Kinetik des ruminalen in situ-Nährstoffabbaus von Grünlandaufwüchsen des Alpenraumes unterschiedlicher Vegetationsstadien sowie von Maissilagen und Heu: Ein Beitrag zur Weiterentwicklung der Rationsgestaltung für Milchkühe

Das alpenländische Grünlandfutter unterscheidet sich aufgrund der Standort- und Bewirtschaftungsverhältnisse sowie seiner Artenvielfalt nicht nur in Hinblick auf die chemische Zusammensetzung, sondern auch bezüglich des ruminalen Abbaus und damit des Futterwertes von den weidelgrasbetonten und oftmals in höherer Düngung stehenden Pflanzenbeständen der milderen Gunstlagen. Bei der Zusammenstellung einer dem genetischen Potential hochleistender Milchkühe angepassten Ration auf Basis von sehr heterogenem Grundfutter, wie es frisches Wiesenfutter darstellt, ist den sich mit dem Vegetationsstadium verändernden ruminalen Abbaueigenschaften durch Kombination mit geeigneten Konzentratfuttermitteln Rechnung zu tragen. Die vorliegende Arbeit wurde mit dem Ziel erstellt, mittels einer in situ-Methode den Einfluss des Vegetationsstadiums von Grünlandaufwüchsen des Alpenraumes auf Ausmaß und Geschwindigkeit des ruminalen Abbaus der Faserfraktionen und des Rohproteins zu untersuchen. Besonderes Augenmerk lag dabei auf dem synchronen Abbau von N- und energieliefernden Substanzen und der Möglichkeit einer Optimierung der Ration durch Kombination der Grünlandaufwüchse mit variierenden Mengen von Konzentratfuttermitteln unterschiedlicher Fermentationsgeschwindigkeiten. Des weiteren wurden Möglichkeiten zur Schätzung des ruminalen Rohproteinabbaus anhand von chemischer Fraktionierung des Rohproteins geprüft

A new protein evaluation system for horse feed from literature data

Few data on apparent pre-caecal digestibility (APCD) of crude protein (CP) and particularly amino acids (AA) are available from studies with horses. Protein bound in cell walls (i.e. neutral detergent insoluble CP (NDICP)) is unlikely to be decomposed by digestive enzymes in the small intestine. In contrast the corresponding analytical fraction of neutral detergent soluble CP (NDSCP) (NDSCP = CP-NDICP) is likely to be available for auto-enzymatic digestion. A literature analysis on the relationship between NDICP/NDSCP and pre-caecal indigestible/digestible CP was carried out. There was a strong positive relationship between NDICP and pre-caecal indigestible CP, which suggests that NDICP can be used to estimate the part of protein that is not available for digestion in the small intestine. There was also a correlation between NDSCP and pre-caecal digestible protein. The slope of the linear regression line between NDICP and pre-caecal digestible CP was 0.9, suggesting an APCD of NDSCP of 90 %. Thus pre-caecal digestible CP may be predicted by multiplying NDSCP by 0.9. Because the literature identifies a similar AA profile in NDICP and NDSCP within a given feed the presented concept may preliminarily be transferred to AA. The proposed system can at any time be adapted to the scientific progress without altering its structure. Such adaptations would be necessary particularly when new knowledge exist on the distribution of AA onto NDICP/NDSCP, the APCD of individual AA from NDSCP, and the impact of feed processing and chewing on particle sizes and protein digestibility

A new protein evaluation system for horse feed from literature data

Few data on apparent pre-caecal digestibility (APCD) of crude protein (CP) and particularly amino acids (AA) are available from studies with horses. Protein bound in cell walls (i.e. neutral detergent insoluble CP (NDICP)) is unlikely to be decomposed by digestive enzymes in the small intestine. In contrast the corresponding analytical fraction of neutral detergent soluble CP (NDSCP) (NDSCP = CP-NDICP) is likely to be available for auto-enzymatic digestion. A literature analysis on the relationship between NDICP/NDSCP and pre-caecal indigestible/digestible CP was carried out. There was a strong positive relationship between NDICP and pre-caecal indigestible CP, which suggests that NDICP can be used to estimate the part of protein that is not available for digestion in the small intestine. There was also a correlation between NDSCP and pre-caecal digestible protein. The slope of the linear regression line between NDICP and pre-caecal digestible CP was 0.9, suggesting an APCD of NDSCP of 90 %. Thus pre-caecal digestible CP may be predicted by multiplying NDSCP by 0.9. Because the literature identifies a similar AA profile in NDICP and NDSCP within a given feed the presented concept may preliminarily be transferred to AA. The proposed system can at any time be adapted to the scientific progress without altering its structure. Such adaptations would be necessary particularly when new knowledge exist on the distribution of AA onto NDICP/NDSCP, the APCD of individual AA from NDSCP, and the impact of feed processing and chewing on particle sizes and protein digestibility

Epifluorescence imaging of electrochemically Switchable Langmuir-Blodgett films of Nafion

Reforestation of riparian zones is increasingly practiced in many regions for purposes of biodiversity conservation, bank stabilisation, and improvement in water quality. This is in spite of the actual benefits of reforestation for recovering underlying soil properties and function remaining poorly understood. Here we compare remnant riparian rainforest, pasture and reforestation plantings aged 2-20 years in an Australian subtropical catchment on ferrosols to determine the extent to which reforestation restores key soil properties. Of the nine soil attributes measured (total nitrogen, nitrate and ammonium concentrations, net nitrification and ammonification rates, organic carbon, bulk density, fine root biomass and water infiltration rates), only infiltration rates were significantly lower in pasture than remnant riparian rainforest. Within reforestation plantings, bulk density decreased up to 1.4-fold and infiltration rates increased up to 60-fold with time post-reforestation. Our results suggest that the main outcome of belowground processes of early reforestation is the recovery of the soils' physical structure, with potential beneficial ecosystem services including reduced runoff, erosion and associated sediment and nutrient loads in waterways. We also demonstrate differential impacts of two commonly planted tree species on a subset of soil properties suggesting that preferential planting of select species could accelerate progress on specific restoration objectives

Global Prospective Safety Analysis of Rivaroxaban.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. OBJECTIVES: This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. METHODS: A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. RESULTS: Overall, 11,121 patients were included (mean age 70.5 ± 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient-years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). CONCLUSIONS: This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban-treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788)

Causes of death in patients with atrial fibrillation anticoagulated with rivaroxaban:a pooled analysis of XANTUS

Aims: Anticoagulation can prevent stroke and prolong lives in patients with atrial fibrillation (AF). However, anticoagulated patients with AF remain at risk of death. The aim of this study was to investigate the causes of death and factors associated with all-cause and cardiovascular death in the XANTUS population. Methods and results: Causes of death occurring within a year after rivaroxaban initiation in patients in the XANTUS programme studies were adjudicated by a central adjudication committee and classified following international guidance. Baseline characteristics associated with all-cause or cardiovascular death were identified. Of 11 040 patients, 187 (1.7%) died. Almost half of these deaths were due to cardiovascular causes other than bleeding (n = 82, 43.9%), particularly heart failure (n = 38, 20.3%) and sudden or unwitnessed death (n = 24, 12.8%). Fatal stroke (n = 8, 4.3%), which was classified as a type of cardiovascular death, and fatal bleeding (n = 17, 9.1%) were less common causes of death. Independent factors associated with all-cause or cardiovascular death included age, AF type, body mass index, left ventricular ejection fraction, hospitalization at baseline, rivaroxaban dose, and anaemia. Conclusion: The overall risk of death due to stroke or bleeding was low in XANTUS. Anticoagulated patients with AF remain at risk of death due to heart failure and sudden death. Potential interventions to reduce cardiovascular deaths in anticoagulated patients with AF require further investigation, e.g. early rhythm control therapy and AF ablation. Trial registration numbers: NCT01606995, NCT01750788, NCT0180000

Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary

In 2013, the European Heart Rhythm Association (EHRA) published a Practical Guide on the use of non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) (Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, European Heart Rhythm A. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-2106). The document received widespread interest, not only from cardiologists but also from neurologists, geriatricians, and general practitioners, as became evident from the distribution of > 350 000 copies of its pocket version (the EHRA Key Message Booklet) world-wide. Since 2013, numerous new studies have appeared on different aspects of NOAC therapy in AF patients. Therefore, EHRA updated the Practical Guide, including new information but also providing balanced guiding in the many areas where prospective data are still lacking. The outline of the original guide that addressed 15 clinical scenarios has been preserved, but all chapters have been rewritten. Main changes in the Update comprise a discussion on the definition of 'non-valvular AF' and eligibility for NOAC therapy, inclusion of finalized information on the recently approved edoxaban, tailored dosing information dependent on concomitant drugs, and/or clinical characteristics, an expanded chapter on neurologic scenarios (ischaemic stroke or intracranial haemorrhage under NOAC), an updated anticoagulation card and more specifics on start-up and follow-up issues. There are also many new flow charts, like on appropriate switching between anticoagulants (VKA to NOAC or vice versa), default scenarios for acute management of coronary interventions, step-down schemes for longterm combined antiplatelet-anticoagulant management in coronary heart disease, management of bleeding, and cardioversion under NOAC therapy. The Updated Guide is available in full in EP Europace (Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, HackeW, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, Advisors. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507), while additional resources can be found at the related ESC/EHRA website (www.NOACforAF.eu)

Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/−), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/− atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use

Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24 hours

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHRE) ≥ 24 hours and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared to no anticoagulation in these patients.METHODS: This secondary prespecified analysis of NOAH-AFNET 6 examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared to placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and ECG-diagnosed atrial fibrillation.RESULTS: AHRE ≥24 hours were present at baseline in 259/2389 patients enrolled in NOAH-AFNET 6 (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc score 4). Clinical characteristics were not different from patients with shorter AHRE. During a median follow-up of 1.8 years, the primary outcome occurred in 9/132 patients with AHRE ≥24 hours (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). AHRE duration did not interact with the efficacy (p-interaction = 0.65) or safety (p-interaction = 0.98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 hours developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; p &lt; 0.001).CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.</p

Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies

This thesis is focused on the development and characterization of Diels Alder hydrogels as injectable drug delivery system for the intraocular application of antibodies. Currently, hydrogels are already used for a number of different applications in ophthalmology. For instance, they are used as in situ gelling eye drops, soft contact lenses, intraocular lenses and adhesives for ocular wound repair or are investigated as vitreous substitutes and intravitreal drug delivery systems (Chapter 2). Although significant progress has been made in the field of soft contact lenses, in situ gelling eye drops and adhesives for ocular wound repair, many challenges remain to improve the safety and clinical performance of intraocularly applied hydrogels. More research is particularly needed to improve hydrogels as intravitreal drug delivery systems for the treatment of severe, vision-threatening diseases, such as age-related macular degeneration or proliferative diabetic retinopathy. There are a number of general requirements that intraocularly applied hydrogels must fulfill. Ideally, these hydrogels are injectable and offer sustained drug release over several weeks. So-called in situ gelling hydrogels, which are injected prior to gelation and form a semi-solid drug depot at the application site, offer such characteristics. After gelation the mechanical properties of the resulting hydrogel should be comparable to those of the environment in order to cause no foreign body sensation. Moreover, the hydrogel should be designed for simple and effective drug loading procedures, especially for proteins and antibodies. Therefore, suitable cross-linking processes are necessary to permit fast gelation without inactivating the entrapped proteins. Besides appropriate loading procedures, a complete, yet sustained release of still active drugs is of particular importance. One of the main challenges of hydrogels is the control of drug release over several weeks due to their high water content. After complete drug release, the hydrogel should degrade without releasing any toxic degradation product. Although, a multitude of polymers and cross-linking possibilities have already been tested, there is no product commercially available until today. Promising materials are chemically cross-linked PEG-based hydrogels. Due to their excellent biocompatibility they are used for several biomedical applications. As in situ gelling systems they can be easily injected by minimally invasive techniques and hold great promise as drug delivery systems. Nevertheless, most established cross-linking mechanisms are associated with significant disadvantages, such as the formation of potentially harmful radicals or unwanted side reactions with incorporated protein drugs. To overcome these limitations, new cross-linking reactions for PEG-based hydrogels have to be developed. Since the Diels-Alder reaction proceeds in water without any initiator or metal catalyst, it is considered as an effective and non-toxic cross-linking possibility (Chapter 3). For the hydrogel preparation, two complementary macromonomers were synthesized by functionalizing star-shaped PEG with furyl and maleimide groups. The influence of the macromonomer concentration, molecular weight and branching factor on gel characteristics, such as rheology and swelling behavior, were investigated. Surprisingly, the covalently cross-linked hydrogels dissolved within days to weeks. To investigate this unexpected degradation behavior of PEG-based Diels-Alder hydrogels in detail, further experiments were performed (Chapter 4). UV spectroscopy was used to analyze the hydrolytic stability of maleimide functionalized star-shaped PEG as a function of temperature and pH. Finally, molecular modeling studies of Diels-Alder and retro-Diels-Alder moieties were performed to investigate the influence of these reactions for the degradation process. Besides the degradability, the permeability of entrapped drugs, such as proteins or antibodies, is crucial for success or failure of the system. The mesh size or correlation length is an important parameter that characterizes the permeability. It is defined as “the average distance between consecutive cross-links” and indicates the maximum size of solutes that can pass through the gel network. In Chapter 5 swelling studies, rheology and low field NMR spectroscopy were used to calculate the mesh size of the prepared Diels-Alder hydrogels. The knowledge of the mesh size, in combination with the size of the entrapped molecule, allows the estimation of the drug release rate and the evaluation of the general suitability of the resulting hydrogels for controlled release of entrapped, therapeutic antibodies. As a proof of concept, fluorescein-labeled dextrans of different molecular weight were entrapped into the hydrogel and release studies were performed. Finally, the data of those in vitro studies were compared to theoretical predictions. However, slow gelation and comparatively fast degradation may limit the application of Diels-Alder hydrogels as injectable drug delivery systems. To overcome these limitations the macromonomers were modified with lysine and/or 6-aminohexanoic acid residues in order to increase the hydrolytic stability of maleimide and to double the number of reactive groups per macromonomer (Chapter 6). To prove the feasibility of the optimized Diels-Alder hydrogels as drug delivery systems, the gels were loaded with bevacizumab, a vascular endothelial growth factor-neutralizing antibody used in the treatment of age-related macular degeneration. Afterwards, the release profiles of the entrapped antibody were determined by fluorescence spectroscopy