Red-carpet rodent care: making the most of dollars and sense in the animal facility

Cutting-edge biomedical research programs have entered an era in which phenotypic characterizations for genetically altered rodents can facilitate appropriate care. The veterinary care requirements necessary to support such animal models can include the procedures already adapted as standard practice in companion animal hospitals, and can decrease data variability while increasing survival rates.     

Training nonhuman primates to perform behaviors useful in biomedical research

Data collected from NHPs that are trained to participate voluntarily in husbandry, veterinary, and research procedures are likely to have particular value. The authors present the results of a series of studies that examined the effects of PRT on the performance by chimpanzees of a variety of biomedically relevant behaviors: presenting their perineum for pinworm testing, providing a semen sample, presenting for an s.c. injection, and presenting for an i.m. injection. The overall trends across studies indicate that PRT techniques have significant value in the handling and management of NHPs in many laboratory research settings, including less variability in the data collected and fewer potential confounding variables, which should lead to important refinements in the definition of NHPs as biomedical research models.     

Guidelines for the veterinary care of laboratory animals: report of the FELASA/ECLAM/ESLAV Joint Working Group on Veterinary Care

Veterinary professionals working in partnership with other competent persons are essential for a successful animal care and use programme. A veterinarian's primary responsibilities are defined by their own professional regulatory bodies, but in this area of work there are further opportunities for contribution, which will assist in safeguarding the health and welfare of animals used in research. These guidelines are aimed not only at veterinarians to explain their duties, and outline the opportunities to improve the health and welfare of animals under their care, but also at employers and regulators to help them meet their responsibilities. They describe the desirability for postgraduate education towards specialization in laboratory animal medicine and detail the many competencies necessary to fulfil the role of the laboratory animal veterinarian. They detail the need for veterinary expertise to promote good health and good welfare of animals used in biomedical research during husbandry as well as when under experimental procedures. Regulatory and ethical aspects are covered as are the involvement of the veterinarian in education and training of others working in the animal care and use programme. Managerial aspects, including occupational health and safety, are also areas where the veterinarian's input can assist in the successful implementation of the programme.     

A comparison of pentobarbital, fentanyl-droperidol, ketamine-xylazine and ketamine-diazepam anesthesia in adult male rats

Proper use of anesthetics is of paramount importance for humane animal care. Current research trends show a greater reliance on rats for laboratory investigations. This study compared several dosages for four different drugs, (pentobarbital, fentanyl-droperidol, ketamine-xylazine and ketamine-diazepam) for use in the laboratory rat. Each drug was evaluated in respect to its onset, duration of effect, recovery, adverse effects and mortality. A quantitative assessment of the depth of anesthesia also was obtained for all dosages of each drug. Results showed that all tested dosages of pentobarbital, ketamine-xylazine and ketamine-diazepam were suitable anesthetics for use in the laboratory rat. Low dosages of fentanyl-droperidol (Innovar-Vet), however, appeared to produce a state known as neuroleptanalgesia as opposed to anesthesia seen with the other agents.     

Training strategies for research investigators and technicians

Training programs for research personnel are discussed as a key resource that must be part of an effective animal care and use program. Because of the legal responsibility to ensure that research staff are qualified to use animals, many institutions have justified the necessity for a training coordinator and/or trainers for their animal care and use programs. Effective training programs for research personnel must meet the needs of the client base (research scientists and staff) so that they are relevant, practical, and timely. To meet these objectives, it is useful to involve the scientific staff in the analysis of their learning needs. To meet a performance standard necessary for quality research, a large percentage of the institutional staff must participate in the training program. Often it is the principal investigators who set the tone for their staff members regarding the importance of receiving training. Garnering support from this client base will create a culture that encourages training and engenders a positive attitude about humane animal care and use. One effective approach is to incorporate nonanimal models as alternatives to live animals to teach humane handling techniques and methods, thereby contributing to refinement, reduction, and replacement (the 3Rs). Also discussed are the necessity of timely feedback from clients, documentation of personnel training for regulatory purposes, and the collection of training metrics, which assists in providing justification for the granting of additional fiscal support for the program. Finally, the compliance procedures and opportunities for essential refresher training are discussed and related to high performance standards, humane animal use, and quality research, all of which contribute to the 3Rs.     

IACUC Challenges in Invertebrate Research

With billions of individuals and possibly hundreds of thousands of genera, invertebrates represent the largest number and greatest diversity of all animals used in research. Although the capacity for nociception is recognized in many invertebrate taxa, researchers and IACUC members are challenged by a lack of clear understanding of invertebrate welfare and by differing standards of moral concern for these taxa. In practice this has led IACUCs to consider invertebrates in two major groups: species worthy of increased moral concern approximating that shown to vertebrate species (this group includes cephalopods and to some extent decapod crustaceans) and all others. This dichotomy has led to differences in how invertebrate research is regulated and documented. This article presents two case studies illustrating specific concerns in invertebrate research protocols and then provides relevant information to address practical IACUC matters related to regulatory and ethical issues, sourcing and record keeping, risk management, assessment of pain and nociception in invertebrates, housing and husbandry, invasive procedures, veterinary care, and humane endpoints.     

Fundamental training for individuals involved in the care and use of laboratory animals: a review and update of the 1991 NRC Core Training Module

Public trust demands that individuals who do research, testing, or teaching with animals use humane, ethical, and scientifically sound methods. Furthermore, the Animal Welfare Act and the Public Health Service Policy require research institutions to provide basic training and to ensure that anyone who cares for and/or works with laboratory animals has the appropriate training or experience relevant to their job responsibilities. Institutions accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International must also provide training programs and ensure the qualifications of personnel. The primary goal of this training is to provide individuals with basic knowledge and to reinforce attitudes and behaviors that help to ensure humane animal care and use. This article provides an overview of the core training module outline and content from the 1991 report of the Institute for Laboratory Animal Research, Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs, as well as pertinent updates for introducing personnel to information regarding the care and use of laboratory animals. Both mandatory and suggested training topics are reviewed, including relevant regulations and standards, ethical considerations, humane methods of animal experimentation and maintenance, and other pertinent topics. Although the fundamental training course content and delivery will vary depending on the nature and complexity of an institution's animal care and use program, this basic training provides the foundation for more in-depth training programs and supports humane and ethical animal care and use.     

Veterinary care of Asian timber elephants in India: Historical accounts and current observations

We discuss herein some of the historical factors that have influenced present day veterinary treatment and husbandry of Asian elephants used for timber extraction by Indian state forest departments. The British incorporated both indigenous and European practices into the veterinary management of timber elephants, and invested considerable time and energy to improve care and humane standards. The paper examines selected aspects of preventive and clinical treatment based on records from the Madras Presidency and present day Tamilnadu state. © 1995 Wiley-Liss, Inc.     

Veterinary and human vaccine evaluation methods

Despite the universal importance of vaccines, approaches to human and veterinary vaccine evaluation differ markedly. For human vaccines, vaccine efficacy is the proportion of vaccinated individuals protected by the vaccine against a defined outcome under ideal conditions, whereas for veterinary vaccines the term is used for a range of measures of vaccine protection. The evaluation of vaccine effectiveness, vaccine protection assessed under routine programme conditions, is largely limited to human vaccines. Challenge studies under controlled conditions and sero-conversion studies are widely used when evaluating veterinary vaccines, whereas human vaccines are generally evaluated in terms of protection against natural challenge assessed in trials or post-marketing observational studies. Although challenge studies provide a standardized platform on which to compare different vaccines, they do not capture the variation that occurs under field conditions. Field studies of vaccine effectiveness are needed to assess the performance of a vaccination programme. However, if vaccination is performed without central co-ordination, as is often the case for veterinary vaccines, evaluation will be limited. This paper reviews approaches to veterinary vaccine evaluation in comparison to evaluation methods used for human vaccines. Foot-and-mouth disease has been used to illustrate the veterinary approach. Recommendations are made for standardization of terminology and for rigorous evaluation of veterinary vaccines.     

Commissioning a national programme of research and development on the interface between primary and secondary care.

The first call for applications to the NHS research and development programme on the interface between primary and secondary care was advertised in February 1994. A total of 674 outline proposals were submitted and 54 (8%) secured funding. Projects have been commissioned in 16 of the 21 priority areas and around 6m pounds has been committed. Analysis shows that multidisciplinary applications are more likely to be funded and that the odds for a successful application are on average nearly doubled for each discipline represented up to five. A survey of applicants and peer reviewers found satisfaction with much of the commissioning process, but peer review and feedback were subject to criticism, particularly by unsuccessful applicants. The programme shows that it is possible to commission a large number of projects in an innovative area of research and development and has identified refinements that will further increase the efficiency and acceptability of the process.     

A sample postapproval monitoring program in academia

The primary goal of an animal care and use program (ACUP) should be to ensure animal well-being while fostering progressive science. Both the Animal Welfare Act (and associated regulations) and the Public Health Service (PHS) Policy require the institutional animal care and use committee (IACUC) to provide oversight of the animal program through continuing reviews to ensure that procedures are performed as approved by the committee. But for many committees the semiannual assessment does not provide an opportunity to observe research procedures being performed. Furthermore, IACUC members are typically volunteers with other full-time commitments and may not be able to dedicate sufficient time to observe protocol performance. Postapproval monitoring (PAM) is a tool that the IACUC can use to ensure that the institution fulfills its regulatory obligation for animal program oversight. When performed by attentive and observant individuals, PAM can extend the IACUC's oversight, management, training, and communication resources, regardless of program size or complexity. No defined PAM process fits all institutions or all situations; rather, the monitoring must match the program under review. Nonetheless, certain concepts, concerns, and conditions affect all PAM processes; they are described in this article. Regardless of the style or depth of PAM chosen for a given program, one thing is sure: failure of the IACUC to engage all available and effective oversight methods to ensure humane, compassionate, efficient, and progressive animal care and use is a disservice to the institution, to the research community and to the animals used for biomedical research, testing, or teaching.     

Postapproval monitoring and the IACUC

Monitoring of the use of live vertebrate animals in research, teaching, and testing after approval of their use by an institutional animal care and use committee (IACUC) are receiving increased attention in the laboratory animal community. In this article the author provides his opinions on the value of postapproval monitoring (PAM) to the overall self-regulation that is the responsibility of an IACUC. PAM must never supersede or replace federally mandated IACUC responsibilities, but an efficient PAM process can provide significant additional information that enables an institution to be confident that it is meeting both the letter and the spirit of the federal regulations developed to ensure humane animal care. PAM personnel should be excellent communicators and able to maintain a professional demeanor in challenging circumstances. Their knowledge of laboratory animal care, invasive procedures, and regulations will enable them to align the pursuit of scientific research with adherence to these regulations. An effective PAM program involves knowledgeable individuals who can, on behalf of the IACUC, monitor new procedures and personnel and provide IACUC-mandated training or retraining.     

Microsurgical vasectomy reversal: results and predictors of success

Microsurgical vasectomy reversal is a challenge for the physician but successful treatment depends on the experience and skills of the surgeon. Fertility can often be restored, thus avoiding the need for artificial reproductive techniques. Also, the surgical procedures can be combined with sperm aspiration and cryopreservation, to be used for Intracytoplasmic sperm injection (ICSI) in cases of surgical failure. We describe the results of 217 vasovasostomy procedures, with special emphasis on recent technical refinements and prognostic indicators. Between 1998 and 2002 we performed 217 vasovasostomy-procedures in an outpatient clinic setting. Refertilisation was successful in 76.5%, spontaneous pregnancy occurred in 42% of the couples after, a follow-up of at least 1 year. The main prognostic factors determining the outcome of the surgery was the interval between vasectomy and refertilisation and the age of the female partner: patency was 89% after an interval of less than 5 years and pregnancy occurred in 56% of these couples. After an interval of more than 10 years patency decreased to 75% and pregnancy results dropped to 24%. Epididymal dysfunction with poor motility score and secondary epididymal obstruction appeared to be common after a long interval. Furthermore, in men with partners older than 35 years of age pregnancy was only 21%, indicating limited ovarian reserve as an important factor in determining the final outcome. In men with a long obstructive interval between vasectomy and reversal an obstruction of the epididymis can be found due to a blow-out of the epididymal tubule with subsequent leakage of semen in the organ and fibrosis. A vaso-epididymostomy procedure is needed to treat the obstruction. Recently, surgical refinements, such as the invagination technique, have been introduced for the vaso-epididymostomy procedure, showing promising first results. This simplified technique enables less experienced microsurgeons to perform this difficult operation successfully. The results of vasectomy reversal procedures can be improved substantially if the surgeon is able to perform a vaso-epididymostomy in cases of a secondary epididymal obstruction, occurring in about 25% of men with an interval of more than 10 years.     

Human platelet myosin. I. Purification by a rapid method applicable to other nonmuscle cells

Using refinements of established procedures and a new two buffer gel filtration method, it is possible to prepare human platelet myosin which by gel electrophoresis is free from actin and over 95% pure. This method with minor modifications is useful for the purification of myosin from several other nonmuscle cells.     

Selection, acclimation, training, and preparation of dogs for the research setting

Dogs have made and will continue to make valuable contributions as animal models in biomedical research. A comprehensive approach from time of breeding through completion of in-life usage is necessary to ensure that high-quality dog models are used in studies. This approach ensures good care and minimizes the impact of interanimal variability on experimental results. Guidance related to choosing and developing high-quality laboratory dogs and managing canine research colonies is provided in this article. Ensuring that dogs are healthy, well adapted, and cooperative involves good communication between vendors, veterinarians, care staff, and researchers to develop appropriate dog husbandry programs. These programs are designed to minimize animal stress and distress from the postweaning period through the transfer and acclimation period within the research facility. Canine socialization and training programs provided by skilled personnel, together with comprehensive veterinary health programs, can further enhance animal welfare and minimize interanimal and group variability in studies.     

Regulatory issues surrounding the use of companion animals in clinical investigations,trials, and studies

Laboratory animal veterinarians sometimes encounter animals with rare conditions and may subsequently become involved in the performance of related animal research outside the laboratory, in homes, in veterinary clinics, or in universities to which owners have donated their animals for study. Similarly, veterinarians may monitor animal companion vaccination studies, performed to optimize preventive health care or minimize physiological variability and research confounders associated with a preventive medicine program for dogs and cats utilized for research procedures. These nontraditional uses of dogs, cats, and other companion animals in research have spurred the establishment of regulations to ensure that the animals benefit from clinical veterinary products and techniques. Included and described are the 2002 Public Health Service Policy, the Animal Welfare Act (AWA), the Federal Food, Drug, and Cosmetic Act, and the regulations of the US Department of Agriculture in response to the AWA. The complexities of clinical research with companion animals outside standard biomedical research facilities are discussed.     

Objective measures of health and well-being in laboratory rhesus monkeys (Macaca mulatta)

BACKGROUND: Non-human primates are an invaluable part of biomedical research. Strict regulations insure animals have a maximum likelihood of well-being and optimum health during the course of experimental procedures. Objective assessment of well-being is a critical component of these assurances. METHODS: Here we describe an objective and quantitative system we used to identify two well-being concerns in laboratory rhesus monkeys (Macaca mulatta). We provide a series of indicators for use by laboratory personnel to promote laboratory primate well-being. The indicators measure (1) potentially life threatening clinical concerns, (2) developing clinical issues, (3) atypical behaviors, and (4) laboratory performance. We include specific criteria to facilitate veterinary intervention. RESULTS: The assessment, applied to two case studies reported here, enabled swift veterinary intervention returning the animals to a healthy state. CONCLUSIONS: The measures described here provide a battery of observable and objective measures across multiple dimensions that can further ensure both excellent science and veterinary care.     

Ultra-high dimensional variable selection for doubly robust causal inference

Causal inference has been increasingly reliant on observational studies with rich covariate information. To build tractable causal procedures, such as the doubly robust estimators, it is imperative to first extract important features from high or even ultra-high dimensional data. In this paper, we propose causal ball screening for confounder selection from modern ultra-high dimensional data sets. Unlike the familiar task of variable selection for prediction modeling, our confounder selection procedure aims to control for confounding while improving efficiency in the resulting causal effect estimate. Previous empirical and theoretical studies suggest excluding causes of the treatment that are not confounders. Motivated by these results, our goal is to keep all the predictors of the outcome in both the propensity score and outcome regression models. A distinctive feature of our proposal is that we use an outcome model-free procedure for propensity score model selection, thereby maintaining double robustness in the resulting causal effect estimator. Our theoretical analyses show that the proposed procedure enjoys a number of properties, including model selection consistency and pointwise normality. Synthetic and real data analysis show that our proposal performs favorably with existing methods in a range of realistic settings. Data used in preparation of this paper were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.