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Tuberculosis in nonhuman primates as a threat to humans.

Nonhuman primates are used in many laboratories either as modest systems for studies of disease processes or as a source of these tissues for cell culture and vaccine production. Much too frequently, the health of these donor animals is taken for granted, although T.B. testing is one of the few procedures routinely performed. In spite of this screening, outbreaks of T.B. among various simian species are still sufficiently commonplace to make maintenance and use of these animals a continuing source of danger to the human population. Development of rampant fatal tuberculosis in established colony animals (chimpanzees, baboons, others) previously tested as tuberculin negative suggests the need for continuing monitoring as well as extreme caution in handling of these animals, especially at necropsy. Further, use of complete Freund's adjuvant or isoniazid either experimentally or therapeutically will obscure the interpretation of the skin test. Present lack of concern by many investigators for biohazards associated with use of nonhuman primates makes the problem of laboratory-associated infections a major source of concern. Positive conversion of animal handlers has occurred a sufficient number of times to make development of tuberculosis in a colony of animals a matter of more than academic interest.

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Atrial receptor modulation of renal nerve activity in the nonhuman primate.

Experiments were done in the nonhuman primate Macaca fascicularis to determine the extent to which low-pressure receptors modulate renal nerve activity (RNA). Left atrial pressure (LAP) was increased either by inflating a balloon in the left atrium or by intravascular volume expansion. Arterial pressure (AP) was increased by the administration of epinephrine. Balloon inflation produced variable changes in RNA when all reflexes were intact. In the bilateral vagotomized animal, balloon inflation significantly increased RNA. Compared with the intact state, neither carotid sinus denervation nor sinoaortic denervation had a significant influence on RNA during balloon inflation. The response of both baroreceptor-denervated groups, however, was significantly less than that of the vagotomized group. Vagotomy plus sinoaortic denervation essentially prevented any effect of balloon inflation on RNA. Volume expansion produced a greater inhibition of RNA per increase in AP than did epinephrine. However, this difference was abolished after bilateral cervical vagotomy. These experiments demonstrate a significant influence and interplay of low- and high-pressure receptors on RNA in the nonhuman primate.

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Nonhuman primate models of menopause workshop.

The Nonhuman Primate Models of Menopause Workshop was held on the National Institutes of Health campus in January 2001. The purpose of this workshop, sponsored by the National Institute on Aging, was to review what is known about the female reproductive aging process in various species of monkeys (particularly rhesus, baboons, cynomolgus, and chimpanzees), including hormone profiles during the menopausal transition, occurrence of hot flashes, extent of age-related and menopause-associated changes in hormone levels on metabolism, bone loss, and impaired cardiovascular and cognitive function. Many aspects of the female reproductive aging process appear to be concordant between humans and these monkey species, but several important features may be species-specific. Those features that appear to parallel human menopause and aging include general similarity of hormone profiles across the menopausal transition, progression to cycle termination through irregular cycles, declining fertility with age, age-related gains in weight and percentage body fat content (with tendencies toward insulin resistance and glucose intolerance), increased low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol, declines in serum dehydroepiandrosterone, similarities in temperature-regulation systems, protective responses to estrogen replacement following ovariectomy in terms of bone metabolism, lipid profiles, and cognitive changes. Important differences include relatively short postmenopausal life span, timing in menopause-related changes in hormone secretion, and seasonal menstrual cycles. In addition, the question of whether ovariectomy in young adults is an appropriate model for the consequences of natural or surgical menopause in middle-aged and older adults is unresolved, and the numbers of older female animals available for research on menopause are very limited. The use of animal models is seen by workshop participants to be crucial for a mechanistic understanding of the human menopausal process and its connections to postmenopausal health problems; however, extensive in-depth and broad-based research is required to determine if nonhuman primates are appropriate models of human menopause.

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Chemokine networks and in vivo T-lymphocyte trafficking in nonhuman primates.

T-lymphocyte migratory circuits in human and nonhuman primates remain largely unexplored due to the difficulty of defining cell trafficking in vivo. However, this knowledge may reveal critical aspects of immunity and T-lymphocyte homeostasis in both health and disease. Furthermore, in vivo T-lymphocyte trafficking studies may facilitate defining mechanism(s) of immune dysfunction in the nonhuman primate model for acquired immunodeficiency syndrome (AIDS). Here, we developed a model for in vivo T-lymphocyte trafficking in nonhuman primates, and delineated homing characteristics of unstimulated peripheral blood mononuclear cells (PBMCs) to lymphoid and nonlymphoid compartments in healthy rhesus macaques. T-lymphocyte homing of autologous, carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled PBMCs was defined within 48 h of intravenous transfer. The highest relative frequency of CFSE+ T lymphocytes was observed in peripheral blood and spleen. Expression of chemokine receptor CCR7 and its ligands correlated with recirculation of T lymphocytes through the periphery and homing to paracortical regions of lymph node, where cells remained largely excluded from B-cell follicles. T-lymphocyte trafficking was also detected to the liver and bone marrow, and at low levels to the thymus and small intestine. The liver contained the highest proportion of CD45RA- T lymphocytes, consistent with homing of activated/memory T lymphocytes to this nonlymphoid site. Our data suggest that lymphoid and nonlymphoid organs are under continuous immunosurveillance in healthy macaques, and that this model may serve to investigate aberrant patterns in disease.

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Development of Y-chromosomal microsatellite markers for nonhuman primates.

We have analysed 136 newly identified human Y-chromosomal microsatellites in five (sub)species of nonhuman primates. We identified 83 male-specific loci for central chimpanzees, 82 for western chimpanzees, 67 for gorillas, 45 for orangutans and 19 loci for mandrills. Polymorphism was detected at 56 loci in central chimpanzees, 29 in western chimpanzees, 24 in western gorillas, 17 in orangutans and at three in mandrills. Success in male-specific amplification of human Y-chromosomal microsatellites in nonhuman primates was significantly negatively correlated with divergence time from the human lineage. We observed significantly more Y-chromosomal microsatellite diversity in central chimpanzees than in western chimpanzees. There were significantly more male-specific loci with longer alleles in humans than with longer alleles in the nonhuman primates; however, this significant difference disappeared when only the loci which are polymorphic in nonhuman primates were analysed, suggesting that ascertainment bias is responsible. This study provides primatologists with a large number of polymorphic, male-specific microsatellite markers that will be valuable for investigating relevant questions in behavioural ecology such as male reproductive strategies, kin-based cooperation among males and male-specific dispersal patterns in wild groups of nonhuman primates.

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Simultaneous detection of antibodies to six nonhuman-primate viruses by multiplex microbead immunoassay.

To maintain healthy nonhuman primates for use in biomedical research, animals are routinely screened for several infectious agents at most facilities. Commonly, monkey serum samples are tested by conventional immunoassays, such as enzyme-linked immunosorbent assays (ELISAs) or Western blotting, for antibodies to specific infectious agents. For testing for antibodies against multiple agents in each sample, conventional immunoassays are laborious and time-consuming. More efficient immunoassays are needed. Accordingly, we have developed a novel multiplex serodiagnostic system based on individually identifiable, fluorescent microbead sets, where each bead set is coated with antigens from a purified preparation of a specific virus. The coated bead sets are mixed to enable the detection of antibodies to multiple viruses in one serum or plasma sample. These viruses include four agents that are routinely tested for maintenance of specific-pathogen-free monkeys, namely, simian immunodeficiency virus, simian type D retrovirus, simian T-cell lymphotropic virus, and herpes B virus, as well as simian foamy virus and rhesus cytomegalovirus, both of which are commonly found in nonhuman primates. This multiplex microbead immunoassay (MMIA) enabled the simultaneous detection of antibodies to all six viruses in single serum samples as small as 1 microliter. The results obtained by MMIA analysis correlated with results of conventional ELISAs, which detect antibodies to single agents. Thus, this multiplex microbead detection system is an efficient diagnostic modality for serosurveillance of nonhuman primates.

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Effects on human and nonhuman primate immune response of a new rat anti-CD2 monoclonal antibody.

BACKGROUND: Nonhuman primate models are highly clinically relevant in transplantation. The development of immunosuppressive tools or a tolerogenic regimen for primate models therefore represents an important goal of transplantation immunological research. Hence, we have developed a rat monoclonal antibody (mAb) that recognizes the CD2 molecule (LO-CD2b) on both human and nonhuman primate cells. METHODS: The LO-CD2b mAb has been characterized by flow cytometry, E-rosetting inhibition, and Western blotting. In vitro inhibition of immune responses by LO-CD2b was assessed after both mitogenic and allogeneic stimulation in mixed lymphocyte reactions (MLR). Several LO-CD2b dose and time responses were tested. In vivo, peripheral and lymph node T-cell depletion was examined both by flow cytometry and immunohistology in 10 baboons that received intravenous injection of LO-CD2b at different doses and time courses. Xenosensitization (anti-rat) was assessed by ELISA. Renal allograft survival was followed in two baboons treated with iterative LO-CD2b injections. RESULTS: In vitro, LO-CD2b binds a lymphocyte antigenic determinant of 52 kDa that is recognized by other well-characterized anti-CD2 mAbs (T11, Leu5b). LO-CD2b recognized natural killer CD2+ cells. Administration of 200 ng/ml LO-CD2b almost completely inhibited human and baboon mitogenic stimulation. Allogeneic baboon and human MLR were completely inhibited by the addition of LO-CD2b (at 312 ng/ml) on the day of the initiation of culture; when added after 1 or 2 days, LO-CD2b still provided a significant MLR inhibition (>50%). Incubation of LO-CD2b with baboon peripheral blood mononuclear cells produced very low cytokine levels (interferon-y, tumor necrosis factor-alpha, interleukin 2). In secondary MLR, baboon peripheral blood mononuclear cells previously incubated with LO-CD2b were unable to respond to a second allogeneic stimulation but were able to react to mitogens. In vivo, within the first hour after LO-CD2b injection (at 0.15, 0.5, and 2 mg/kg), an 85-90% peripheral depletion of CD2+ cells was observed. A partial T-cell depletion in inguinal lymph nodes was seen after 1 week. The mechanism of peripheral T-cell depletion could have been antibody-dependent cell cytotoxicity or opsonization but was complement independent. Iterative LO-CD2b injections (12 days at 0.35 mg/kg) slightly prolonged the renal allograft survival in two baboons. CONCLUSION: LO-CD2b is a nonactivating rat anti-CD2 mAb able to strongly inhibit both mitogenic and allogeneic responses in human and nonhuman primates. In vivo, LO-CD2b provides a rapid peripheral T-cell depletion, which is reversible within days after the cessation of injections. This rat mAb represents a very important tool for in vivo experimental investigation in nonhuman primates because it similarly reacts against human T cells in vitro.

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Nonhuman primate models in biogerontology.

A variety of animal models are utilized in biogerontological studies including yeast, nematodes, fruit flies, hamsters, mice, rats, and nonhuman primates. Species selection for research is based on many factors including economic feasibility, husbandry, generalizability of findings, available background information, adaptability to experimentation, and often, relevance to human aging. Each model offers its own strengths and limitations; however, nonhuman primates offer the unique advantage of phylogenetic proximity to humans. Among others, costs to purchase and maintain research subjects represent major limitations of nonhuman primate models. Although several nonhuman primate species have been utilized in aging research, rhesus monkeys (Macaca mulatta) are the best characterized and most extensively studied in biomedical gerontology. Nonhuman primate models have been employed as models for human aging in many research areas including neurobiology, skeletal, and reproductive aging and age-related diseases such as cardiovascular disease and diabetes. Primate models are now also being utilized to study interventions into aging such as caloric restriction. It will be several more years until definitive conclusions regarding lifespan effects can be made. However, existing data strongly suggest that many of the beneficial effects reported in rodents on CR also occur in primate models thereby strengthening the possibility that this nutritional paradigm may also impact favorably upon human aging.

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Antiretroviral drug studies in nonhuman primates: a valid animal model for innovative drug efficacy and pathogenesis experiments.

Several nonhuman primate models are used in HIV and AIDS research. In contrast to HIV-1 infection of chimpanzees, infection of macaque species with simian immunodeficiency virus (SIV) isolates results in a disease (simian AIDS) that shares many similarities with HIV infection and AIDS in humans. Although each animal model has its limitations and can never completely mimic HIV infection of humans, a carefully designed study allows experimental approaches, such as the control of certain variables, that are not feasible in humans, but that are often the most direct way to gain better insights in disease pathogenesis and provide proof-of-concept for novel intervention strategies. In the early days of the HIV pandemic, nonhuman primate models played a relatively minor role in the anti-HIV drug development process. During the past decade, however, the development of better virologic and immunologic assays, a better understanding of disease pathogenesis, and the availability of better drugs have made these animal models more practical for drug studies. In particular, nonhuman primate models have played an important role in demonstrating: (i) preclinical efficacy of novel drugs such as tenofovir; (ii) the benefits of chemoprophylaxis, early treatment and immunotherapeutic strategies; (iii) the virulence and clinical significance of drug-resistant viral mutants; and (iv) the role of antiviral immune responses during drug therapy. Comparison of results obtained in primate models with those observed in human studies will lead to further validation and improvement of these animal models. Accordingly, well-designed drug studies in nonhuman primates can continue to provide a solid scientific basis to advance our scientific knowledge and to guide future clinical trials.

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Expression of two-pore domain potassium channels in nonhuman primate sperm.

OBJECTIVE: Two-pore domain potassium channels (K(2P)) play integral roles in cell signaling pathways by modifying cell membrane resting potential. Here we describe the expression and function of K(2P) channels in nonhuman primate sperm. DESIGN: Experimental animal study, randomized blinded concentration-response experiments. SETTING: University-affiliated primate research center. ANIMAL(S): Male nonhuman primates. INTERVENTION(S): Western blot and immunofluorescent analysis of epididymal sperm samples. Kinematic measures (curvilinear velocity and lateral head displacement) and acrosome status were studied in epididymal sperm samples exposed to K(2P) agonist (docosahexaenoic acid) and antagonist (gadolinium). MAIN OUTCOME MEASURE(S): Semiquantitative protein expression and cellular localization and quantitative changes in specific kinematic parameters and acrosome integrity. RESULT(S): Molecular analysis demonstrated expression and specific regional distribution of TRAAK, TREK-1, and TASK-2 in nonhuman primate sperm. Docosahexaenoic acid produced a concentration-dependent increase in curvilinear velocity (P<.0001) with concomitant concentration-dependent reductions in lateral head displacement (P=.005). Gadolinium reduced velocity measures (P<.01) without significantly affecting lateral head displacement. CONCLUSION(S): The results demonstrated expression and function of K(2P) potassium channels in nonhuman primate sperm for the first time. The unique, discrete distributions of K(2P) channels in nonhuman primate sperm suggest specific roles for this subfamily of ion channels in primate sperm function.

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Analysis of large-scale nonhuman primate islet isolations.

AIMS: It is important to have clinically relevant large animal models, especially nonhuman primates, to improve the efficacy of islet isolation and transplantation prior to clinical trials. The aim of this study was to improve the efficacy of islet isolation by analyzing large-scale nonhuman primate islet isolations. METHODS: Sixty-one islet isolations were evaluated using nonhuman primates. An automated isolation method was scaled down for islet isolation. Islet yields of prepurification, postpurification, and postculture, purity of islets, viability of islets, and functionality with glucose stimulation test were assessed. Initially, we analyzed relationships between endpoints then analyzed additional factors for successful islet isolation. Those factors included donor characteristics, the two-layer method (TLM) of pancreas preservation, trypsin inhibition during digestion, and digestion and collection time. RESULTS: Prepurification islet yields were strongly correlated with postpurification yields and postculture yields. It weakly but significantly correlated with purity, viability, and functionality. The average prepurification yield was 16,267 IE/g with each case divided into either above-average (high-yield group) or below-average groups (low-yield group). In 8 cases, TLM and trypsin inhibition were used and all cases belonged to the high-yield group. There were no significant differences between high- and low-yield groups in terms of donor age, body weight, pancreas weight, and cold ischemic time. The high-yield group had significantly longer digestion times and shorter collection times. CONCLUSIONS: TLM, trypsin inhibition, complete digestion, and quick collections were key for successful islet isolation. Analysis of nonhuman primate islet isolation techniques provided useful information, which should help to improve clinical islet transplantation.

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Nonhuman primates as models for the study of human diabetes mellitus.

Nonhuman primates have been used for a variety of studies on diabetes mellitus. Spontaneous, natural forms of diabetes have been well documented in several species; there are limited data on numerous other species that indicate diabetes or a diabetes-like syndrome. The causes and manifestations of spontaneous diabetes, their prevalence, and their severity vary among species. Diabetes has also been induced in nonhuman primates with streptozotocin, alloxan, hypothalamic lesions, or pancreatectomy. The extent and severity of metabolic and hormonal abnormalities vary according to the method of induction, the individual monkey, and the species. Metabolic, hormonal, and pathologic abnormalities present in human diabetics also occur in monkeys with either spontaneous or induced diabetes. Hyperglycemia and impaired glucose clearance are common, lipid concentrations are elevated, and hemoglobin A1c concentrations are increased in hyperglycemic monkeys. Monkeys may have fasting hypo- or hyperinsulinemia; insulin responses are often impaired in glucose tolerance tests. Glucagon concentrations may be increased. Aortic atherosclerosis, muscle capillary microangiopathies, cataracts, and glomerulosclerosis have been documented. Primate size and longevity allow longitudinal studies with procedures that may not be feasible in smaller animals or in human beings. Nonhuman primates may be the models of choice for studies on selected aspects of diabetes and its secondary complications.

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Behavioral abnormalities in captive nonhuman primates.

In this study, we dealt with 11 species of nonhuman primates across 10 zoos in India. We recorded behavior as instantaneous scans between 9 a.m. and 5 p.m. In the study, we segregated behaviors for analyses into abnormal, undesirable, active, and resting. The 4 types of abnormal behavior exhibited included floating limb, self-biting, self-clasping, and stereotypic pacing. In the study, we recorded 2 types of undesirable behavior: autoerotic stimulation and begging. Langurs and group-housed macaques did not exhibit undesirable behaviors. A male lion-tailed macaque and a male gibbon exhibited begging behavior. autoerotic stimulation and self-biting occurred rarely. Males exhibited higher levels of undesirable behavior than did females. Animals confiscated from touring zoos, circuses, and animal traders exhibited higher levels of abnormal behaviors than did animals reared in larger, recognized zoos. The stump-tailed macaque was the only species to exhibit floating limb, autoerotic stimulation, self-biting, and self-clasping. Our results show that rearing experience and group composition influence the proportions of abnormal behavior exhibited by nonhuman primates in captivity. The history of early social and environmental deprivation in these species of captive nonhuman primates probably is critical in the development of behavioral pathologies. Establishing this will require further research.

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Historical perspective of genetic research with nonhuman primates.

Genetics became firmly established as a scientific discipline early in the twentieth century, but major genetic research programs that involve nonhuman primates have been initiated only in the last two decades. Considerable activity in this area has been stimulated by the concurrent development of powerful techniques for detecting variability in chromosomes, proteins, and DNA; the establishment of pedigreed breeding colonies; and the recognition that nonhuman primates are ideally suited as models of human disease and social structure. The subdisciplines of cytogenetics, immunogenetics, and biochemical genetics have established a firm basis for biomedical and evolutionary research with nonhuman primates, and they will contribute greatly to future research initiatives. More recently, the advent of molecular genetics has enhanced the opportunities for research; and the exploration of nonhuman primates as potential models for genetically mediated diseases has been richly rewarded. We stand at the threshold of a new and exciting era in genetic research with nonhuman primates. The results of research programs already underway not only will provide more definitive answers about the origin of man, but also will play a critical role in solving the health-related problems of the present and of the future.

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Remodeling of coronary arteries in human and nonhuman primates.

OBJECTIVE: To compare coronary artery remodeling (compensatory enlargement) in human and nonhuman primates. DESIGN: Coronary artery data were analyzed retrospectively for 416 nonhuman primates and 100 men and women. SETTING: The monkeys had been in experiments involving diet-induced coronary artery atherosclerosis. The human hearts were obtained from the North Carolina Baptist Hospital, Winston-Salem, and age greater than 25 years was the only criterion. PATIENTS AND OTHER PARTICIPANTS: The left anterior descending coronary arteries from 100 humans, 328 cynomolgus monkeys, and 88 male rhesus monkeys were used. INTERVENTIONS: None; this was a cross-sectional observational study. MAIN OUTCOME MEASURES: Coronary artery size, lumen area, and plaque size. In the humans, we also examined demographic characteristics (ethnicity, sex, and history of hypertension) and pathologic criteria (eccentricity or concentricity of plaque area). RESULTS: On average, lumen size remained unaffected by plaque size. Lumen size was variable and could not be predicted by traditional risk factors for coronary heart disease. However, lack of compensation (decreased lumen size as plaques enlarged) and history of coronary heart disease were significantly correlated. CONCLUSIONS: The similarity of remodeling in human and nonhuman primates suggests that the process has general biologic significance. Lack of remodelling may be a major determinant of whether a person with coronary artery atherosclerosis develops its complications.

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Neurobiology of early life stress: nonhuman primate models.

Numerous studies have shown that early life stress in nonhuman primates produces profound and long-lasting changes in behavior and biological function. We review several aspects of the neurobiology of early life stress, focusing on nonhuman primate experimental paradigms. There is experimental evidence that even prenatal stress can produce profound alterations in biological factors such as regulation of the hypothalamic-pituitary-adrenal (HPA) axis, biogenic amines, and immune function, as well as in behavioral measures of attention and sociability. An ongoing struggle in research studies is defining the relative contributions of nature and nurture in mediating the long-term effects of stress. Studies of social support contend that this has the capacity to buffer the deleterious effects of stressful early rearing environments, whereas social deprivations appear to have negative behavioral and medical outcomes, most notably deficits in immune function. From studies involving variable foraging demand (VFD)-reared nonhuman primates and other models, we suggest that many of the behavioral and biochemical changes produced resemble those seen in humans who suffer from depressive and anxiety conditions. Finally, there appears to be remarkable consistency of key neurobiological findings across species.

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Leishmania major: the suitability of East African nonhuman primates as animal models for cutaneous leishmaniasis.

The susceptibility of four species of East African nonhuman primates to experimental infection with Leishmania major was investigated. Four Syke's monkeys (Cercopithecus mitis), two vervet monkeys (Cercopithecus aethiops), two baboons (Papio cynocephalus), and two brown bushbabies (Galago garnettii) were each inoculated intradermally on the left eyelid, left ear, and nose with 0.1 ml of medium containing 1 x 10(7) promastigotes of a characterized L. major strain. All the nonhuman primates except the bushbabies developed erythema and conspicuous nodules on the eyelids and ears by 3 weeks PI. The nodules increased rapidly in size and ulceration was evident on the eyelids and ears by 49 days PI in the vervets, Syke's, and baboons. The aspirates were positive in culture or smears at 35, 49, 63, and 77 days PI. No parasites were observed in cultures or smears at 92, 105, 128, 147, and 161 days PI. The lesions in these animals began resolving by 84 days PI and were completely healed by 112 days PI. The exception was one baboon in which lesion healing did not start until around 147 days and was completely healed by 182 days PI. Cultures from the liver failed to demonstrate visceralization of the parasite in any of the animals throughout the 68 weeks of the experiment. Challenge with the same strain of L. major 6 months PI, corresponding to about 3 months after self cure, failed to produce infection in any of these experimental hosts. All the nonhuman primates except the bushbaby when challenged with the same strain of L. major at 12 months PI developed lesions and were positive for parasites at 14 and 28 days PI. Positive cultures were obtained from the eyelid and ear of one vervet up to 42 days PI. However, the lesion sizes in all these animals were smaller than in the initial infection and did not ulcerate. The nodules disappeared within 6 to 8 weeks as compared to 16 weeks in the initial infection. The histopathological appearance of the lesions varied from diffuse infiltration of plasma cells and lymphocytes which increased progressively to granulomata with epitheloid cells. This study shows that the vervets, Syke's, and the baboons are equally susceptible to L. major infection, while bushbabies are refractory. The vervets, Syke's, and baboons demonstrate a self-healing phenomenon within about 3 months which is comparable to that observed in humans infected with L. major. These three species of nonhuman primates are therefore considered as suitable models for drug or vaccine trials against human zoonotic cutaneous leishmaniasis.

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The use of recombinant human bone morphogenetic protein 2 (rhBMP-2) to promote spinal fusion in a nonhuman primate anterior interbody fusion model.

STUDY DESIGN: A study on the efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in a nonhuman primate anterior interbody fusion model. OBJECTIVES: To investigate the efficacy of rhBMP-2 with an absorbable collagen sponge carrier to promote spinal fusion in a nonhuman primate anterior interbody fusion model. SUMMARY OF BACKGROUND DATA: RhBMP-2 is an osteoinductive growth factor capable of inducing new bone formation in vivo. Although dosage studies using rhBMP-2 have been performed on species of lower phylogenetic level, they cannot be extrapolated to the primate. Dosage studies on nonhuman primates are essential before proceeding with human primate application. METHODS: Six female adult Macaca mulatta (rhesus macaque) monkeys underwent an anterior L7-S1 interbody lumbar fusion. All six sites were assigned randomly to one of two fusion methods: 1) autogenous bone graft within a single freeze-dried smooth cortical dowel allograft cylinder (control) or 2) rhBMP-2-soaked absorbable collagen sponges within a single freeze-dried smooth cortical dowel allograft cylinder also soaked in rhBMP-2. The animals underwent a baseline computed tomography scan followed by 3- and 6-month postoperation scans. Anteroposterior and lateral radiographs of the lumbosacral spine were performed monthly. After the monkeys were killed, the lumbar spine fusion sites were evaluated. Histologic evaluation of all fusion sites was performed. RESULTS: The three monkeys receiving rhBMP-2-soaked collagen sponges with a freeze-dried allograft demonstrated radiographic signs of fusion as early as 8 weeks. The control animals were slower to reveal new bone formation. The computed tomography scans revealed extensive fusion of the L7-S1 lumbar vertebrae in the group with rhBMP-2. A pseudarthrosis was present in two of the control animals. CONCLUSIONS: This study was able to document the efficacy of rhBMP-2 with an absorbable collagen sponge carrier and a cortical dowel allograft to promote anterior interbody fusion in a nonhuman primate model at a dose of 0.4 mg per implant site (1.5 mg/mL concentration). The late of new bone formation and fusion with the use of rhBMP-2 and cortical dowel allograft appears to be far superior to that of autogenous cancellous iliac crest graft with cortical dowel allograft.

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