The Freedom SOLO bovine pericardial stentless valve

Abstract: The third-generation bovine pericardium Freedom SOLO (FS) stentless valve emerged in 2004 as a modified version of the Pericarbon Freedom stentless valve and as a very attractive alternative to stented bioprostheses. The design, choice of tissue, and anticalcification treatment fulfill most, if not all, requirements for an ideal valve substitute. The FS combines the single-suture, subcoronary implantation technique with the latest-generation bovine pericardial tissue and novel anticalcification treatment. The design allows imitation of the native healthy valve through unrestricted adaption to the patient's anatomy, reproducing a normal valve/root complex. However, despite hemodynamic performance superior to stented valves, we are approaching a critical observation period as superior durability, freedom from structural valve deterioration, and nonstructural failure has not been proven as expected. However, optimal performance and freedom from structural valve deterioration depend on correct sizing and perfect symmetric implantation, to ensure low leaflet stress. Any malpositioning can lead to tissue fatigue over time. Furthermore, the potential for better outcomes depends on optimal patient selection and observance of the limitations for the use of stentless valves, particularly for the FS. Clearly, stentless valve implantation techniques are less reproducible and standardized, and require surgeon-dependent experience and skill. Regardless of whether or not stentless valve durability surpasses third-generation stented bioprostheses, they will continue to play a role in the surgical repertoire. This review intends to help practitioners avoid pitfalls, observe limitations, and improve patient selection for optimal long-term outcome with the attractive FS stentless valve.

Kinetics and kinematics of the tölt: effects of rider interaction and shoeing manipulations

Introduction . Compared to most equine horse breeds which are able to walk, trot and canter /gallop, the gait repertoire of the Icelandic horses additionally includes the lateral gait tölt and frequently also the pace. With respect to the tölt gait, special shoeing, saddling and riding techniques have been developed for Icelandic horses in order to enhance its expressiveness and regularity. Toes are left unnaturally long and heavy shoes and paddings, as well as weighted boots are used to enforce the individual gait predisposition. For the same reason, the rider is placed more caudally to the horse's centre of mass as compared to other riding techniques. The biomechanical impact of these methods on the health of the locomotor system has so far never been subject of systematic research. Objectives . The aims of the presented study are (1) to describe the kinetic and kinematic characteristics of the tölt performed on a treadmill, (2) to understand the mechanical consequences of shoeing manipulation (long hooves, weighted boots) on the loading and protraction movement of the limbs, as well as (3) to study the pressure distribution and effects on the gait pattern of 3 different saddle types used for riding Icelandic horses. Materials and methods . Gait analysis was carried out in 13 Icelandic horses at walk and at slow and medium tölting and trotting speeds on a high-speed treadmill instrumented for measuring vertical ground reaction forces as well as temporal and spatial gait variables. Kinematic data of horse, rider and saddle were measured simultaneously. Gait analysis was first carried out with high, long hooves (SH) without and in combination with weighted boots (ad aim (2)). Afterwards, horses were re-shod according to current horseshoeing standards (SN) and gait analysis was repeated (ad aims (1) and (2)). In a second trial, horses were additionally equipped with a pressure sensitive saddle mat and were ridden with a dressage-like saddle (SDres), an Icelandic saddle (Slcel) and a saddle cushion (SCush) in the standard saddle position (ad aim 3). Results and conclusions . Compared to trot at the same speed, tölting horses had a higher stride rate and lower stride impulses. At the tölt loading of the forelimbs was increased in form of higher peak vertical forces (Fzpeak) due to shorter relative stance durations (StDrel). Conversely, in the hindlimbs, longer StDrel resulted in lower Fzpeak. Despite the higher head-neck position at tölt, there was no measurable shift in weight to the hindlimbs. Footfall rhythm was in most horses laterally coupled at the tölt and frequently had a slight fourbeat and a very short suspension phase at trot; underlining the fact that performance of correct gaits in Icelandic horses needs special training. Gait performance as it is currently judged in competition could be improved using a shoeing with SH, resulting in a 21 ± 5 mm longer dorsal hoof wall, but also a weight gain of 273 ± 50 g at the distal limb due to heavier shoeing material. Compared to SN, SH led to a lower stride rate, a longer stride length and a higher, but not wider, forelimb protraction arc, which were also positively associated with speed. At the tölt, the footfall rhythm showed less tendency to lateral couplets and at the trot, the suspension phase was longer. However, on the long term, SH may have negative implications for the health of the palmar structures of the distal foot by increased limb impulses, higher torques at breakover (up to 20%); as well as peak vertical forces at faster speeds. Compared to the shoeing style, the saddle type had less influence on limb forces or movements. The slight weight shift to the rear with SCush and Slcel may be explained by the more caudal position of the rider relative to the horse's back. With SCush, pressure was highest under the cranial part of the saddle, whereas the saddles with trees had more pressure under the caudal area.

Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system

The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure-activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.

Natural anti-FcepsilonRIalpha autoantibodies may interfere with diagnostic tests for autoimmune urticaria.

IgG autoantibodies against the alpha-chain of the high affinity IgE receptor are claimed to play a pathogenetic role in autoimmune urticaria. The best methods for detection of functional autoantibodies are currently the autologous serum skin test and the basophil histamine release assay. A simplified and feasible screening test would facilitate the diagnosis of autoimmune urticaria. Here we offer an explanation for the difficulties in establishing a screening test for autoantibodies directed against the alpha-chain of the high affinity IgE receptor in autoimmune urticaria. Identical autoantibodies in chronic urticaria patients and healthy donors belonging to the natural autoantibody repertoire were found by sequence analysis of anti-alpha-chain autoantibodies isolated by repertoire cloning from antibody libraries. These natural autoantibodies bound to the receptor and triggered histamine release but only if IgE was previously removed from the receptor. Diagnostic assays used for detection of antibodies directed against the IgE receptor may require signal comparison with and without the artificial removal of IgE, immune complexes, and complement in order to avoid false positive or negative results. After IgE removal diagnostic tests will detect natural autoantibodies against the high affinity IgE receptor regardless of whether they are pathogenic or not.

A highly conserved interspecies V(H) in the human genome.

Idiotype conservation between human and mouse antibodies has been observed in association with various infectious and autoimmune diseases. We have isolated a human anti-idiotypic antibody to a mouse monoclonal anti-IgE antibody (BSW17) suggesting a conserved interspecies idiotype associated with an anti-IgE response. To find the homologue of BSW17 in the human genome we applied the guided selection strategy. Combining V(H) of BSW17 with a human V(L) repertoire resulted in three light chains. The three V(L) chains were then combined with a human V(H) repertoire resulting in three clones specific for human IgE. Surprisingly, one clone, Hu41, had the same epitope specificity and functional in vitro activity as BSW17 and V(H) complementarity-determining regions identical with that of BSW17. Real-time PCR analysis confirmed the presence of the Hu41 V(H) sequence in the human genome. These data document the first example of the isolation of a human antibody where high sequence similarity to the original murine V(H) sequence is associated with common antigen and epitope specificity.

A high-affinity natural autoantibody from human cord blood defines a physiologically relevant epitope on the FcepsilonRIalpha.

Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the alpha domain of the high-affinity IgE receptor (FcepsilonRIalpha) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-FcepsilonRIalpha Abs are present in the germline repertoire, we constructed a phage Fab display library from human cord blood, which represents the naive immune repertoire before exposure to exogenous Ags. All isolated clones specific to the FcepsilonRIalpha had the same sequence. This single IgM Ab, named CBMalpha8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the FcepsilonRIalpha recognized by both CBMalpha8 and the previously isolated anti-FcepsilonRIalpha Abs from autoimmune and healthy donors. This common epitope on FcepsilonRIalpha coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBMalpha8-like specificity, but with a significantly lower affinity in i.v. Ig, a therapeutic multidonor IgG preparation. We propose a hypothesis of escape mutants, whereby the resulting lower affinity IgG anti-FcepsilonRIalpha Abs are rendered less likely to compete with IgE for binding to FcepsilonRIalpha.

Itineraries of pottery: a mixed methods approach to mobility

Neolithic wetland sites in the Swiss Plateau provide an extraordinary database for the study of mobilities, entanglements and transformations in material culture. Based on dendrochronologically dated settlements between 3900 and 3500 BC, two regional pottery styles and their local variations are well known, Pfyn and Cortaillod. The vessels share the same habitus and were made of local raw materials. However, some vessels specific to other pottery styles are also present in the sites. By focusing on itineraries of vessels and shifts in pottery knowledge, their appropriation in different contexts and the resulting material entanglements, we want to approach the multiple regimes of mobility: At Lake Constance - known for Pfyn pottery - specific Michelsberg vessels like tulip beakers and lugged jars occur in small numbers. These travelling objects were produced with exogenous raw materials and transported to the sites from Southern Germany. At Concise (Lake Neuchâtel) besides the local Cortaillod pottery the whole repertoire of NMB pottery, characteristic for Eastern France, was also produced. Further cases from the same space-time frame point to other regimes of mobility. In our two PhD-projects we compare pottery practices - styles, techniques, raw materials - from over 20 key sites in the region. Based on Bourdieu’s reflexive anthropology, we apply different qualitative and quantitative archaeological and archaeometrical methods, thus striving for a deeper understanding of habitus and the transformative potential of moving people, objects and ideas on local and regional scales and related social contexts.

The ribosome as novel target for stress-induced small regulatory RNAs

Small non-protein-coding RNA (ncRNA) molecules represent major contributors to regulatory networks in controlling gene expression in a highly efficient manner. All of the recently discovered regulatory ncRNAs that act on translation (e.g. microRNAs, siRNAs or antisense RNAs) target the mRNA rather than the ribosome. To address the question, whether small ncRNA regulators exist that are capable of modulating the rate of protein production by directly interacting with the ribosome, we have analyzed the small ncRNA interactomes of ribosomes Deep-sequencing and subsequent bioinformatic analyses revealed thousands of putative ribosome-associated ncRNAs in various model organisms (1,2). For a subset of these ncRNA candidates we have gathered experimental evidence that they associate with ribosomes in a stress-dependent manner and are capable of regulating gene expression by fine-tuning the rate of protein biosynthesis (3,4). Many of the investigated ribosome-bound small ncRNA appear to be processing products from larger functional RNAs, such as tRNAs (2,3) or mRNAs (3). Post-transcriptional cleavage of RNA molecules to generate smaller fragments is a widespread mechanism that enlarges the structural and functional complexity of cellular RNomes. Our data reveal the ribosome as a target for small regulatory ncRNAs and demonstrate the existence of a yet unknown mechanism of translation regulation. Ribosome-associated ncRNAs (rancRNAs) are found in all domains of life and represent a prevalent but so far largely unexplored class of regulatory molecules (5). Future work on the small ncRNA interactomes of ribosomes in a variety of model systems will allow deeper insight into the conservation and functional repertoire of this emerging class of regulatory ncRNA molecules.

Diagnosing Organizational Identity Beliefs by Eliciting Complex, Multi-Modal Metaphors

The purpose of this article is to extend the organizational development diagnostics repertoire by advancing an approach that surfaces organizational identity beliefs through the elicitation of complex, multimodal metaphors by organizational members. We illustrate the use of such "Type IV" metaphors in a postmerger context, in which individuals sought to make sense of the implications of the merger process for the identity of their organization. This approach contributes to both constructive and discursive new organizational development approaches; and offers a multimodal way of researching organizational identity that goes beyond the dominant, mainly textual modality.

Overcoming Liability of Newness through Socialization : How Legitimation Strategies of a New Venture evolve

Liability of newness, the tendency of new ventures to die early after market entry, results from lacking legitimacy in their new cultural context and according failure to acquire resources. Based on a longitudinal case study on repeated resource acquisition attempts of a new venture, we found that overcoming liability of newness depended on the socialization of the new venture to the normative environment on which it depended on for resources. Over time and across repeated resource acquisition attempts, socialization - the process of learning the use of legitimate symbols and their culturally contingent meanings - enabled the new venture to become the skillful cultural operator on which legitimation and resource acquisition was contingent. From our data, 'Accumulating a repertoire of legitimate symbols' and 'Assimilating the evaluations of resource-holders' emerged as the two primary mechanisms for new venture socialization. The study's contributions to related literature and its broader theoretical implications are discussed

On the Dark Side of Therapies with Immunoglobulin Concentrates: The Adverse Events

Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.

The outer mucus layer hosts a distinct intestinal microbial niche

The overall composition of the mammalian intestinal microbiota varies between individuals: within each individual there are differences along the length of the intestinal tract related to host nutrition, intestinal motility and secretions. Mucus is a highly regenerative protective lubricant glycoprotein sheet secreted by host intestinal goblet cells; the inner mucus layer is nearly sterile. Here we show that the outer mucus of the large intestine forms a unique microbial niche with distinct communities, including bacteria without specialized mucolytic capability. Bacterial species present in the mucus show differential proliferation and resource utilization compared with the same species in the intestinal lumen, with high recovery of bioavailable iron and consumption of epithelial-derived carbon sources according to their genome-encoded metabolic repertoire. Functional competition for existence in this intimate layer is likely to be a major determinant of microbiota composition and microbial molecular exchange with the host.

The bilateral responsiveness between intestinal microbes and IgA

The immune system has developed strategies to maintain a homeostatic relationship with the resident microbiota. IgA is central in holding this relationship, as the most dominant immunoglobulin isotype at the mucosal surface of the intestine. Recent studies report a role for IgA in shaping the composition of the intestinal microbiota and exploit strategies to characterise IgA-binding bacteria for their inflammatory potential. We review these findings here, and place them in context of the current understanding of the range of microorganisms that contribute to the IgA repertoire and the pathways that determine the quality of the IgA response. We examine why only certain intestinal microbes are coated with IgA, and discuss how understanding the determinants of this specific responsiveness may provide insight into diseases associated with dysbiosis.

«Einige Zeit aufs Singen verwendet». Musik als Kernressource dörflicher Kultur am Beispiel des schweizerischen 18. Jahrhunderts

Dealing with popular music in premodern times historical research usually focuses on so called “Volksmusik”. But already in the 18th century researchers were disappointed to find only few traces of imaginary “traditional” music in Switzerland. They unfortunately overlooked that common people kept on with their own stubborn musical culture: Beginning with the Reformation the authorities encouraged the communities to employ schoolmasters who were able to teach music. Their goal was that everybody should be able to participate in liturgical music actively. Over generations even people with no special musical talent adopted their own repertoire of psalms plus techniques of reading music and polyphonic singing. Spontaneous choral singing evolved into a common everyday practice. The most ambitious and brightest teachers even taught instrumental lessons at home on their proper pianos and chamber organs or encouraged the villagers to build new prestigious organs in their churches. The financial burden of such instruments weighted heavily on the communities. Some of them received financial support from the government, albeit unwillingly because it was obvious to the rulers that the villages just wanted to overtop each other. Homemade music was the most important issue in the cultural life of most parishes. Rich communes spent a lot of money to win the best voices on-site for their church choirs. Belonging to an elitists’ singer association paved the way to the farmer-village’s highlevel sociability.

SFRP4 regulation of Wnt7a signaling and cellular proliferation in the endometrium

In the endometrium, hormonal effects on epithelial cells are often elicited through stromal hormone receptors via unknown paracrine mechanisms. Several lines of evidence support the hypothesis that Wnts participate in stromal-epithelial cell communication and thus mediate hormone action. Characterization of specific Wnt signaling components in the endometrium was performed using cellular localization studies and evaluating hormone effects in a rat model. Wnt7a was expressed in the luminal epithelium, whereas the extracellular Wnt modulator, SFRP4, was localized to the endometrial stroma. SFRP4 expression is significantly decreased in endometrial carcinoma and aberrant Wnt7a signaling has been shown to cause uterine defects and contribute to the onset of disease. The specific Fzds and SFRPs that bind Wnt7a and the particular signal transduction pathway each Wnt7a-Fzd pair activates have not been identified. Additionally, the function of Wnt7a and SFRP4 in the endometrium has not been addressed. A survey of all Wnt signaling proteins expressed in the endometrium was conducted and Fzd5 and Fzd10 were identified as two receptors capable of transducing the Wnt7a signal. Biologically active recombinant Wnt7a and SFRP4 proteins were purified for quantitative biochemical studies. In Ishikawa cells, Wnt7a binding to Fzd5 activated β-catenin/canonical Wnt signaling and increased cellular proliferation. Wnt7a signaling mediated by Fzd10 induced a non-canonical/JNK-responsive pathway. SFRP4 suppressed Wnt7a action in both an autocrine and paracrine manner. Treatment with SFRP4 protein and overexpression of SFRP4 inhibited endometrial cancer cell growth and induced apoptosis in vitro. A split-eGFP complementation assay was developed to visually detect Wnt7a-Fzd interactions and subsequent pathway activation in cells. By employing a unique ELISA-based protein-protein binding technique, it was demonstrated that Wnt7a binds to SFRP4 and Fzd5 with equal nanomolar affinity. The development of these novel biological tools could lead to a better understanding of Wnt-protein interactions and the identification of new modulators of Wnt signaling. This study supports a mechanism by which the nature of the Wnt7a signal in the endometrium is dependent upon the Fzd repertoire of the cell and can be regulated by SFRP4. The potential tumor suppressor function of SFRP4 suggests it may serve as a therapeutic target for endometrial carcinoma. ^