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White H.S.,University of Utah | Loscher W.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience
Neurotherapeutics | Year: 2014

A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic. © 2014 The American Society for Experimental NeuroTherapeutics, Inc.


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.


Moennig V.,University of Veterinary Medicine Hannover
Frontiers in Microbiology | Year: 2015

Classical swine fever (CSF) is a viral disease with severe economic consequences for domestic pigs. Natural hosts for the CSF virus (CSFV) are members of the family Suidae, i.e., Eurasian wild boar (sus scrofa) are also susceptible. CSF in wild boar poses a serious threat to domestic pigs. CSFV is an enveloped RNA virus belonging to the pestivirus genus of the Flaviviridae family. Transmission of the infection is usually by direct contact or by feeding of contaminated meat products. In recent decades CSF has been successfully eradicated from Australia, North America, and the European Union. In areas with dense wild boar populations CSF tends to become endemic whereas it is often self-limiting in small, less dense populations. In recent decades eradication strategies of CSF in wild boar have been improved considerably. The reduction of the number of susceptible animals to a threshold level where the basic reproductive number is R0 < 1 is the major goal of all control efforts. Depending on the epidemiological situation, hunting measures combined with strict hygiene may be effective in areas with a relatively low density of wild boar. Oral immunization was shown to be highly effective in endemic situations in areas with a high density of wild boar. © 2015 Moennig.


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.


Amann R.P.,Colorado State University | Waberski D.,University of Veterinary Medicine Hannover
Theriogenology | Year: 2014

Computer-assisted sperm analysis (CASA) systems have evolved over approximately 40 years, through advances in devices to capture the image from a microscope, huge increases in computational power concurrent with amazing reduction in size of computers, new computer languages, and updated/expanded software algorithms. Remarkably, basic concepts for identifying sperm and their motion patterns are little changed. Older and slower systems remain in use. Most major spermatology laboratories and semen processing facilities have a CASA system, but the extent of reliance thereon ranges widely. This review describes capabilities and limitations of present CASA technology used with boar, bull, and stallion sperm, followed by possible future developments. Each marketed system is different. Modern CASA systems can automatically view multiple fields in a shallow specimen chamber to capture strobe-like images of 500 to >2000 sperm, at 50 or 60 frames per second, in clear or complex extenders, and in <2 minutes, store information for ≥30 frames and provide summary data for each spermatozoon and the population. A few systems evaluate sperm morphology concurrent with motion. CASA cannot accurately predict 'fertility' that will be obtained with a semen sample or subject. However, when carefully validated, current CASA systems provide information important for quality assurance of semen planned for marketing, and for the understanding of the diversity of sperm responses to changes in the microenvironment in research. The four take-home messages from this review are: (1) animal species, extender or medium, specimen chamber, intensity of illumination, imaging hardware and software, instrument settings, technician, etc., all affect accuracy and precision of output values; (2) semen production facilities probably do not need a substantially different CASA system whereas biology laboratories would benefit from systems capable of imaging and tracking sperm in deep chambers for a flexible period of time; (3) software should enable grouping of individual sperm based on one or more attributes so outputs reflect subpopulations or clusters of similar sperm with unique properties; means or medians for the total population are insufficient; and (4) a field-use, portable CASA system for measuring one motion and two or three morphology attributes of individual sperm is needed for field theriogenologists or andrologists working with human sperm outside urban centers; appropriate hardware to capture images and process data apparently are available. © 2014 Elsevier Inc.


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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