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PubMed2000

Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary.

Energy dissipating mechanisms and their regulatory components represent key elements of metabolism and may offer novel targets in the treatment of metabolic disorders, such as obesity and diabetes. Recent studies have shown that a mitochondrial uncoupling protein (UCP2), which uncouples mitochondrial oxidation from phosphorylation, is expressed in the rodent brain by neurons that are known to regulate autonomic, metabolic, and endocrine processes. To help establish the relevance of these rodent data to primate physiology, we now examined UCP2 messenger RNA and peptide expressions in the brain and pituitary gland of nonhuman primates. In situ hybridization histochemistry showed that UCP2 messenger RNA is expressed in the paraventricular, supraoptic, suprachiasmatic, and arcuate nuclei of the primate hypothalamus and also in the anterior lobe of the pituitary gland. Immunocytochemistry revealed abundant UCP2 expression in cell bodies and axonal processes in the aforementioned nuclei as well as in other hypothalamic and brain stem regions and all parts of the pituitary gland. In the hypothalamus, UCP2 was coexpressed with neuropeptide Y, CRH, oxytocin, and vasopressin. In the pituitary, vasopressin and oxytocin-producing axonal processes in the posterior lobe and POMC cells in the intermediate and anterior lobes expressed UCP2. On the other hand, none of the GH-producing cells of the anterior pituitary was found to produce UCP2. The abundance and distribution pattern of UCP2 in the primate brain and pituitary suggest that this protein is evolutionary conserved and may relate to central autonomic, endocrine and metabolic regulation.

Animals↗
PubMed2000

Comparative aspects of the metabolism and excretion of cortisol in three individual nonhuman primates.

A radiometabolism study is described to provide the first comparative data on the time course, route, and characteristics of excreted [3H]cortisol metabolites in three nonhuman primates: the common marmoset (Callithrix jacchus), the long-tailed macaque (Macacafascicularis), and the chimpanzee (Pan troglodytes). A low dose (40-100 microCi) of 3H-labeled cortisol was administered intravenously to one adult male of each species and the excreta collected over a 5-day period postinjection. The major proportion of radioactivity was excreted in the urine (>80%). Peak radioactivity in urine was recovered within 5.5 h following injection in all three species, while in the feces peak levels of radioactivity were recovered within 26 h postinjection. In all three species, urinary metabolites were primarily excreted as conjugates (61-87%), whereas the percentage of conjugated metabolites in feces was 50% or less. The number and relative abundance of urinary and fecal [3H]cortisol metabolites were determined by reverse-phase high-performance liquid chromatography (HPLC) and immunoreactivity of the radioactivity peaks was assessed by screening HPLC fractions with established cortisol, corticosterone, and 11-oxoetiocholanolone enzyme immunoassays (EIA), the latter being a group-specific assay for measuring 11,17-dioxoandrostanes. HPLC separation of urinary and fecal extracts revealed multiple peaks of radioactivity, several of which were common to all three species. The relative proportion of these peaks, however, differed considerably among species and between urine and feces. HPLC indicated that native cortisol was a major urinary excretory product in the marmoset, while comparatively small amounts were present in the urine of the macaque and chimpanzee. In contrast, in feces, cortisol was only detected in low amounts in the marmoset and was virtually absent in the macaque and chimpanzee. In all three species, one of the major radioactivity peaks showed a retention time comparable to 11-oxoetiocholanolone and high immunoreactivity in the 11-oxoetiocholanolone EIA. The measurement of urinary- and/or fecal-immunoreactive 11,17-dioxoandrostanes is therefore implicated for noninvasive assessment of adrenal function in Old World monkeys, New World monkeys, and great apes.

Animals↗
PubMed2004

Adaptive behavior of cortical neurons during a perturbed arm-reaching movement in a nonhuman primate.

This chapter provides evidence of spatial and temporal changes in the behavior of neurons within Areas 5 and 4 of the sensorimotor cortex of a nonhuman primate while it was executing a perturbed arm-reaching task. Chronically implanted electrode arrays were used to record simultaneously from 37 to 58 neurons. Also measured were the trajectory of arm movement, EMG activity in selected arm muscles and the perturbation force applied to the arm. The adaptation in Area 4 neurons' behavior usually involved a reduction in the latency from the onset of the perturbation to the peak-firing rate of the cell. In contrast, Area 5 neurons exhibited no such adaptive change in this latency. In each cortical area, the adaptation was not uniform across all neurons, and the spatial pattern of neuronal population behavior changed over the period of behavioral adaptation. We also found that the direction of arm movement and its configuration were important in determining which control strategy (predictive trajectory compensation or stiffness control) the animal used to overcome the externally applied perturbation for an improved performance of the reaching task.

Adaptation, Physiological↗
PubMed1975

Ontogenic growth changes of the skull base in four genera of nonhuman primates.

Cross-sectional studies of the degree of the cranial base flexion were carried out in infant, juvenile and adult skulls in four genera of nonhuman primates (P. paniscus, H. lar, P. urinus, and M. mullatta). The cephalometric observations of the cranial base included linear and angular measurements of each specimen. The data obtained in this study showed that the anterior portion of the cranial base exhibits a significant shortening trend as the mammalian evolutionary scale ascends. Moreover, the growth pattern of the anterior portion of the skull base follows that of the facial bony structures. The ontogenic growth changes of the posterior portion of the skull base follows the growth pattern of the endocranial cavity. The significant trend of elongation in this area directly contributes to the posterior migration of the foramen magnum. The magnitude of these growth changes decreases as the evolutionary scale ascends. The angular measurements of the cranial flexion showed a less obtuse cranial base angle in young specimens and the ones higher on the mammalian scale. The skull kyphosis was less pronounced in these specimens and the anatomical features of the cranial base were more humanlike, including the balance of the head expressed by the position of the foramen magnum.

Age Factors↗
PubMed1998

Assessment of a Canine Crown Reduction Technique in Nonhuman Primates.

The purpose of the study reported here was to evaluate the applicability of a pulpotomy technique used in human dentistry for canine crown reduction in nonhuman primates. General anesthesia was induced on seven male rhesus monkeys, and their canine teeth were amputated at the level of the occlusal surface of the premolars and incisors, using a water-cooled highspeed dental handpiece and a tapered diamond burr. A pulpal access cavity was established. Teeth with vital pulps were capped with calcium hydroxide, varnish, and amalgam. Disarmed canine teeth were evaluated clinically and radiographically during the subsequent 19 weeks. At the conclusion of this period, the monkeys were euthanatized, and the canine teeth were collected for histomorphologic assessment. At the end of the 19-week period, all 27 teeth had intact amalgam seals, 26 had a normal radiographic periodontal ligament space, and 26 had viable pulp, as determined on the basis of histomorphologic evaluation. Thus, 26 of 27 (96%) of the teeth on which the pulpotomy technique was performed were considered viable and, hence, had a successful outcome.

Journal Article↗
PubMed1981

Physical characterization of lymph chylomicrons and very low density lipoproteins from nonhuman primates fed saturated dietary fat.

Differential scanning calorimetry (DSC) and x-ray diffraction studies were performed on chylomicrons and very low density lipoproteins (VLDL), from nonhuman primates fed saturated fat, isolated from lymph at two different temperatures (15 and 39 degrees C). When heated from -10 leads to 60 degrees C, chylomicrons and VLDL isolated at 15 degrees C had two endothermic transitions resulting from the melting of triglycerides (TG). Cooling resulted in the onset of crystallization of the TG core at 16-19 degrees C; 50% of the TG in the particles remained fluid at 4 degrees C. The initial DSC pattern was reproduced not on immediate reheating, but by storing samples at 4 degrees C overnight. Chylomicrons isolated at 39 degrees C contained a metastable (undercooled) TG core until cooled to the onset of TG crystallization at 16-19 degrees C. Reheating the particles with crystalline TG to body temperature (39 degrees C) resulted in a partially crystalline TG core, not an undercooled liquid. To ascertain the effect of particle structure on the TG physical properties, intact particles were compared with heat denatured particles and extracted lipids. The onset of crystallization was lower and the time necessary for isothermal crystallization was much greater for intact versus denatured particles or lipids. Only minor differences in physical properties as a function of particle size were found. It was concluded that: 1) the physical state of chylomicrons and VLDL TG core can be modified by isolation temperature; 2) particle structure affects crystallization but not melting of chylomicrons and VLDL TG; and 3) chylomicrons particle size does not markedly influence the physical properties of the TG core.

Animals↗
PubMed1977

Some guidelines for collection and reporting of nonhuman primate growth data.

Some basic guidelines were offered to aid researches in planning and implementing the collection and reporting of data on growth and development of nonhuman primates. Weight and linear dimensions are the most frequently used measures of growth, and asseous and dental development are the most useful indicators of general bodily maturity. Estimates of sexual development can be made from general bodily maturity but more accurate assessments are based on the appearance of certain secondary sex characters. The most useful growth data are obtained from repeated, regularly scheduled examinations of the same individual. Standard procedures for measuring the external body utilize certain specific measuring points and measurements. Serial radiographs are also extremely valuable. When reporting data, age of subjects should be given in years and decimals. Means and other measures of central tendency and variability should be reported separately for each species, subspecies, and sex.

Animals↗
PubMed1988

Primates.

Nonhuman primates demonstrate marked similarities to humans in almost all aspects of their anatomy, endocrinology, and physiology. These similarities underlie the value of these animals for appropriate studies in neurobiology, immunology, pathology, reproductive biology, teratology, neonatology, endocrinology, cardiology, and psychology. Investigations with nonhuman primates has made, and continues to make, significant contributions to biomedical and behavioral research. This review provides an overview of basic and applied studies for which primates are appropriate subjects and a summary of the advantages and problems of using nonhuman primates in research.

Aging↗
PubMed1988

A nonhuman primate model of panic disorder.

In this article we report on the reliable production of several features of panic attacks following subcutaneous administration of sodium lactate to nonhuman primates. Unrestrained monkeys were evaluated by an observer without knowledge of the subjects' treatment with either sodium lactate or a dextrose control solution. The lactate produced temporally circumscribed episodes of agitation, wariness, and motor responses, normally elicited under stressful or threatening conditions. In an initial pharmacological intervention, we found that pretreatment with imipramine blocked the response to lactate. The further development of this model offers promise for the systematic examination of etiological factors in susceptibility to lactate induction of panic attacks, the physiological basis of the response, and new modes of treatment of panic disorder.

Agoraphobia↗
PubMed2002

Safety and systemic absorption of pulmonary delivered human IFN-beta1a in the nonhuman primate: comparison with subcutaneous dosing.

Safety and bioavailability of pulmonary delivered interferon-beta 1a (IFN-beta1a, AVONEX, Biogen, Inc., Cambridge, MA) was evaluated in the nonhuman primate. Pulmonary bioavailability following intratracheal (i.t.) instillation of 50 microg/kg IFN-beta1a to rhesus macaques was approximately 10%. To evaluate pulmonary safety, IFN-beta1a was administered intrabronchially to rhesus and cynomolgus macaques at a dose of 60 microg/dose one, three, or seven times per week for 4 weeks. At scheduled termination, lungs were evaluated for gross and histomorphologic changes. IFN-beta1a or vehicle (human serum albumin [HSA] in phosphate-buffered saline [PBS]) treatment resulted in minimal to mild subchronic alveolitis, located primarily near the instillation sites. These responses were considered nonspecific and consistent with either instillation of a foreign protein or minor injury associated with the instillation procedure. In one rhesus macaque treated every day for 4 weeks, IFN-beta1a induced mild to moderate eosinophilic alveolitis, considered possibly an isolated type I hypersensitivity response to HSA or IFN-beta1a. Partial resolution of pulmonary lesions was seen in all recovery animals killed 2 weeks after cessation of treatment. In conclusion, this study shows that pulmonary administration of human IFN-beta1a is safe and that the pulmonary route of administration is a possible alternate route for the systemic delivery of IFN-beta1a.

Absorption↗
PubMed1992

Direct gene transfer into nonhuman primate myofibers in vivo.

Previously, we showed that rodent muscle has the ability to take up and express plasmid genes injected intramuscularly. This study now demonstrates that nonhuman primate muscle also has this ability to express injected plasmids. A scaled-up version of the standard large preparation of plasmid DNA allowed several tens of milligrams of CCC plasmid DNA to be relatively easily produced and administered to monkeys. After the injection of the E. coli beta-galactosidase reporter gene in pRSVLac-Z, foreign gene expression was localized to both type I and type II myofibers. The luciferase reporter gene in pRSVL was used to quantify the amount of expression. The multiple implantation of plasmid DNA pellets was more efficient in expressing luciferase than the injection of DNA in normal saline. Luciferase activity persisted for at least 4 months after injection. However, the luciferase expression was considerably less than that in rodents. Preliminary studies explored why expression was less in monkeys. Of particular interest was the increased thickness of the perimysium of monkeys as compared to that in rodents. This increased connective tissue may decrease delivery of the plasmid DNA to the myofibers. Anti-nuclear or anti-DNA antibodies were not observed, even after repetitive DNA administrations, and no adverse effects were observed in any of the monkeys.

Adenosine Triphosphatases↗
PubMed1999

Tolerance in a concordant nonhuman primate model.

BACKGROUND: We have previously demonstrated that induction of mixed lymphohematopoietic chimerism resulted in donor specific renal allograft tolerance without the need for chronic immunosuppression in nonhuman primates. Here we have tested whether tolerance can be similarly induced for baboon to cynomolgus renal xenografts. METHODS: After preconditioning with anti-thymocyte globulin (ATG), nonlethal total body irradiation, and thymic irradiation, cynomolgus monkeys underwent splenectomy, native nephrectomies, and baboon marrow and renal transplants. Postoperative cyclosporine was given for 28 days. RESULTS: In Group 1 (n=2, survival= 13, 14 days), both animals developed anti-donor immunoglobulin G, had biopsy findings consistent with humoral rejection, and showed rapidly progressive xenograft failure. In Group 2 (n=5, survival=1, 16, 33, 112, 190 days), 15-deoxyspergualine was added to the regimen (Day 0-13). In one long-term survivor, donor specific hyporesponsiveness was first observed (mixed lymphocyte culture [(MLR]) on Day 48. MLR reactivity returned on Day 64 together with the development of anti-donor antibody and subsequent xenograft failure on Day 112. Donor specific T-cell hyporesponsiveness was detected in the other long-term survivor for the first 133 days, after which a donor-specific skin xenograft was placed, (survival 24 days). Following the skin graft rejection, a rise in the MLR, development of anti-donor antibody and progressive rejection of the renal xenograft were observed. CONCLUSIONS: Antibody-mediated rejection seems to constitute the major difference between concordant xenografts and allografts. Addition of 15-deoxyspergualine for 2 weeks posttransplant extended concordant primate xenograft survival to 6 months without chronic immunosuppression. In contrast to the allogeneic model, renal transplant acceptance in this xenogeneic system was interrupted by placement of a donor-specific skin graft.

Animals↗
PubMed1996

Evaluation of anti-human antibodies for immunohistochemistry on archival nonhuman primate tissues.

A panel of commercially available antibodies which recognize specific antigens on human tissues was developed for use in immunohistochemistry on tissues from eight species of nonhuman primates. Antibodies were selected for potential usefulness in diagnostic pathology, and for effectiveness in formalin-fixed, paraffin-embedded tissues. Tissues from four species of macaques and four New World monkeys were evaluated. Using these antibodies we were able to identify 17/21 antigens examined in all eight species, and 21/21 antigens in the four species of macaques. Detailed immunohistochemistry protocols are presented, along with a systematic approach to developing a protocol for a new antibody.

Animals↗
PubMed1984

Head-up tilt in the nonhuman primate. Effects of renal denervation.

Experiments were performed to determine the role of the renal nerves in mediating the antinatriuresis of head-up tilt in the nonhuman primate. Male Macaca fascicularis monkeys underwent chronic bilateral renal denervation or sham surgery and were allowed a 1- to 2-week recovery period. After that time, each animal was anesthetized with sodium pentobarbital and subjected to 40 min of 35 degrees head-up tilt. Renal perfusion pressure was maintained constant throughout the experiment. Tilt caused significant decreases in urine flow, sodium excretion and osmolar clearance and increases in urine osmolality in both groups. Creatinine and para-aminohippurate clearances decreased in the sham-operated animals but were unchanged in the denervated animals. Although the pattern of the renal excretory responses showed some group differences in that a significant antidiuresis and antinatriuresis occurred after 10 min of tilt in the sham-operated group but not until 20 min in the denervated group, the magnitudes of these excretory responses were similar in both groups throughout the entire tilt procedure. These results suggest that, in this species, the renal nerves are not necessary for eliciting the overall antinatriuretic response to orthostasis but may have some minor involvement in the onset of the response.

Animals↗
PubMed2003

The acute cerebrovascular effects of intracarotid adenosine in nonhuman primates.

UNLABELLED: In this study we sought to determine the acute cerebrovascular effects of intracarotid adenosine by using real-time cerebral blood flow (CBF) measurements in nonhuman primates. The internal carotid arteries of healthy anesthetized baboons were transfemorally cannulated. Changes in CBF were continuously measured at baseline and with 6 increasing doses of adenosine (0.002 to 1.5 mg/min) by use of an intraparenchymal thermal diffusion (TD) probe. Each infusion lasted 5 min. At baseline and at the largest dose of adenosine, CBF was also determined by the intraarterial (133)Xe technique. TD measurements revealed a dose-dependent increase in CBF from 32 +/- 6 mL x l00 g(-1) x min(-1) at baseline to 90 +/- 38 mL x l00 g(-1) x min(-1) with the largest dose of adenosine (n = 5; P < 0.0001). A similar magnitude of increase in CBF was also observed with (133)Xe CBF measurements. No significant increases in intracranial pressure or adverse systemic hemodynamic side effects were observed during adenosine infusion. The increase in CBF after adenosine lasted only for the duration of drug infusion. In conclusion, the transient cerebrovascular effects of intracarotid adenosine make it suitable for a trial of intraarterial vasodilator therapy and for controlled manipulation of cerebrovascular resistance. IMPLICATIONS: Using a real-time cerebral blood flow (CBF) measurement technique, we evaluated the acute cerebrovascular effects of intracarotid adenosine in anesthetized baboons. The increase in CBF lasted only for the duration of the adenosine infusion. Adenosine might be a suitable drug for trial as an intraarterial vasodilator for the treatment of cerebral vasospasm.

Adenosine↗
PubMedDate not supplied

A nonhuman primate model of Gilbert's syndrome.

A Bolivian population of squirrel monkeys, Saimiri sciureus, exhibits several features of Gilbert's syndrome in man, and is proposed as a nonhuman primate model of the condition. The Bolivian population was found to have higher fasting (40.6 +/- 2.7 microM; mean +/- S.E.) and postcibal (9.9 +/- 0.9 microM) plasma unconjugated bilirubin concentrations (p less than 0.001) than a closely related Brazilian population (fasting 5.5 +/- 0.7 microM); postcibal (2.4 +/- 0.7 microM). After intravenous administration of [3H]bilirubin as a tracer dose or at 3.4 mumoles per kg body weight, there was delayed plasma clearance in the Bolivian monkeys. Hepatic UDP-glucuronyl transferase activity for bilirubin (164 +/- 25 nmoles per 30 min per gm liver) and biliary bilirubin diglucuronide to monoglucuronide ratios (2.9 +/- 0.2) were lower in Bolivian monkeys than in Brazilians (421 +/- 36 nmoles per 30 min per gm liver--p less than 0.01 and 4.1 +/- 0.1--p less than 0.02, respectively). Hepatic cytosol glutathione-S-transferase B activity (ligandin) levels were similar for the two populations. After phenobarbital therapy, fasting (11.1 +/- 0.9 microM) and postcibal (5.3 +/- 1 microM) plasma bilirubin concentrations in Bolivian monkeys were significantly reduced (p less than 0.001). Sulfobromophthalein clearance was slightly slower in the Bolivian than in the Brazilian monkeys. SGOT, lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase activities were not increased in Bolivians. Fasting serum conjugated bile salt concentrations in Bolivian monkeys were lower than that in Brazilian monkeys (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Oral administration of cyclosporin does not prevent expansion of antigen-specific, gut-associated, and spleen lymphocyte populations during Chlamydia trachomatis proctitis in nonhuman primates.

To study the effects of oral cyclosporin (CsA) administration on immune responses in the gastrointestinal tract, humoral and cellular immune responses were studied in CsA-treated nonhuman primates having Chlamydia trachomatis proctitis (lymphogranuloma venereum, LGV). There was no apparent effect of CsA treatment on the gross or microscopic appearance of LGV proctitis, but CsA-treated animals, with or without LGV infection, had lymphoid hyperplasia of spleen and mesenteric lymph nodes. CsA treatment inhibited the primary antibody response to LGV, inhibited peripheral blood lymphocyte mitogen-induced proliferation and IL-2 production, and inhibited LGV-specific proliferation of peripheral blood lymphocytes. In contrast, mitogen-stimulated proliferation of spleen, mesenteric lymph node, and lamina propria lymphocytes was not significantly inhibited in CsA-treated animals. In addition, LGV-specific proliferation of spleen and mesenteric lymph node lymphocytes was not inhibited. High mitogen-stimulated IL-2 production of lamina propria lymphocytes was only partially inhibited in CsA-treated animals. In vitro CsA treatment had the expected inhibitory effects on mitogen- and antigen-induced proliferation of spleen and mesenteric lymph node lymphocytes. Thus, although oral cyclosporin inhibits the antibody and proliferative responses of peripheral blood lymphocytes to antigens and mitogens in animals having Chlamydia trachomatis proctitis, it does not prevent the expansion of antigen-specific, gut-associated, and spleen lymphocyte populations.

Administration, Oral↗
PubMed1999

Adenoviral vector-mediated expression of physiologic levels of human factor VIII in nonhuman primates.

An E1-, E2a-, E3-deleted adenoviral vector (Av3H82) encoding an epitope-tagged B domain-deleted human factor VIII cDNA (flagged FVIII) was evaluated in nonhuman primates. Twelve cynomolgus monkeys received intravenous administration of Av3H82; 6 monkeys received 6 x 10(11) particles/kg and another 6 received 3 x 10(12) particles/kg. Adenoviral vector transduction of the liver was efficient, reproducible, and linearly dose dependent. Physiologic levels of flagged FVIII were readily detected in plasma samples obtained from monkeys that received the higher dose of vector and human FVIII mRNA was detected in their livers. Expression of transgene mRNA was restricted to the liver by the albumin promoter. Although vector DNA was readily detected in the liver of monkeys that received the lower dose, neither human FVIII mRNA nor flagged FVIII protein could be detected. Vector distribution was widespread, with the highest levels observed in liver and spleen. Histopathology, hematology, and serum chemistry analysis identified the liver and blood as major sites of toxicity. Transient mild serum elevations of liver enzymes were observed, along with a dose-dependent inflammatory response in the liver. In addition, mild lymphoid hyperplasia was observed in the spleen. Mild anemia and a transient decrease in platelet count were observed, as was marrow hyperplasia and extramedullary hematopoiesis.

Adenoviridae↗