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PubMed2000

In vitro oxidation of low-density lipoprotein in two species of nonhuman primates subjected to caloric restriction.

Caloric restriction (CR), which increases longevity and retards age-associated diseases in laboratory rodents, is being evaluated in nonhuman primate trials. CR reduces oxidative stress in rodents and appears to improve risk factors for cardiovascular disease in nonhuman primates. We tested the hypothesis that low-density lipoprotein (LDL) oxidizability is reduced in two monkey species (rhesus and cynomolgus) subjected to chronic CR. In both species, no significant differences occurred between CR and control animals on total, LDL, or high-density lipoprotein (HDL) cholesterol. In rhesus monkeys, triglycerides were higher in controls than CR (139 +/- 23 vs 66 +/- 8 mg/dl,p < .01, respectively). LDL from CR rhesus monkeys was reduced in triglyceride content and molecular weight compared to controls, whereas LDL composition in cynomolgus monkeys was similar in CR and control animals. In keeping with minor deviations in lipids, antioxidants, and LDL composition, no consistent differences in in vitro LDL oxidizability were apparent between CR and controls in either species.

Animals↗
PubMed1986

Fetal lung development in male and female nonhuman primates.

Indices of lung maturation were assessed in 58 rhesus fetuses at five gestational ages during the last trimester of nonhuman primate pregnancy to determine whether fetal sex influences lung maturation. In addition to analysis of whole lung phospholipids, glycogen, protein, DNA, and pressure-volume curves surfactant fraction phosphatidylcholine (PC) was quantitated following isolation by sucrose gradient centrifugation and a combination of predictors were assessed by all possible subsets regression to attain a composite "maturity index." For the total population, there was a uniform progression in physical growth characteristics, lung destensibility and stability and phospholipids with advancing gestation. The quantitative change in surfactant fraction PC concentration for both sexes was considerably greater than that observed for whole lung PC between 135 days gestation and term. Further, the increase in surfactant PC occurred in association with improving lung destensibility and deflation stability prior to maximum changes in the whole lung PC or disaturated PC concentration. There were no statistically discernible differences in biochemical or physiological assessment between sexes at any gestational age. These data in nonhuman primates suggest that documented differences in survival from the respiratory distress syndrome between males and females do not result from a discordance in lung maturation as a function of time throughout the last trimester of gestation.

Animals↗
PubMed2004

Cholesterol-lowering independent regression and stabilization of atherosclerotic lesions by pravastatin and by antimonocyte chemoattractant protein-1 therapy in nonhuman primates.

OBJECTIVE: Anti-atherosclerotic effects of statins might be mediated partly by pleiotropic cholesterol-lowering independent mechanisms. We used nonhuman primates and examined whether treatment with pravastatin or antimonocyte chemoattractant protein-1 (MCP-1) therapy can induce regression and stabilization of established atherosclerotic lesions through cholesterol-lowering independent mechanisms. METHODS AND RESULTS: Advanced atherosclerosis was induced in the abdominal aorta and the common iliac artery of cynomolgus monkeys by undergoing balloon injury and giving atherogenic diet for 6 months. At 6 months, the diet was changed to normal chow, and the animals were allocated to 4 treatment groups: control vehicle group and other groups treated with pravastatin (1 or 10 mg/kg) or with mutant MCP-1 gene transfection for additional 6 months. Each compound was treated instead of the atherogenic diet, and cholesterol contents in pravastatin-treated groups were adjusted to equalize plasma cholesterol level among groups. Pravastatin reduced neointimal formation in the aorta, but not in the common iliac artery. Pravastatin reduced intimal macrophage area and other markers of plaque destabilization in the common iliac artery. Equivalent inhibitory effects were observed in animals that received mutant MCP-1 gene transfection. No serious side effects were noted by 2 therapeutic modalities. CONCLUSIONS: This study demonstrated cholesterol-lowering independent regression and stabilization of established atherosclerotic lesions by pravastatin and by anti-MCP-1 therapy in nonhuman primates. An anti-inflammatory mechanism may be involved in the beneficial effects of pravastatin.

Angiotensin II↗
PubMed1996

Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate.

OBJECTIVE: To determine whether the angiogenic peptide vascular endothelial growth factor (VEGF) is sufficient to produce iris neovascularization in a nonhuman primate (Macaca fascicularis). METHODS: Eight eyes of 4 animals were studied. The 165-amino acid isoform of human recombinant VEGF (VEGF165) was injected into the vitreous of 5 cynomolgus monkey eyes (doses ranging from 0.25-2.5 micrograms per injection). Equal amounts of inactivated human recombinant VEGF (2 eyes) or vehicle (1 eye) were injected into contralateral control eyes. Eyes were assessed by slitlamp biomicroscopy, tonometry, iris color photography, fluorescein angiography, histopathologic examination, and immunostaining with antibodies against proliferating cell nuclear antigen. RESULTS: All 5 bioactive VEGF-injected eyes developed neovascularization with dilated and tortuous iris vessels that leaked fluorescein. None of the 3 control eyes exhibited any iris vascular changes. Inflammation was absent in both treatment groups. A dose response to VEGF was observed in the single animal that received 2.5 micrograms and 0.25 microgram in the right and left eyes, respectively. Iris vessel endothelial cells were positive for proliferating cell nuclear antigen in the bioactive VEGF-injected eyes only. Injections of 1.25 micrograms of VEGF every 3 days during a 30-day period produced advanced iris neovascularization, ectropion uvea, and neovascular glaucoma. CONCLUSIONS: Intravitreal injections of recombinant human VEGF165 in amounts comparable with those measured in eyes with active neovascularization are sufficient to produce noninflammatory iris neovascularization in a nonhuman primate. Prolonged exposure to VEGF165 can produce ectropion uveae and neovascular glaucoma.

Animals↗
PubMed1987

Polymorphism of glycophorins in nonhuman primate erythrocytes.

Using immunoblotting techniques and polyclonal antisera to human erythrocyte alpha glycophorin, we show that erythrocytes of several species of nonhuman primates, including representatives of anthropoid apes (19 chimpanzees, 3 gorillas, 6 orangutans, and 3 gibbons) and Old World monkeys (3 baboons, 5 rhesus monkeys, and 6 cynomolgus macaques), contain human alpha glycophorin-like molecules. Each species displays a unique glycophorin profile; in anthropoid apes the profile is more complex than in Old World monkeys and more similar to that seen in humans. The chimpanzee was the only species in which human delta-like glycophorin was detected but it differed from its human counterpart in electrophoretic mobility and reaction with M-specific monoclonal antibody. In contrast to humans, highly polymorphic glycophorin profiles were observed in each species of anthropoid apes and three distinct patterns were defined in each. No such polymorphism has been found so far among the Old World monkeys in the limited number of animals studied. The major glycophorins in all species but the chimpanzees failed to react with M- or N-specific monoclonal antibodies, suggesting structural differences from the human within the amino terminal regions. The reaction with the minor glycophorins showed inter- and intraspecies variability. All glycophorins, except delta-like glycophorin in the chimpanzee, reacted with the antiserum to the carboxyl terminal fragment of human alpha glycophorin, indicating a structural relation to the human in this region. An unexpected correlation was observed, in the chimpanzee, between the patterns of electrophoretically resolved glycophorins and the V-A-B-D blood-group phenotypes, allowing the assignment of each determinant to specific glycophorin bands. The basis for the differences observed between human and nonhuman primate glycophorins is not clear but the possibilities include a common nonpolymorphic ancestor and differences in selective pressures.

Animals↗
PubMedDate not supplied

Progress and challenges in therapies for AIDS in nonhuman primate models.

Efforts to develop animal models for human immunodeficiency virus type-1 (HIV-1) vaccine testing have focused on lentivirus infection of nonhuman primates. A long-term goal of this primate research is to utilize the models to understand the mechanisms of pathogenesis leading to AIDS. Because the time to disease is compressed relative to HIV infection in humans, therapeutic strategies and compounds can be tested in nonhuman primate models in a shorter time frame and under more controlled conditions than are possible in many clinical studies. Recent interventive studies in primates using antiviral drugs or passive immune globulin (IgG) have demonstrated that multiple log reductions in plasma virus can be achieved and sustained, with accompanying health benefits. Information gained about timing and dosage may be of utility in designing clinical studies. The development of reliable and predictable animal models for effective therapies and vaccines against AIDS remains a critical priority for primate research.

AIDS Vaccines↗
PubMed1998

Effects of Mpl ligands on platelet production and function in nonhuman primates.

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates dose-dependentbyinducing megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human TPO, nonpegylated or pegylated recombinant human megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover), platelet TPO receptor density, and marrow megakaryocyte volume, ploidy, number and mass. Mpl ligand therapy sustains normal peripheral platelet concentrations following myelosuppressive chemotherapy in baboons and corrects peripheral platelet counts in HIV-infected chimpanzees with severe thrombocytopenia. Whereas Mpl ligands do not directly induce platelet aggregation in vitro, they enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo following treatment with Mpl ligands. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the direct effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.

Animals↗
PubMed2003

Microarray analysis of nonhuman primates: validation of experimental models in neurological disorders.

Nonhuman primates (NHPs) have provided robust experimental animal models for many human-related diseases due to their similar physiologies. Nonetheless, profound differences remain in the acquisition, progression, and outcome of important diseases such as AIDS and Alzheimer's, for which the underlying basis remains obscure. We explored the utility of human high-density oligonucleotide arrays to survey the transcription profile of NHP genomes. Total RNA from prefrontal cortices of human (Homo sapiens), common chimpanzee (Pan troglodytes), cynomolgous macaque (Macaca fascicularis), and common marmoset (Callithrix jacchus) was labeled and hybridized to Affymetrix U95A GeneChip probe arrays. Corresponding data obtained previously from common chimpanzee and orangutan (Pongo pygmaeus) were added for comparison. Qualitative (present or not detected) and quantitative (expression level) analysis indicated that many genes known to be involved in human neurological disorders were present and regulated in NHPs. A gene involved in dopamine metabolism (catechol-O-methyltransferase) was absent in macaque and marmoset. Glutamate receptor 2 was up-regulated, and transcription-associated genes were down-regulated in NHPs compared with humans. We demonstrate that transcript profiling of NHPs could provide comparative genomic data to validate and better focus experimental animal models of human neurological disorders.

Adult↗
PubMed1993

Nonhuman primate responses to murine and humanized OKT4A.

A nonhuman primate antimurine response (MAMA) has been observed in 17 cynomolgus renal allograft recipients of murine OKT 4A. Neither cyclosporine, nor total-lymphoid irradiation, nor donor bone marrow preparation inhibited this antixenogeneic response. In an attempt to alter the antimurine basis of the response, a humanized chimeric OKT4A (IgG4) containing the entire variable portion of the murine OKT4A and a humanized CDR grafted OKT4A mAb sharing only the Complementarity Determining Region from the murine OKT4A, were administered to 8 cynomolgus allograft recipients. MAMA was detected in each recipient. In contrast to sera from recipients of murine OKT4A, sera from recipients of humanized OKT4A displayed no reactivity to other murine mAbs. MAMA specificity did not assay constant (C) region differences between the murine and humanized mAb; however, C region homology in humans should preclude a human antimouse antibody (HAMA) to the Fc portion of a humanized mAb. Furthermore, cynomolgus recipient serum levels of the humanized OKT4A mAb were maintained (> 1 microgram/ml) for a longer period than following treatment with murine OKT4A (murine < 12 days versus between 12 and 24 days for the humanized). If the HAMA response to humanized mAb in future clinical trials, were to be predictably anti-idiotypic, then the opportunity for treatment with sequential mAbs of differing idiotypes would be retained. Moreover, these current studies also suggest that humanized construction may influence the duration of therapeutic mAb levels. Thus, anti-idiotypic reactivity may not be as consequential to the clinical administration of humanized mAb to allograft recipients.

Animals↗
PubMed1976

Diagnosis of pregnancy in chimpanzees using the nonhuman primate pregnancy test kit.

The usefulness of The Nonhuman Primate Pregnancy Test kit for diagnosis of pregnancy in chimpanzees was determined. This hemagglutination inhibition test for urinary chorionic gonadotropin accurately indicated conception by positive responses in 151 to 153 specimens collected between 20 and 133 days after the estimated day of fertilization. The rate of false positive responses did not exceed 1%.

Animals↗
PubMed2005

Tilt psychophysics measured in nonhuman primates.

A method to measure tilt psychophysics in nonhuman primates has been developed and tested. Two rhesus monkeys were trained to orient a light bar parallel to the direction of gravity by rotating a small steering wheel attached to the primate chair. After adequate training, they performed this task during motion paradigms that rotated the gravitoinertial force (GIF) in the roll plane. The animals accurately aligned the light bar with the direction of gravity during and following roll tilts. Subtle aspects of perceived roll tilt previously recorded in human subjects were also observed in the monkeys. During centrifugation and linear translation, an interaural inertial force rotates the GIF in the roll plane. Similar to humans, the animals' perceived direction of gravity shifted toward alignment with the GIF during these paradigms, and the dynamics of these shifts demonstrated an interaction between the otolith afferents that transduce the GIF and rotational cues from the semicircular canals. Finally, optokinetic roll stimulation induced an illusion of roll tilt that was dependent on head orientation, similar to results described in human subjects. Taken together, these findings validate the methodology employed to measure tilt psychophysics; the monkeys' responses were qualitatively similar to those described in human subjects and also recapitulated subtle aspects of the perceptual response observed in humans. This new methodology sets the stage for innovative experimental approaches that will help to elucidate the neural mechanisms underlying the perception of spatial orientation.

Animals↗
PubMed2000

Evaluation of a human immunometric assay for the determination of thyroid-stimulating hormone in nonhuman primates.

Sera from nine species of clinically healthy nonhuman primates were assayed for T4 and thyroid-stimulating hormone (TSH) using human immunoassays (a fluorescence polarization immunoassay for T4, a microparticle enzyme immunoassay for TSH). The T4 levels ranged from 20 to 132 nmol/L (x +/- SD = 62.8 +/- 24.7 nmol/L). Levels of TSH were detected only in western lowland gorillas (Gorilla gorilla gorilla) and Sumatran orangutans (Pongo pygmaeus abelii) (range, 0.4-10.8 mIU/L; detectable limit = 0.01 mIU/L). The results suggest that the antibodies used in the commercial TSH immunoassay assessed in this study cross-react with gorilla and orang-utan TSH but not with TSH of primates of the genera Macaca, Papio, Erythrocebus, Ateles, Leontopithecus, and Lemur.

Animals↗
PubMed1976

A nonhuman primate vascular shunt model for thrombus generation.

A nonhuman primate model for thrombus generation was developed. Three different types of test devices constructed of polystyrene or polyethylene-Silastic were exposed to flowing blood in arterioarterial or arteriovenous vascular shunts in rhesus monkeys. The test device design included a simple tube, a vortical flow device, and a turbulent flow device. The amount of thrombus deposited within each individual test device after a 15-minute exposure to blood flowing through the shunt was determined gravimetrically. These studies indicate that a test device designed to include an area of vortical flow generated the greatest amount of thrombus. Test devices fabricated from polystyrene consistently generated larger thrombus deposits than did similar test devices fabricated from polyethylene-Silastic. Arteriovenous shunts proved superior to arterioarterial shunts in that flow was predictable in the former and unpredictable in the latter; venovenous shunts thrombosed quickly. Hematologic studies indicated a progressive fall in platelet count during the 4-hour test interval in all animals, whereas in only a few animals were there a shortening of partial thromboplastin time values, a fall in fibrinogen levels, and the appearance of fibrin degradation products. An optimal model for thrombus generation appears to include vortical flow test devices fabricated of polystyrene exposed to flowing blood in an arteriovenous shunt.

Animals↗
PubMed1995

Histopathology of IQ-induced hepatocarcinogenesis in nonhuman primates.

This study describes histopathological findings in 26 nonhuman primates (cynomolgus and rhesus monkeys) with liver tumors after dosing with IQ for time periods of 27 to 72 months. In most of the cases 2-5 well-defined tumor nodules were present in the liver at the time of autopsy. In 5 cases there were numerous nodules occupying most of the liver. Intrahepatic vascular invasion was observed in 14 cases, and lung metastases in 6 cases. The histology of 72 nodules from 21 cases with well-defined tumors and the 5 cases with massive involvement was studied. The majority of the tumors represented well to moderately well-differentiated hepatocellular carcinoma (HCC). Trabecular pattern was most common, followed by solid and pseudoglandular patterns. Five nodules displayed poorly differentiated pleomorphic variant of HCC with large, often multinucleated, tumor cells. Spindle cell and clear cell variants of HCC were seen in one nodule each. Two nodules were classified as cholangiocarcinomas. Immunostaining for cytokeratins 7 and 19 did not prove to be reliable markers for tumors of bile duct origin, since they were also expressed in some of the poorly differentiated HCC. The most common microscopic finding of the noncancerous portions of the liver were clear cell foci, composed of large, glycogen rich hepatocytes with small eccentric nuclei. Other lesions commonly found were dysplastic hepatocyte foci around the central veins and proliferating bile ductular-like (oval) cells along the portal areas and portal tracts.

Animals↗
PubMed1984

Delineation of lymphocyte subsets in lymph nodes of nonhuman primates.

Monoclonal antibodies which recognize specific surface antigens on human lymphocytes were used with an avidin-biotin immunoperoxidase technique to stain lymph nodes from nonhuman primates. Cells in lymph nodes from three macaque species and two new-world primate species could be stained to define T11, T4, T8, and B1 lymphocyte subsets. This approach will facilitate the study of many important spontaneous and experimentally induced diseases of nonhuman primates.

Animals↗
PubMed2004

Comparative study of lung cytologic features in normal rhesus (Macaca mulatta), cynomolgus (Macaca fasicularis), and African green (Chlorocebus aethiops) nonhuman primates by use of bronchoscopy.

Invasive bronchoscopy and bronchoaveolar lavage (BAL) fluid collection represents an important tool in studies of the respiratory system of nonhuman primates. Bronchoscopy and BAL fluid collection was performed on groups of rhesus (Macaca mulatta) and cynomolgus (Macaca fasicularis) macaques and African green monkeys (Chlorocebus aethiops), and the resulting comparative lavage cytologic features are described. Analysis of the BAL fluid did not reveal significant differences among species with respect to total cells recovered or differential cellular composition. This description of the method used to lavage the nonhuman primates and the resulting lung cytologic findings provide important comparative data for three species commonly used in biomedical research.

Animals↗
PubMed1999

Combined use of T1-weighted MRI and MRA for stereotaxic lesioning of the nonhuman primate brain: application to the rhinal cortex.

Stereotaxic brain lesioning is widely used to develop experimental models of human brain disease in the nonhuman primate. To avoid intraoperative vascular complications such as intracranial hemorrhage, we developed a methodology that is easy to implement. This method combines T1-weighted magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). This technique is applied to produce bilateral neurotoxic lesions of the rhinal cortex, a structure located medially in the temporal lobe, in eight baboons (including five sham-operated animals with needle descents but no ibotenic acid injection). Two other baboons were lesioned before the MRA technology was available. The MRA sequence (two-dimensional time-of-flight, axial acquisition) was used to localize the blood vessels in the needle trajectories, i.e., the highly vascularized sylvian fissure and temporal gyri. The vessel coordinates were transposed onto the coronal MRI-TI images, onto which the injection sites were determined and the planned needle tracks drawn. In the eight baboons that had MRA, 26.8% of these needle tracks had to be slightly displaced because of the presence of blood vessels. The stereotaxic coordinates of the final target sites were then calculated with respect to six skull landmarks that also served as a reference during surgery. No intracranial hemorrhage occurred in any of the eight baboons in which MRA was performed, in contrast to one of the two baboons not studied with MRA. The histological analysis showed a good extent of the rhinal lesions in all lesioned animals, with minimal damage to areas other than those that were targeted. Thus, combined use of MRI-TI and MRA proved to be reliable in reducing vascular complications, affording new advances for stereotaxic surgery in nonhuman primates.

Animals↗
PubMed2003

Detection by PCR and isolation assays of the anaerobic intestinal spirochete Brachyspira aalborgi from the feces of captive nonhuman primates.

The purpose of this study was to investigate the presence of the anaerobic intestinal spirochetes Brachyspira aalborgi and Brachyspira pilosicoli in the feces of captive nonhuman primates (n = 35) from 19 species housed at the Zoological Gardens, Perth, Western Australia. Both spirochete species are known to infect human beings. DNA was extracted from freshly collected feces with a commercially available QIAamp DNA stool minikit and subjected to PCR protocols amplifying portions of the 16S rRNA genes of the two spirochete species. The feces were also subjected to selective culture for the spirochetes. Subsequently, feces from 62 other captive animals or birds representing 39 species at the zoo were examined by PCR to determine whether they were reservoirs of infection. Six fecal samples from individuals from four primate species (two vervet monkeys, two Tonkean macaques, one Japanese macaque, and one hamadryas baboon) tested positive in the B. aalborgi PCR. B. aalborgi was not detected by PCR in any of the other animal or bird species tested, and B. pilosicoli was not detected in the primates or any of the other animals or birds. B. aalborgi was isolated from both PCR-positive vervet monkeys. This is the first time that B. aalborgi has been isolated from nonhuman primates and the first time that it has been isolated from the feces of any species.

Animals↗