In vivo testing of a novel adjustable glaucoma drainage device.

PURPOSE: We report on the in vivo testing of a novel noninvasively adjustable glaucoma drainage device (AGDD), which features an adjustable outflow resistance, and assess the safety and efficiency of this implant. METHODS: Under general anesthesia, the AGDD was implanted on seven white New Zealand rabbits for a duration of 4 months under a scleral flap in a way analogous to the Ex-PRESS device and set in an operationally closed position. The IOP was measured on a regular basis on the operated and control eyes using a rebound tonometer. Once a month the AGDD was adjusted noninvasively from its fully closed to its fully open position and the resulting pressure drop was measured. The contralateral eye was not operated and served as control. After euthanization, the eyes were collected for histology evaluation. RESULTS: The mean preoperative IOP was 11.1 ± 2.4 mm Hg. The IOP was significantly lower for the operated eye (6.8 ± 2 mm Hg) compared to the nonoperated eye (13.1 ± 1.6 mm Hg) during the first 8 days after surgery. When opening the AGDD from its fully closed to fully open position, the IOP dropped significantly from 11.2 ± 2.9 to 4.8 ± 0.9 mm Hg (P < 0.05). CONCLUSIONS: Implanting the AGDD is a safe and uncomplicated surgical procedure. The fluidic resistance was noninvasively adjustable during the postoperative period with the AGDD between its fully closed and fully open positions.

Testing advances in molecular discrimination among Chinook salmon life histories: evidence from a blind test.

The application of DNA-based markers toward the task of discriminating among alternate salmon runs has evolved in accordance with ongoing genomic developments and increasingly has enabled resolution of which genetic markers associate with important life-history differences. Accurate and efficient identification of the most likely origin for salmon encountered during ocean fisheries, or at salvage from fresh water diversion and monitoring facilities, has far-reaching consequences for improving measures for management, restoration and conservation. Near-real-time provision of high-resolution identity information enables prompt response to changes in encounter rates. We thus continue to develop new tools to provide the greatest statistical power for run identification. As a proof of concept for genetic identification improvements, we conducted simulation and blind tests for 623 known-origin Chinook salmon (Oncorhynchus tshawytscha) to compare and contrast the accuracy of different population sampling baselines and microsatellite loci panels. This test included 35 microsatellite loci (1266 alleles), some known to be associated with specific coding regions of functional significance, such as the circadian rhythm cryptochrome genes, and others not known to be associated with any functional importance. The identification of fall run with unprecedented accuracy was demonstrated. Overall, the top performing panel and baseline (HMSC21) were predicted to have a success rate of 98%, but the blind-test success rate was 84%. Findings for bias or non-bias are discussed to target primary areas for further research and resolution.

The utility of rhesus monkey (Macaca mulatta) and other non-human primate models for preclinical testing of Leishmania candidate vaccines

Leishmaniasis causes significant morbidity and mortality, constituting an important global health problem for which there are few effective drugs. Given the urgent need to identify a safe and effective Leishmania vaccine to help prevent the two million new cases of human leishmaniasis worldwide each year, all reasonable efforts to achieve this goal should be made. This includes the use of animal models that are as close to leishmanial infection in humans as is practical and feasible. Old world monkey species (macaques, baboons, mandrills etc.) have the closest evolutionary relatedness to humans among the approachable animal models. The Asian rhesus macaques (Macaca mulatta) are quite susceptible to leishmanial infection, develop a human-like disease, exhibit antibodies to Leishmania and parasite-specific T-cell mediated immune responses both in vivo and in vitro, and can be protected effectively by vaccination. Results from macaque vaccine studies could also prove useful in guiding the design of human vaccine trials. This review summarizes our current knowledge on this topic and proposes potential approaches that may result in the more effective use of the macaque model to maximize its potential to help the development of an effective vaccine for human leishmaniasis.

Multiplex polymerase chain reaction to identify and determine the toxigenicity of Corynebacterium spp with zoonotic potential and an overview of human and animal infections

Corynebacterium diphtheriae, Corynebacterium ulcerans and Corynebacterium pseudotuberculosis constitute a group of potentially toxigenic microorganisms that are related to different infectious processes in animal and human hosts. Currently, there is a lack of information on the prevalence of disease caused by these pathogens, which is partially due to a reduction in the frequency of routine laboratory testing. In this study, a multiplex polymerase chain reaction (mPCR) assay that can simultaneously identify and determine the toxigenicity of these corynebacterial species with zoonotic potential was developed. This assay uses five primer pairs targeting the following genes: rpoB (Corynebacterium spp), 16S rRNA (C. ulcerans and C. pseudotuberculosis), pld (C. pseudotuberculosis), dtxR (C. diphtheriae) and tox [diphtheria toxin (DT) ]. In addition to describing this assay, we review the literature regarding the diseases caused by these pathogens. Of the 213 coryneform strains tested, the mPCR results for all toxigenic and non-toxigenic strains of C . diphtheriae, C. ulcerans and C. pseudotuberculosis were in 100% agreement with the results of standard biochemical tests and PCR-DT. As an alternative to conventional methods, due to its advantages of specificity and speed, the mPCR assay used in this study may successfully be applied for the diagnosis of human and/or animal diseases caused by potentially toxigenic corynebacterial species.

A la recherche de symptômes de désorientation dépendant d'un déficit d'intégration multisensorielle chez l'animal : un éclairage sur les mécanismes fondamentaux de la schizophrénie

Abstract Fundamental research in psychiatric neurosciences assumes that psychiatric disorders are associated with neurobiological factors. Identification of these factors would provide therapeutic targets as well as a better understanding of the relationship between- brain and behaviour in pathological processes. We conducted experiments in an animal model of schizophrenia. Several behavioural tasks were used to evaluate spatial and working memory in these animals. The model is based on glutathione deficit during cerebral development. Indeed, a 50% decrease of glutathione has been reported in prefrontal cortex of patients with schizophrenia. Glutathione is a major antioxidant in the brain and its deficit could lead to abnormal brain connectivity. The glutathione deficit was induced in rats by perinatal (PS-P16) subcutaneous injections with Lbuthionine-(S,R)-sullfoximine (BSO), an inhibitor of glutathione synthesis. This treatment leads to a transitory 50% glutathione levels during brain development. In parallel, we conducted behavioural testing in rats with a medial prefrontal cortex lesion. This allowed us to compare early damage induced by BSO treatment with a focal lesion in adults of a brain area known to present anomalies in schizophrenia. Finally, we conducted a series of experiments in senescent rats to evaluate if cognitive deficits could be related to neurobiological changes. Our results show that an early glutathione deficit provokes cognitive deficits in adulthood. These spatial and working memory deficits resemble the cognitive deficits observed in schizophrenia. The comparison with prefrontal rats revealed that the early brain glutathione deficit provoked more severe cognitive deficits than the prefrontal lesion in adult rats. Moreover, in both cases, we observed a dissociation in memory deficits depending on the type of locomotion that was used in behavioural experiments. Indeed, BSO treated rats as well as prefrontal rats showed place learning or working memory deficits in tasks conducted on dry surfaces where they had to walk. In contrast, they showed no deficit when the same cognitive functions were tested in the water maze. This dissociation might be sustained by a difference in requirement of sensory integration between walking and swimming tasks. Résumé La recherche fondamentale en neurosciences psychiatriques repose sur le présupposé selon lequel les symptômes manifestés dans les troubles psychiatriques auraient des concomitants neurobiologiques. Ceux-ci, une fois identifiés, offriraient des cibles pour une démarche thérapeutique ainsi que des modèles permettant de mieux comprendre les soubassements biologiques du comportement et des activités mentales. Nos expériences s'articulent autour de la question de la modélisation de la schizophrénie chez l'animal. Nous avons recherché chez ces animaux des troubles cognitifs et sensoriels associés à la schizophrénie. En effet, chez l'homme comme chez l'animal, la mémoire spatiale et la mémoire de travail dépendent fortement de la capacité d'intégration et d'organisation des informations sensorielles. Les premières expériences ont été menées suite à une perturbation périnatale du développement cérébral. Celle-ci visait à reproduire une diminution du taux de glutathion dans le cerveau, des recherches précédentes ayant observé une diminution de 50% du taux de glutathion dans le cortex préfrontal de patients schizophrènes. Le glutathion étant un antioxydant majeur dans le cerveau, son déficit pourrait conduire à des perturbations de la circuiterie cérébrale. Nous avons reproduit ce déficit chez le rat, par injection de Lbuthionine-(S,R)-sullfoximine (BSO), un inhibiteur de la synthèse du glutathion... Ce traitement a été administré pendant la période périnatale (du jour postnatal 5 au jour 16) provoquant une diminution de 50% du taux de glutathion. Nous avons ensuite évalué lës répercussions de cette atteinte précoce sur le comportement des rats à l'âge adulte. Ce modèle s'inscrit donc dans l'hypothèse neurodéveloppementale qui associe la schizophrénie à une atteinte du développement cérébral normal. Nous avons ensuite conduit des expériences similaires chez des rats ayant subi une lésion du cortex préfrontal pour comparer les répercussions du traitement périnatal avec une lésion, à l'âge adulte, d'une aire cérébrale connue pour présenter des anomalies chez les patients. Finalement, nous avons évalué si les processus sensoriels et cognitifs précédemment étudiés pouvaient également être affectés lors du vieillissement normal en recherchant des corrélats biologiques des déficits de mémoire liés à l'âge avancé. Nos résultats montrent que ce déficit précoce en glutathion peut avoir des répercussions surale comportement à l'âge adulte. On a relevé une similarité avec les déficits cognitifs associés.à la schizophrénie, incluant des déficits de mémoire de travail ainsi que des déficits de mémoire spatiale. Ces déficits étaient fortement liés au type de locomotion utilisée et n'ont été observés que dans les tâches où les animaux devaient rejoindre un but en marchant mais pas dans lés tests dans lesquels ils devaient localiser une cible en nageant. Les déficits induits par la lésion préfrontale chez l'adulte étaient beaucoup plus légers que ceux découlant de l'atteinte périnatale mais présentaient une dissociation analogue en fonction du type de locomotion. De plus, des tests similaires menés au cours du vieillissement confirment que la mémoire de travail peut être affectée sélectivement par le vieillissement dans une tâche où les animaux doivent marcher, tout en restant intacte dans le bassin de Morris. Les déficits cognitifs liés au vieillissement étaient significativement corrélés à des différences de niveaux des protéines post-synaptiques PSD95 (postsynaptic density 95). L'ensemble des résultats montre que les tests qui sont fréquemment utilisés pour évaluer la mémoire chez l'animal pourraient faire appel à des processus différents. Cette différence pourrait notamment tenir au niveau d'intégration sensorielle requis pour résoudre la tâche, qui est particulièrement sollicitée au cours d'une locomotion intermittente.

A new alternative method for testing skin irritation using a human skin model: a pilot study.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo. To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test). Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization). We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were <0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI). This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Field Testing and Evaluation of a Demonstration Timber Bridge, February 2012

Asphalt wearing surfaces are commonly used on timber bridges with transverse glued-laminated deck panel systems to help protect the timber components. However, poor performance of these asphalt wearing surfaces in the past has resulted in repeated repair and increased maintenance costs. This report describes the field demonstration and testing of a newly-constructed, glued-laminated timber girder bridge. Previous field work revealed that differential panel deflections in the glued-laminated deck were one significant factor resulting in the premature failure of the asphalt wearing surfaces on these bridges. In addition, laboratory work subsequent to the field testing attempted to address the problematic asphalt cracking common in transverse glued-laminated panel decks by testing several deck joint connection alternatives. The field demonstration project described in this report showcases the retrofit detail that was determined to provide the best field performance. The project was a cooperative effort between the Bridge Engineering Center (BEC) at Iowa State University and the United States Department of Agriculture (USDA) Forest Service Forest Products Laboratory (FPL).

Investigation of Two Bridge Alternatives for Low Volume Roads, Volume 1 of 2 Concept 1: Precast Steel Beam Units, HR-382, 1997

Recent reports have indicated that 23.5% of the nation's highway bridges are structurally deficient and 17.7% are functionally obsolete. A significant number of these bridges are on the Iowa secondary road system where over 86% of the rural bridge management responsibilities are assigned to the counties. Some of the bridges can be strengthened or otherwise rehabilitated, but many more are in need of immediate replacement. In a recent investigation (HR-365 "Evaluation of Bridge Replacement Alternatives for the County Bridge System") several types of replacement bridges that are currently being used on low volume roads were identified. It was also determined that a large number of counties (69%) have the ability and are interested in utilizing their own forces to design and construct short span bridges. In reviewing the results from HR-365, the research team developed one "new" bridge replacement concept and a modification of a replacement system currently being used. Both of these bridge replacement alternatives were investigated in this study, the results of which are presented in two volumes. This volume (Volume 1) presents the results of Concept 1 - Steel Beam Precast Units. Concept 2 - Modification of the Beam-in-Slab Bridge is presented in Volume 2. Concept 1, involves the fabrication of precast units (two steel beams connected by a concrete slab) by county work forces. Deck thickness is limited so that the units can be fabricated at one site and then transported to the bridge site where they are connected and the remaining portion of the deck placed. Since Concept 1 bridge is primarily intended for use on low-volume roads, the precast units can be constructed with new or used beams. In the experimental part of the investigation, there were three types of static load tests: small scale connector tests, "handling strength" tests, and service and overload tests of a model bridge. Three finite element models for analyzing the bridge in various states of construction were also developed. Small scale connector tests were completed to determine the best method of connecting the precast double-T (PCDT) units. "Handling strength" tests on an individual PCDT unit were performed to determine the strength and behavior of the precast unit in this configuration. The majority of the testing was completed on the model bridge [L=9,750 mm (32 ft), W=6,400 mm (21 ft)] which was fabricated using the precast units developed. Some of the variables investigated in the model bridge tests were number of connectors required to connect adjacent precast units, contribution of diaphragms to load distribution, influence of position of diaphragms on bridge strength and load distribution, and effect of cast-in-place portion of deck on load distribution. In addition to the service load tests, the bridge was also subjected to overload conditions. Using the finite element models developed, one can predict the behavior and strength of bridges similar to the laboratory model as well as design them. Concept 1 has successfully passed all laboratory testing; the next step is to field test it.

Investigation of Two Bridge Alternatives for Low Volume Roads - Phase II Volume 1 of 2 Concept 1: Steel Beam Precast Units, TR-410, 2000

This project continues the research which addresses the numerous bridge problems on the Iowa secondary road system. It is a continuation (Phase 2) of Project HR-382, in which two replacement alternatives (Concept 1: Steel Beam Precast Units and Concept 2: Modification of the Benton County Beam-in-Slab Bridge) were investigated. In previous research for concept 1, a precast unit bridge was developed through laboratory testing. The steel-beam precast unit bridge requires the fabrication of precast double-tee (PCDT) units, each consisting of two steel beams connected by a reinforced concrete deck. The weight of each PCDT unit is minimized by limiting the deck thickness to 4 in., which permits the units to be constructed off-site and then transported to the bridge site. The number of units required is a function of the width of bridge desired. Once the PCDT units are connected, a cast-in-place reinforced concrete deck is cast over the PCDT units and the bridge railing attached. Since the steel beam PCDT unit bridge design is intended primarily for use on low-volume roads, used steel beams can be utilized for a significant cost savings. In previous research for concept 2, an alternate shear connector (ASC) was developed and subjected to static loading. In this investigation, the ASC was subjected to cyclic loading in both pushout specimens and composite beam tests. Based on these tests, the fatigue strength of the ASC was determined to be significantly greater than that required in typical low volume road single span bridges. Based upon the construction and service load testing, the steel-beam precast unit bridge was successfully shown to be a viable low volume road bridge alternative. The construction process utilized standard methods resulting in a simple system that can be completed with a limited staff. Results from the service load tests indicated adequate strength for all legal loads. An inspection of the bridge one year after its construction revealed no change in the bridge's performance. Each of the systems previously described are relatively easy to construct. Use of the ASC rather than the welded studs significantly simplified the work, equipment, and materials required to develop composite action between the steel beams and the concrete deck.

Investigation of Two Bridge Alternatives for Low Volume Roads - Phase II Volume 2 of 2, Concept 2: Beam in Slab Bridge, TR-410, 2000

This project continues the research which addresses the numerous bridge problems on the Iowa secondary road system. It is a continuation (Phase 2) of Project HR-382, in which two replacement alternatives (Concept 1: Steel Beam Precast Units and Concept 2: Modification of the Benton County Beam-in-Slab Bridge) were investigated. In previous research for concept 1, a precast unit bridge was developed through laboratory testing. The steel-beam precast unit bridge requires the fabrication of precast double-tee (PCDT) units, each consisting of two steel beams connected by a reinforced concrete deck. The weight of each PCDT unit is minimized by limiting the deck thickness to 4 in., which permits the units to be constructed off-site and then transported to the bridge site. The number of units required is a function of the width of bridge desired. Once the PCDT units are connected, a cast-in-place reinforced concrete deck is cast over the PCDT units and the bridge railing attached. Since the steel beam PCDT unit bridge design is intended primarily for use on low-volume roads, used steel beams can be utilized for a significant cost savings. In previous research for concept 2, an alternate shear connector (ASC) was developed and subjected to static loading. In this investigation, the ASC was subjected to cyclic loading in both pushout specimens and composite beam tests. Based on these tests, the fatigue strength of the ASC was determined to be significantly greater than that required in typical low volume road single span bridges. Based upon the construction and service load testing, the steel-beam precast unit bridge was successfully shown to be a viable low volume road bridge alternative. The construction process utilized standard methods resulting in a simple system that can be completed with a limited staff. Results from the service load tests indicated adequate strength for all legal loads. An inspection of the bridge one year after its construction revealed no change in the bridge's performance. Each of the systems previously described are relatively easy to construct. Use of the ASC rather than the welded studs significantly simplified the work, equipment, and materials required to develop composite action between the steel beams and the concrete deck.

Testing the competitive exclusion principle using various niche parameters in a native (Natrix maura) and an introduced (N. tessellata) colubrid

Despite the increase of animal and plant introductions worldwide and the strong augmentation of the reptile trade, few invasive snake populations have been studied. Dice snakes (Natrix tessellata) were introduced to the shores of Lake Geneva (Switzerland) in the early 1920s, and are now well established. This region of introduction was previously inhabited by Viperine snakes (N. maura). Ever since these two species have been under monitoring (which began in 1996) the Viperine snake population has shown drastic decline. We examine here the possibility of trophic competition by analysing diet composition, prey size and trophic niche overlap. Spatial distribution is also assessed in order to address the question of spatial competitive exclusion. We found very similar diets, and thus a high trophic niche overlap, indicating no partitioning of the trophic resource. No arguments in favour of spatial competitive exclusion were found. Our study suggests that trophic competition may occur between the two natricines and that it may give an explanation for the drastic decline of the Viperine snake in this area. Other pathways potentially playing a role in the exclusion of the Viperine snake are discussed.

A general theory of rank testing

This paper develops an approach to rank testing that nests all existing rank tests andsimplifies their asymptotics. The approach is based on the fact that implicit in every ranktest there are estimators of the null spaces of the matrix in question. The approach yieldsmany new insights about the behavior of rank testing statistics under the null as well as localand global alternatives in both the standard and the cointegration setting. The approach alsosuggests many new rank tests based on alternative estimates of the null spaces as well as thenew fixed-b theory. A brief Monte Carlo study illustrates the results.

Towards an alternative testing strategy for nanomaterials used in nanomedicine: Lessons from NanoTEST.

In spite of recent advances in describing the health outcomes of exposure to nanoparticles (NPs), it still remains unclear how exactly NPs interact with their cellular targets. Size, surface, mass, geometry, and composition may all play a beneficial role as well as causing toxicity. Concerns of scientists, politicians and the public about potential health hazards associated with NPs need to be answered. With the variety of exposure routes available, there is potential for NPs to reach every organ in the body but we know little about the impact this might have. The main objective of the FP7 NanoTEST project ( www.nanotest-fp7.eu ) was a better understanding of mechanisms of interactions of NPs employed in nanomedicine with cells, tissues and organs and to address critical issues relating to toxicity testing especially with respect to alternatives to tests on animals. Here we describe an approach towards alternative testing strategies for hazard and risk assessment of nanomaterials, highlighting the adaptation of standard methods demanded by the special physicochemical features of nanomaterials and bioavailability studies. The work has assessed a broad range of toxicity tests, cell models and NP types and concentrations taking into account the inherent impact of NP properties and the effects of changes in experimental conditions using well-characterized NPs. The results of the studies have been used to generate recommendations for a suitable and robust testing strategy which can be applied to new medical NPs as they are developed.

Testing pigs of non-technified rearing farms for serum antibodies against Taenia solium in a region of the state of São Paulo, Brazil

Abstract: Taenia solium is a zoonotic tapeworm of great importance in developing countries, due to the occurrence of human taeniasis and cysticercosis. Pigs have an important role in the biological cycle of the parasite as intermediate hosts. The scientific literature has been describing risk factors associated with the occurrence of this disease that must be avoided in countries with poor sanitation, in order to reduce the exposure of swine to the parasite eggs. This research focused on testing pigs of non-technified rearing farms for serum antibodies against Taenia solium in the region of Jaboticabal municipality, in the state of São Paulo, Brazil. The found prevalence was 6.82% (CI 95% 4.18 - 9.45) at animal level and 28.87% (CI 95% 16.74 - 40.40) at herd level. These figures are probably associated with low technification adoption during animal rearing in the studied area, which increased the exposure of the animals to risk factors associated with the occurrence of Taenia solium complex. The results found based on serological evidences of swine cysticercosis in the studied region serves as a warning to public sanitary authorities to improve public health and control T. solium.

The use of non-human primates as animal models for the study of hepatitis viruses

Hepatitis viruses belong to different families and have in common a striking hepatotropism and restrictions for propagation in cell culture. The transmissibility of hepatitis is in great part limited to non-human primates. Enterically transmitted hepatitis viruses (hepatitis A virus and hepatitis E virus) can induce hepatitis in a number of Old World and New World monkey species, while the host range of non-human primates susceptible to hepatitis viruses transmitted by the parenteral route (hepatitis B virus, hepatitis C virus and hepatitis delta virus) is restricted to few species of Old World monkeys, especially the chimpanzee. Experimental studies on non-human primates have provided an invaluable source of information regarding the biology and pathogenesis of these viruses, and represent a still indispensable tool for vaccine and drug testing.