Use of Pre- and Intensified Postprocedural Physiotherapy in Patients with Symptomatic Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement Study (the 4P-TAVR Study).

BACKGROUND: Physiotherapy prior to open-heart surgery lowers the rate of pneumonia and length of the hospital stay. Pneumonia is a major contributor to short-term mortality following transcatheter aortic valve replacement (TAVR). Hence, we hypothesized that pre- and intensified postprocedural physiotherapy in patients undergoing TAVR might impact the net functional and clinical outcome. METHODS AND RESULTS: The 4P-TAVR study was a prospective, monocentric, randomized trial. The study was designed to compare the efficacy and safety of intensified periprocedural physiotherapy including inspiratory muscle training versus standard postprocedural physiotherapy. Patients were randomized in a 1 : 1 fashion. 108 patients were included and followed up for 90 days after TAVR. While patients in group A (control group: 50 patients, age: 81.7 ± 5.0 years, 52% male) did not receive physiotherapy prior to TAVR, group B (intervention group: 58 patients, age: 82.2 ± 5.82 years, 47% male) participated in intensive physiotherapy. Compared to the control group, patients in the interventional group showed a lower incidence of postinterventional pneumonia (10 [20.0%] vs. 3 [5.1%], p=0.016) and had a 3-day shorter mean hospital stay (13.5 ± 6.1 days vs. 10.1 ± 4.7 days, p=0.02). The primary composite endpoint of mortality and rehospitalization was not different between the groups. CONCLUSION: Intensified physiotherapy is safe and has positive effects on clinical outcomes up to 90 days after TAVR but has no impact on the primary combined endpoint of mortality and rehospitalization. Longer follow-up, a multicenter design, and a higher number of subjects are needed to confirm these preliminary results. This trial is registered with DRKS00017239.

Survey of antimicrobial susceptibility of bacterial pathogens isolated from dogs and cats with respiratory tract infections in Europe: ComPath results.

AIMS: To present antimicrobial susceptibilities for bacteria from dogs and cats with respiratory tract infection (RTI) across Europe in 2013-2014 and compare with data from 2008-2010. METHODS AND RESULTS: Minimal inhibitory concentrations were determined for 464 isolates following Clinical and Laboratory Standards Institute standards using antibiotics approved for RTI treatment. Where possible, susceptibility was calculated using predominantly human-derived breakpoints whilst some antibiotics had no breakpoints. The main pathogen from dogs was Staphylococcus pseudintermedius which was > 90% susceptible to fluoroquinolones and oxacillin (92·5%; six isolates confirmed mecA-positive) and 53·8, 80·0 and 88·8% susceptible to tetracycline, penicillin and trimethoprim/sulfamethoxazole. Streptococci, Escherichia coli, Bordetella bronchiseptica, Staphylococcus aureus and Pseudomonas aeruginosa were also present in dog RTI. Streptococci were fully susceptible to penicillin, ampicillin and pradofloxacin. None were enrofloxacin-resistant but 31·4% had intermediate susceptibility. The least active agent against streptococci was tetracycline (51·4% susceptible). For E. coli, 90·9% were amoxicillin/clavulanic acid-susceptible; susceptibility to other compounds ranged from 63·6 to 81·8%. There are no breakpoints for B. bronchiseptica and Ps. aeruginosa. For Staph. aureus, penicillin susceptibility was low (34·8%); for other compounds 87·0-100%. The main RTI pathogen from cats was Pasteurella multocida, where only pradofloxacin has breakpoints (100% susceptible). Susceptibility of coagulase-negative staphylococci ranged from 66·7% (penicillin) to 97·2% (pradofloxacin). Streptococci from cats were 100% susceptible to all antibiotics except enrofloxacin and tetracycline (both 65·2% susceptible). CONCLUSIONS: Overall, antimicrobial resistance was low to medium in RTI in dogs and cats, although susceptibility varied widely among pathogens studied. SIGNIFICANCE AND IMPACT OF THE STUDY: Responsible use of antibiotics is crucial to maintain susceptibility and continued resistance monitoring is important to support this goal. These findings support the need for the setting of RTI-specific breakpoints for pathogens of dogs and cats.

Assessment of Brain Derived Neurotrophic Factor in hair to study stress responses: A pilot investigation.

To study pathogenic stress-effects in health and disease, it is paramount to define easy access parameters for non-invasive analysis of biological change in response to stress. Hair samples successfully provide this access for the study of hypothalamus-pituitary-adrenal axis (HPA) changes. In this study, we assess the hair expression and corresponding epigenetic changes of a neurotrophin essential for autonomic nervous system function and mental health: brain derived neurotrophic factor (BDNF). In three independent studies in healthy academic volunteers (study I: German students, N=36; study II, German academic population sample, N=28; study III: Mexican students, N=115), BDNF protein expression or BDNF gene (BDNF) histone acetylation was determined. Simultaneously, mental distress and distress-associated somatic complaints were assessed by self-report. In study I, we found a negative correlation between hair-BDNF protein level and hair-cortisol as well as between hair-BDNF and somatic complaints, while hair-cortisol correlated positively with mental distress. In study II, we found a negative correlation between H4 histone acetylation at the BDNF gene P4-promoter and somatic complaints. Regression analysis confirmed confounder stability of associations in both studies. In study III, we confirmed study I and found lower hair-BDNF protein level in volunteers with high somatic complaints, who also reported higher mental distress during the end of term exams. The results indicate that BDNF protein levels can be detected in clipped hair and are associated with somatic complaints and stress in life. In addition, we concluded that plucked hair can provide material for the study of epigenetic changes in stress-affected tissues. These tools can prove valuable for future studies on distress, both under experimental and field conditions.

Antimicrobial susceptibility monitoring of dermatological bacterial pathogens isolated from diseased dogs and cats across Europe (ComPath results).

AIMS: The ComPath project is a pan-European programme dedicated to the monitoring of antimicrobial susceptibility of pathogens from diseased dogs and cats using standardized methods and centralized minimum inhibitory concentration (MIC) determination. Here, the susceptibility of major pathogens is reported from antimicrobial nontreated animals with acute clinical signs of skin, wound or ear infections in 2008-2010. METHODS AND RESULTS: MICs were determined by agar dilution for commonly used antibiotics and interpreted using CLSI breakpoints, if available. Of the 1408 strains recovered, the main canine species was Staphylococcus pseudintermedius, followed by Pseudomonas and Streptococcus. In cats, Pasteurella multocida and Staph. pseudintermedius were most prevalent. For Staph. pseudintermedius, resistance was 18·4-25·2% for penicillin, clindamycin and chloramphenicol, but below 11% for ampicillin, amoxi/clav and fluoroquinolones. For Staphylococcus aureus, beta-lactam resistance was high (26·7-62·1%) but low (0·0-4·4%) for other antibiotics. 6·3% of Staph. pseudintermedius and 5·4% of Staph. aureus were confirmed mecA-positive. Gentamicin and fluoroquinolones exhibited moderate activity against Pseudomonas aeruginosa. For streptococci, resistance was absent/very low for penicillin, ampicillin, chloramphenicol and fluoroquinolones. For Escherichia coli, resistance was low to fluoroquinolones, chloramphenicol and gentamicin. No resistance was observed in Past. multocida. CONCLUSIONS: Overall, antimicrobial resistance was low in skin and soft tissue infections in dogs and cats. The results show the need for ongoing monitoring. SIGNIFICANCE AND IMPACT OF THE STUDY: The results are a reference baseline for future surveillance. The paucity of clinical breakpoints underlines the need to set breakpoints for relevant antibiotics.

Efficacy and tolerability of early administration of valnemulin hydrochloride premix on epizootic rabbit enteropathy.

A blinded, randomised, placebo-controlled clinical trial was conducted to evaluate the efficacy and safety of valnemulin hydrochloride premix during an outbreak of epizootic rabbit enteropathy (ERE) when administered in feed for 21 consecutive days after confirmation of the first ERE case. Administration of valnemulin at 20 and 35 parts per million (ppm) significantly reduced mortality by 11% and 7.6%, respectively, when compared with the non-medicated control group (23% mortality). Non-ERE related adverse events, including dysbacteriosis, enterotoxaemia and pneumonia, occurred in all groups at similar frequencies (untreated: 1.8%; 20 ppm valnemulin: 2.8%; 35 ppm valnemulin: 1.3%). Administration of valnemulin did not affect feed consumption or body weight gain; treated rabbits had sustained weight gain and feed conversion rates (FCRs). However, from days 7 to 21 of the outbreak, untreated rabbits had significantly lower daily weight gains and higher FCRs than medicated rabbits, suggesting a protective effect of valnemulin during the peak of the disease. Untreated rabbits exhibited compensatory growth from days 21 to 28, when the last observation was made. FCRs for the entire study were similar among all three groups. Impaction and diarrhoea were more frequent in untreated animals, with a poor prognosis, while tympanism was more common in valnemulin-treated rabbits that survived. In conclusion, early administration of valnemulin hydrochloride premix at 20 or 35 ppm is efficacious and safe for the treatment of naturally occurring ERE.

Pan-European resistance monitoring programmes encompassing food-borne bacteria and target pathogens of food-producing and companion animals.

Antimicrobial resistance is a concern both for animal and human health. Veterinary programmes monitoring resistance of animal and zoonotic pathogens are therefore essential. Various European countries have implemented national surveillance programmes, particularly for zoonotic and commensal bacteria, and the European Food Safety Authority (EFSA) is compiling the data. However, harmonisation is identified as a weakness and an essential need in order to compare data across countries. Comparisons of resistance monitoring data among national programmes are hampered by differences between programmes, such as sampling and testing methodology, and different epidemiological cut-off values or clinical breakpoints. Moreover, only very few valid data are available regarding target pathogens both of farm and companion animals. The European Animal Health Study Centre (CEESA) attempts to fill these gaps. The resistance monitoring programmes of CEESA have been a collaboration of veterinary pharmaceutical companies for over a decade and include two different projects: the European Antimicrobial Susceptibility Surveillance in Animals (EASSA) programme, which collects food-borne bacteria at slaughter from healthy animals, and the pathogen programmes that collect first-intention target pathogens from acutely diseased animals. The latter comprises three subprogrammes: VetPath; MycoPath; and ComPath. All CEESA projects include uniform sample collection and bacterial identification to species level in various European Union (EU) member states. A central laboratory conducts quantitative susceptibility testing to antimicrobial agents either important in human medicine or commonly used in veterinary medicine. This 'methodology harmonisation' allows easy comparisons among EU member states and makes the CEESA programmes invaluable to address food safety and antibiotic efficacy.

L-Proline transport into renal OK epithelial cells: a second renal proline transport system is induced by amino acid deprivation.

Influx of [(3)H]-L-proline into renal OK cells revealed that basal transport was mediated by the transporter SIT1. When cells were submitted for 8 h to amino acid deprivation, uptake of L-proline was now dominated by a low-affinity system with an apparent K (m) of 4.4 +/- 0.6 mM and a V (max) of 10.2 +/- 0.6 nmol/mg of protein/min operating in addition to the high-affinity SIT1 system with a K (m) of 0.12 +/- 0.01 mM and a V (max) of 0.28 +/- 0.04 nmol/mg of protein/min. The low- and high-affinity proline transporting systems were sensitive to inhibitors of JNK and PI-3 kinases, whereas a GSK-3 inhibitor affected only the upregulated transport system. Ion-replacement studies and experiments assessing substrate specificities for both systems provided strong evidence that SNAT2, that showed two- to threefold increased mRNA levels, is the responsible transporter mediating the increased proline influx under conditions of amino acid deprivation.

The activity and compatibility of the antibiotic tiamulin with other drugs in poultry medicine--A review.

Tiamulin hydrogen fumarate is a semisynthetic derivative of the diterpene antibiotic pleuromutilin used in poultry medicine to treat mainly Mycoplasma- and Brachyspira-related diseases. Its use over 30 yr has not generally increased the development of resistance to these pathogens but occasionally resistant isolates are encountered. Tiamulin administered at therapeutic levels is relatively quickly absorbed, metabolized in the liver, and eliminated from the body of the bird after a withdrawal period of 72 h, and as a result, meat products can be safely consumed. A zero withdrawal period for eggs has been granted in several European Union states. When administered with different drugs, tiamulin has been shown to have an enhanced activity with the tetracyclines. There is a strong interaction, even death, with the ionophore anticoccidials monensin, narasin, and salinomycin when tiamulin is used at therapeutic levels, but this is dose-related and low doses do not interact. It is thought to be caused by the preferential metabolism of tiamulin in the liver resulting in a build up of the ionophore leading to clinical signs of overdosage. Tiamulin shows a milder interaction, such as temporary growth depression, with maduramicin and semduramicin but is compatible with lasalocid. Although tiamulin shows small benefits in improving performance in healthy animals, its main production benefit is in the face of infection, as a true therapeutic antibiotic.

[Cyberstalking]. / Cyberstalking.

The term cyberstalking appears in the media with increasing frequency. So far epidemiological studies are sparse. Since researchers have used different definitions and study samples for cyberstalking, widely varying prevalence rates have been published. We report here a case of cyberstalking and discuss available empirical data. Cyberstalking may cause psychological distress similar to that of real world stalking. The need for a scientific definition of cyberstalking and for future studies is presented. Since it is likely that psychiatrists will encounter victims of cyberstalking they should have knowledge of this phenomenon.

Compatibility of a combination of tiamulin and chlortetracycline with salinomycin in feed during a pulsed medication program coadministration in broilers.

In an earlier study, the continuous medication of broiler feed with a combination of tiamulin (TIA; 20 mg/kg), chlortetracycline (CTC; 60 mg/kg), and the ionophore anticoccidial salinomycin (SAL; 60 mg/kg) caused an initial increase in BW and feed efficiency (FE; g of weight gain/kg of feed intake). However, as doses increased to combinations of 30 mg/kg of TIA and 90 mg/kg of CTC or 50 mg/kg of TIA and 150 mg/kg of CTC, there was a dose-related reduction in growth rate and FE. This was thought to be due to the interaction between TIA and SAL. In this study, using a protocol similar to the previous trial, broiler chicks were administered SAL at 60 mg/kg via the feed and the same inclusion rates of TIA + CTC. However, instead of feeding the birds continuously, considering the cost of TIA and possibly to compensate for the depressed growth attributable to the interaction with SAL, they were pulse-dosed for 1 to 10 d and again at 21 to 27 d, and the whole trial lasted 35 d to see if the intermittent pulses might reduce production losses. A total of 200 straight-run 1-d-old broiler chicks (Hubbard classic) were randomly distributed into 4 groups, with each group consisting of 5 cages containing 10 birds. The 20 cages were allocated to the 4 treatment groups on a random basis. The control diet, containing only SAL at 60 mg/kg, was fed to all birds throughout the 35-d trial, including the period during the gaps between dosing (i.e., d 11 to 20 and d 28 to 35). Feed and water were available for the whole trial period. Several serum enzymes (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase) were determined from blood samples taken on d 35. Blood samples were also collected at 1, 19, and 35 d of age and were examined for antibody titers to Mycoplasma gallisepticum and Mycoplasma synoviae. Necropsy and histopathology of the birds (n = >or=4) were conducted during weekly intervals. There was no significant difference in weight gain, feed intake, and FE when the groups treated with TIA + CTC were compared with the control group (P > 0.05). There was no relationship between mortality and inclusion rates of the medication. No clinical signs of an interaction were exhibited during the trial, which was supported by necropsy and serum enzyme results. Maternally derived antibodies against M. gallisepticum were identified at the start of the trial but disappeared within 19 d, and infection with M. gallisepticum or M. synoviae was found neither serologically nor clinically during the trial. The results demonstrated that intermittent pulse administration of TIA at 50 mg/kg + CTC at 150 mg/kg from d 1 to 10 and d 21 to 27, along with continuous feeding of SAL (60 mg/kg), would be possible without altering performance and while maintaining the health status of the broilers. However, further research is required on the presence of artificial infections with Mycoplasma pathogens to determine the efficacy of the combination of TIA +CTC.

Lack of CD56 expression on myeloma cells is not a marker for poor prognosis in patients treated by high-dose chemotherapy and is associated with translocation t(11;14).

Lack of CD56 expression was reported to be associated with a poor prognosis in multiple myeloma (MM) patients treated with conventional chemotherapy. Aim of our retrospective study was to analyse whether CD56 expression on MM cells reveals as a prognostic factor in patients treated with high-dose chemotherapy. MM cells of 99 patients prior to treatment with high-dose chemotherapy were analysed for CD56 expression by flow cytometry. Multivariable analysis of event-free survival in these patients showed no statistically significant difference between the CD56(-) (n=28) and the CD56(+) (n=71) group. The lack of CD56 expression on MM cells of these patients correlated significantly with the presence of translocation (11;14) (t(11;14)) (estimated correlation coefficient=0.655 95%, confidence interval (0.481; 0.779)). In summary, our results indicate that lack of CD56 expression on MM cells is not a prognostic marker in patients treated with high-dose chemotherapy, but is associated with t(11;14).

Aptamer-based isolation and subsequent imaging of mesenchymal stem cells in ischemic myocard by magnetic resonance imaging.

PURPOSE: Mesenchymal stem cells (MSC) seem to be a promising cell source for cellular cardiomyoplasty. We recently developed a new aptamer-based specific selection of MSC to provide "ready to transplant" cells directly after isolation. We evaluated MRI tracking of newly isolated and freshly transplanted MSC in the heart using one short ex vivo selection step combining specific aptamer-based isolation and labeling of the cells. MATERIALS AND METHODS: Bone marrow (BM) was collected from healthy pigs. The animals were euthanized and the heart was placed in a perfusion model. During cold ischemia, immunomagnetic isolation of MSC from the BM by MSC-specific aptamers labeled with Dynabeads was performed within 2 h. For histological identification the cells were additionally stained with PKH26. Approx. 3 x 10(6) of the freshly aptamer-isolated cells were injected into the ramus interventricularis anterior (RIVA) and 5 x 10(5) cells were injected directly into myocardial tissue after damaging the respective area by freezing (cryo-scar). 3 x 10(6) of the aptamer-isolated cells were kept for further characterization (FACS and differentiation assays). 20 h after cell transplantation, MRI of the heart using a clinical 3.0 Tesla whole body scanner (Magnetom Trio, Siemens, Germany) was performed followed by histological examinations. RESULTS: The average yield of sorted cells from 120 ml BM was 7 x 10(6) cells. The cells were cultured and showed MSC-like properties. MRI showed reproducible artifacts within the RIVA-perfusion area and the cryo-scar with surprisingly excellent quality. The histological examination of the biopsies showed PKH26-positive cells within the areas which were positive in the MRI in contrast to the control biopsies. CONCLUSION: Immunomagnetic separation of MSC by specific aptamers linked to magnetic particles is feasible, effective and combines a specific separation and labeling technique to a "one stop shop" strategy.

[Angioneurotic orolingual edema associated with the use of rt-PA following a stroke]. / Angioneurotisches orolinguales Odem nach rt-PA-Lyse eines Schlaganfalls.

Angioneurotic orolingual edema associated with the use of rt-PA (recombinant tissue plasminogen activator) for systemic thrombolysis are described in the literature, but only as isolated case reports. Strangely, the rate of anaphylactic reactions to rt-PA is higher (1.9%) when they are used in the treatment of acute stroke than when they are given to treat acute myocardial infarction (0.02%). Patients who are taking ACE inhibitors seem to be at increased risk of such a potentially life-threatening event. We now report on two patients, in each of whom asymmetric angioneurotic edema was observed following successful thrombolysis with rt-PA. Both these patients were taking ACE inhibitors. It was possible to avoid intubation and ventilation in both cases. Therapy with ranitidine, clemastine, and a C1 esterase inhibitor resulted in the resolution of symptomatic angioneurotic edema within hours.

[Emergency treatment of thoracic trauma]. / Erstversorgung bei Thoraxtrauma.

Thoracic trauma, most often associated with other serious injuries, is the main cause of death in the first 45 years of life. The percentage of chest injuries in multiple trauma, mainly from blunt impact, has remained relatively constant at 80% during the last 30 years. Isolated thoracic injuries comprise only 25% of all trauma cases, 90% of chest injuries are due to blunt impact, while penetrating injuries make up 5-10%. Since 25% of deaths from trauma are attributable to chest injuries, they determine the survival rate in multiple trauma to a significant extent. The pattern of chest injuries is variable, frequently in different combinations comprising rib cage and diaphragm, lung parenchyma, airway and mediastinal organs. This article details the immediate simultaneous diagnostic and therapeutic procedures in the prehospital phase, management in the emergency room, the relative importance of computed tomography, ultrasound examination and endoscopy in the primary diagnostic evaluation and the principles of anaesthetic management of thoracic trauma.

New insights into the phenotype and cell derivation of B cell chronic lymphocytic leukemia.

For many decades, B cell chronic lymphocytic leukemia (B-CLL) stood out as a B cell-derived malignancy that was difficult to position within the framework of the available B cell differentiation scheme: First, the histology as well as the immunophenotype did not quite resemble that of any normal lymphocyte; second, in contrast to almost all other B cell tumor subtypes, the immunoglobulin variable region (IgV) genes of B-CLL cases could be either unmutated or somatically mutated; third, the genomic lesions observed in B-CLL were markedly distinct from those of the other major B cell malignancies, which typically exhibit balanced chromosome translocations. Recent advances in the characterization of both B-CLL and normal B cell subpopulations by phenotypic analysis, global gene expression profiling, as well as extensive IgV gene repertoire analyses have shed new light on the phenotype and the cell derivation of B-CLL and provided novel hypotheses concerning its pathogenesis. Here we summarize recent work relevant to these issues and conclude that B-CLL may be derived from a cell that can be referred to as a marginal zone B cell. Moreover, we propose that the lack of chromosomal translocations in B-CLL may be related to their derivation from marginal zone B cells, since somatic hypermutation and Ig class switch, the processes that generate chromosome translocations in most germinal center (GC)-derived malignancies, are no longer active in marginal zone B cells. Also, we discuss similarities and differences between B-CLL and hairy cell leukemia (HCL) and suggest that also HCL may be derived from a post-GC memory or marginal zone B cell.

Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.

Conventional treatment or autologous transplantation has not been able to achieve long-term remission in patients with multiple myeloma (MM). Nonmyeloablative allogeneic transplantation might offer an option for cure without the high mortality associated with conventional conditioning. Here we present a retrospective analysis of patients with high-risk MM treated with nonmyeloablative allogeneic transplantation. In all, 52 patients with relapsed MM or high-risk features at diagnosis received 2 Gy TBI alone (n=3) or with fludarabine (n=49) as conditioning. Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. Regimen-related toxicity was low. Acute graft-versus-host disease II-IV occurred in 37% of patients, and 70% experienced chronic graft-versus-host disease (cGvHD). Median follow-up was 567 days, and transplant-related mortality was 17% in total. Estimated progression-free and overall survival at 18 months was 29.4 and 41.1%, respectively. Patients with cGvHD had a significantly higher progression-free survival, as did patients with up to eight cycles of pretreatment chemotherapy vs those with nine or more. In this highly pretreated patient group, disease control was unsatisfactory and our results suggest that a potential strategy might be to perform allogeneic transplant earlier in the course of the disease.

Detection and imaging of atmospheric radio flashes from cosmic ray air showers.

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.