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Research with animals: requirement, responsibility, welfare.

Recognition of unacceptable cruelty to animals in pasttimes such as bull-baiting, dates in Britain from the early 19th century. The Society for the Prevention of Cruelty to Animals was founded in 1824. Several bills to curb cruelty were discussed in Parliament, and the Cruel and Improper Treatment of Cattle Act was passed in 1822. Other Acts have followed over the years. Cruelty in the form of painful scientific experiments, including dissection of living, conscious animals, vivisection, was proscribed by the Cruelty to Animals Act 1876. That Act required anyone wishing to experiment with animals to obtain a licence from the Secretary of State. Conditions for issue of licences were strict and remain so to this day. The Act is still valid, and is enforced by the Home Office, with its medical and veterinary Inspectors. The Cruelty to Animals Act 1876 allows experiments on animals under strictly controlled conditions. Experiments must have the clear objective of improving the welfare of man and/or animals. Benefits from experiments carried out under the Act have been enormous, covering every aspect of diagnosis, treatment, and prophylaxis in human and veterinary medicine. Coincidentally, the welfare of laboratory animals has also been greatly improved. There has always been some opposition to the use of animals in biomedical research. The subject is emotive but, by and large, discussion has been rational and within the law. In recent years, however, the morality of using experimental animals has been examined more closely. The possibility of replacing them by alternative methods has been investigated. Where these alternatives are applicable, they are used and further research on them continues. The questioning of animal experiments has emphasized the need to look constantly at animal welfare to ensure humane treatment of all animals, especially those restricted in a laboratory or on a farm. Attention has been drawn in this work to our existing laws protecting animals, but new legislation is being demanded, not only by some lay welfare groups but also by scientists. Hence, it has become very important to discuss various ways of ensuring animal welfare, including by legislation, especially with those knowledgeable in laboratory animal science and animal experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Advisory Committees↗

[I. P. Pavlov on animal experiments].

The paper is dedicated to the 150th anniversary of academician I.P. Pavlov's birthday. Pavlov's points of view on vivisection are analyzed and are compared with the modern conception of ethics of carrying out experiments on animals. It is discovered that Pavlov's points of view are in accordance with the key positions of modern requirements to ethics of experimenting on animals which are adopted in the world practice.

Animals↗

The public science of Louis Pasteur: the experiment on anthrax vaccine in the popular press of the time.

The paper focuses on Pasteur's public experimentation of the anthrax vaccine (Pouilly-le-Fort, 1881) as portrayed in the English and French popular press of the time. It is argued that this 'popular' level of representation did not merely provide additional publicity for Pasteur's ideas. Rather, the nature and meaning of the experiment itself and of the related controversy on immunisation were substantially negotiated and shaped within the public arena. The multifold consequences of this framing at the public level are explored. In particular, attention is drawn to the relationships that in such process were established with other issues debated at the same time in the arena, namely homeopathy, vivisection and vaccination.

Animals↗

Biomedical image visualization research using the Visible Human Datasets.

The practice of medicine and conduct of research in major segments of the biologic sciences have always relied on visualizations to study the relationship of anatomic structure to biologic function. Traditionally, these visualizations have either been direct, via vivisection and postmortem examination, or have required extensive mental reconstruction. The revolutionary capabilities of 3-D and 4-D medical imaging modalities, together with computer reconstruction and rendering of multidimensional medical and histological volume image data, obviate the need for physical dissection or abstract assembly. The availability of the Visible Human Datasets from the National Library of Medicine, coupled with the development of advanced computer algorithms to accurately and rapidly process, segment, register, measure, and display high resolution 3-D images, has provided a rich opportunity to help advance these important new imaging, visualization, and analysis methodologies from scientific theory to clinical practice.

Algorithms↗

Controlled trial of laparoscopic-assisted vs open colon resection in a porcine model.

BACKGROUND: Several series of laparoscopic colon resection have been reported in the literature with varied results; however, no controlled series of laparoscopic vs open colon resection has been reported. The purpose of this study was to determine the relative safety and adequacy of laparoscopic colon resection in a controlled trial using a porcine model. METHODS: Domestic pigs (n = 23) were randomly divided into two groups. Animals underwent either an open or laparoscopic-assisted segmental resection of the sigmoid colon. The open resections were performed through a 20-cm midline incision and the laparoscopic technique utilized five 12-mm ports. Laparoscopic resection took twice as long to complete as open resection (P < 0.001). Return of gastric function was significantly faster in the laparoscopic group than in the open group (P < 0.032). RESULTS: No significant differences were found in total length of resection, proximal or distal margins, number of lymph nodes recovered, length of mesenteric vessel resected, or time to return of bowel function. At vivisection, more adhesions to the abdominal wall were noted in the open group (P < 0.002). One death occurred in the laparoscopic group 2 h postoperatively (8.3% mortality) while all open group pigs survived. However, there was no statistically significant difference in mortality rates by chi-square analysis (P > 0.5). CONCLUSIONS: Despite longer operative time, laparoscopic intervention is technically feasible, safe, and may offer significant postoperative benefits due to fewer abdominal adhesions.

Anastomosis, Surgical↗

Pictures, preparations, and living processes: the production of immediate visual perception (anschauung) in the late-19th-century physiology.

This paper addresses the visual culture of the late-19th-century experimental physiology. Taking this case of Johann Nopomuk Czermak (1828-1873) as a key example, it argues that images played a crucial role in acquiring experimental physiological skills. Czermak, Emil Du Bois-Reymond (1818-1896) and other late-19th-century physiologists sought to present the achievements and perspective of their discipline by way of "immediate visual perception (unmittelbare Anschauung)." However, the images they produced and presented for this purpose were strongly mediated. By means of specifically designed instruments, such as the "cardioscope," the "contraction telegraph," and the "frog pistol," and specifically constructed rooms, so-called "spectatoriums," physiologists trained and controlled experiments on their own. Studying the material culture of physiological image production reveals that technological resources such as telegraphy, photography, and even railways contributed to making physiological facts anschaulich. At the same time, it shows that the more traditional image techniques of anatomy played an important role in physiological lecture halls, especially when it came to displaying the details of vivisection experiments to the public. Thus, the images of late 19th century physiology stood half-way between machines and organisms, between books and instruments.

History, 19th Century↗

Aflatoxin B1-adduct formation in rat and human small bowel enterocytes.

BACKGROUND/AIMS: Hepatic CYP3A enzymes have been implicated in the bioactivation of aflatoxin B1 (AFB1) to DNA binding metabolites. CYP3A enzymes are also abundant in the small bowel, and we therefore examined the ability of this tissue to form intracellular AFB1 adducts. METHODS: Immunohistochemistry using a antibody to the stable AFB1-DNA adduct was performed on small bowel sections obtained from rats orally gavaged with AFB1 and on human small bowel biopsy specimens maintained in explant culture. 3H-AFB1 was instilled into a loop of small bowel of untreated rats and rats pretreated with the CYP3A inducer dexamethasone during vivisection. DNA was isolated from the loop 2 hours later and assayed for specific activity. RESULTS: In both rats and humans, AFB1-adducts were detected exclusively in mature enterocytes in a pattern similar to the distribution of CYP3A enzymes. Induction of enterocyte CYP3A in rats resulted in an increase in enterocyte immunoreactive AFB1 adducts and in a 1.8-fold increase in 3H-AFB1-nucleic acid adducts (P = 0.01). CONCLUSIONS: Intracellular AFB1 adducts are formed in the small intestine, and this reflects, at least in part, the catalytic activity of CYP3A enzymes. Because these AFB1 adducts should ultimately pass in stool, enterocyte CYP3A may represent a regulatable barrier to dietary aflatoxins.

Aflatoxin B1↗

The United States cover-up of Japanese wartime medical atrocities: complicity committed in the national interest and two proposals for contemporary action.

To monopolize the scientific data gained by Japanese physicians and researchers from vivisections and other barbarous experiments performed on living humans in biological warfare programs such as Unit 731, immediately after the war the United States (US) government secretly granted those involved immunity from war crimes prosecution, withdrew vital information from the International Military Tribunal for the Far East, and publicly denounced otherwise irrefutable evidence from other sources such as the Russian Khabarovsk trial. Acting in "the national interest" and for the security of the US, authorities in the US tramped justice and morality, and engaged in what the English common law tradition clearly defines as "complicity after the fact." To repair this historical injustice, the US government should issue an official apology and offer appropriate compensation for having covered up Japanese medical war crimes for six decades. To help prevent similar acts of aiding principal offender(s) in the future, international declarations or codes of human rights and medical ethics should include a clause banning any kind of complicity in any unethical medicine-whether before or after the fact-by any state or group for whatever reasons.

Biological Warfare↗

Three-dimensional echocardiography of the thoracic aorta.

OBJECTIVES: The feasibility and diagnostic potential of three-dimensional echocardiography, using transoesophageal multiplane echocardiography for the assessment of thoracic aortic pathology, has not been evaluated. METHODS: We studied 21 patients (10 women, 11 men), mean age 52.1 years (range 20-78). Images for three-dimensional reconstruction were acquired during a diagnostic multiplane transoesophageal echocardiographic examination. In all, 30 acquisitions were performed: 19 of the ascending aorta and 11 of the arch and descending aorta. Three-dimensional reconstruction was performed to visualize normal aortic segments in three patients with a normal thoracic aorta, postoperative anatomy in seven, chronic aortic dissection in two, non-dissecting aneurysm in seven (three patients had coexisting thrombi) and protruding aortic atheroma in two. RESULTS: Three-dimensional image quality was scored excellent in 17 acquisitions (57%), adequate in 10 (33%) and inadequate in three (10%). Anyplane two-dimensional views of regions of interest of the aorta were reconstructed off-line from the data sets, which provided improved analysis with potential for quantitation. Advanced computer-assisted imaging modalities (electronic vivisection, lumen cast display, detail extraction) were feasible. CONCLUSIONS: We conclude that three-dimensional echocardiography of the thoracic aorta is feasible. Adequate image quality is obtained in the vast majority of patients, which adds additional qualitative and quantitative information to routine multiplane transoesophageal echocardiographic studies.

Adult↗

Galen: a pioneer of spine research.

Galen of Pergamum AD (2nd century), the most eminent Greek physician after Hippocrates, marked the history of medicine for more than 14 centuries. His doctrines, expressed in his voluminous work, combined the medical heritage of the Hippocratic, the Alexandrian, and some of the most important medical schools of antiquity. The strong influence of the Hippocratic tradition can characteristically be traced in orthopaedics and particularly in Galen's presentation of the spine. Based on his observations, derived from dissection and vivisection of animals, Galen established a pioneer model for the study of human spine. His research ended in an accurate description of the vertebral column and the spinal cord. He also described the course and the distribution of the nerves emerging from the spine. In addition, he dealt with the diseases affecting these structures focusing on spinal tuberculosis and the injuries of the spine and the spinal marrow. Galen was the first physician to demonstrate the neurological implications following transection of the spinal cord at several levels. The predominant feature in Galen's reference to spine is its teleological perspective; the great physician tended to attribute the prodigious structure of the spine to nature's providence. Despite the inevitable anatomical errors, Galen's inspired experiments remained the only thorough approach of spinal anatomy and pathology until the recent centuries, when the evolution of sophisticated technical aids opened new pathways to spine research.

Greece, Ancient↗

Statutory definitions of death and the management of terminally ill patients who may become organ donors after death.

The law stipulates that death is irreversible. Patients treated in accord with the Pittsburgh protocol have death pronounced when their condition might well be reversed by intervention that is intentionally withheld. Nevertheless, the protocol is in accord with the medical "Guidelines for the Determination of Death." However, the Guidelines fail to capture the intent of the law, which turns out to be a good thing, for the law embodies a faulty definition of death. The inclusion of "irreversible" in the legal definition makes that definition excessively demanding and out of step with the ordinary concept of death. On this basis the protocol is absolved of the moral but not the legal charge that it involves vivisection.

Death↗

Noninvasive three-dimensional viewing of the motion and anatomical structure of the heart, lungs, and circulatory system by high speed computerized X-ray tomography.

A new generation X-ray computerized tomography system now under construction, the Dynamic Spatial Reconstructor (DSR), will record 1680 multiple view X-ray video images of the chest or other segments of the body per second. This allows com0utation of stop-action and 60-per-second instant replay motion pictures of the dynamic three-dimensional changes in shape and dimensions of the full anatomic extents of the internal and external surfaces of the heart chambers or the vascular anatomy and circulatory dynamics in any region of the body. Current commercially available scanners require one or more seconds per cross-sectional scan and lack the synchronous volumetric scanning capabilities of the DSR. These capabilities allow nondestructive mathematical selection and removal of any subvolume of interest from a reconstructed volume. The associated abilities to "zoom in" and "section" this subvolume so as to examine its structure and physiologic function in detail allow direct visualization of the internal anatomy and function of organ systems within the body. These capabilities of "noninvasive numerical biopsy" and "vivisection" have heretofore been the preserve of pathologists at autopsy or surgeons at the operating table. Possible future availability of these techniques to the practicing internist carries promise of revolutionary improvements in clinical diagnosis and treatment of the myriad of disease processes, including cancer, which may affect the heart, lungs, vascular anatomy or circulatory dynamics in any region of the body.

Blood Vessels↗

[I. P. Pavlov's teacher of physiology I. F. Tsion (1842-1912)].

In 1866, at the C. Ludwig's laboratory, E. F. Cyon discovered n. depressor, and after C. Bernard's presentation he was awarded with the Montion Prize of the Paris Academy of Sciences. In 1867, together with his brother M. Cyon, he discovered nn. accelerantes of heart, which increase the heart rate when being stimulated. From 1868 to 1874 he was a privatdocent an professor of physiology at Saint-Petersburg University, where under his guidance I.P. Pavlov mastered the brilliant technique of vivisection experiment and accomplished his first works on the physiology of circulation and digestion. From 1872 to 1874 E. F. Cyon was physiology professor at Saint-Petersburg Medical-Surgical Academy. He published "Course of Physiology" in 2 volumes, the official speech "Heart and Brain" and others, proposed an original theory of inhibition, improved the reflex theory. He published 197 works, including 151 in German and French. I. P. Pavlov paid a worthy tribute to his teacher and continued the main direction of his investigations.

History, 19th Century↗

[The significance of animals in biomedical research].

The mission of medicine is maintenance of health, elimination of suffering and prolongation of life. These aims can be achieved by medicine based on experimental determination, because only then it becomes a real science. The nature of human mind has led the man since the beginning of humanity on the earth to the cognition of his environment and himself. Being intellectually superior than other living creatures, the man got power over them. In his endless efforts to expand knowledge about living organisms, including his own, he started to use animals. The man has used animals for cognitive purposes for ages and is still doing it, however his motivation has changed and is still changing. Cognition of functions of living organisms on the basis of observation solely, without any interference into the living body gave a lot of important information, yet, generally, this method was of little use for the development of science. Only the use of animals could give information about this what was earlier unknown and impossible. The long-lasting evolution of experimental studies of living functions of higher organisms resulted in achieving a perfect level in biomedical studies. Vivisection, as it was understood years ago, has become history. For a chronic experiment, an animal is surgically prepared according to the researcher's intention. The surgery and the postoperative period follow the principles used in human surgery. After the convalesce period, the animal is used for further experiments. On such prepared animals, the investigations in experimental cardiology, neurophysiology, gastroenterology and other medical disciplines are performed. The animal prepared for longlasting experiments do not suffer from pain during both the experiments and intervals between them. Another important achievement in chronic experiments is considerable reduction of the number of animals used in experimental medicine. Undoubtedly, the greatest achievements in medicine in the 19th and 20th centuries were possible due to the use of animals. There is a strong relationship between a rapid progress in experiments on animals and evident progress in clinical medicine. In the second half of the 20th century the man left the globe for the first time and reached another planet. Tis unusual event in the history of humanity was possible due to space medicine based on biomedical experiments with the use of animals. Also, the man's ability to reach the depths of oceans cost the lives of many experimental animals. Despite advances that have already been made, we are still in the early stages of understanding the complex workings of the body. This makes the replacement of animal experiments a slow process. At the same time, our increasing knowledge is opening up whole new areas of medical research which in turn give rise to a need for further animal use. While it may be difficult to envisage total replacement, the proposition of work that can be done without animals is increasing all the time. Many efforts are being made to find alternatives to animal experiments, to increase the usefulness of those that already exist, and to refine animal research methods. But at present days biomedicine, with its experiments on animals, reveals the laws of nature which the clinical and his patient can use to improve the life quality, prolong the life span and eliminate suffering. We all want to lead a healthy and enjoyable life. Most of us want the benefits of modern medical research-benefits that we would not have without the contribution of animal research. Yet, the health and well being of animals is important too. Clearly, those involved in this research have a moral and legal obligation to ensure that laboratory animals are well housed and cared for, any distress is kept to a minimum and that as few animals as possible are used. In the end, the question of whether animals should be used in medicines research is one everyone must answer for themselves, but the decision is more c

Animal Welfare↗

[Is brain surgery on primates in basic research morally acceptable?]

In the contemporary controversy about the legitimacy of vivisection a few basic assumptions are shared by nearly all participants of the discussion. (I) Pure Research in the service of medicine is of great value for humankind. It contributes to prolonging human life and the alleviation and prevention of human suffering. (II) Brain surgery for the sole purpose of pure research is morally unacceptable in the case of any human being. (III) Primates are sensitive beings which lead a rich social life and are endowed with remarkable intellectual capacities. (IV) Primates have a moral standing, possibly to a lesser degree compared with human beings, certain acts are therefore an injustice toward them. The controversy then is about the question whether premise (I) outweighs (IV), i.e. whether the benefit of the pure research is from a moral point of view more important than the suffering of innocent primates. I shall present four arguments against such a conclusion. 1) According to premise (I) brain surgery on human beings for the sole purpose of pure research is morally unacceptable. Since this prohibition is meant to include all human beings it cannot rest on the exclusive human possession of reason because e.g. some mentally handicapped human beings lack this faculty. All other properties which may be named as basis for the ascription of a moral status which forbids brain surgery for pure research, are possessed also by some animals, especially primates; therefore it is impossible to deny them the same moral status. 2) Brain surgery on primates is confronted with an insoluble dilemma: If the characteristics of the primate brain are very similar to that of human beings, the scientific benefit is obvious, but the procedure appears to be morally unacceptable exactly because of this similarity. If, on the other hand, the characteristics differ significantly, brain surgery may seem legitimate but the scientific benefit becomes doubtful at best. 3) We could quite easily save hundreds of human lives if e.g. speed limits would be reduced (say) by half. Most of us, however, are unwilling to accept such a loss of quality of life in order to save a certain number of human lives. Since we are no prepared to pay this comparatively modest price, we have, in my eyes, no moral right to impose considerable pain and suffering on a primate to save human lives. 4) Pure research in the service of human medicine is from a moral point of view of great importance. Since most of the work in this area is done or financed by private corporations and not by state institutions, from a economical point of view the aim consists in making profit. Since the latter aspect has gained more and more weight in the last years the moral worth of pure research cannot rule out any other moral concern.

Journal Article↗

[Galen on the seat of the mind: medical experiment and philosophical tradition].

In books I-VI of his On the doctrines of Hippocrates and Plato, the medical scientist and philosopher Galen of Pergamon (c. 129-210 CE) defends the platonic tripartition and trilocation of the soul against the cardiocentric theory endorsed by the Aristotelians, Stoics and many physicians. This article concentrates on Galen's anatomical experiments (vivisections) concerned with the nervous and arterial systems. These experiments are embedded in a theoretical framework derived in large part from Aristotelian theory of science. Though Galen is to some extent aware of certain theoretical problems involved in experimentation, notably that of experimental error, he remains in many respects a captive of a traditional debate, which is marked by a limited set of available options. Thus his experiments serve the purpose of confirming the platonic position, even though they are sometimes open to alternative interpretations.

Brain↗

The discovery of the body: human dissection and its cultural contexts in ancient Greece.

In the first half of the third century B.C, two Greeks, Herophilus of Chalcedon and his younger contemporary Erasistratus of Ceos, became the first and last ancient scientists to perform systematic dissections of human cadavers. In all probability, they also conducted vivisections of condemned criminals. Their anatomical and physiological discoveries were extraordinary. The uniqueness of these events presents an intriguing historical puzzle. Animals had been dissected by Aristotle in the preceding century (and partly dissected by other Greeks in earlier centuries), and, later, Galen (second century A.D.) and others again systematically dissected numerous animals. But no ancient scientists ever seem to have resumed systematic human dissection. This paper explores, first, the cultural factors--including traditional Greek attitudes to the corpse and to the skin, also as manifested in Greek sacred laws--that may have prevented systematic human dissection during almost all of Greek antiquity, from the Pre-Socratic philosopher-scientists of the sixth and fifth centuries B.C. to distinguished Greek physicians of the later Roman Empire. Second, the exceptional constellation of cultural, political, and social circumstances in early Alexandria that might have emboldened Herophilus to overcome the pressures of cultural traditions and to initiate systematic human dissection, is analyzed. Finally, the paper explores possible reasons for the mysteriously abrupt disappearance of systematic human dissection from Greek science after the death of Erasistratus and Herophilus.

Animals↗

Initial experience in small animal tumor imaging with a clinical positron emission tomography/computed tomography scanner using 2-[F-18]fluoro-2-deoxy-D-glucose.

The feasibility of small animal imaging using a clinical positron emission tomography/computed tomography (PET/CT) scanner with [F-18]-fluoro-2-deoxy-D-glucose (FDG) was evaluated. As tumor-bearing small animal models, rabbits with VX-2 liver tumors, rats with mammary tumors on the back, and mice with LS174T human colon tumor xenografts were prepared. Two-dimensional PET, CT, and fused PET/CT images were obtained and reconstructed with a combined PET/CT system using a conventional protocol for humans and dedicated high-resolution mode protocols specialized for each species. Estimated radioactivity concentrations in tumors and normal organs determined noninvasively on FDG-PET/CT were compared with the actual tissue radioactivity levels determined from gamma-counting after vivisection in rats. In addition, recovery-corrected radioactivity concentrations were calculated and evaluated using the tumor/normal organ sizes measured on CT. Tumors in rabbits and rats were clearly visualized by FDG-PET/CT in the dedicated protocols, and images were considered suitable for research purposes. With the aid of thin-slice CT-mapping images, FDG uptake was correctly localized in the viable tumor regions. In mice, increased FDG uptake in tumors with varying activity levels was observed, but detailed anatomical information was not optimally provided from the images, even using specialized protocols. The estimated radioactivity concentrations of tumors and normal organs were close to the actual radioactivity concentrations obtained by gamma-counting (r = 0.97, P < 0.001, the estimated/actual slope: 1) when recovery correction was applied using the sample sizes measured on CT. FDG-PET/CT imaging with a modern clinical scanner was demonstrated to be feasible, of excellent quality, and quite quantitatively accurate for research in rabbits or rats with tumors of appropriate size (>2 cm without recovery correction and >1 cm with recovery correction). Evaluation of FDG uptake within a tumor was possible with the aid of CT images. Dedicated small animal PET/CT scanner would be better suited for evaluating tumor-bearing mice and likely could enhance imaging smaller tumors in rabbits or rats. Although it has limitations, small animal imaging with a clinical PET/CT scanner may be quite adequate for sequential noninvasive imaging in oncology research because the CT is of high resolution, allowing for localization of PET findings and for more precise noninvasive estimation of radioactivity concentration through partial volume corrections.

Animals↗