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.
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.
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.
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.
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.