A survey to understand public opinion regarding animal use in medical training.

A random survey was performed by ORC International Telephone CARAVAN®, on 24-27 March 2016, by trained interviewers. The aim of this survey was to gain further understanding of public perceptions in the United States of laboratory animal use, specifically for the purposes of medical training. Five statements were read in random order to the participants, who were then asked whether they agreed or disagreed with the statement. Survey responses were obtained from 1011 participants. For the combined statements: "If effective non-animal methods are available to train a) medical students and physicians, b) emergency physicians and paramedics, and c) paediatricians, those methods should be used instead of live animals", most respondents (82-83%) agreed. For the statement: "You want your doctor to be trained by using methods that replicate human anatomy instead of live animals", most respondents (84%) agreed. For the statement: "If effective non-animal methods are available, it is morally wrong or unethical to use live animals to train medical students, physicians and paramedics", 67% of respondents agreed. Responses were similar among the 15 pre-specified demographic subgroups. Given that effective non-animal training methods are readily available, the survey suggests that a substantial majority of the public wants the use of animals in medical training to cease.

Animal research for type 2 diabetes mellitus, its limited translation for clinical benefit, and the way forward.

Obesity and type 2 diabetes mellitus (T2DM) have reached pandemic proportions worldwide, and considerable research efforts have been dedicated to investigating disease pathology and therapeutic options. The two hallmark features of T2DM, insulin resistance and pancreatic dysfunction, have been studied extensively by using various animal models. Despite the knowledge acquired from such models, particularly mechanistic discoveries that sometimes mimic human T2DM mechanisms or pathways, many details of human T2DM pathogenesis remain unknown, therapeutic options remain limited, and a cure has eluded research. Emerging human data have raised concern regarding inter-species differences at many levels (e.g. in gene regulation, pancreatic cytoarchitecture, glucose transport, and insulin secretion regulation), and the subsequent impact of these differences on the clinical translation of animal research findings. Therefore, it is important to recognise and address the translational gap between basic animal-based research and the clinical advances needed to prevent and treat T2DM. The purpose of this report is to identify some limitations of T2DM animal research, and to propose how greater human relevance and applicability of hypothesis-driven basic T2DM research could be achieved through the use of human-based data acquisition at various biological levels. This report addresses how in vitro, in vivo and in silico technologies could be used to investigate particular aspects of human glucose regulation. We do not propose that T2DM animal research has been without value in the identification of mechanisms, pathways, or potential targets for therapies, nor do we claim that human-based methods can provide all the answers. We recognise that the ultimate goal of T2DM animal research is to identify ways to advance the prevention, recognition and treatment of T2DM in humans, but postulate that this is where the use of animal models falls short, despite decades of effort. The best way to achieve this goal is by prioritising human-centred research.

The human subject: an integrative animal model for 21(st) century heart failure research.

Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21(st) century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research.

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Animal models of Alzheimer disease: historical pitfalls and a path forward.

Alzheimer disease (AD) is a medically and financially overwhelming condition, and incidence rates are expected to triple by 2050.Despite decades of research in animal models of AD, the disease remains incompletely understood, with few treatment options. This review summarizes historical and current AD research efforts, with emphasis on the disparity between preclinical animal studies and the reality of human disease and how this has impacted clinical trials. Ultimately, we provide a mechanism for shifting the focus of AD research away from animal models to focus primarily on human biology as a means to improve the applicability of research findings to human disease. Implementation of these alternatives may hasten development of improved strategies to prevent, detect, ameliorate, and possibly cure this devastating disease.

Of rodents and men: species-specific glucose regulation and type 2 diabetes research.

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions worldwide and animal models mimicking human T2DM are widely used to study mechanisms of disease and to develop pharmacotherapeutics. Over the last three decades, rodent models of T2DM have yielded more than 50 publications per month; however, many details of human T2DM pathogenesis remain unclear, and means of preventing disease progression remain elusive. This review investigates the reasons for this translational discrepancy by analyzing the experimental evidence from rodent models of T2DM. The analysis revealed significant species-specific differences at every level of glucose regulation, from gene/protein expression, cellular signaling, tissue and organ to whole organism level, when compared with data acquired using human cells, tissues, organs, and populations. Given the extensive species-specific barrier that creates an immutable translational gap, there is an urgent need to further employ and develop human-based research strategies to make significant strides against the current T2DM epidemic.

Animal studies in spinal cord injury: a systematic review of methylprednisolone.

The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods.

Animal models in spinal cord injury: a review.

Multiple neuroprotective agents have shown benefit for the treatment of acute spinal cord injury (SCI) in animal studies. However, clinical trials have, thus far, been uniformly disappointing. This review explores reasons for discrepancies between promising animal studies and disappointing clinical trials and potential barriers to extrapolation of research results from animals to humans. The three major barriers disclosed are: differences in injury type between laboratory-induced SCI and clinical SCI, difficulties in interpreting functional outcome in animals, and inter-species and interstrain differences in pathophysiology of SCI. These barriers can impair the effectiveness of animal models of SCI to predict human outcomes. While some of these barriers can be overcome, others are inherent to the animal models.

Coronary artery calcium score and coronary heart disease events in a large cohort of asymptomatic men and women.

Coronary artery calcium (CAC), a measure of subclinical coronary heart disease (CHD), may be useful in identifying asymptomatic persons at risk of CHD events. The current study included 10,746 adults who were 22-96 years of age, were free of known CHD, and had their CAC quantified by electron-beam tomography at baseline as part of a preventive medical examination at the Cooper Clinic (Dallas, Texas) during 1995-2000. During a mean follow-up of 3.5 years, 81 hard events (CHD death, nonfatal myocardial infarction) and 287 total events (hard events plus coronary revascularization) occurred. Age-adjusted rates (per 1,000 person-years) of hard events were computed according to four CAC categories: no detectable CAC and incremental sex-specific thirds of detectable CAC; these rates were, respectively, 0.4, 1.5, 4.8, and 8.7 (trend p<0.0001) for men and 0.7, 2.3, 3.1, and 6.3 (trend p=0.02) for women. CAC levels also were positively associated with rates of total CHD events for women and men (trend p<0.0001 each). The association between CAC and CHD events remained significant after adjustment for CHD risk factors. CAC was associated with CHD events in persons with no baseline CHD risk factors and in younger (aged <40 years) and older (aged >65 years) study participants. These findings show that CAC is associated with an increased risk of CHD events in asymptomatic women and men.