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News Article | May 12, 2017

"Antimicrobial-resistant bacteria pose a complex challenge. This is why Germany, with its German Antimicrobial Resistance Strategy DART2020, is making sustained efforts to protect the health of humans and animals", says BfR President Professor Dr. Dr. Andreas Hensel. "In the spirit of the One Health strategy, this calls for interdisciplinary research by veterinarians and experts in human medicine as well as molecular biologists and epidemiologists, as successfully demonstrated by the RESET and MedVet-Staph network projects." Since 2010, these research networks have been investigating the development, spread and mechanisms of resistance to certain antibiotics in cases of Escherichia coli and Staphylococcus aureus in humans and animals. Alongside the BfR, numerous universities and scientific institutions in Germany are involved in the network projects. The RESET network investigates resistance to the particularly important antibiotic classes of cephalosporins and (fluoro)quinolones in intestinal bacteria such as Escherichia (E.) coli. Some strains of these bacteria can destroy cephalosporins. In this process, they use enzymes known as "extended-spectrum beta-lactamases" (ESBLs) and AmpC beta-lactamases (AmpCs). The strains can pass on this destructive capability to other bacteria. Analyses conducted in the RESET network have shown that ESBL- or AmpC-producing E. coli are widespread in livestock. These bacteria were detected in all investigated poultry-rearing businesses. They were also found in 85% of investigated pig production and dairy cattle businesses as well as in 70% of cattle production businesses. Moreover, E. coli and Salmonella that can additionally destroy carbapenems were found in livestock in Germany for the first time. These antibiotics are used in hospitals to treat infections with multi-resistant bacteria. The administration of antibiotics is not always responsible for the occurrence of resistant bacteria. E. coli that produce ESBLs or AmpCs also occur in groups of animals (in particular in broilers) that have had no contact with antibiotics. The bacteria and resistance genes can be transferred along the production chain and be transmitted to other foods in the kitchen. In studies, ESBL-E. coli were found in 6.3% of the healthy general population and with similar frequency among pig farmers. In German hospitals, the share of ESBL-positive E. coli and Klebsiellae among all hospital acquired infections with these enterobacteria increased from 11.9% to 15.4% between 2007 and 2012. Overall, the molecular biology analyses showed that various ESBL-forming bacteria possess the ability to be exchanged between humans, animals and their environment. Direct transmission of the bacteria with their resistance genes is evidently relatively seldom. Nevertheless, the resistance genes can be exchanged between different bacteria, and this makes it more difficult to trace them. It is therefore currently not possible to exactly assess the significance of livestock for the colonisation and infection of humans with ESBL- or AmpC-forming enterobacteria. RESET coordinator Professor Dr. Lothar Kreienbrock at the University of Veterinary Medicine Hannover says: "Our newly created joint database enables us to perform overarching analyses of both the data on the origin of samples from humans, animals, food and the environment as well as the data on the properties of the bacteria strains. Based on this joint strain and data collection, for example, we have succeeded for the first time in detecting the transmissible colistin resistance gene (mcr - 1) in E. coli from German livestock." He adds that the task now is therefore to further extend and consolidate these options developed together with the German Research Platform for Zoonoses and the TMF (technology and methodology platform for interconnected medical research) in the spirit of the One Health strategy. The MedVet-Staph network focuses on the importance of the transmission of antimicrobial-resistant staphylococci including the methicillin-resistant Staphylococcus aureus strains (MRSA) between animals and humans. MRSA colonises around 0.8% of healthy people in the general German population (mostly in the nasal or throat area). By comparing the genetic fingerprint, it is possible to distinguish livestock-associated MRSA types from MRSA typically found in hospital acquired infections. Network coordinator PD Dr. med. Robin Köck from the University of Münster says: "The findings of the MedVet-Staph network have underlined that the transmission path between animals and humans is something that it is essential to bear in mind if we want to understand the spread of MRSA. We have shown that in particular direct contact with MRSA-carrying livestock, as occurs with farmers or vets, constitutes a high risk for transmission. More than 80% of farmers involved in pig production carry the bacterium." MRSA is found with increasing frequency as a wound infection pathogen not only in livestock but increasingly also in horses, cats and dogs. The MRSA detected in these animals differs from the MRSA in livestock, however. During the course of the project, it was not only MRSA but also other bacteria that were detected in livestock and farmers - bacteria such as enterococci and coagulase-negative staphylococci, which are resistant to substances such as linezolid or daptomycin - which are used in human medicine as reserve antibiotics. Further research is therefore necessary on the occurrence of antimicrobial-resistant bacteria in livestock and food as well as in pets and the environment. The MedVet-Staph research network also investigated the extent to which livestock-associated MRSA can lead to disease in humans. The frequency of livestock-associated MRSA clones has increased overall in Germany, although there are marked regional differences: in individual regions with intensive livestock farming (in the northern region of North Rhine-Westphalia, for example), these bacteria are responsible for over 10% of severe MRSA infections in humans. However, not all cases of detection in humans can be attributed to direct contact with positive animals. The MedVet-Staph network proved that 38% of the people in rural regions colonised with livestock-associated MRSA types had no direct contact with livestock. It must therefore be assumed that the bacteria are also passed on via other routes (e.g. human to human). According to research findings of the BfR and from Denmark, there are similarities between MRSA from poultry meat, in particular turkey meat, and bacteria isolates from humans. This suggests that, in individual cases, livestock-associated MRSA can also be transmitted to humans via food. Experimental studies with broiler meat were conducted at the BfR in this regard. It was shown that the processing and preparation of contaminated food in domestic kitchens can result in the migration of MRSA and ESBL-forming E. coli to other foods which are then consumed by people without further heating. At the same time, however, the significance of this transmission path appears to be relatively minor. The RESET and MedVet-Staph research networks are funded by the Federal Ministry of Education and Research (BMBF) and are each made up of scientists from the fields of human and veterinary medicine, basic research and applied research. You can find more information (in German) about RESET and MedVet-Staph at

Loscher W.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience
Neuroscience and Biobehavioral Reviews | Year: 2010

Circling or rotational behavior is the most studied indicator of cerebral asymmetry in the rat. In humans, disturbances in cerebral asymmetry are involved in the etiology of several psychiatric disorders, including schizophrenia, Tourette syndrome and attention-deficit hyperactivity disorder. Abnormal rotational behavior in rodents is indicative of either an imbalance of forebrain dopamine systems, particularly an imbalance of nigrostriatal function, or an inner ear disease affecting the vestibular (balance) system. Abnormally enhanced circling behavior has been described in several mutant rat and mouse strains both with and without defects of the vestibular system. However, the relationship between vestibular defects and lateralized circling in rodents is only incompletely understood. In this review, we describe and discuss various spontaneous mutations associated with abnormal circling behavior in different rat strains and their potential relevance to model specific brain dysfunctions. The circling rat mutants described in this review illustrate how genetic animal models may serve to study multifaceted brain functions and dysfunctions, including disorders of the basal ganglia and vestibular system. © 2009 Elsevier Ltd. All rights reserved.

Kuerpick B.,University of Veterinary Medicine Hannover
Berliner und Münchener tierärztliche Wochenschrift | Year: 2012

The liver fluke Fasciola (F) hepatica is one of the most important trematodes in cattle farming worldwide. Fasciolosis in dairy cows is leading to production losses due to decreased milk yield, liver condemnation and impaired reproduction. The treatment of dairy cows is unsatisfactory, because available drugs are either effective against adult flukes only or have long withdrawal times or in some countries may not be used at all. In the present study the prevalence of F. hepatica in dairy farms located in East Frisia, which is part of the federal state Lower Saxony, was investigated. East Frisia is considered a high risk area for Fasciola hepatica infections, because of its coastal location, high precipitation and moist pastures. About 750 bulk milk samples were collected in January and November 2006 and analysed for F. hepatica antibodies using the Pourquier ELISA. In addition, questionnaires, which were answered by 260 of the participating farmers, were evaluated to analyse management-related factors associated with fasciolosis. In January and November, 52.1% and 53.6% of the bulk milk samples, respectively, showed positive results. Thereby, 88.1% of the examined farms showed an unchanged infection status, whereas 6.2% of the farms became seropositive during the grazing season and 5.8% of the dairy herds turned seronegative. Statistical analysis revealed a significant negative association between average annual milk production and the frequency of infections with F. hepatica.

Loscher W.,University of Veterinary Medicine Hannover | Brandt C.,Center for Systems Neuroscience
Pharmacological Reviews | Year: 2010

Diverse brain insults, including traumatic brain injury, stroke, infections, tumors, neurodegenerative diseases, and prolonged acute symptomatic seizures, such as complex febrile seizures or status epilepticus (SE), can induce "epileptogenesis," a process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. Furthermore, epileptogenesis operates in cryptogenic causes of epilepsy. In view of the accumulating information about cellular and molecular mechanisms of epileptogenesis, it should be possible to intervene in this process before the onset of seizures and thereby either prevent the development of epilepsy in patients at risk or increase the potential for better long-term outcome, which constitutes a major clinical need. For identifying pharmacological interventions that prevent, interrupt or reverse the epileptogenic process in people at risk, two groups of animal models, kindling and SE-induced recurrent seizures, have been recommended as potentially useful tools. Furthermore, genetic rodent models of epileptogenesis are increasingly used in assessing antiepileptogenic treatments. Two approaches have been used in these different model categories: screening of clinically established antiepileptic drugs (AEDs) for antiepileptogenic or disease-modifying potential, and targeting the key causal mechanisms that underlie epileptogenesis. The first approach indicated that among various AEDs, topiramate, levetiracetam, carisbamate, and valproate may be the most promising. On the basis of these experimental findings, two ongoing clinical trials will address the antiepileptogenic potential of topiramate and levetiracetam in patients with traumatic brain injury, hopefully translating laboratory discoveries into successful therapies. The second approach has highlighted neurodegeneration, inflammation and up-regulation of immune responses, and neuronal hyperexcitability as potential targets for antiepileptogenesis or disease modification. This article reviews these areas of progress and discusses the challenges associated with discovery of antiepileptogenic therapies. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

Loscher W.,University of Veterinary Medicine Hannover | Schmidt D.,Epilepsy Research Group
Epilepsia | Year: 2011

Despite the development of various new antiepileptic drugs (AEDs) since the early 1990s, the available evidence indicates that the efficacy and tolerability of drug treatment of epilepsy has not substantially improved. What are the reasons for this apparent failure of modern AED development to discover drugs with higher efficacy? One reason is certainly the fact that, with few exceptions, all AEDs have been discovered by the same conventional animal models, particularly the maximal electroshock seizure test (MES) in rodents, which served as a critical gatekeeper. These tests have led to useful new AEDs, but obviously did not help developing AEDs with higher efficacy in as yet AED-resistant patients. This concern is not new but, surprisingly, has largely been unappreciated for several decades. A second-admittedly speculative-reason is that progress in pharmacologic treatment of drug-resistant epilepsy will not be made unless and until we develop drugs that specifically target the underlying disease. Although better preclinical approaches will not be able to circumvent regulatory requirements, more efficacious drugs may allow us to abandon clinically questionable trials with intentionally less efficacious controls and noninferiority designs, and require evidence for comparative effectiveness. The failure of AED development has led to increasing disappointment among clinicians, basic scientists, and industry and may halt any further improvement in the treatment of epilepsy unless we find ways out of this dilemma. Therefore, we need new concepts and fresh thinking about how to radically change and improve AED discovery and development. In this respect, the authors of this critical review will discuss several new ideas that may hopefully lead to more efficacious drug treatment of epilepsy in the future. © Wiley Periodicals, Inc. 2011 International League Against Epilepsy.

Klein G.,University of Veterinary Medicine Hannover
Foodborne Pathogens and Disease | Year: 2011

The evaluation of the safety of probiotic strains includes the exclusion of antibiotic resistance of clinical importance. Ninety-two strains from the genus Lactobacillus isolated from probiotics, food, and clinical sources were included in the investigation. Species tested were the L. acidophilus group, L. casei group, L. reuteri/fermentum group, and L. sakei/curvatus group. Cell and colony morphology, fermentation patterns, and growth characteristics as well as soluble whole cell proteins were analyzed. Antibiotic resistance against clinically important agents was determined by broth dilution tests. The vanA and tet genes were confirmed. Resistances occurred mainly against gentamicin, ciprofloxacin, clindamycin, sulfonamides, and, in some cases, glycopeptides. The natural glycopeptide resistance within the L. casei group and L. reuteri appears to be not of clinical relevance, as there was no vanA gene present. Therefore, the transfer of this resistance is very unlikely. Tet-(A), -(B), -(C), -(M), or -(O) gene could not be detected. The protein fingerprinting within the L. casei group proved that L. rhamnosus strains of clinical origin clustered together with probiotic strains. For safety evaluations resistance patterns of a broad range of strains are a useful criterion together with the exclusion of known resistance genes (like the vanA gene) and can be used for decision making on the safety of probiotics, both by authorization bodies and manufacturers. © Copyright 2011, Mary Ann Liebert, Inc. 2011.

Loscher W.,University of Veterinary Medicine Hannover
Epilepsia | Year: 2012

The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ-aminobutyric acid (GABA) on GABA(A) receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABA(A) receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABA(A) -receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent as a GABA(A) -receptor modulator than pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABA(A) receptors (possibly including extrasynaptic receptors containing δ subunits); and reduced activity at other ion channel targets, including voltage-gated calcium channels. In recent years, substantial progress has been made in defining the structural features of GABA(A) receptors responsible for gating and allosteric modulation by drugs. Although the precise sites of action of barbiturates have not yet been defined, the second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β-subunit methionine 286 as well as α-subunit methionine 236. In addition to effects on GABA(A) receptors, barbiturates block AMPA/kainate receptors, and they inhibit glutamate release through an effect on P/Q-type high-voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities. Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Boar spermatozoa are sensitive to storage temperatures below 15 °C. Chilling injury causes loss of motility and membrane integrity in a minority of cells, whereas the main population displays sublethal changes compromising fertility. In this study, changes of the response to capacitation conditions in hypothermically stored boar spermatozoa have been examined using a kinetic approach with well-defined test and control media. Ejaculates of seven boars were diluted in Beltsville Thawing Solution kept for 3 h at 22 °C or cooled to 17, 10 and 5 °C and stored for 24 and 96 h. At each time point, the standard sperm parameters motility and membrane integrity were evaluated. Subsequently, washed subsamples were incubated in capacitating and control medium before flow cytometric analysis of intracellular calcium content using the Fluo-3 probe and changes in phospholipid disorder using merocyanine. Kinetic changes of response parameters were monitored in viable (plasma membrane intact) cells. Chilling led to a loss of standard sperm quality traits in a minor subpopulation of cells, whereas storage length had no effect on these parameters. However, responses to incubation as determined by the loss of live cells with low intracellular calcium content showed marked changes in relation to storage conditions. The specific responsiveness to capacitation conditions decreased in close relation to storage temperature and length. In contrast, the merocyanine probe revealed to be limited to detect effects of hypothermic storage. Using Fourier transform infrared spectroscopy, no influence of chilling on membrane phase behaviour was found that might implicate decreased sperm function. In conclusion, assessment of response to capacitating media by monitoring intracellular calcium levels provides a sensitive measure for chilling injury in extended boar semen, and therefore, deserves implementation in hypothermic storage tests. © 2013 American Society of Andrology and European Academy of Andrology.

Fulde M.,University of Veterinary Medicine Hannover
Frontiers in cellular and infection microbiology | Year: 2014

The arginine-ornithine antiporter (ArcD) is part of the Arginine Deiminase System (ADS), a catabolic, energy-providing pathway found in a variety of different bacterial species, including the porcine zoonotic pathogen Streptococcus suis. The ADS has recently been shown to play a role in the pathogenicity of S. suis, in particular in its survival in host cells. The contribution of arginine and arginine transport mediated by ArcD, however, has yet to be clarified. In the present study, we showed by experiments using [U-(13)C6]arginine as a tracer molecule that S. suis is auxotrophic for arginine and that bacterial growth depends on the uptake of extracellular arginine. To further study the role of ArcD in arginine metabolism, we generated an arcD-specific mutant strain and characterized its growth compared to the wild-type (WT) strain, a virulent serotype 2 strain. The mutant strain showed a markedly reduced growth in chemically defined media supplemented with arginine when compared to the WT strain, suggesting that ArcD promotes arginine uptake. To further evaluate the in vivo relevance of ArcD, we studied the intracellular bacterial survival of the arcD mutant strain in an epithelial cell culture infection model. The mutant strain was substantially attenuated, and its reduced intracellular survival rate correlated with a lower ability to neutralize the acidified environment. Based on these results, we propose that ArcD, by its function as an arginine-ornithine antiporter, is important for supplying arginine as substrate of the ADS and, thereby, contributes to biological fitness and virulence of S. suis in the host.

Distl O.,University of Veterinary Medicine Hannover
Veterinary Journal | Year: 2013

Osteochondrosis (OC) develops in growing horses due to disturbed differentiation and maturation of cartilage, particularly at the predilection sites of the fetlock, hock and stifle joints. Horses with osteochondrotic lesions are at a high risk of developing orthopaedic problems later in life. This article briefly reviews the published heritability estimates for OC and offers perspectives for selection in the horse industry. Heritabilities for OC in Warmblood and Standardbred horses have been estimated at 0.1-0.4 in animal threshold models.Whole genome scans using microsatellites have identified 14 quantitative trait loci (QTL) and the eight most important QTL have been refined using dense marker maps. Genome-wide association studies with single nucleotide polymorphisms revealed further QTL in Thoroughbred, Standardbred and Hanoverian horses. Only a few QTL have corresponding locations among the different breeds. Comparative genomics using positional candidate genes and next-generation-sequencing may lead to new insights into the genetic determination of equine OC and might help in understanding the molecular mechanisms of its pathogenesis. Implementation of selection schemes based on breeding values, or even genomic selection against OC, should be considered as an option for improving equine musculoskeletal health. © 2013 Elsevier Ltd.

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