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Abstract

Simple Summary: Legislation and guidelines governing biomedical research with humans and non-human primates (NHPs) rely on different ethical frameworks. In this paper we argue that the main ethical framework used to assess and justify NHP experimentation is inadequate for its purpose. We propose a change of framework that we believe would benefit NHPs and improve research quality. Abstract: Basic and applied laboratory research, whenever intrusive or invasive, presents substantial ethical challenges for ethical committees, be it with human beings or with non-human animals. In this paper we discuss the use of non-human primates (NHPs), mostly as animal models, in laboratory based research. We examine the two ethical frameworks that support current legislation and guidelines: deontology and utilitarianism. While human based research is regulated under deontological principles, guidelines for laboratory animal research rely on utilitarianism. We argue that the utilitarian framework is inadequate for this purpose: on the one hand, it is almost impossible to accurately predict the benefits of a study for all potential stakeholders; and on the other hand, harm inflicted on NHPs (and other animals) used in laboratory research is extensive despite the increasing efforts of ethics committees and the research community to address this. Although deontology and utilitarianism are both valid ethical frameworks, we advocate that a deontological approach is more suitable, since we arguably have moral duties to NHPs. We provide suggestions on how to ensure that research currently conducted in laboratory settings shifts towards approaches that abide by deontological principles. We assert that this would not impede reasonable scientific research.
animals
Article
Ethical and Scientific Pitfalls Concerning Laboratory
Research with Non-Human Primates, and
Possible Solutions
Constança Carvalho 1, * , Augusta Gaspar 2, Andrew Knight 3and Luís Vicente 1
1Centre for Philosophy of Science of the University of Lisbon, Department Animal Biology,
Faculty of Sciences, University of Lisbon, Lisbon 1749-016, Portugal; lmvicente@fc.ul.pt
2Catolica Research Center for Psychological, Family and Social Wellbeing (CRC-W), Universidade Católica
Portuguesa, Palma de Cima, Lisboa 1649-023, Portugal; augusta.gaspar@fch.lisboa.ucp.pt
3Centre for Animal Welfare, Faculty of Humanities and Social Sciences, University of Winchester,
Winchester SO22 4NR, UK; Andrew.Knight@winchester.ac.uk
*Correspondence: constanca.carvalho@sapo.pt; Tel.: +351-919943195
Received: 21 July 2018; Accepted: 24 December 2018; Published: 29 December 2018
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Simple Summary:
Legislation and guidelines governing biomedical research with humans and
non-human primates (NHPs) rely on different ethical frameworks. In this paper we argue that the
main ethical framework used to assess and justify NHP experimentation is inadequate for its purpose.
We propose a change of framework that we believe would benefit NHPs and improve research quality.
Abstract:
Basic and applied laboratory research, whenever intrusive or invasive, presents substantial
ethical challenges for ethical committees, be it with human beings or with non-human animals.
In this paper we discuss the use of non-human primates (NHPs), mostly as animal models, in
laboratory based research. We examine the two ethical frameworks that support current legislation
and guidelines: deontology and utilitarianism. While human based research is regulated under
deontological principles, guidelines for laboratory animal research rely on utilitarianism. We argue
that the utilitarian framework is inadequate for this purpose: on the one hand, it is almost impossible
to accurately predict the benefits of a study for all potential stakeholders; and on the other hand, harm
inflicted on NHPs (and other animals) used in laboratory research is extensive despite the increasing
efforts of ethics committees and the research community to address this. Although deontology and
utilitarianism are both valid ethical frameworks, we advocate that a deontological approach is more
suitable, since we arguably have moral duties to NHPs. We provide suggestions on how to ensure
that research currently conducted in laboratory settings shifts towards approaches that abide by
deontological principles. We assert that this would not impede reasonable scientific research.
Keywords:
non-human primate research; biomedical research; deontology; utilitarianism; animal
use alternatives
1. Non-Human Primates in Laboratory Research
Since the mid twentieth century, non-human primates (NHPs) have been widely used in laboratory
research, mostly in biomedical research [1], and mostly in the cognitive sciences [2].
In recent years, due to public pressure and legislation, the number of NHPs used in biomedical
research has been significantly reduced in the European Union and the United States [
3
,
4
], but has
increased dramatically in some other countries, particularly China [5].
Some researchers claim that the use of NHPs in biomedical research is crucial, due to their
similarities with humans [
6
,
7
], and state that a total ban on such research would compromise medical
Animals 2019,9, 12; doi:10.3390/ani9010012 www.mdpi.com/journal/animals
Animals 2019,9, 12 2 of 17
advances in several fields, such as those focused on infectious diseases, cardiovascular diseases,
endocrine diseases, reproductive diseases, neurological disorders, ophthalmic diseases [
5
,
6
] asthma,
certain types of cancer [
1
], transplants [
8
] and psychiatric disorders [
4
]. However, for many years
the presumed benefits of NHP research for medical advances were not subjected to rigorous critical
evaluation. In recent years however, evidence-based assessments have been conducted, frequently
demonstrating that NHP models have provided disappointing contributions toward human medical
advancements [912].
In the cognition and behaviour domains, studies with captive primates have made relevant
contributions to psychology and neuroscience, as exemplified by Harlow’s experiments on “the nature
of love” [
13
] or Selemon and Goldman Rakic’s [
14
] early brain topography studies. In both cases, as in
many others, discoveries were made which incurred high costs to NHP subjects, including suffering
and death. The ecological validity of behavioural and cognitive studies conducted on captive NHPs
has also been questioned [15].
2. Similarities between Humans and Non-Human Primates
Moral concerns raised by the use of NHPs in intrusive or invasive research result from their
sentience, consciousness and affective states. In those aspects, NHPs are very similar to humans, which
makes it reasonable to give them similar protection to that afforded to human subjects. However, they
are very different in other aspects, so they are not necessarily good models for human biology.
From the mid-twentieth century onwards, it became clear that NHPs and humans shared so many
traits that trying to categorise any trait as wholly human became something of a futile exercise. Below,
we present a few examples of studies that brought a greater awareness of the high similarity (and
evolutionary continuity) between humans and NHPs.
Some of the very first “humanlike” capabilities that attracted considerable scientific interest
were the discoveries that NHPs build and use tools [
16
,
17
], solve new problems, and develop and
pass on cultural behaviour [
18
,
19
]. NHPs of several species have also demonstrated the ability
to recognise themselves in a mirror—an ability that has been largely interpreted as evidence of
self-awareness [
20
,
21
]. This was once thought to be a uniquely human ability. All NHPs that have
been studied to date, from rhesus monkeys to chimpanzees and gorillas, have also been shown to have
distinct personalities with complex behavioural patterns, as occurs with humans [
22
]. Furthermore,
all NHPs establish strong social bonds [
23
,
24
], and most live in complex societies [
25
]. Like humans,
NHPs experience and display emotions [
26
], strong mother–infant and other familial bonds [
27
] and
are capable of experiencing empathy and behaving sympathetically (e.g., [
28
,
29
]). In addition, an
increasing amount of evidence has accumulated that they have notions of justice and unfairness [
30
].
NHPs communicate effectively through vocalisations, gestures, and facial expressions [
31
35
]. They
possess a linguistic and lateralised brain which allows them to learn and use sign language, among
other skills [
36
,
37
]. NHP cognitive abilities have been astounding us for many years. NHPs can
create lasting memories [
38
,
39
], possess mathematical skills [
40
], and can even outperform university
students in numerical memory [
41
]. They can solve complex problems that require intelligence [
42
44
].
These skills are not exclusive to NHPs and can be found across a number of other non-human
animal species. However, NHP behaviour and skills are among the most well documented. The fact
that they are our closest living relatives has probably facilitated the recognition and social acceptance
of their cognitive abilities and emotional lives and has probably made them a preferred target for
cognitive research.
Collectively, these and many other studies addressing primate cognition, emotion, and social
behaviour have become the scientific basis for arguing that NHPs should be afforded a significant
moral status, for some authors [
45
,
46
]. It has also been pointed out that the similarities between humans
and NHPs are the main ethical obstacle regarding the laboratory confinement and use of NHPs [
47
].
This is indeed a controversial issue within the scientific community, and for the wider public [
48
,
49
],
but the recognition that there are significant ethical concerns to be addressed is nearly universal.
Animals 2019,9, 12 3 of 17
Because of their anatomical and physiological similarity to humans [
50
], as well as such cognitive,
behavioural, and social similarities, NHPs have been portrayed as ideal animal models for some
biomedical and cognitive research problems.
However, such similarities do not automatically make NHPs ideal models for humans within
biomedical research [
15
]. For example, major evolutionary jumps have occurred since the last common
ancestor humans shared with chimpanzees, with homologous brain areas being recruited in humans
for new functions, and new structures emerging altogether [51].
3. The Ethical Frameworks of Deontology and Utilitarianism
Biomedical research, with both humans and non-human animals, presents considerable ethical
challenges, since it is not uncommonly invasive or intrusive, causing pain, stress or discomfort. For
example, xenotransplantation experiments are classified under the current legislation as “severe”
procedures, since they are likely to compromise the general health of the animal in the case of organ
rejection. However, NHPs are still presently used in this sort of research [52,53].
In modern human societies, laws should express and enforce society’s moral codes [
54
].
Legislation and ethical guidelines have arisen to guide scientists through ethical dilemmas and prevent
forms of abuse that were more common in the past. Classical examples include the use of orphans to
carry smallpox live vaccine through arm-to-arm transportation across the Atlantic Ocean during the
19th century—this involves vaccinating a child and then transferring the vaccine to another as soon as
the infectious pustule forms [
55
]; medical research conducted with prisoners by German doctors; and
the infamous Tuskegee research, in which African-Americans that had syphilis unknowingly were
not given treatment so the doctors could study the natural progress of the disease in rural American
areas between 1932 and 1972 [
56
]. After World War II and the subsequent Nuremberg trials, rules
and principles to guide research with human beings emerged. The general rules that guide modern
research with human subjects were written by the Council for International Organizations of Medical
Sciences (CIOMS) in collaboration with the World Health Organization (WHO) in 1982 and revised in
1993 and 2002 [
57
]. The International Ethical Guidelines for Biomedical Research Involving Human
Subjects—which has been transposed into legislation or guidelines in most countries, established four
basic ethical principles: respect for persons, beneficence, non-maleficence and justice.
Respect for persons includes the principle of autonomy (as described by Beauchamp and
Childress [
58
]), and the protection of individuals with impaired autonomy [
57
]. The beneficence
principle refers to the obligation to maximise benefit, whilst the non-maleficence principle refers to
minimising harm [
57
,
58
], in keeping with the utilitarianism view (see section below), except that in
this case the permissible harm must be mild, regardless of expected benefits [
58
,
59
]. The principle
of justice requires the equitable distribution of resources, which in the case of biomedical research
translates to an equal distribution of burdens and benefits amongst research participants [58,60].
The same principles are stated in The Belmont Report, a document created in the USA in 1978 by
the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.
This is a critical document for those involved in basic and clinical research with human beings [61].
Regarding clinical research, the regulations and mechanisms mentioned above seem to be effective
in solving most of the ethical challenges [
62
], but that is not the case with invasive animal experiments,
particularly those using NHPs [
63
,
64
]. The main reason for these inconsistencies seems to be the use of
different frameworks to evaluate and guide research with humans and NHPs [
65
]. Guidelines and
legislation that regulate human research rely on mostly deontological principles, while those that
regulate animal research rely on utilitarianism.
The use of different ethical frameworks for humans and NHPs may even result in opposing
ethical recommendations: genetic experiments, which are often restricted from an ethical point of view
when it comes to human beings [
59
,
66
], may be encouraged from an ethical point of view when it
comes to NHPs [6,67].
Animals 2019,9, 12 4 of 17
In the next sections, we briefly describe both ethical frameworks and analyse how each applies to
current NHP research.
3.1. Deontology
Deontological ethics is the normative ethical position often associated with the philosopher
Immanuel Kant, which judges the morality of an action based on the action
'
s adherence to a rule or
rules [
68
,
69
]. The underlying assumption is that something is good because it is the right thing to
do [
70
]. Deontology stands for principles that must be fulfilled regardless of their consequences [
71
]
and, according to Kant, there are hypothetical imperatives, which apply to someone who wishes to
achieve a certain goal, and categorical imperatives, which are universal, absolute, and unconditional
requirements that must be obeyed in all circumstances. Subsequent deontological philosophers, such
as Ross [
72
], included the concept of moral relativism in deontology, which states that the morally
right act is relative to the circumstances.
Ross [
72
] also postulated seven prima facie duties: (1) duty of beneficence (help other people to
increase their pleasure, improve their character, and so on); (2) duty of non-maleficence (avoid harming
other people); (3) duty of justice (to ensure people get what they deserve); (4) duty of self-improvement
(to improve oneself); (5) duty of reparation (to repay someone for acting wrongly towards them);
(6) duty of gratitude (to benefit people who have benefited oneself); (7) duty of promise-keeping (to
act according to explicit and implicit promises, including the implicit promise to tell the truth). It is
noteworthy that current legislation and guidelines on research with human subjects encompass the
first three.
Deontology was established as an anthropocentric and rationalist framework due to the firm
belief of rationalist philosophers that humankind is separated from the rest of animal kingdom
by an exclusive capacity of reasoning. Since we now know that reasoning is not an exclusively
human capacity, there is no reason why deontology should not be applied to non-human animals,
as proposed by the American philosopher Tom Regan [
73
]. His theory of animal rights [
73
] asserts
that every individual who is the subject of a life has inherent value. Such an animal is worthy of
moral consideration, regardless of his/her species. According to Regan [
73
], individuals that fulfil
the following criteria are “subjects of a life”: those who have beliefs and desires, perception, memory,
and a sense of future, including their own future, an emotional life together with feelings of pleasure
and pain, preference and welfare interests, the ability to initiate an action in pursuit of a goal, a
psychophysical identity over time; and an individual welfare in the sense that their experiential life
fares well or ill for them. According to Regan [
73
], “subjects of a life” ought to be respected and must
not be treated as means to an end.
Deontology in Contemporary NHP Research
Within biomedical research, NHPs are usually seen as merely means to an end. For example,
xenotransplantation research aims for engineered animals lacking certain antigens so that their organs
can be used for transplantation into human patients, with a reduced chance of immune rejection [
8
]. In
such cases, the animal is being used as a means to an end. Although the same institutions (e.g., CIOMS)
that wrote regulations and legislations to conduct clinical research also did so for animal research [
74
],
the deontological principles that guided the former are totally absent in the latter. Nevertheless,
European Directive 2010/63/EU on the protection of animals used for scientific purposes states that
“the performance of procedures that result in severe pain, suffering or distress, which is likely to be
long-lasting and cannot be ameliorated, should be prohibited” [
75
]. This incorporates, to some extent,
the non-maleficence principle.
Even though the beneficence and non-maleficence principles can be found—to a certain extent—in
some NHP laboratory research, the principle of justice is totally absent. As for the principle of
autonomy, this can be found occasionally in cognitive research projects, when the test apparatus is
built or presented in a way that animals enrol in the experiment of their own volition [41].
Animals 2019,9, 12 5 of 17
Several authors have recommended that NHPs (amongst other animals) involved in biomedical
research should receive ethical consideration similar to that granted to humans, as well as analogous
protection [
46
,
60
,
76
,
77
]. Most deontological guidelines require that the participant give informed
consent prior to participation in research [
59
], but there are humans who cannot give valid informed
consent (e.g., children or mentally incompetent adult patients). In such cases, the same deontological
principles apply to research conducted on them, resorting to legal guardians, and specific legislation
with greater restrictions. In most countries, humans who cannot consent may only be engaged in
research that benefits them directly [78,79].
According to the legislation in most countries, research protocols for human studies—especially
for humans who cannot provide consent—must be approved by independent experts (e.g.,
paediatricians in the case of children). Similar criteria could be used for NHPs who cannot consent,
but who can effectively communicate their wishes through behavioural traits interpretable by an
experienced primatologist. Additionally, if NHPs who are enrolled in a research experience had legal
guardians, whose consent was mandatory prior to commencing research—as occurs with humans
unable to understand or communicate informed consent [
60
,
77
], and as occurs in studies involving
owners together with their companion animals [
80
]—then we believe that research involving NHPs
would likely become more transparent and less exploitative than has sometimes reportedly been the
case [81].
In sum, within research involving human subjects unable to consent, it is usually mandatory
to have consent from (a) a legal guardian and (b) an expert on the condition that makes the human
unable to consent. In NHP research, both conditions are usually absent: Not only there are no legal
guardians whose task is to safeguard each NHP’s individual interests, but independent experts in
primate behaviour do not normally verify protocol suitability for each animal.
It is interesting to note that it is largely amongst primatologists interested in studying NHPs
by themselves, and not as models for humans, that we find the use of deontological principles and
guidelines—mostly the beneficence and non-maleficence principles. For example, guidelines on
darting arboreal primates state that darting cannot occur if the animal is facing the shooter, since the
chest, face, neck, shoulder, thorax and lumber region, head or abdomen are unsuitable target sites that
might harm the animals [
82
,
83
]. Similarly, semi-arboreal NHPs can only be darted on the ground [
84
].
These might exclude some animals from the sample in the same way some human participants are
excluded from biomedical research, if they are at significantly increased risk of being harmed from an
intervention or procedure [57].
3.2. Utilitarianism
Utilitarianism is a consequentialist ethical position which asserts that the value of an action is
determined by the utility of its consequences, i.e., the morally right act is the one whose consequences
maximise some form of utility (e.g., pleasure, wealth, wellbeing), for the majority [
85
]. However, the
magnitude of pleasure and pain for all affected should receive equal consideration [
86
,
87
]. For example,
it is morally justified to donate blood, because even though the number of individuals harmed is
greater than the number of individuals who benefit from this action, it is a small harm, offset by a
major gain.
The most popular utilitarian views maintain that all sentient beings are moral subjects and their
interests should receive equal consideration when deciding what is the morally right act [
87
]. NHPs
are, beyond doubt, sentient beings. Hence, when using a utilitarian framework to evaluate the ethics
of a biomedical procedure, the interests of NHPs that will be used as research subjects must receive the
same consideration as the interests of those human beings who will benefit from the procedure. As a
consequence, if the procedure is likely to cause serious harm (e.g., the death of NHP subjects) without
bringing a substantial good (e.g., saving a greater number of human lives), it should not be conducted.
Importantly, the ethical rules and laws that guide animal experimentation rely heavily
on utilitarianism [
59
,
81
,
88
]. Most legislation on the protection of animals used for scientific
Animals 2019,9, 12 6 of 17
purposes—including the current European Directive 2010/63/EU [
75
] states that the potential benefit
of each research project should be balanced against the likely harm inflicted on the animals.
In many cases, the funding agencies evaluate potential benefits, while animal care committees
review proposals in terms of animal harms. These committees do not directly interact, arguably
impeding efforts to compare potential harms and benefits.
Even when this is not the case, the weighting scale is often misused either in predicting the
benefits of the experiments, or in calculating expected harms. Below, we provide evidence of this,
as it is virtually impossible to accurately predict the benefits, and in the calculation of harms, many
variables are commonly left aside.
3.2.1. Predicting Benefits from a Utilitarian Standpoint
NHPs are frequently used in drug trials which are often considered very promising [
6
]. However,
retrospective examinations have demonstrated that the majority of those promising trials failed to
translate to humans, or to produce the expected benefits [
11
], usually because of failures of safety or
efficacy [
89
]. In fact, data from the Food and Drug Administration showed that 92% of drugs that
succeed in preclinical tests fail to achieve their purpose within human clinical trials, and never reach
the market [
90
]. These data were previously published in 2004, but more recent papers on the subject
have demonstrated that there has not been a significant improvement: the success rate reportedly
varies from 0.4% (in Alzheimer’s trials [91]) to 20% [92].
One of us (Andrew Knight) has systematically evaluated the contribution of chimpanzee research
to biomedical progress, showing that approximately half of all publications describing chimpanzee
research identified in a large-scale study were never cited by any subsequent paper, in any field, thereby
making little obvious contribution to the ongoing advancement of knowledge. Even those chimpanzee
studies that were cited by subsequent medical literature rarely made significant contributions to
the development of therapeutic methods with significant potential for aiding human patients [
9
].
Bailey [
10
] also evaluated the role of chimpanzees in AIDS vaccine research, concluding that claims
that chimpanzees have played a critical role in basic understanding of HIV-1 [93] were overstated.
More recently, Bailey and Taylor evaluated the contribution of NHPs to neuroscience research,
demonstrating that there is a lack of robust evidence to support claims that NHPs are relevant and
beneficial to human medical progress. These authors also concluded that human research methods,
like functional magnetic resonance imaging with electrocorticography, are being simultaneously used
in humans and NHPs for the same purpose, which, in their opinion, makes these NHP studies
redundant [
12
]. Garner [
89
], on the other hand, maintains that the reason animal studies produce such
poor results is the way they are performed, instead of the limitations of animal models.
The fact that one can frequently only evaluate the benefits achieved retrospectively markedly
limits the suitability of utilitarianism in assisting an ethics committee to make an informed decision
about whether a procedure should be permitted.
It is also important to mention the use of NHPs in experiments that will never reach human trials,
due to ethical and legal limitations. Such is the case for experiments using NHP embryos or cloning
experiments, which use NHPs due to their similarities with humans, although the use of humans in
such experiments would be strictly forbidden [
94
]. Hence, potential benefits for human patients are
absent or severely limited.
When predicting the potential benefits of a biomedical research project, all of humanity is usually
considered to be potential beneficiaries. However, that is rarely if ever the case. According to the
World Health Organization, approximately one-third of the people living in developing countries are
unable to receive or purchase essential medicines on a regular basis [95].
Finally, all basic research produces knowledge, which is in itself a benefit to humankind, since
scientific knowledge has cultural value in itself. Nonetheless, this benefit is hard to quantify, or to
balance against concrete and substantial costs.
Animals 2019,9, 12 7 of 17
3.2.2. Assessing and Predicting Harms from a Utilitarian Standpoint
While addressing the harms inflicted on non-human animals, including NHPs, researchers tend
to focus on the severity of the procedures described in the experimental protocols and overlook other
harms. In fact, European Directive 2010/63/UE, with the aim of regulating the level of severity
inflicted on laboratory animals, includes an annex on the severity classification of procedures [
75
].
This may reinforce the propensity to disregard other sources of pain and distress.
Unlike humans, NHPs cannot be informed about their procedures—hence, even a painless
procedure like an MRI can be terrifying for a naïve NHP [
46
,
76
]. To always classify this procedure as
“mild”, in accordance with current European legislation, ignores subjective experiences, such as fear,
that might vary individually.
Wild-caught NHPs also experience anxiety and pain during capture, in holding facilities, and
often lengthy transportation and confinement, whereas laboratory-bred NHPs may undergo suffering
during breeding, and from maternal separation, potentially much earlier than would occur in the
wild [
96
,
97
]. It is noteworthy to mention that due to the intense stress caused by wild capture, the UK
banned the wild capture of primates for their use in research in 1996. Similarly, European Directive
2010/63/EU states that only the offspring of wild-caught NHPs can be used in research experiments.
NHPs who live under laboratory confinement conditions may experience pain and distress not
only during procedures, but also during many other situations that are not normally considered when
evaluating the harms and benefits of the research. Self-injurious behaviour is an obvious sign of stress
that has been extensively described in NHPs living in laboratories (for a review, see Reference [
98
]).
Similarly, floating limb syndrome, which can be defined as raising the arms or legs without an obvious
function, is a readily identifiable stress-related behaviour [
99
]. Another easily recognisable sign of
stress in NHPs is the freezing response. In both humans and NHPs, this response is a common and
immediate response to threat situations that allows the individual to evaluate the danger and decide
how to deal with it [
100
]. When there is a dysregulation in fear response (e.g., post-traumatic stress
disorder—PTSD), this behaviour may emerge in non-threatening or mildly threatening situations and
may last for prolonged periods [
100
]. Hence, inappropriate freezing behaviour is a signal of fear and
anxiety that researchers should not ignore, regardless of the stimulus. Some types of behaviour, such
as a high frequency of self-grooming, are stereotypic abnormal behaviours in some species but not in
others [
100
]. However, checking species-specific ethograms and normal activity time budgets could
help to identify such abnormal behaviours.
Species ethograms can also be helpful in identifying the naturally occurring behavioural repertoire.
In laboratory housing, most NHPs face restrictions on performing certain natural behaviour patterns.
This is not usually considered when assessing harms. The same may occur when an NHP witnesses the
harming or killing of peers [
96
]. Additionally, experiencing stress, especially at an early age, impacts
the NHP immune system and brain structures [
101
,
102
]. These long-term stress-related harms are not
normally considered when assessing animal welfare impacts and might even reduce the suitability of
some NHPs as models for humans [101].
Facial expressions could be an important tool to understand NHP emotional states, since they
often convey emotion or pain in many different NHP species (for reviews, see
References [32,103,104])
.
In the case of chimpanzees, for example, the expression of a full closed grin as described by Goodall [
27
]
is reliably associated with fear, distress, and painful contexts [
32
,
103
]. Similarly, in rhesus monkeys, a
grin signals fear or submission [
26
]. In recent years, the facial action coding system (FACS) developed
by Ekman and Friesen [
105
] has been adapted to several NHP species, like chimpanzees [
106
],
rhesus monkeys [
107
], gibbons [
108
], and orangutans [
109
]. This tool could help researchers to
more objectively assess NHP emotions.
With the help of such tools, it would become easier to evaluate which procedures should be
prohibited or modified in order to spare NHPs from severe pain or stress. Their use has been suggested
for NHPs [46,61], but has not yet been widely implemented [81].
Animals 2019,9, 12 8 of 17
4. Ethical limitations of 3Rs Principles
Current policies underpinning animal experimentation follow the 3Rs principles, first described
by Russell and Burch [
110
]. These principles assert that whenever possible, animal models should be
replaced with alternative methods; the number of animals used in experiments should be reduced
to a minimum; and their suffering should, whenever possible, be ameliorated, e.g., through humane
endpoints, less invasive procedures, and the use of anaesthesia (refinement).
Replacement is the first and, in our view, the most important of the 3Rs. Its achievement in
a particular case makes implementation of additional Rs unnecessary. However, replacement is
often grounded in the unverified assumption that animals are good models for human diseases—an
assumption that is increasingly challenged by empirical evidence (for a review, see [
111
]). To gain
regulatory acceptance and/or be funded, alternative methods often need to demonstrate that they can
provide equivalent or superior data to those obtained through animal testing, even when the current
animal model results are variable rather than consistent, and even when these models have often failed
to reliably predict human responses to drugs [
112
]. This status quo approach delays the development
of promising non-animal methods in toxicity and drug testing and diverts biomedical research away
from non-animal methods.
These 3Rs principles underpin virtually all legislation and guidelines concerning the use
of animals in scientific procedures. However, they do not offer a philosophically consistent
ethical framework and are insufficient to address ethical concerns regarding NHP use within
biomedical research.
The 3R policies comply—to some extent—with utilitarianism, since reduction and refinement
are tools used to try to minimise the total amount of harm inflicted. However, they do not provide
tools to predict benefits, or the extent of long-term harm, which makes them insufficient to fulfil the
requirements of utilitarian analysis.
Whilst public health advancement might be a justifiable goal, from a utilitarian standpoint, the
pursuit of biomedical NHP research (that might provide only modest benefit) might not be justifiable.
From a deontological point of view, the 3Rs are largely irrelevant, since they do not prevent the research
subjects from being used as means to an end. Additionally, the 3Rs do not comply with principles of
autonomy or justice, which are crucial within the deontological approach prescribed by Beauchamp
and Childress [58].
5. Societal Determination of Ethical Frameworks
Whenever animal-based research is the topic of discussion, the balance between competing
perspectives is often decided at the societal level, and the prevailing culture enables or proscribes a
certain type of scientific activity [113].
When it comes to science, people tend to support animal experiments according to utilitarian
principles, i.e., people consider the potential benefits for humanity when assessing their level
of support for certain research [
15
,
48
,
113
115
]. However, when it comes to animals that people
consider companions, such as domesticated dogs, the number of people who support their use
in scientific research decreases dramatically, regardless of the perceived potential benefits for
humankind [
48
]. With these animals, people shift their ethical paradigm, applying the beneficence and
non-maleficence principles.
The emergence of ethical decisions is influenced by the feeling of discomfort that most people
experience when confronted with the suffering of others, and their own sense of wellbeing and
fulfilment when contributing to the alleviation of pain or the promotion of happiness [
116
,
117
].
However, these decisions rely on available information about the phenomenological experiences of
others. Closeness, familiarity, and knowledge of animals, including NHPs, have all been variables
linked to increased empathy for animals [
118
] and less tolerance for animal use in invasive or harmful
scientific research [113].
Animals 2019,9, 12 9 of 17
People are more willing to accept research on nonhuman animals, including NHPs, if they believe
animals are comfortable and well cared for, and in the mid-20th century, according to the National
Opinion Research Centre, 75% of the public believed that medical schools treated laboratory animals as
well as individual owners would [
114
]. Most owners consider their pets as individuals with intrinsic
value, and veterinary clinical research conducted on pet dogs follows deontological principles similar
to the ones used in human clinical research [119].
The way animal husbandry is portrayed, as well as the level of familiarity people have with
different species, are thus critical features of engaging society with either utilitarian or deontological
ethical frameworks. Accurate portrayal of the actual state of both variables, as well as a realistic
portrayal of human healthcare benefits that arise from animal research, would, in our opinion, lead to
stronger support for application of the deontological framework.
6. Ethical Research with NHPs
There is no robust evidence that we need NHPs to model specific human diseases [
9
11
];
therefore, there is no overwhelming moral or scientific reason to confine NHPs within laboratories,
to be invasively used as defective models for human disorders. In fact, Garner and colleagues
recently [89,120]
suggested that in order for biomedical research using non-human animals to be more
effective, they should be treated as patients. We agree with this view but emphasise that this is not
possible for animals confined in a laboratory.
6.1. Ethical Research with Possible Healthcare Applications
Disorders that affect humans and NHPs should ideally be studied using NHPs who suffer
naturally from the disorder concerned, either in wild populations, or in captive NHPs who
need treatment.
In 1966, Jane Goodall witnessed a polio outbreak in wild chimpanzees living at Gombe Stream
National Park (Tanzania). In some individuals, the subsequent disability was so severe that some
animals were euthanized [
121
]. Instead of infecting healthy laboratory animals with polio, these wild
chimpanzees who succumbed to polio from natural causes could theoretically have been studied to
understand polio. The knowledge acquired from these studies would have been useful for science in
general, and for infected chimpanzees specifically—hence upholding the justice principle. It might or
might not have been useful for humans but, given the more natural induction and progression of the
disease, it could have been more useful than similar research performed on laboratory chimpanzees.
Although the laboratory environment allows for the control of possibly confounding variables, and
manipulation of the exact time of infection, this level of control and information is rarely possible
with human patients. Wild animals that naturally acquire a disease occurring in humans and other
species can be a better model than laboratory animals, since—just like human patients—they are living
in a complex environment where social and natural variables can modulate disease progression. In
human patients, it is very hard or even impossible to determine the exact time of infection and what
other variables (e.g., inadvertent exposure to external viruses) could interfere with disease progression
and/or clinical trial results. Even researchers that support the use of animals as models for human
disorders acknowledge that standardisation of too many variables in the laboratory can be a limitation,
rather than a strength [89].
There are NHPs previously used by industries (e.g., entertainment, biomedical research)
and subsequently suffering from psychological and behavioural disorders, for whom
psychiatric/psychological treatment is not only appropriate, but also a moral imperative [
122
124
].
Using these animals as research patients for PTSD, for example, could benefit both science and these
particular animals. Again, the data obtained might or might not be useful for human healthcare, but
the results obtained from laboratory animals would not necessarily be more useful.
Epidemiological studies with wild populations can also be conducted with minimal disturbance
of the animals [125,126], hence respecting the autonomy principle.
Animals 2019,9, 12 10 of 17
6.2. Basic Ethical Research
Some may argue that NHP research facilities are useful for purposes other than medical research.
This is the case for basic research, which, according to the Frascati Manual [
127
], is “experimental
or theoretical work undertaken primarily to acquire new knowledge of the underlying foundation
of phenomena and observable facts, without any particular application or use in view” [
127
]. The
majority of such basic research is laboratory-based.
However, a large amount of such research can be conducted in non-invasive field studies, using
wild populations—hence respecting the individuals as subjects with inherent value. For example, Kano
and colleagues used a laboratory apparatus to study differences in gaze behaviour in chimpanzees and
bonobos, concluding that bonobos pay more attention to the eyes and face of other individuals [
128
]. On
the other hand, Fröhlich and colleagues reached the exact same conclusion by observing communicative
interactions in mother-infant dyads of wild populations [
129
]. Similarly, Fujita and colleagues created
an experimental laboratory procedure to study capuchin monkeys’ deceptive behaviours [
130
], while
others [
31
] were able to study tactical deception of the same species in the wild, gathering more robust
and reliable data on the subject. Another good example which has been widely studied is chimpanzee
communication: while in captivity, only 31 gestures were described [
131
], observations in the wild
raised this number to 66 distinct gesture types to communicate at least 19 different messages [
33
]. In
fact, most of what we know about behaviour and the ecology of NHPs has come from long-term field
studies [
17
,
27
,
132
134
], and recent field studies continue to amaze us by revealing new species [
135
],
as well as unexpected behaviour from well-known species, such as bonobo hunting [
136
], and some
behaviours that might be ritual practices amongst wild chimpanzees [137,138].
These studies have been conducted respecting the beneficence and non-maleficence principles,
and even the principle of justice, since the knowledge obtained from those data, some of it also
presented as documentaries and in other forms for widespread media dissemination, raises awareness
of animal emotion and cognition [
139
], potentially increasing empathy towards these NHPs, and
ultimately increasing the impetus for their conservation.
However, there are research questions, either in safety and efficacy testing or fundamental
research, where it is not possible to obtain knowledge using only observational techniques (e.g.,
genetics, neuroscience). However, there are ways of continuing this research without overlooking
ethical constraints.
In questionable situations, it is always pertinent to ask whether the knowledge acquired through
the suffering of other animals complies with the bioethical principles described by Beauchamp and
Childress [
58
]. In the literature, we can find examples of basic research with non-human animals that
fulfil these principles. Berns and colleagues [
140
] used positive reinforcement to train dogs to stay still
within a functional MRI device. The dogs were unrestrained and free to leave the device at all times,
including during training sessions (autonomy principle). Without harm or distress, much fundamental
knowledge on the canine brain was obtained (non-maleficence principle), which may ultimately benefit
the wider canine population (principle of justice). The researchers would gradually play louder sounds
in the surrounding environment so that animals would not get startled by MRI sounds (principle
of non-maleficence). This innovative method has been providing exciting insights into the canine
brain [
141
143
], and a similar technique could be used to study NHPs living under semi-natural
conditions, replacing neuroscience NHP laboratories where even the least invasive techniques [
144
]
require temporarily restraining fearful animals. Some NHPs share habitat with human beings (e.g.,
rhesus monkeys in India or Nepal) and sometimes even enter and explore human homes, which
should make it possible to conduct experiments with these animals similar to those described above
with dogs. Some NHPs species are particularly harmless and cooperative (e.g., marmosets or capuchin
monkeys). Individuals from those species who are held captive for other reasons (e.g., rescued animals
living in sanctuaries) could also be enrolled in experiments similar to the ones conducted by Bern and
colleagues on dogs [
140
143
]. Even potentially dangerous NHPs, such as chimpanzees, can participate
in experiments consensually, in the same way human participants do [41].
Animals 2019,9, 12 11 of 17
7. Conclusions
In light of the current knowledge, the use of NHPs in basic research warrants something of a
paradigm shift. We propose that basic research with NHPs should continue only if carried out under
the same ethical deontological criteria that guide basic research with human beings.
Whenever non-invasive basic research protocols require the use of NHPs, the participants should
be recruited from sanctuaries or similar facilities. Local legal guardians of NHPs should evaluate the
procedures to verify whether the principles of autonomy, beneficence, non-maleficence and justice, as
defined by Beauchamp and Childress [
58
], have been fully incorporated. That being the case, the legal
guardian would provide the necessary informed consent.
By complying with such standards, we would not only grant other primates a level of respect
and protection consistent with that we provide to members of our own species, but we would also
be encouraging researchers to develop better research protocols and higher standards for captive
management, which could, in turn, result in improvements in data quality, and in the reliability of
some research results.
Author Contributions:
All authors contributed to the conceptualization of this paper and agree on its final content.
First Author (C.C.) was responsible for most of the writing. C.C., A.G. and A.K., were involved in the original
draft preparation and writing, and further reviewing and editing; A.K. and L.V. were also involved in supervision
and in Funding acquisition.
Funding:
First author (C.C.) is sponsored by Animalfree Research Foundation (Switzerland) and by Portuguese
National Funds through CFCUL research unit funding UID/FIL/00678/2013. Second author (A.G.) is
sponsored by Catolica Research Centre for Psychological, Family and Social Wellbeing (CRC-W), third author
(A.K.) is sponsored by the Ketty and Leif Hjordt Foundation, and L.V. by CFCUL research unit funding
UID/FIL/00678/2013.
Acknowledgments:
We wish to express our gratitude to the editor and anonymous referees for their detailed
comments that greatly helped us improve the quality of the manuscript.
Conflicts of Interest:
The authors declare no conflict of interest. The founding sponsors had no role in the design
of the study; the writing of the manuscript, or the decision to publish the results.
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... 13,16 Although the use of primates for biomedical research appears to have declined in Europe and the United States compared to the levels a few decades ago, it has increased in places like China, even though such use has made disappointingly few contributions to human medical advancements. 17 In the Greater Mekong region, Cambodia, Laos and Viet Nam are known to breed and export macaques for toxicological, pharmaceutical and biomedical research. 12 It is likely that many of the recipient research facilities, which do not prioritise animal welfare, are laundering wild-caught primates through legal trade. ...
... Over 100 primate species are traded globally for use in traditional medicines, 13,18 including almost 60 per cent of the primate species in Asia. The demand created by traditional practices worldwide drives this trade 17 and encourages commercial hunting. ...
... The use of primate parts in medicine varies, with some being put in tonics, as is common in Viet Nam, while others are used to make amulets to protect against disease. 17 While there is no evidence of the efficacy of these treatments, the use and trade of primates may spread dangerous diseases. 19 Shared biological traits increase the risk of viral mutation and spread from primates to humans. ...
Technical Report
Full-text available
A WWF report, highlighting the diversity of lorises, macaques, langurs and gibbons that occur in the five Greater Mekong (GM) countries - Cambodia, Laos, Myanmar, Thailand, and Viet Nam. The report compiles the latest information on taxonomy, Red List status, threats and conservation efforts for the 44 species of primates in the GM (including 19 species endemic to the GM). It places a particular emphasis on the huge threat the primates face from hunting, consumption and trade for wild meat and traditional medicine. The report also briefly profiles the primate conservation efforts of WWF and other conservation organizations in the Greater Mekong. More details: https://greatermekong.panda.org/discovering_the_greater_mekong/species/primates_of_the_greater_mekong/
... Moreover, although "all NHPs are housed with visual and auditory contact with conspecifics" ( [91], p. 4), and thus not necessarily in groups, this is certainly not enough to satisfy their complex social needs. Furthermore, depending on the experimental procedures and on the legal requirements of the countries in which NHPs are housed (see below), NHPs may also experience suffering from early maternal separation [92][93][94][95]. In Europe, for instance, macaques are usually weaned around 8 months [91], a developmental stage in which infants are still largely dependent on their mothers under natural conditions [96], whereas transgenic monkeys are usually separated from their mothers from birth (see [91]) with a strong negative impact on their behaviour and physiology [97]. ...
... Its main limit is that it implies an assessment of all the costs and benefits linked to invasive research [113]. First, it is often hard to reliably predict the benefits that a research project really provides, and, indeed, the majority of invasive studies on animals fail to translate to humans [94,111,114]. Second, it is extremely difficult to objectively compare the costs and benefits that involve different species [115][116][117][118][119]. As noted by Arnason [115], benefits to humans often appear to compensate the costs to NHPs only if NHP interests are highly disregarded. ...
... In theory, all procedures reducing the welfare of NHPs imply some costs, from distress and the impossibility to express the species-specific behavioural repertoire to malnutrition, discomfort, pain, injury, isolation, diseases, and negative valence emotions (e.g., fear, anxiety, and anger), depending on the exact procedures used and their severity (see [120]; see previous sections). These sources of stress can have a strong negative impact on NHP health and welfare, as discussed above [94,121]. ...
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Invasive research on primates (i.e., laboratory research that implies body manipulations causing pain or distress that is not aimed to directly improve the individuals’ well-being) has a long history. Although some invasive studies have allowed answering research questions that we could not have addressed with other methods (or at least not as quickly), the use of primates in invasive research also raises ethical concerns. In this review, we will discuss (i) recent advances in the study of primates that show evidence of complex behaviour and cognition, (ii) welfare issues that might arise when using primates in invasive research, (iii) the main ethical issues that have been raised about invasive research on primates, (iv) the legal protection that primates are granted in several countries, with a special focus on the principle of the 3Rs, and (v) previous and current attempts to ban the use of primates in invasive research. Based on this analysis, we suggest that the importance of a research question cannot justify the costs of invasive research on primates, and that non-invasive methods should be considered the only possible approach in the study of primates.
... The importance of long-tailed macaques for pre-clinical testing has the potential to exert significant pressure on wild populations, particularly because of the unit value per macaque that has been shown in these results. Whilst there has been a long-term trend for pharmaceutical companies to source their requirements from captive bred monkeys raised in farms (Carvalho et al., 2019), there may not be sufficient stock to cope with sustained periods of high demand for live monkeys used in pre-clinical testing procedures (Nature, 2021;Tian, 2021). Ongoing research will seek to determine if the additional (COVID era) demand for long-tailed macaques from the pharmaceutical sector has compromised efforts over the last decade to promote improved protection, better law enforcement and trade regulation regarding illegal wildlife trade (SSN, 2012(SSN, , 2015a. ...
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Non-human primates (primates) are regarded as key research subjects for pre-clinical trials of several drugs aimed to alleviate human suffering. It has long been suggested that the predominant species in the international trade in live primates for use in research is the long-tailed macaque (Macaca fascicularis). However, little is still known about the value of this international trade. Whilst the international trade to supply the requirement for biomedical testing is known to encourage illegal wildlife trade, we lack a detailed understanding of the overall value and magnitude of this trade. Such information is vital to facilitate the design of effective conservation strategies in range countries, in order to mitigate the exploitation of wild populations by organized crime networks. Here, data from CITES and the UN Comtrade databases were combined to calculate the value of this trade. We also compared the number of individual primates traded as reported in the two databases to investigate possible correlations. Results show that, from 2010 to 2019, the international trade in long-tailed macaques constituted a market worth of ∼US $1.25 billion. We found a positive correlation between individual primates traded in the UN Comtrade Database and individual long-tailed macaques reported in the CITES Trade Database, suggesting that we can use the UN Comtrade database to investigate values and magnitude of the international legal trade in wildlife, and that legal trade in live primates is primarily constituted of long-tailed macaques alone.
... NHP models are limited by the associated ethical considerations. It has been argued that the study of NHPs is justified and necessary due to their homology with humans, while others view it as unnecessary due to the lack of significant scientific discovery arising from use of these models (92). The primary consideration when initiating research with NHPs is the potential for benefit to humans. ...
Article
Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials.
... 9,10 Of course, primate eyes also possess relative proximity to humans 11 but are costly and pose ethical issues. 12,13 The rabbit is another animal model that is commonly used in ophthalmic research, [14][15][16][17] f with anatomical references dating back to the 17 th century. 14 The rabbit eye model is ideal for ophthalmic research for several reasons: i) it is similar to humans, ii) the animal is relatively docile in nature, iii) they come in various sizes (breed-dependent), and iv) they are more economical compared to other mammals (i.e., primates). ...
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Ocular barriers to drug transport make delivery of effective doses to posterior targets exceptionally difficult. Animal models have commonly been used to evaluate drug distribution and penetrability, but translational tools to determine human dosing are lacking. Here we present a framework for modeling interspecies variation by simulating oxygen distribution in the posterior eye, from outer vitreous to the sclera. Posterior eye models of mouse, rabbit, and human are presented with modifications based solely on species-dependent anatomical and physiological differences. The model includes tissue and vascular contributions to transport. In addition to oxygen, nitric oxide and its impact on oxygen metabolism is simulated. Depth-dependent retinal oxygen partial pressure profiles are in good agreement with experimental data for all three species. The model can be further extended to evaluate the variations of retinal oxygenation in response to various drugs, formulations, administration protocols, and treatment plans. Further, this framework of ocular physiologically based pharmacokinetic/pharmacodynamic models could support animal to human translation, a critical step in the drug development process.
... The use of NHP models has provided guidance and information on the safety and efficacy of vaccine and drug treatments. However, they are also costly to maintain, have restrictions on group size, and their use is surrounded by ethical considerations [19]. Therefore, the integration of NHPs into studies characterizing how transmission route impacts disease outcome is limited. ...
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Full-text available
Zika virus (ZIKV) is a mosquito-borne flavivirus that is primarily transmitted to humans through the bite of an infected mosquito. ZIKV causes disease in infected humans with added complications of Guillain-Barré syndrome and birth defects in infants born to mothers infected during pregnancy. There are several large immunocompetent animal models for ZIKV including non-human primates (NHPs). NHP models closely reflect human infection; however, due to sample size restrictions, investigations into the effects of transmission route and the impacts on disease dynamics have been understudied. Mice have been widely used for modeling ZIKV infection, yet there are few ZIKV-susceptible immunocompetent mouse models and none of these have been used to investigate sexual transmission. In an effort to identify a small immunocompetent animal model to characterize sexual transmission of ZIKV, we attempt experimental infection of multimammate mice, New Zealand white rabbits, and Hartley guinea pigs. The multimammate mouse is the natural reservoir of Lassa fever virus and has been identified to harbor other human pathogens. Likewise, while NZW rabbits are susceptible to West Nile virus, they have not yet been examined for their susceptibility to infection with ZIKV. Guinea pigs have been successfully used as models for ZIKV infection, but only in immunocompromised life stages (young or pregnant). Here, it was found that the multimammate mouse and New Zealand White (NZW) rabbits are not susceptible ZIKV infection as determined by a lack viral RNA in tissues and fluids collected. Sexually mature male Hartley guinea pigs were inoculated subcutaneously and by mosquito bite, but found to be refractory to ZIKV infection, contrary to findings of other studies in young and pregnant guinea pigs. Interestingly, here it is shown that adult male guinea pigs are not susceptible to ZIKV infection, even when infected by natural route (e.g., mosquito bite). Although a new small animal model for the sexual transmission for ZIKV was not established through this study, these findings provide information on outbred animal species that are not permissive to infection (NZW rabbits and multimammate mice) and new information surrounding limitations of a previously established animal model (guinea pigs).
... Minimally invasive and safe methods can www.nature.com/scientificreports/ prevent the possible loss of the experimental animal, and lead to a "reduction" in the suffering and "refinement" of the welfare of laboratory animals 34 . Third, the zirconia MCAO model uses fluoroscopy, which means that vessel occlusion and model success can be checked for in real-time while creating the model. ...
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Full-text available
The failure of neuroprotective treatment-related clinical trials may be partially caused by unestablished animal models. Existing animal models are less likely to provide occlusion confined to the middle cerebral artery (MCA), making transarterial intervention difficult. We aimed to develop a novel focal stroke model using a microcatheter and zirconium dioxide that is non-magnetic under fluoroscopic guidance, which can monitor MCA occlusion and can improve hemorrhagic complications. Using male Sprague Dawley rats (n = 10), a microcatheter was navigated from the caudal ventral artery to the left internal carotid artery using an X-ray fluoroscopy to establish local occlusion. All rat cerebral angiographies were successful. No rats had hemorrhagic complications. Eight (80%) rats underwent occlusion of the MCA bifurcation by zirconium dioxide. Accidentally, the left posterior cerebral artery was failure embolized in 2 rats (20%). The median operating time was 8 min. All rats of occlusion MCA revealed an incomplete hemiparesis on the right side with neurological deficit score ranging from 1 to 3 (median 1, interquartile range 1–3) at 24 h after the induction of ischemia. Moreover, 2% 2,3,5-triphenyl tetrazolium chloride staining showed that the median infarct volume (mm3) was 280 (interquartile range 267–333) 24 h after the left MCA bifurcation occlusion. We present a novel rat model for focal stroke using a microcatheter and zirconium dioxide which does not affect the MRI. The model is predictable which is well confined within the territory supplied by the MCA, and reproducibility of this model is 80%. Fluoroscopy was able to identify which the MCA occlusion and model success while creating the model. It permitted exclusion of animals with complications from the experiment.
... Endovascular treatment has become safe for such cases [1,2]. On the other hand, despite the 3Rs principles for using experimental animals [3], no reports describe specific methodologies for implementing "refinement" in practice. We believe that there are several reasons for this gap: ...
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Surgery in humans is continuously evolving and promoted minimally invasive treatment. On the other hand, despite the importance of the 3Rs principles for experimental animals is well documented, no reports describe specific methodologies for implementing "refinement" in practice. Here, we describe a new technique, the "Ohta Method" for caudal arthrocentesis in the pursuit of the 3Rs for animal experiments and the development of innovative methods for investigating systemic organ arteries through minimally invasive procedures. This procedure requires only a percutaneous puncture of the caudal artery without any injury to the limb or body trunk. In addition, it does not cut down the artery, making hemostasis easier and recovering arterial damage easier. We will show multiple organ artery angiographies in marmoset for the first time in the world. The principle described in this paper could also be applied to many other small animals, such as rats. Moreover, using this method, multiple doses of the drug or cells can be administered to the target organ at the time of therapeutic intervention, thereby enabling the establishment of more sophisticated and complex therapeutic intervention studies as translational research.
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The domestic pig shares many similarities with humans in anatomy, physiology, and immunology. As such it is an attractive animal model to study human tuberculosis (TB). In this study, we examined disease outcome in pigs challenged via two different routes with either the human TB bacillus Mycobacterium tuberculosis Erdman (M. tb) or bovine TB bacillus M. bovis AF2122/97 in head-to-head comparisons. Pigs challenged intravenously with M. bovis exhibited greater morbidity and rapid onset of mortality, higher bacterial burden and tissue necrosis compared to pigs challenged similarly with M. tb. Concordantly, pigs challenged with aerosolized M. bovis exhibited reduced weight gain and more severe pathology than pigs challenged similarly with M. tb. Specifically, M. bovis challenged pigs presented a spectrum of granulomatous lung lesions similar to that in human TB. In contrast, pigs challenged with M. tb presented mostly early-stage granulomas. Irrespective of challenge dose and pathology however, peripheral IFN-γ responses were similar in both M. bovis and M. tb aerosol challenged pigs. Although M. bovis appears to be more virulent than M. tb, both can be used to model different facets of human TB in pigs, depending on whether one seeks to recapitulate active or latent forms of the disease.
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