Using non-human primates to benefit humans: research and organ transplantation.

Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates") and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use.

A removable silicone elastomer seal reduces granulation tissue growth and maintains the sterility of recording chambers for primate neurophysiology.

The maintenance of the sterility of craniotomies for serial acute neurophysiological recordings is exacting and time consuming yet is vital to the health of valuable experimental animals. We have developed a method to seal the craniotomy with surgical grade silicone elastomer (Silastic) in a hermetically sealed chamber. Under these conditions the tissues in the craniotomy and the inside surface of the chamber remain unpopulated by bacteria. The silicone elastomer sealant retarded the growth of granulation tissue on the dura and reduced the procedures required to maintain ideal conditions for neurophysiological recordings.

Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here?

The ability to genetically engineer pigs that no longer express the Galalpha1,3Gal (Gal) oligosaccharide has been a significant step toward the clinical applicability of xenotransplantation. Using a chronic immunosuppressive regimen based on costimulatory blockade, hearts from these pigs have survived from 2 to 6 months in baboons. Graft failure was predominantly from the development of a thrombotic microangiopathy. Potential contributing factors include the presence of preformed anti-nonGal antibodies or the development of low levels of elicited antibodies to nonGal antigens, natural killer (NK) cell or macrophage activity, and inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an "anticoagulant" gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. The identification of the targets for anti-nonGal antibodies and/or human macrophages might allow further genetic modification of the pig, and xenogeneic NK cell recognition and activation may be inhibited by the transgenic expression of human leukocyte antigen molecules and/or by blocking the function of activating NK receptors. The ultimate goal of induction of T-cell tolerance may be possible only if these hurdles in the coagulation system and innate immunity can be overcome.

Facial restoration after trauma - nasolabial in monkey bugio - Alouatta caraya (Humboldt, 1812) - first case report / [Restauração facial pós trauma nasolabial em macaco bugio - Alouatta caraya (Humboldt, 1812) - relato de caso]

In the last decades in the State of Mato Grosso do Sul - Brazil, the reduction in the preservation of areas due to the degradation of the biome and destruction of the natural environment has caused animals, mainly in the order of non-human primates, to come closer to towns and highways, increasing the number of accidents and in some cases, deaths. New surgical techniques have been developed that favor these species as explained in this report. The howler monkey patient was traumatized in the facial region damaging important vital structures such as facial muscle groups responsible for swallowing food, chewing, breathing, defense, and communication (vocalization and mimicry), in addition to the cartilaginous nasal structures. However, reconstructive facial surgical techniques, used on humans, showed satisfactory results from an anatomical, functional, and aesthetic point of view in howler monkey, with acceptance of the animal with a safe postoperative period for a full recovery of the primate patient.(AU)

Nas últimas décadas, no estado do Mato Grosso do Sul - Brasil, a redução de áreas preservadas pela degradação de biomas e pela destruição de habitat naturais tem favorecido a aproximação de animais - muitos desses, primatas não humanos - em cidades e rodovias, aumentando o número de acidentes e, em alguns casos, de mortes. Novas técnicas cirúrgicas têm sido desenvolvidas, favorecendo essas espécies, como reportado neste trabalho. O paciente macaco bugio foi traumatizado em região facial, envolvendo importantes estruturas vitais, como grupos musculares faciais responsáveis pela apreensão alimentar, mastigação, respiração, defesa e comunicação (vocalização e mímicas), além das estruturas cartilaginosas nasais. No entanto, técnicas cirúrgicas reconstrutivas em face aplicadas e descritas em humanos apresentaram resultados satisfatórios dos pontos de vista anatômico, fisiológico e visual nos macacos bugio, com aceitação deles diante do estresse, com pós-operatório seguro, resultando na reabilitação do paciente primata.(AU)

Medical Rejuvenation in Georgia in the past: the Sukhumi Station.

If youth and body appearance enhancement is as old as Homo Sapiens, reliable medical technology for such activities is only about 100 years old. At the dawn of the 20th century, surgical operations performed under the Voronoff's treatment plan (monkey gonads' tissue grafting into humans) or the Steinach's technique (vasoligation) offered a promise of longevity, beauty and therefore youth restoration. The many links with a newly recognized discipline, endocrinology, offer a critical insight on the strong interactions between medicine and surgery in the promise of successful antiaging. On the front-line of scientific research, the Institute of Experimental Endocrinology's primate station in Sukhumi (West Georgia, now Abkhazia, on the Black Sea coast) developed a leadership role in the medical research, including rejuvenation with testis' tissues. Authors focus their attention to the everlasting commitment to experimental and clinical research as developed by Sukhumi scholars and the related moral, practical and ideological implications.

Neurosurgical access to cortical areas in the lateral fissure of primates.

In this report, a method is presented for gaining direct access to cortical areas within the lateral fissure of primates for neuroanatomical tracer injections and electrode array implantation. Compared to areas on the surface of the brain, the anatomical and physiological properties of areas within the fissure are poorly understood. Typically, access to these areas is indirectly achieved by ablating or passing through intervening areas. To enable direct experimental access, a neurosurgical technique was developed in primates whereby the banks of the lateral fissure were retracted with sparing of the vascular network and intervening areas. In some animals, anatomical tracers were directly injected into target fields without contamination of other areas. In others, multichannel electrode arrays were implanted into target areas for chronic recording of neural activity. Since, these techniques could be adapted for exploration of areas within other sulci, the approach represents an important advance in efforts to elucidate the functional organization of the primate cerebral cortex.

Striatal tissue transplantation in non-human primates.

The caudate nucleus and putamen form part of a complex but topographically connected circuitry that links the cortex, the basal ganglia and the thalamus. Within this complex system lie a series of functionally and anatomically segregated loops that allow the concurrent processing of a wide range of cognitive and motor information (Alexander et al., 1986; Alexander and Crutcher, 1990). As a constituent of these loops it has been shown that the striatum is involved in movement initiation, response selection and attentional processes (Robbins and Brown, 1990; Alexander, 1994; Lawrence et al., 1998). Although it is the medium spiny GABAergic projection neurones that are primarily lost in HD, it is not sufficient merely to replace the GABA. Instead it is crucial for striatal tissue transplants to integrate with the host tissue in such a way that the cortico-striatal-thalamic circuitry is restored and is functional. Rodent studies have progressed a long way in establishing the principle that striatal grafts can, at least partially, restore function and integrate appropriately with the host (Dunnett and Svendsen, 1993; Björklund et al., 1994; Sanberg et al., 1998) but the limited behavioural repertoire and the undifferentiated striatum meant that it was inevitable that studies should progress into primate models. Anatomical tracing studies have demonstrated that motor, premotor and somatosensory cortical areas send corticostriatal projections primarily to the putamen region in primates, whereas the head and body of the caudate nucleus mostly receive efferent input from associative cortical areas (Kemp and Powell, 1970; Kunzle, 1975, 1977, 1978; Selemon and Goldman-Rakic, 1985). Based on such anatomical, and functional, studies Alexander and colleagues have proposed the existence of at least five cortico-striatal-thalamic loops including a motor, a dorsolateral-prefrontal and an orbito-frontal loop (Alexander et al., 1986). The concentration of motor inputs to the putamen region suggests a particular involvement of this structure in the motor loop. Indeed, unilateral lesions of the putamen disrupt motor performance in the marmoset and generate apomorphine-induced dyskinesias in larger primates (Burns et al., 1995; Kendall et al., 2000). The implantation of striatal grafts into marmosets that had previously received unilateral putamen lesions ameliorated some of the motor impairments, which suggested at least partial restoration of the motor loop. In support of this we found direct evidence of host-graft cortico-striatal connectivity using an anterograde tracer injected in the primary motor cortical region (Kendall et al., 1998a). In larger primates, with lesions of the caudate and putamen, striatal [figure: see text] allografts and xenografts have been shown to reduce apomorphine-induced dyskinesias (Isacson et al., 1989; Hantraye et al., 1992; Palfi et al., 1998). The mechanism by which dyskinesias are elicited is not fully understood but alterations in firing patterns within both segments of the globus pallidus have been identified during dyskinetic movements (Matsumura et al., 1995). It seems likely that it would actually require re-establishment of afferent connections between the implanted putamen and the globus pallidus as well as of functioning dopamine receptors within the graft for the reduction in the dyskinetic profile to be observed. Certainly there is evidence, from rodent studies and the marmoset study described here, that close proximity of the graft to the globus pallidus yields better functional recovery (Isacson et al., 1986). In addition, anatomical tracing studies in rats have demonstrated connections between the implanted tissue and the host globus pallidus (Wictorin et al., 1989b, 1990) However, the relationship between graft placement and functional recovery remains to be fully substantiated.

Anterior cervical microsurgical approach for exposure of the pituitary and infundibulum in primates: technical note.

Previous operative techniques for exposure of the pituitary gland and infundibulum in nonhuman primates have significant limitations. We describe an anterior cervical microsurgical approach that is safe, simple, and reliable. It is applicable to juvenile as well as adult animals.

Surgical stapling of the spleen, pancreas, liver, and urogenital tract.

Stapling instrumentation designed primarily for specific gastrointestinal procedures and transection of vascular pedicles have been adapted for use in parenchymal organs of the abdomen and urogenital tract. This article reviews current veterinary clinical and experimental use of stapling instrumentation for splenic, pancreatic, hepatic, and urogenital surgery.

Analgesic use in nonhuman primates undergoing neurosurgical procedures.

Animals experiencing major invasive surgery during biomedical research must receive appropriate and sufficient analgesia. The concept of pain management in veterinary medicine has evolved over the past several decades, and a multimodal, preemptive approach to postoperative analgesia is the current standard of care. Here, the pathophysiology of pain and a multimodal approach to analgesia for neurosurgical procedures is discussed, with emphasis on those involving nonhuman primates.

An implantable triple-function device for local drug delivery, cerebrospinal fluid removal and EEG recording in the cranial subdural/subarachnoid space of primates.

Transmeningeal pharmacotherapy for cerebral cortical disorders requires drug delivery through the subdural/subarachnoid space, ideally with a feedback controlled mechanism. We have developed a device suitable for this function. The first novel component of the apparatus is a silicone rubber strip equipped with (a) fluid-exchange ports for both drug delivery and local cerebrospinal fluid (CSF) removal, and (b) EEG recording electrode contacts. This strip can be positioned between the dura and pia maters. The second novel component is an implantable dual minipump that directs fluid movement to and from the silicone strip and is accessible for refilling and emptying the drug and CSF reservoirs, respectively. This minipump is regulated by a battery-powered microcontroller integrating a bi-directional radiofrequency (RF) communication module. The entire apparatus was implanted in 5 macaque monkeys, with the subdural strip positioned over the frontal cortex and the minipump assembly secured to the cranium under a protective cap. The system was successfully tested for up to 8 months for (1) transmeningeal drug delivery using acetylcholine (ACh) and muscimol as test compounds, (2) RF-transmission of neocortical EEG data to assess the efficacy of drug delivery, and (3) local CSF removal for subsequent diagnostic analyses. The device can be used for (a) monitoring neocortical electrophysiology and neurochemistry in freely behaving nonhuman primates for more than 6 months, (b) determining the neurobiological impact of subdural/subarachnoid drug delivery interfaces, (c) obtaining novel neuropharmacological data on the effects of central nervous system (CNS) drugs, and (d) performing translational studies to develop subdural pharmacotherapy devices.

Animal models for translational research on shoulder pathologies: from bench to bedside.

Several animal models have been used for in vivo and in vitro shoulder research. In vitro models, consisting of cadaveric specimens, are useful in providing basic understanding of the functioning of the shoulder and for biomechanical experiments. In vivo models provide the means to model living phenomena, such as tendon healing process, tendinopathy, instability, and adaptive responses to surgery. However, intrinsic differences among different species make translation to human shoulder pathologies difficult. Most of the animals used in experimental settings are quadrupeds, using the forelimbs for weight-bearing during locomotion, with no or minimal overhead activity. The various animal models already used to study shoulder pathologies are presented in this article. However, there is a lack of validation for these animal models, which provides challenge to the further research in this field.

Intraoperative intracerebral MRI-guided navigation for accurate targeting in nonhuman primates.

During in vivo intracerebral infusions, the ability to perform accurate targeting towards a 3D-specific point allows control of the anatomical variable and identification of the effects of variations in other factors. Intraoperative MRI navigation systems are currently being used in the clinic, yet their use in nonhuman primates and MRI monitoring of intracerebral infusions has not been reported. In this study rhesus monkeys were placed in a MRI-compatible stereotaxic frame. T1 MRIs in the three planes were obtained in a 3.0T GE scanner to identify the target and plan the trajectory to ventral postcommisural putamen. A craniotomy was performed under sterile surgical conditions at the trajectory entry point. A modified MRI-compatible trajectory guide base (Medtronic Inc.) was secured above the cranial opening and the alignment stem applied. Scans were taken to define the position of the alignment stem. When the projection of the catheter in the three planes matched the desired trajectory to the target, the base was locked in position. A catheter replaced the alignment stem and was slowly introduced to the final target structure. Additional scans were performed to confirm trajectory and during the infusion of a solution of gadoteridol (ProHance, Bracco Diagnostics; 2 mM/L) and bromophenol blue (0.16 mg/ml) in saline. Monitoring of the pressure in the infusion lines was performed using pressure monitoring and infusion pump controller system (Engineering Resources Group Inc.) in combination with a MRI-compatible infusion pump (Harvard). MRI during infusion confirmed successful targeting and matched postmortem visualization of bromophenol blue. Assessment of the accuracy of the targeting revealed an overall 3D mean ± SD distance error of 1.2 ± 0.6 mm and angular distance error of 0.9 ± 0.5 mm. Our results in nonhuman primates confirm the accuracy of intraoperative MRI intracerebral navigation combined with an adaptable, pivot point-based targeting system and validates its use for preclinical intracerebral procedures.