George Langan

TNF-α and Microglial Hormetic Involvement in Neurological Health & Migraine.

Environmental enrichment, i.e., increased intellectual, social, and physical activity makes brain more resilient to subsequent neurological disease. The mechanisms for this effect remain incompletely defined, but evidence shows tumor necrosis factor-alpha (TNF-α) is involved. TNF-α, at acutely high levels, possesses the intrinsic capacity to enhance injury associated with neurological disease. Conversely, the effect of TNF-α at low-levels is nutritive over time, consistent with physiological conditioning hormesis. Evidence shows that neural activity triggers low-level pro-inflammatory signaling involving TNF-α. This low-level TNF-α signaling alters gene expression, resulting in an enhanced resilience to disease. Brain-immune signaling may become maladaptive when increased activity is chronic without sufficient periods of reduced activity necessary for nutritive adaptation. Such tonically increased activity may explain, for example, the transformation of episodic to chronic migraine with related increased susceptibility to spreading depression, the most likely underlying cause of this malady. Thus, TNF-α, whose function is to alter gene expression, and its principal cellular source, microglia, seem powerfully positioned to orchestrate hormetic immune signaling that establishes the phenotype of neurological health and disease from brain activity.

Respiratory Diseases of Rodents and Rabbits

This article is written to provide differential diagnostic help for the practitioner who suspects respiratory disease in rodents or rabbits. The authors are laboratory animal veterinarians who work with rodents and rabbits on a herd health basis but also have considerable experience dealing with individual mice, rats, guinea pigs, hamsters, gerbils, and rabbits. The article presents descriptions of the presentation, pathology, treatment, and control of the primary respiratory pathogens of these species, along with an explanation of conditions that may confuse the diagnostic efforts. The article also mentions reported pathogens of secondary importance and provides extensive references.

Response to Protocol Review Scenario: A need for more justification

1. United States Department of Agriculture. Animal Welfare Act regulations (2013). 2. Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals 8th edn. (National Academies Press, Washington, DC, 2011). 3. Public Health Service. Policy on Humane Care and Use of Laboratory Animals. (US Department of Health and Human Services, Washington, DC, 1986; revised 2015). 4. Amateau, S.K. & McCarthy, M.M. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat. Neurosci. 7, 643–650 (2004). 5. Arendt, D. & Nubler-Jung, K. Comparison of early nerve cord development in insects and vertebrates. Development 126, 2309-2325 (1999).

Developing a Business Plan for Your Gnotobiotics Program

Abstract With the recent rebirth in the use of gnotobiotic animals, many researchers are looking to establish gnotobiotic technology as part of their research program. Gnotobiotic animal colonies require rigorous attention to detail and strict management practices to maintain their microbial status. Because of intensity of these operations, the cost associated with maintaining these animals can be significant. Before considering the establishment of a gnotobiotic facility, an operational and business plan should be developed to assure all parties involved understand how the facility will operate and how it will be financially supported. There are many ways to operate and financially support these facilities, so that one size does not fit all. This chapter will outline the financial and management issues to be considered when establishing and operating a gnotobiotic facility and will guide the reader in preparing an operational business plan for the facility.

Reconsider, communicate, collaborate.

parameters might not be indicators that an animal requires treatment or has reached a humane endpoint. The IACUC should reconsider this study. Hodges does not seem to understand the difference between humane and experimental endpoints, why they are important and how they relate to the study. The IACUC should take this opportunity to educate him about these concepts. In addition, the IACUC, the veterinarians and Hodges should work together to assess the types of data being collected, determine which data are clinically relevant and develop better humane endpoints. The IACUC should also encourage the use of the remote monitoring system because it will enable more aggressive monitoring, thus addressing the animal welfare concerns, while allowing the investigator to conduct this work with limited staff and funds. This is especially important in today’s funding climate. Furthermore, the Most of this monitoring appears to have been designed to assure that his animals can reach the experimental endpoint. However, the monitoring plan described in his protocol does not take advantage of data that could be used to determine early euthanasia criteria, such as the rats’ appearance in the images he is collecting. In addition, by indicating that animals with severe hypoglycemia or excessively high or low body temperature would simply be excluded from the study rather than treated or humanely euthanized, Hodges has failed to identify humane endpoints. The IACUC seems to be asking Hodges to define humane endpoints on the basis of abnormalities in the physiologic data, even if some of these abnormalities do not always indicate pain or distress. For example, bradycardia, tachycardia and cardiac arrhythmia can be benign or clinically insignificant, and mild or moderate hypoglycemia is often subclinical. Taken by themselves, these ReSponSe

Cost: benefit evaluations for research protocols. Response: IACUC or granting agency.

A cost:benefit analysis is done to some degree in the US, but there is room for improvement in this area. The IACUC and the National Institutes of Health (NIH) share the responsibility of considering the importance and rationale of every NIHfunded study before it is approved, as Covelli asserts about Rosinski’s work in this scenario. But the IACUC should not simply defer the analysis to the NIH, according to The IACUC Handbook1 and the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy)2. Other funding or grant agencies may carry out peer review that considers scientific merit or cost:benefit analysis for projects that they sponsor. The IACUC alone, however, accepts responsibility for review of scientific merit or cost:benefit analysis, if this is not considered elsewhere. The IACUC proposal form requires a Principal Investigator to provide an explanation of the importance and rationale of the research before any procedure is done on animals. This prompts the investigator to carry out a cost:benefit analysis of each study in order to convince the IACUC that the animal use is justified. In accordance with Animal Welfare Regulations3 and PHS Policy (including the nine US Government Principles)2, US IACUCs should approve only those protocols that are “consistent with sound research design,” that include a “rationale for involving animals” and in which “discomfort and injury be limited to what is unavoidable in the conduct of scientifical ly valuable research.” of Health (NIH) and that such grants require approval by a scientific board of experts after review of the importance of the scientific question to be answered, the quality of the proposed methods and the Principal Investigator’s ability to carry out the study. The NIH scientific study section considers additional factors in its review of the grant proposal that may address some of the concerns raised. Proposals are reviewed for importance and innovation, and the vertebrate use section specifically requires a description of the rationale for the use of animals in the study. These additional review topics further address Paulson’s concerns about the importance of the work to be done and about whether the study would truly provide new information. The IACUC has an important role in evaluating the cost:benefit ratio of a study, because it not only reviews the aforementioned issues of animal use justification but also determines the level of care provided to the animals, determines whether and how analgesia is provided and approves appropriate humane endpoints to eliminate or reduce any pain and distress the animals may be exposed to during the study. Thus, the IACUC can be seen as the entity that minimizes the ‘cost’ of the study in terms of the cost:benefit ratio, as it makes the final decision to allow the study to be done. Together, the NIH and the IACUC share the responsibility of evaluating the cost:benefit ratio of the research study. Such evaluations should consider the near-universally accepted principles of the 3Rs: reduction in animal numbers or unnecessary duplication of studies, refinement of procedures and species utilized, and replacement of animal models where possible1. In England, protocol or proposal review is accomplished through an application for a Project Licence through the United Kingdom Home Office. This office operates under the provisions of the Animals Scientific Procedure Act of 1986 (http://scienceandresearch.homeoffice.gov. uk/). Though structured and implemented slightly differently, the oversight of the United Kingdom Home Office is analogous to the regulatory and ethical oversight of the NIH and IACUC, in accordance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals2 and the Animal Welfare Act3, in the US. pondered by philosophers for hundreds of years, so far without a clear consensus, and I won’t try to solve it here. Even though ethical review is not mandated and is nearly impossible to carry out, if an IACUC member doesn’t believe that a question to be answered is of any value, how, in good conscience, can he or she justify the suffering of animals to answer that question? If such concerns exist, the burden of proof must fall to the investigator to provide a description of the perceived benefits of the study to the satisfaction of the committee. If there is still disagreement, the IACUC vote should always be the deciding factor.