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Comparative and Laboratory Animal Medicine Commons

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Activation Of A Cryptic 5′ Splice Site Reverses The Impact Of Pathogenic Splice Site Mutations In The Spinal Muscular Atrophy Gene, Natalia N. Singh, Jose Bruno Del Rio-Malewski, Diou Luo, Eric W. Ottesen, Matthew D. Howell, Ravindra N. Singh 2017 Iowa State University

Activation Of A Cryptic 5′ Splice Site Reverses The Impact Of Pathogenic Splice Site Mutations In The Spinal Muscular Atrophy Gene, Natalia N. Singh, Jose Bruno Del Rio-Malewski, Diou Luo, Eric W. Ottesen, Matthew D. Howell, Ravindra N. Singh

Biomedical Sciences Publications

Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5′ splice site (5′ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5′ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7. We ...


A Multilayered Control Of The Human Survival Motor Neuron Gene Expression By Alu Elements, Eric W. Ottesen, Joonbae Seo, Natalia N. Singh, Ravindra N. Singh 2017 Iowa State University

A Multilayered Control Of The Human Survival Motor Neuron Gene Expression By Alu Elements, Eric W. Ottesen, Joonbae Seo, Natalia N. Singh, Ravindra N. Singh

Biomedical Sciences Publications

Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1, which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein. In addition, SMNΔ7 is less functional due to the lack of a critical C-terminus of ...


How The Discovery Of Iss-N1 Led To The First Medical Therapy For Spinal Muscular Atrophy, Natalia N. Singh, Matthew D. Howell, Elliot J. Androphy, Ravindra N. Singh 2017 Iowa State University

How The Discovery Of Iss-N1 Led To The First Medical Therapy For Spinal Muscular Atrophy, Natalia N. Singh, Matthew D. Howell, Elliot J. Androphy, Ravindra N. Singh

Biomedical Sciences Publications

Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University ...


Comparison Of Humoral And T-Cell-Mediated Immune Responses To A Single Dose Of Bovela® Live Double Deleted Bvdv Vaccine Or To A Field Bvdv Strain, Ratree Platt, Lyle Kesl, Christian Guidarini, Chong Wang, James A. Roth 2017 Iowa State University

Comparison Of Humoral And T-Cell-Mediated Immune Responses To A Single Dose Of Bovela® Live Double Deleted Bvdv Vaccine Or To A Field Bvdv Strain, Ratree Platt, Lyle Kesl, Christian Guidarini, Chong Wang, James A. Roth

Chong Wang

The objective of this study was to determine and compare the humoral and cellular immune responses of calves exposed to a single dose of Bovela® bovine viral diarrhea virus (BVDV) live double deleted vaccine or a field strain virus (FSV) of BVDV type 2 (strain 890). Thirty seronegative, colostrum-deprived 5 month-old Holstein steer calves that tested negative for persistent BVDV by ear notch immunohistochemistry and seronegative to BVDV types 1 and 2 were used. Calves were screened by multi-parameter flow cytometry (MP-FCM) 1 week before vaccination to ensure that they were negative for T cell responses to the BVDV types ...


Comparison Of Humoral And T-Cell-Mediated Immune Responses To A Single Dose Of Bovela® Live Double Deleted Bvdv Vaccine Or To A Field Bvdv Strain, Ratree Platt, Lyle Kesl, Christian Guidarini, Chong Wang, James A. Roth 2017 Iowa State University

Comparison Of Humoral And T-Cell-Mediated Immune Responses To A Single Dose Of Bovela® Live Double Deleted Bvdv Vaccine Or To A Field Bvdv Strain, Ratree Platt, Lyle Kesl, Christian Guidarini, Chong Wang, James A. Roth

Veterinary Microbiology and Preventive Medicine Publications

The objective of this study was to determine and compare the humoral and cellular immune responses of calves exposed to a single dose of Bovela® bovine viral diarrhea virus (BVDV) live double deleted vaccine or a field strain virus (FSV) of BVDV type 2 (strain 890). Thirty seronegative, colostrum-deprived 5 month-old Holstein steer calves that tested negative for persistent BVDV by ear notch immunohistochemistry and seronegative to BVDV types 1 and 2 were used. Calves were screened by multi-parameter flow cytometry (MP-FCM) 1 week before vaccination to ensure that they were negative for T cell responses to the BVDV types ...


Bioavailability And Biochemical Effects Of Diclofenac Sodium 0.1% Ophthalmic Solution In The Domestic Chicken (Gallus Gallus Domesticus), Angela N. Griggs, Taylor J. Yaw, Joseph S. Haynes, Gil Ben-Shlomo, Kyle L. Tofflemire, Rachel A. Allbaugh 2017 Iowa State University

Bioavailability And Biochemical Effects Of Diclofenac Sodium 0.1% Ophthalmic Solution In The Domestic Chicken (Gallus Gallus Domesticus), Angela N. Griggs, Taylor J. Yaw, Joseph S. Haynes, Gil Ben-Shlomo, Kyle L. Tofflemire, Rachel A. Allbaugh

Veterinary Clinical Sciences Publications

Objective To determine if topical ophthalmic diclofenac sodium 0.1% solution alters renal parameters in the domestic chicken, and to determine if the drug is detectable in plasma after topical ophthalmic administration.

Animals Thirty healthy domestic chickens

Procedures Over seven days, 6 birds were treated unilaterally with 1 drop of artificial tear solution (group 1), 12 birds were treated unilaterally (group 2) and 12 bilaterally (group 3) with diclofenac sodium 0.1% ophthalmic solution. Treatments were provided for 7 days, every 12 hours in all groups. Pre- and post-treatment plasma samples from all birds were evaluated for changes in albumin ...


Outcomes Of Spatially Fractionated Radiotherapy (Grid) For Bulky Soft Tissue Sarcomas In A Large Animal Model, Michael W. Nolan, Tracy L. Gieger, Alexander A. Karakashian, Mariana N. Nikolova‑Karakashian, Lysa P. Posner, Donald M. Roback, Judith N. Rivera, Sha Chang 2017 North Carolina State University

Outcomes Of Spatially Fractionated Radiotherapy (Grid) For Bulky Soft Tissue Sarcomas In A Large Animal Model, Michael W. Nolan, Tracy L. Gieger, Alexander A. Karakashian, Mariana N. Nikolova‑Karakashian, Lysa P. Posner, Donald M. Roback, Judith N. Rivera, Sha Chang

Physiology Faculty Publications

GRID directs alternating regions of high- and low-dose radiation at tumors. A large animal model mimicking the geometries of human treatments is needed to complement existing rodent systems (eg, microbeam) and clarify the physical and biological attributes of GRID. A pilot study was undertaken in pet dogs with spontaneous soft tissue sarcomas to characterize responses to GRID. Subjects were treated with either 20 Gy (3 dogs) or 25 Gy (3 dogs), delivered using 6 MV X-rays and a commercial GRID collimator. Acute toxicity and tumor responses were assessed 2, 4, and 6 weeks later. Acute Radiation Therapy Oncology Group grade ...


The Effects Of Methamphetamine Exposure On Cardiovascular Development In Combination With Hypoxia In Danio Rerio, Sarah Donaldson 2017 University of Akron

The Effects Of Methamphetamine Exposure On Cardiovascular Development In Combination With Hypoxia In Danio Rerio, Sarah Donaldson

Honors Research Projects

The purpose of this study was to determine the effects of methamphetamine combined with hypoxia on the development and function of the cardiovascular system in Danio rerio embryos. It was hypothesized that the combined effect of the drug and decreased oxygen concentration would result in decreased cardiac parameters due to underdevelopment of the ventricle and vessels resulting from cardiomyopathy and lack of blood flow to tissues. It was found that methamphetamine exposure correlated to an increase in stroke volume, caudal artery and vein diameters and RBC velocities alone, while having a multiplicative effect of increasing arterial RBC velocity when combined ...


Model-Based Reverse Translation Between Veterinary And Human Medicine: The One Health Initiative, Benjamin Schneider, Violeta Balbas-Martinez, Albert E. Jergens, Inaki F. Troconiz, Karin Allenspach, Jonathan P. Mochel 2017 Iowa State University

Model-Based Reverse Translation Between Veterinary And Human Medicine: The One Health Initiative, Benjamin Schneider, Violeta Balbas-Martinez, Albert E. Jergens, Inaki F. Troconiz, Karin Allenspach, Jonathan P. Mochel

Biomedical Sciences Publications

There is growing concern about the limitations of rodent models with regard to recapitulation of human disease pathogenesis. Computational modeling of data from humans and animals sharing similar diseases provides an opportunity for parallel drug development in human and veterinary medicine. This “reverse translational” approach needs to be supported by continuing efforts to refine the in silico tools that allow extrapolation of results between species.


Mathematical Modeling And Simulation In Animal Health. Part Iii: Using Nonlinear Mixed-Effects To Characterize And Quantify Variability In Drug Pharmacokinetics, C. Bon, P. L. Toutain, D. Concordet, R. Gehring, T. Martin-Jimenez, J. Smith, L. Pelligand, M. Martinez, T. Whittem, J. E. Riviere, J. P. Mochel 2017 Roche Innovation Center, Basel, Switzerland

Mathematical Modeling And Simulation In Animal Health. Part Iii: Using Nonlinear Mixed-Effects To Characterize And Quantify Variability In Drug Pharmacokinetics, C. Bon, P. L. Toutain, D. Concordet, R. Gehring, T. Martin-Jimenez, J. Smith, L. Pelligand, M. Martinez, T. Whittem, J. E. Riviere, J. P. Mochel

Biomedical Sciences Publications

A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in ...


Explanation And Elaboration Document For The Strobe-Vet Statement: Strengthening The Reporting Of Observational Studies In Epidemiology – Veterinary Extension, Annette M. O'Connor, J. M. Sargeant, I. R. Dohoo, H. N. Erb, M. Cevallos, M. Egger, A. K. Ersboll, S. W. Martin, L. R. Nielsen, D. L. Pearl, D. U. Pfeiffer, J. Sanchez, M. E. Torrence, H. Vigre, C. Waldner, M. P. Ward 2016 Iowa State University

Explanation And Elaboration Document For The Strobe-Vet Statement: Strengthening The Reporting Of Observational Studies In Epidemiology – Veterinary Extension, Annette M. O'Connor, J. M. Sargeant, I. R. Dohoo, H. N. Erb, M. Cevallos, M. Egger, A. K. Ersboll, S. W. Martin, L. R. Nielsen, D. L. Pearl, D. U. Pfeiffer, J. Sanchez, M. E. Torrence, H. Vigre, C. Waldner, M. P. Ward

Veterinary Diagnostic and Production Animal Medicine Publications

The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement was first published in 2007 and again in 2014. The purpose of the original STROBE was to provide guidance for authors, reviewers and editors to improve the comprehensiveness of reporting; however, STROBE has a unique focus on observational studies. Although much of the guidance provided by the original STROBE document is directly applicable, it was deemed useful to map those statements to veterinary concepts, provide veterinary examples and highlight unique aspects of reporting in veterinary observational studies. Here, we present the examples and explanations for the checklist items included ...


Animal Carcinogenicity Studies: 1. Poor Human Predictivity, Andrew Knight, Jarrod Bailey, Jonathan Balcombe 2016 Animal Consultants International

Animal Carcinogenicity Studies: 1. Poor Human Predictivity, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, Ph.D.

The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the ...


Animal Carcinogenicity Studies: Implications For The Reach System, Andrew Knight, Jarrod Bailey, Jonathan Balcombe 2016 Animal Consultants International

Animal Carcinogenicity Studies: Implications For The Reach System, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, Ph.D.

The 2001 European Commission proposal for the Registration, Evaluation and Authorisation of Chemicals (REACH) aims to improve public and environmental health by assessing the toxicity of, and restricting exposure to, potentially toxic chemicals. The greatest benefits are expected to accrue from decreased cancer incidences. Hence the accurate identification of chemical carcinogens must be a top priority for the REACH system. Due to a paucity of human clinical data, the identification of potential human carcinogens has conventionally relied on animal tests. However, our survey of the US Environmental Protection Agency’s (EPA’s) toxic chemicals database revealed that, for a majority ...


Which Drugs Cause Cancer?, Andrew Knight, Jarrod Bailey, Jonathan Balcombe 2016 Animal Consultants International

Which Drugs Cause Cancer?, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, Ph.D.

Animal tests yield misleading results.


Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe 2016 Animal Consultants International

Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, Ph.D.

The regulation of human exposures to potential carcinogens constitutes society’s most important use of animal carcinogenicity data. However, for environmental contaminants of greatest U.S. concern, we found that in most cases (58.1%; 93/160) the U.S. Environmental Protection Agency (EPA) considered the animal data inadequate to support a classification of probable human carcinogen or noncarcinogen.

The World Health Organisation’s International Agency for Research on Cancer (IARC) is a leading international authority on carcinogenicity assessments. For chemicals lacking human exposure data (the great majority), IARC classifications of identical chemicals were significantly more conservative than EPA classifications ...


The Future Of Teratology Research Is In Vitro, Jarrod Bailey, Andrew Knight, Jonathan Balcombe 2016 University of Newcastle-upon-Tyne

The Future Of Teratology Research Is In Vitro, Jarrod Bailey, Andrew Knight, Jonathan Balcombe

Jarrod Bailey, Ph.D.

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and manhours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite ...


Temporal Resolution Of Misfolded Prion Protein Transport, Accumulation, Glial Activation, And Neuronal Death In The Retinas Of Mice Inoculated With Scrapie, M. Heather West Greenlee, Melissa Lind, Robyn Kokemuller, Najiba Mammadova, Naveen Kondru, Sireesha Manne, Jodi Smith, Anumantha Kanthasamy, Justin Greenlee 2016 Iowa State University

Temporal Resolution Of Misfolded Prion Protein Transport, Accumulation, Glial Activation, And Neuronal Death In The Retinas Of Mice Inoculated With Scrapie, M. Heather West Greenlee, Melissa Lind, Robyn Kokemuller, Najiba Mammadova, Naveen Kondru, Sireesha Manne, Jodi Smith, Anumantha Kanthasamy, Justin Greenlee

Biomedical Sciences Publications

Currently, there is a lack of pathological landmarks to describe the progression of prion disease in vivo. Our goal was to use an experimental model to determine the temporal relationship between the transport of misfolded prion protein (PrPSc) from the brain to the retina, the accumulation of PrPSc in the retina, the response of the surrounding retinal tissue, and loss of neurons. Retinal samples from mice inoculated with RML scrapie were collected at 30, 60, 90, 105, and 120 days post inoculation (dpi) or at the onset of clinical signs of disease (153 dpi). Retinal homogenates were tested ...


Potential For Meta-Analysis In The Realm Of Preharvest Food Safety, Jan M. Sargeant, Annette M. O'Connor 2016 Ontario Veterinary College

Potential For Meta-Analysis In The Realm Of Preharvest Food Safety, Jan M. Sargeant, Annette M. O'Connor

Veterinary Diagnostic and Production Animal Medicine Publications

Meta-analysis, the statistical combination of results from multiple studies, can be used to summarize all of the available research on an intervention, etiology, descriptive, or diagnostic test accuracy question. Meta-analysis should be conducted as a component of a systematic review, to increase transparency in the selection of studies and to incorporate an evaluation of the risk of bias in the individual studies included in the meta-analysis. The process of meta-analysis may include a forest plot to graphically display the study results and the calculation of a weighted average summary effect size. Heterogeneity (differences in the effect size between studies) can ...


Chimpanzees In Research: Past, Present, And Future, Kathleen M. Conlee, Sarah T. Boysen 2016 The Humane Society of the United States

Chimpanzees In Research: Past, Present, And Future, Kathleen M. Conlee, Sarah T. Boysen

Sarah Boysen, Ph.D.

Although the welfare of chimpanzees encompasses many issues, this chapter addresses their use in research, including their historical and current use in the United States, ethical and scientific concerns, public opinion, international legislation, and future directions.


Addressing Distress And Pain In Animal Research: The Veterinary, Research, Societal, Regulatory And Ethical Contexts For Moving Forward, Kathleen Conlee, Martin Stephens, Andrew N. Rowan 2016 The Humane Society of the United States

Addressing Distress And Pain In Animal Research: The Veterinary, Research, Societal, Regulatory And Ethical Contexts For Moving Forward, Kathleen Conlee, Martin Stephens, Andrew N. Rowan

Martin Stephens, Ph.D.

While most people recognize that biomedical scientists are searching for knowledge that will improve the health of humans and animals, the image of someone deliberately causing harm to an animal in order to produce data that may lead to some future benefit has always prompted an uncomfortable reaction outside the laboratory. However, proponents of animal research have usually justified the practice by reference to greater benefits (new knowledge and medical treatments) over lesser costs (in animal suffering and death). Given that one of the costs of animal research is the suffering experienced by the animals, the goal of eliminating distress ...


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