Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.

Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.

Primary immunosuppressive TNI-based conditioning regimens in pediatric patients treated with haploidentical hematopoietic cell transplantation.

PURPOSE: This retrospective analysis aims to address the toxicity and efficacy of a modified total nodal irradiation (TNI)-based conditioning regimen before haploidentical hematopoietic cell transplantation (HCT) in pediatric patients. MATERIALS AND METHODS: Patient data including long-term follow-up were evaluated of 7 pediatric patients with malignant (n = 2) and non-malignant diseases (n = 5) who were treated by a primary TNI-based conditioning regimen. TNI was performed using anterior/posterior opposing fields. All patients received 7 Gy single-dose TNI combined with systemic agents followed by an infusion of peripheral blood stem cells (n = 7). All children had haploidentical family donors. RESULTS: Engraftment was reached in 6/7 children after a median time of 9.5 days; 1 child had primary graft failure but was successfully reconditioned shortly thereafter. After an average follow-up time of 103.5 months (range 8.8-138.5 months), event-free (EFS) and overall survival (OS) rates were 71.4% and 85.7%, respectively. One child with a non-malignant disease died 8.8 months after transplantation due to a relapse and a multiple organ failure. Follow-up data was available for 5/6 long-term survivors with a median follow-up (FU) of 106.2 months (range 54.5-138.5 months). Hypothyroidism and deficiency of sexual hormones was present in 3/5 patients each. Mean forced expiratory volume in 1 s (FEV1) after TNI was 71%; mean vital capacity (VC) was 78%. Growth failure (< 10th percentile) occurred in 2/5 patients (height) and 1/5 patient (weight). No secondary malignancies were reported. CONCLUSION: In this group of patients, a primary single-dose 7 Gy TNI-based conditioning regimen before HCT in pediatric patients allowed sustained engraftment combined with a tolerable toxicity profile leading to long-term OS/EFS. Late toxicity after a median FU of over 9 years includes growth failure, manageable hormonal deficiencies, and acceptable decrease in lung function.

Finite-Volume Spectrum of π

The ab initio understanding of hadronic three-body systems above threshold, such as exotic resonances or the baryon spectrum, requires the mapping of the finite-volume eigenvalue spectrum, produced in lattice QCD calculations, to the infinite volume. We present the first application of such a formalism to a physical system in form of three interacting positively charged pions. The results for the ground state energies agree with the available lattice QCD results by the NPLQCD collaboration at unphysical pion masses. Extrapolations to physical pion masses are performed using input from effective field theory. The excited energy spectrum is predicted. This demonstrates the feasibility to determine three-body amplitudes above threshold from lattice QCD, including resonance properties of axial mesons, exotics, and excited baryons.

Kaon Photoproduction and the Λ Decay Parameter α_{-}.

The weak decay parameter α_{-} of the Λ is an important quantity for the extraction of polarization observables in various experiments. Moreover, in combination with α_{+} from Λ[over ¯] decay it provides a measure for matter-antimatter asymmetry. The weak decay parameter also affects the decay parameters of the Ξ and Ω baryons and, in general, any quantity in which the polarization of the Λ is relevant. The recently reported value by the BESIII Collaboration of 0.750(9)(4) is significantly larger than the previous PDG value of 0.642(13) that had been accepted and used for over 40 years. In this work we make an independent estimate of α_{-}, using an extensive set of polarization data measured in kaon photoproduction in the baryon resonance region and constraints set by spin algebra. The obtained value is 0.721(6)(5). The result is corroborated by multiple statistical tests as well as a modern phenomenological model, showing that our new value yields the best description of the data in question. Our analysis supports the new BESIII finding that α_{-} is significantly larger than the previous PDG value. Any experimental quantity relying on the value of α_{-} should therefore be reconsidered.

Excess of exercise increases the risk of atrial fibrillation.

An interesting and still not well-understood example for old medical wisdom "Sola dosis facit venenum" is the increased prevalence of atrial fibrillation (AF) in athletes. Numerous studies have shown a fourfold to eightfold increased risk of AF in athletes compared to the normal population. Analysis of the existing data suggests a dose-dependent effect of exercise. Moderate exercise seems to have a protective effect and decreases the risk of AF, whereas excessive exercise seems to increase the risk of AF. The described cases illustrate clinical manifestations within the spectrum of AF in elderly athletes, that is, exercise-induced AF, vagal AF, chronic AF, and atrial flutter. As the arrhythmia worsened quality of life and exercise capacity in all patients, recovery of sinus rhythm was desired in all described cases. As the atrial disease was advanced on different levels, different treatment regimes were applied. Lifestyle modification and temporary anti-arrhythmic drug therapy could stabilize sinus rhythm in one patient, whereas others needed radiofrequency ablation to achieve a stable sinus rhythm. The patient with the most advanced atrial disease necessitated anti-arrhythmic drug therapy and another left atrial ablation. All described patients remained in sinus rhythm during the long-term follow-up.

Two-Flavor Simulations of ρ(770) and the Role of the KK[over ¯] Channel.

The ρ(770) meson is the most extensively studied resonance in lattice QCD simulations in two (N_{f}=2) and three (N_{f}=2+1) flavor formulations. We analyze N_{f}=2 lattice scattering data using unitarized chiral perturbation theory, allowing not only for the extrapolation in mass but also in flavor, N_{f}=2→N_{f}=2+1. The flavor extrapolation requires information from a global fit to ππ and πK phase shifts from experiment. While the chiral extrapolation of N_{f}=2 lattice data leads to masses of the ρ(770) meson far below the experimental one, we find that the missing KK[over ¯] channel is able to explain this discrepancy.

Antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia.

Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (n = 1) and itraconazole (n = 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (n = 4) and itraconazole (n = 5) groups compared to patients receiving posaconazole (n = 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.

Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation.

Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4%) and three in the voriconazole group (6%). The percentage of patients with adverse events potentially related to clinical drugs were 14% in the voriconazole group, 12% in the itraconazole group, and 8% in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.

[Cement-free and cemented Excia hip shaft prosthesis: comparison of intermediate term results]. / Zementfreie und zementierte Excia-Hüftprothesenschäfte: Vergleich der mittelfristigen Ergebnisse.

AIM OF THE STUDY: For fixation of total hip prostheses, cemented and cement-free techniques are available. Normally, anchoring techniques and the definitive endoprosthesis model are determined preoperatively based on the available information, such as the quality of bone. Some newer endoprosthesis models utilize the same instruments for both implantation techniques. In this way it is possible to decide on the final anchoring technique intraoperatively. Because such a combined endoprosthesis system has been used in our clinic for 10 years, we were interested in the clinical results at the intermediate stage. MATERIAL AND METHODS: In a prospective, non-randomized study 105 pairs from a continuing series were formed from 105 cases treated with cement-free prostheses and the latest cemented shaft implants from the same year. In this way a total of 210 hip shaft endoprostheses from the years 2002 to 2006 were included in the study. After an average time period of 6.3 years (range 4.5-8.2 years) the patients were recalled for a follow-up examination. The clinical results, early and late complications were analyzed. The immediately postoperative X-ray images and those from the follow-up examination were evaluated by an independent external expert with respect to primary positioning, migration and any signs of loosening. RESULTS: At the follow-up examination at an average of 6.3 years the quota was 73%. The indications for cement-free/cemented total hip endoprosthesis were: primary arthritis 87%/98%, secondary arthritis 10%/2% and others 3%/0%. At the time of the last follow-up examination 4 and 14 patients, respectively, had died. The visual analog scale (VAS) for pain was given as 0.72/0.78. The Harris hip score improved from 54/48 to 93/90 points. The implant-related survival rate was 99.5%. Due to a periprosthetic fracture one of the cemented shafts had to be removed. Luxation occurred in 3/2 cases, respectively, of which 4 could be conservatively treated. In one cement-free case a head elongation and a change to an inlay with an anti-luxation shoulder was necessary. A fracture of the trochanter major was conservatively treated and an intraoperative shaft fissure was stabilized with wire cerclage and titan banding. The radiological evaluation showed no implant loosening or statistically significant differences in the shaft positioning. DISCUSSION: Short and intermediate clinical and radiological results showed no differences in patients of similar average age in the sixth decade of life. The significant improvements in the Harris hip score and the range of movement could be confirmed in the intermediate term and are comparable to other current implants. It can be concluded that an intraoperative decision on the fixation technique based on the macroscopically visible bone quality supports the reliably good results of both methods.

Evaluation of the right heart using cardiovascular magnetic resonance imaging in patients with cardiac devices.

BACKGROUND: Patients with cardiac implantable electronic devices (CIED) necessitate comprehensive cardiovascular magnetic resonance (CMR) examinations. The aim of this study was to provide data on CMR image quality and feasibility of functional assessment of the right heart in patients with CIED depending on the device type and imaging sequence used. METHODS: 120 CIED carriers (Insertable cardiac monitoring system, n = 13; implantable loop-recorder, n = 22; pacemaker, n = 30; implantable cardioverter-defibrillator (ICD), n = 43; and cardiac resynchronization therapy defibrillator (CRT-D), n = 12) underwent clinically indicated CMR imaging using a 1.5 T. CMR protocols consisted of cine imaging and myocardial tissue characterization including T1-and T2-weighted blackblood imaging and late gadolinium enhancement (LGE) imaging. Image quality was evaluated with regard to device-related imaging artifacts per right-ventricular (RV) segment. RESULTS: RV segmental evaluability was influenced by the device type and CMR imaging sequence: Cine steady-state-free-precision (SSFP) imaging was found to be non-diagnostic in patients with ICD/CRT-D and implantable loop recorders; a significant improvement of image quality was achieved when using cine turbo-field-echo (TFE) sequences with a further improvement on post-contrast TFE imaging. LGE scans were artifact-free in at least 91% of RV segments with best results in patients with a pacemaker or an insertable cardiac monitoring system. CONCLUSIONS: In patients with CIED, artifact-free CMR imaging of the right ventricle was performed in the majority of patients and resulted in highly reproducible evaluability of RV functional parameters. This finding is of particular importance for the diagnosis and follow-up of right-ventricular diseases.

Poly (Butyl Acrylate)-Graft-Polystyrene Synthesis by Free-Radical Polymerization: Interplay between Structure, Morphology, Mechanical, and Optical Properties.

We report a new method of preparation of poly (butyl acrylate)-g-polystyrene/polystyrene blends by free-radical polymerization. Copolymerization of glycidyl (meth)acrylate with butyl acrylate is followed by a polymer analogous reaction of this copolymer with acrylic acid and subsequent copolymerization of the modified backbone with styrene. Investigation on the number of reactive groups per backbone chain and its molecular weight allows grafting efficiencies of about 35% to be reached, as well as low cross-linking. Blends of nanophase-separated copolymers having a backbone with Mn of around 50 kg/mol and 4 reactive groups per chain are transparent, with haze as low as 14%, tensile strength of around 22 MPa, and elongations at the break of around 3%. Correlation between morphology determined by transmission electron microscopy and properties of the blend is established.

[Brachytherapy of the prostate cancer]. / Brachytherapie des Prostatakarzinoms.

Prostate cancer (PCA) is the most frequent onlocological disease in men. Every year there are ca. 202.000 new cases of prostate cancer in Europe. Curative treatment of this carcinoma via brachytherapy is becoming increasingly significant (20-30% of all curative approaches). Initial staging and thus allocation to risk groups prior to the commencement of therapy is esspecially important for successful brachytherapy treatment.Low-dose-rate (LDR) brachytherapy (i.e. SEED implantation) distinguishes itself both with respect to the procedure as well as the indication from high-dose-rate brachytherapy (afterloading procedure). Both treatment procedures are employed as monotherapy as well as in combination with external radiation.LDR monotherapy is reported to achieve biochemically relapse-free outcome of up to 90% in low-risk tumours during 10-year follow-up periods. Combined HDR tele- and brachytherapy is reported to achieve a biochemically relapse-free outcome of 80-90% with intermediate- and high-risk tumours in long-term follow-up.While randomized studies are as yet missing, it is still possible to derive the following application algorithms from monitoring studies and cohort studies: application of LDR monobrachytherapy must be restricted to low-risk tumorus. Combined HDR tele- and brachytherapy can be sucessfully applied in cases of intermediate- and high-risk tumours. The outcome depends significantly on the initial, pre-therapy PSA value and Gleason score. Posttherapeutically, the nadir value is crucial with respect to predicting the biochemically relapse-free outcome.

Structured pain management reduces patient discomfort after catheter ablation and rhythm device surgery.

BACKGROUND: The goal was to test the effectiveness of a structured pain management programme after invasive electrophysiological interventions in cardiology including ablation of atrial fibrillation (AF) or ventricular tachycardia (VT) and implantation, or explantation, of pacemakers or implantable cardioverter defibrillators. METHODS: This was a prospective study with a pre-/post-design where a post-intervention group (116 consecutive patients) was compared to a pre-intervention group (102 consecutive patients) after implementation of a structured pain-management programme using the numeric rating scale (NRS 0-10) and classified as moderate-to-severe if NRS > 3. Measurements were recorded every two hours during the first 24 h post-operatively. The location of the pain and the amount of analgesic used were also recorded. RESULTS: The proportion of patients who experienced moderate-to-severe pain after the procedure decreased after initiation of the pain-management program: 47% versus 61%; p = 0.048. This difference was driven primarily by reduced pain late (8-24 h) after the procedure; 16% versus 39%; p < 0.001. The risk to develop late (8-24 h) post-procedural pain was reduced approximately three-fold after implementation of the pain-management programme (OR = 0.32, 95% CI 0.16-0.64, p = 0.001). Multivariate analysis indicated chronic pain, early pain (0-6 h), and type of intervention were associated with late post-interventional pain. In contrast, age, diabetes mellitus, BMI, gender and procedure time were not related. CONCLUSION: The findings illustrate the potential value of a structured pain-management programme. The proportion of patients who experienced moderate-to-severe pain after these electrophysiological procedures decreased significantly. SIGNIFICANCE: This is the first exploratory study that evaluates the impact of a multidisciplinary pain-management programme after cardiac electrophysiological interventions. It demonstrates that significant quality improvement is achievable following simple rules together with patient and staff education. The programme reduces the proportion of patients with moderate-to-severe pain after electrophysiological procedures significantly.

The Global Genome Biodiversity Network (GGBN) Data Standard specification.

Genomic samples of non-model organisms are becoming increasingly important in a broad range of studies from developmental biology, biodiversity analyses, to conservation. Genomic sample definition, description, quality, voucher information and metadata all need to be digitized and disseminated across scientific communities. This information needs to be concise and consistent in today's ever-increasing bioinformatic era, for complementary data aggregators to easily map databases to one another. In order to facilitate exchange of information on genomic samples and their derived data, the Global Genome Biodiversity Network (GGBN) Data Standard is intended to provide a platform based on a documented agreement to promote the efficient sharing and usage of genomic sample material and associated specimen information in a consistent way. The new data standard presented here build upon existing standards commonly used within the community extending them with the capability to exchange data on tissue, environmental and DNA sample as well as sequences. The GGBN Data Standard will reveal and democratize the hidden contents of biodiversity biobanks, for the convenience of everyone in the wider biobanking community. Technical tools exist for data providers to easily map their databases to the standard.Database URL: http://terms.tdwg.org/wiki/GGBN_Data_Standard.

Accurate high-speed liquid handling of very small biological samples.

Molecular biology techniques require the accurate pipetting of buffers and solutions with volumes in the microliter range. Traditionally, hand-held pipetting devices are used to fulfill these requirements, but many laboratories have also introduced robotic workstations for the handling of liquids. Piston-operated pumps are commonly used in manually as well as automatically operated pipettors. These devices cannot meet the demands for extremely accurate pipetting of very small volumes at the high speed that would be necessary for certain applications (e.g., in sequencing projects with high throughput). In this paper we describe a technique for the accurate microdispensation of biochemically relevant solutions and suspensions with the aid of a piezoelectric transducer. It is suitable for liquids of a viscosity between 0.5 and 500 milliPascals. The obtainable drop sizes range from 5 picoliters to a few nanoliters with up to 10,000 drops per second. Liquids can be dispensed in single or accumulated drops to handle a wide volume range. The system proved to be excellently suitable for the handling of biological samples. It did not show any detectable negative impact on the biological function of dissolved or suspended molecules or particles.

Stereoselective synthesis of 2-alkylidene-3-iminoindoles by reaction of 1,1-dianions with oxalic acid bis(imidoyl) chlorides

Treatment of dilithiated nitriles and sulfones with oxalic acid bis(imidoyl) chlorides resulted in a new cyclization reaction which provided a variety of (3-imino-2, 3-dihydro-1H-indol-2-ylidene)acetonitriles and -sulfones in good yields. The reactions proceeded by condensation of the dianions with the first imidoyl chloride group of the bis(imidoyl) chloride, subsequent intramolecular attack of the ortho carbon of the arylimino group onto the second imidoyl chloride group, and final aromatization. Excellent stereoselectivities were observed in most cases.

[The mutagenicity of Cordemcura]. / Untersuchung zur Mutagenität von Cordemcura.

The mutagenic potential of Cordemcura was investigated. Cordemcura showed no mutagenic response in the tests, either in the presence or in the absence of an activation system.

Synthesis of cyclic carbonates from epoxides and carbon dioxide catalyzed by an easy-to-handle ionic iron(III) complex.

We report the successful utilization of monometallic, ionic iron(II)- and iron(III)-N2O2-ligand-systems as highly active homogeneous catalysts for the conversion of CO2 with different epoxides to cyclic carbonates. The catalytic tests were performed using propylene oxide (PO) and a range of nine substituted epoxides. Terminal monosubstituted oxides react quantitatively.