuroscan, Hamburg) software package. Cortical activity in the contralateral SII cortex appeared with peak latencies of 118.5+/-10ms. This activity was significantly reduced by clonidine, in parallel with a reduction of pain intensity and enhancement of subjective tiredness and passiveness. There was, however, no significant correlation between MEG and subjective effects. Although both clonidine doses had similar effects, the higher dose induced longer changes. Results indicate that intravenous clonidine is able to relieve pain, but the exact mechanism of clonidine at the level of the SII cortex remains unclear. It is possible that clonidine interacts with the brainstem ascending system regulating vigilance and arousal which would explain the observed decrement of pain induced activity in SII. An additional more specific analgesic action at spinal level cannot be excluded.

Pollen-mediated gene flow and seed exchange in small-scale Zambian maize farming, implications for biosafety assessment.

Gene flow in agricultural crops is important for risk assessment of genetically modified (GM) crops, particularly in countries with a large informal agricultural sector of subsistence cultivation. We present a pollen flow model for maize (Zea mays), a major staple crop in Africa. We use spatial properties of fields (size, position) in three small-scale maize farming communities in Zambia and estimate rates of cross-fertilisation between fields sown with different maize varieties (e.g. conventional and transgene). As an additional factor contributing to gene flow, we present data on seed saving and sharing among farmers that live in the same communities. Our results show that: i) maize fields were small and located in immediate vicinity of neighboring fields; ii) a majority of farmers saved and shared seed; iii) modeled rates of pollen-mediated gene flow showed extensive mixing of germplasm between fields and farms and iv) as a result, segregation of GM and non-GM varieties is not likely to be an option in these systems. We conclude that the overall genetic composition of maize, in this and similar agricultural contexts, will be strongly influenced both by self-organised ecological factors (pollen flow), and by socially mediated intervention (seed recycling and sharing).

A promoter polymorphism -945C>G in the connective tissue growth factor in heart failure patients with mechanical circulatory support: a new marker for bridge to recovery?

OBJECTIVES: Mechanical circulatory support (MCS) creates improvement of cardiac function in a small portion of patients with idiopathic dilated cardiomyopathy (iDCM). Among other factors, cardiomyocyte hypertrophy seems to represent an important prerequisite for MCS-related cardiac recovery. We have previously shown that connective tissue growth factor (CTGF) leads to adaptive cardiomyocyte hypertrophy associated with a protective cardiac function in transgenic mice. To test whether a functional genetic variant in the CTGF promoter impacts MCS-related cardiac recovery, three groups of iDCM patients with and without cardiac recovery on MCS were genotyped. METHODS: The CTGF promoter variant (c.-945C>G) was analysed in 314 patients with iDCM receiving medical treatment only (Group I). Forty-nine iDCM patients who were either weaned from MCS for more than 6 months (Group II; n=20) or bridged to cardiac transplantation (Group III: n=29) were also genotyped. Patients on MCS were followed up for at least 12 months. Clinical characteristics and outcome on MCS were correlated with the respective genotypes. RESULTS: The c.-945C>G allele frequencies in 314 iDCM patients (Group I) were similar to controls deposited in the HapMap database or those published in a recent study. There were no differences in allele prevalence between patients with mild to moderate iDCM (Group I) compared with patients with severe iDCM requiring MCS (Groups II and III). Intriguingly, 50% of patients who were weaned from MCS (Group II) were homozygous for the G allele compared with only 17.2% of patients included in Group III, which is a significant difference (P=0.03). CONCLUSIONS: Homozygosity of the promoter-activating G allele in the CTGF_c.-945C>G variant is overrepresented in patients with cardiac recovery on MCS when compared with iDCM patients without cardiac recovery. Further studies are needed to evaluate c.-945C>G as a genetic predictor for clinical outcome on MCS.

Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines.

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.