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Natural choice in nonhuman primates.

In 5 experiments, 4 monkeys and 1 ape chose between 2 food sources, each held in 1 of the experimenter's hands while he stood in front of a cage. When choosing between 2 sources of the same food that differed in amount, preference for the larger amount decreased as the size of each good proportionately increased. A second finding was that subjects were indifferent between a 2-food mixture and a single food that was part of the mixture if the single food was the preferred food of the mixture, a result suggesting the less preferred food had no value. Experiment 6 replicated these effects in 4 additional monkeys. These effects may be incompatible with previous theorizing about animal choice and may reflect a cognitive difference between nonhuman primates and humans.

Animals↗

Effect of the haloperidol tetrahydropyridine metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine on dopamine receptor and transporter binding. A nonhuman primate 123I-iodobenzamide and 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane single photon emission computed tomographic study.

Researching the biological activities and toxicities of metabolites of drugs is of growing importance and has received increasing attention during the last decade in order to gain a better understanding of the efficacy and safety profile of drugs in clinical use. HPTP (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3, 6-tetrahydropyridine, CAS 52669-92-8), the tetrahydropyridine metabolite of the classical neuroleptic, haloperidol (CAS 52-86-8), has recently been the focus for further understanding the well-known side effect profile of haloperidol. The current study was aimed at investigating the effect of HPTP treatment on dopamine receptor and transporter binding in the nonhuman primate, i.e. the baboon Papio ursinus. The study was performed using the dopamine receptor ligand, 123-I-iodobenzamide (IBZM) and the dopamine transporter ligand, [123]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) in planar scintigraphy and single photon emission computed tomographic (SPECT) protocols. Dopamine receptor binding in the striatum was measured from the time activity curves by calculating the IBZM ratios of the basal ganglia to frontal cortex and of the basal ganglia to cerebellum. 99mTc-HMPAO (hexamethylpropylene amine oxime) SPECT detected no changes in striatal perfusion during HPTP treatment. The transporter binding was measured by dynamic imaging of the basal ganglia, frontal cortex and cerebellum using beta-CIT. IBZM dopamine receptor binding is initially (as measured after 18 weeks treatment) decreased by HPTP treatment in the basal ganglia, frontal cortex (not significantly) and cerebellum but reversed to control values in the frontal cortex, as measured after 58 weeks treatment with HPTP. The binding to the basal ganglia and to a lesser degree the cerebellum is still affected after 58 weeks treatment with HPTP but indicates a tendency to return towards the control values. The results of the planar dynamic study with beta-CIT indicate a decrease in the beta-CIT binding to the dopamine transporters in the basal ganglia and to a lesser extent the cerebellum as measured by the time activity and percentage washout rate of the beta-CIT in the HPTP treated baboons. The effect of HPTP on the serotonin transporters appears to be minimal as observed from the results obtained from the frontal cortex. These results indicate that HPTP treatment influences both presynaptic and postsynaptic neurofunction in the dopaminergic neurones.

Animals↗

Relative size and evolution of the germline repertoire of T-cell receptor beta-chain gene segments in nonhuman primates.

The mammalian T-cell receptor (TCR) gene complexes exist as multiple tandemly arrayed gene segments that have apparently arisen by gene duplication mechanisms. A study of the number of TCR germline gene segments in several primate species might provide insight into the relative rate and patterns of gene duplication and deletion within these gene complexes. DNA probes from the TCR beta-chain variable (TCRBV) region gene segment subfamilies 1 through 25 and the constant region gene segment were sequentially hybridized under low stringency to Southern blots containing genomic DNA of human, gorilla, orangutan, and pig-tailed macaque. The number of gene members in each subfamily was estimated from the number of hybridizing DNA fragments. The results show apparent examples of both TCRB V gene duplication and deletion since speciation of the Hominoids from Cercopithecoid (Old World) primates. For one putative duplication/deletion event involving six TCRBV gene segments, derivation and comparison of germline DNA sequence from macaque and human as well as Southern blot analysis of additional primates demonstrated that this event was a duplication that occurred after the divergence of the family Pongidae (Greater Apes) from Hylobatidae (Lesser Apes). Southern blot analysis of multiple pig-tailed macaques and their offspring suggests a degree of DNA sequence variability in these gene segments similar to that observed in humans. An appreciation of the size and variability of each TCRBV subfamily will be useful when considering the DNA primers and probes necessary to measure the relative usage of these TCRBV genes as part of the immune response in these nonhuman primates.

Animals↗

Maternal, fetal, and neonatal elimination of ethanol in nonhuman primates.

Three cynomolgus and 6 rhesus monkeys (106-160 days gestational age) were administered ethanol (0.8-1.5 g/kg i.v.) over a 30-min period. Blood samples were drawn under anesthesia from catheters in the maternal femoral artery, fetal umbilical circulation and/or neonatal umbilical artery. Comparison of maternal/fetal blood sample pairs from 60 to 300 min after initiation of the ethanol infusion revealed a significant correlation of blood ethanol concentration (r = 0.968, p less than 0.001). Thus, during the elimination phase, maternal blood ethanol concentrations are predictive of fetal blood ethanol concentrations. In three studies where the fetus was delivered 2 h after the infusion of ethanol, the neonatal rates of elimination were observed to be approximately 1/4 those of the mother. These data indicate that during the last third of nonhuman primate pregnancy, the maternal component of ethanol elimination appears to be the predominant factor in the overall rate of fetal ethanol elimination.

Animals↗

Nutritional modulation of aging in nonhuman primates.

Caloric restriction (CR), undernutrition without malnutrition, remains the only experimental paradigm that has been shown consistently to extend lifespan and slow aging in short-lived species. Decades of research, mostly in laboratory rodents, have shown that CR consistently extends lifespan, reduces or delays the onset of many age-related diseases and slows aging in many physiological systems. In recent years gerontologists interested in CR have focused on two unanswered questions. 1) What is the relevance of this nutritional paradigm to human aging? and 2) What biological mechanism(s) underlie the diverse effects of CR leading to a retardation of aging and disease?. To address the question of human relevance, researchers in the Intramural Research Program of the National Institute on Aging began a study of CR in nonhuman primates in the late 1980s. In addition to assessing the effects of CR on aging in primates, a major focus of this work relates to possible metabolic mechanisms of CR. A subsequent study at the University of Wisconsin Madison was initiated in the early 1990s. Certain aspects of experimental design differ between these two important ongoing investigations, but generally these studies compliment each other in many ways and have begun to provide much important data regarding the effects of CR in primates. Emerging data from these studies strongly support that physiological responses to CR in monkeys parallel the extensive findings reported in rodents. Lifespan data will not be available for several years, however, the remarkable consistency with rodent studies, in which lifespan extension is documented extensively, strengthens the possibility that CR will also extend lifespan in primates, perhaps including humans. This review summarizes the major findings from the primate CR studies after over a decade of research in this model.

Aging↗

Pulmonary pneumocystosis in nonhuman primates.

Pulmonary infection with Pneumocystis carinii was detected in two aged owl monkeys (Aotus trivirgatus) and two young chimpanzees (Pan troglodytes). The clinical histories of the owl monkeys were similar and included progressive weight loss, anorexia, failure to thrive, and death. One of the owl monkeys had no concurrent disease, whereas the other had been experimentally inoculated with Treponema pallidum 44 months before death. In both chimpanzees, an underlying myeloproliferative malignant neoplasm was associated with Pneumocystis infection. Pneumocystis organisms were found in alveolar spaces and alveolar lining cells by light and electron microscopy. Pathologic features of these untreated cases and a case in a chimpanzee treated with pentamidine isethionate were similar to those described in humans. To our knowledge, this is the first report of pulmonary pneumocystosis associated with death in nonhuman primates.

Animals↗

Gonadal hormones influence the emergence of cortical function in nonhuman primates.

The role of gonadal hormones in the maturation of the orbital prefrontal cortex (ORB) was studied in normal male and female rhesus monkeys, monkeys given ORB lesions at 50 days of age, and female monkeys given androgen at different ages. Monkeys were tested on an object discrimination reversal task at 75 days of age. Gender influenced the performance of monkeys on the task during normal development and after ORB lesions. Normal males made fewer errors than did normal females. Females treated with androgen performed similarly to normal male monkeys. ORB lesions produced deficits in male monkeys and in females given androgen during late prenatal or early postnatal life, but not in normal females. These findings suggest that gonadal hormones may play an inductive role in the differentiation of higher cortical function in nonhuman primates.

Animals↗

Induction of hepatocellular carcinoma in nonhuman primates by the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated for carcinogenic effects in macaques, primarily cynomolgus monkeys. IQ was administered by gavage five times a week at doses of 10 or 20 mg/kg. IQ induced hepatocellular carcinoma in 55% of the animals at the low dose and in 95% of the animals at 20 mg/kg. The average latent period at the high dose level was 43 months and that at the low dose was 60 months. Generally, the tumor nodules exhibited a well- to moderately well-differentiated hepatocellular carcinoma, and a trabecular pattern was most frequently seen. Pulmonary metastases were also found in several of the monkeys. Thus, IQ is a potent carcinogen in nonhuman primates and is a potential carcinogen for humans.

Animals↗

Biocompatibility of Optibond and XR-Bond adhesive systems in nonhuman primate teeth.

This study evaluated the histologic responses of two different adhesive systems on the teeth of seven healthy adult monkeys. Class V cavities in 128 teeth were observed at 7,21 to 27, and 90 to 97 days. Statistical data showed no significant differences in pulp inflammation between the Optibond (Kerr), XR-Bond (Kerr), and IRM (Caulk) groups in pulps at the three time intervals. Some odontoblastic disruption and inflammation was seen in pulps restored with XR-Primer at the three time intervals. Pulp healing was similar in teeth treated with both direct-capped Optibond and calcium hydroxide, and there was no significant increase in pulpal inflammation with time. No abscesses or necrotic pulps were seen in any teeth. Optibond and XR-Bond adhesive systems are biologically acceptable in nonhuman primate pulp tissues.

Animals↗

Partial lobectomy via a ligature fracture technique: a method for multiple hepatic biopsies in nonhuman primates.

A ligature fracture technique was used to obtain multiple large (2 to 4 g) liver biopsy samples in both African green and cynomolgus monkeys. The technique was performed 195 times in 84 animals using three different surgical approaches, with no associated illness or mortality. In a subset of 18 animals, a slight decline in hematocrit percentage was noted during 14 days postsurgery (44.6 to 39.4%), but total plasma protein remained unchanged (5.98 to 5.95 g/dl). Serum alanine aminotransferase concentrations rose to 178.11 U/l at day 1 postoperatively, from a baseline value of 93.61 U/l. This elevation was transient, however, and declined to 49.65 U/l by day 14. Our experience has shown that the partial lobectomy via the ligature fracture technique is a safe and effective means to obtain multiple large samples of liver in nonhuman primates.

Alanine Transaminase↗

Extrapolation of heterocyclic amine carcinogenesis data from rodents and nonhuman primates to humans.

Twenty different heterocyclic amines have been isolated and identified from cooked foods especially beef, fish, pork and fowl. Other HCAs have also been isolated but their structure remains to be elucidated and new HCAs are likely to be identified in the future. The HCAs are highly mutagenic and all ten HCAs that have been tested for carcinogenic activity, produce tumors in mice and rats. For humans the average daily intake of HCAs is in quantities of 10-20 mg/person/day. The HCAs are procarcinogens and are activated by the cytochrome P450 system especially CYP 1A2. Rodents, monkeys and humans have the capacity to activate HCAs. Studies using hepatic microsomes demonstrated that humans have a greater capacity to activate the majority of HCAs tested than rodents or cynomolgus monkeys. Three HCAs are currently under evaluation in nonhuman primates for carcinogenic activity and one, IQ, is highly carcinogenic inducing primary hepatocellular carcinomas in the majority of cynomolgus monkeys treated. Epidemiological studies, although not definitive, are supportive of an association of HCAs intake to the etiology of human cancer. Risk assessments from animal data show a risk of HCAs to humans in the range of 10(-3) to 10(-4) which is an order of magnitude greater than compounds currently regulated by the U.S. Food and Drug Administration or the Environmental Protection Agency. Taken together evidence from mutagenicity data, activation by various species including humans, carcinogenicity in animals, human consumption data, epidemiological studies and risk assessment, supports the conclusion that HCAs are probable human carcinogens.

Amines↗

Sex-specific differences in olfactory sensitivity for putative human pheromones in nonhuman primates.

In humans, the volatile C19-steroids androsta-4,16-dien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST) have been shown to modulate autonomic nervous system responses, and to cause hypothalamic activation in a gender-specific manner. Using two conditioning paradigms, the authors here show that pigtail macaques and squirrel monkeys of both sexes were able to detect AND and EST at concentrations in the micromolar and mM range, respectively. Male and female spider monkeys, in contrast, differed markedly in their sensitivity to these two odorous steroids, with males not showing any behavioral responses to the highest concentrations of AND tested and females not responding to the highest concentrations of EST. These data provide the first examples of sex-specific bimodal distributions of olfactory sensitivity in a nonhuman primate species.

Androstadienes↗

Immunogenicity and safety of recombinant Helicobacter pylori urease in a nonhuman primate.

Groups of squirrel monkeys (Saimiri spp.), predetermined to be free of Helicobacter infections in the gastric mucosa, were immunized orally with 0.5-4.5 mg of Helicobacter pylori recombinant urease (rUrease) and 25-500 micrograms of Escherichia coli heat-labile enterotoxin (LT) adjuvant. Oral immunization with rUrease resulted in a markedly elevated serum immunoglobulin G (IgG) antibody response with peak levels at 45 days after immunization. No significant gastric inflammation or cytotoxicity was evident in rUrease immunized monkeys as determined by light and electron microscopy. Twenty-five micrograms of LT was a sufficient and safe adjuvant dosage, whereas higher dosages resulted in diarrhea and lethargy. Animals developed a serum IgG antibody response to LT that did not impede the production of anti-rUrease antibody levels. The results of this investigation indicate that rUrease is immunogenic in a nonhuman primate.

Adjuvants, Immunologic↗

Does the mastery of center-embedded linguistic structures distinguish humans from nonhuman primates?

In a recent Science article, Fitch and Hauser (2004; hereafter, F&H) claimed to have demonstrated that cotton-top tamarins fail to learn an artificial language produced by a phrase structure grammar (Chomsky, 1957) generating center-embedded sentences, whereas adult humans easily learn such a language. We report an experiment replicating the results of F&H in humans but also showing that subjects learned the language without exploiting in any way the center-embedded structure. When the procedure was modified to make the processing of this structure mandatory, the subjects no longer showed evidence of learning. We propose a simple interpretation for the difference in performance observed in F&H's task between humans and tamarins and argue that, beyond the specific drawbacks inherent in F&H's study, researching the source of the inability of nonhuman primates to master language within a framework built around Chomsky's hierarchy of grammars is a conceptual dead end.

Animals↗

Experimental infection of a nonhuman primate with Loa loa induces transient strong immune activation followed by peripheral unresponsiveness of helper T cells.

Human infection with the parasite Loa loa is characterized by a good adaptation between the parasite and its host. One portion of the human population harbors only adult worms in subcutaneous tissues, whereas another portion also harbors the L1 microfilarial stage in peripheral circulation. This study was undertaken to understand the mechanisms by which the parasite evades or modulates host immunological attack. The cellular responses, based on T-cell proliferation, to the production of various cytokines (interleukin-2 [IL-2], gamma interferon [IFN-gamma], IL-4, and IL-5) and to expression of cytokine (IL-2, IFN-gamma, IL-4, IL-5, IL-10, and IL-12) mRNAs were investigated during the experimental infection with human parasite L. loa of a nonhuman primate which has been shown to display a spectrum of disease similar to that found in humans. Our results indicate that a T-cell unresponsiveness occurs when female worm products are released into the peripheral circulation, preceded by a transient period of strong T-cell proliferation, cytokine production, and cytokine mRNA expression. In the unresponsive state, only IL-10 mRNA is expressed, suggesting a role for IL-10 in down-regulation and maintenance of unresponsiveness. Taken together, these results indicate that both IL-10 production, which is known to inhibit B7 expression on monocytes, and the massive release of female products in the blood where T cells encounter antigens presented by nonactivated B lymphocytes, which lack costimulatory signals, should contribute to the inactivation of T cells.

Animals↗

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned model of parkinson's disease, with emphasis on mice and nonhuman primates.

Animal models play a critical role in our understanding of the cause of human diseases and provide an opportunity to evaluate new therapeutic treatments. The usefulness of an animal model is dependent, in part, on how closely it resembles neurochemical, neuropathologic, and behavioral features of the human condition. Other considerations that may enhance the value of a model include expense, availability, reproducibility, animal morbidity and mortality, and investigator experience. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by slow movements, tremor, and walking impairment due to loss of midbrain nigrostriatal neurons and depletion of striatal dopamine. In the PD research field, a number of neurotoxic, pharmacologic, and transgenic animal models are available for research studies. We will focus on the advantages and disadvantages of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse and nonhuman primate models of PD. Our goal is to guide researchers in the appropriateness of the MPTP models in their studies by balancing understanding of the models, objectives of the study, and health and safety of the animals. In addition, the technical use and safe handling of MPTP are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

On inequity aversion in nonhuman primates.

P. G. Roma, A. Silberberg, A. M. Ruggiero, and S. J. Suomi (2006) noted that the results S. F. Brosnan and F. B. M. de Waal (2003) attributed to inequity aversion could also be explained as a frustration effect. Roma et al. redressed this confound by designing a procedure that could have supported either of these interpretations. Nevertheless, they found that only a frustration effect accounted for both their data and those of Brosnan and de Waal (2003). The criticisms Brosnan and de Waal (2006) offered of Roma et al. ignored the fact that Brosnan and de Waal's (2003) research design was not capable of offering an unequivocal demonstration of inequity aversion. This conclusion holds no matter what the claimed inadequacies of Roma et al.'s procedures might have been. Caution is urged in inferring the existence of inequity aversion in nonhuman primates.

Animals↗

The effect of caloric restriction on glycation and glycoxidation in skin collagen of nonhuman primates.

The accumulation of Maillard reaction products increases with age in long-lived proteins and can be retarded by caloric restriction. Here we determined whether caloric restriction inhibits formation of glycation and glycoxidation products in skin collagen of squirrel and rhesus monkeys between 1990-1997. Restricted monkeys (n = 11, n = 30, respectively) were maintained at 70% of caloric intake of controls (n = 25, n = 32, respectively). Glycation was assessed by furosine and glycoxidation by pentosidine and carboxymethyl-lysine. With age, the rate of furosine formation moderately but nonsignificantly (p >.05) increased in both control monkey groups. It significantly (p =.011) decreased in the caloric-restricted rhesus, but not squirrel monkeys. Caloric restriction did not significantly decrease the pentosidine or carboxymethyl-lysine rates in either species of monkeys. These results suggest that caloric restriction, when maintained long-term in nonhuman primates, tends to decrease glycation, but not glycoxidation.

Aging↗