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Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11.

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.

Animals↗

Characterization of the MHC class I-related MR1 locus in nonhuman primates.

We characterized the MHC-related 1 ( MR1) locus in two nonhuman primates species, Pongo pygmaeus and Pan troglodytes. MR1 cDNA sequences encoding several isoforms generated through alternative splicing were observed in both species. Amino acid alignment between the five species in which MR1 has been characterized to date - human, chimpanzee, orangutan, mouse, and rat - reveals a very high degree of conservation specially in the alpha1 and alpha2 domains of the molecule. The main differences concentrate in the transmembrane and cytoplasmic domains. In the three primates species there is a lysine residue inside the putative transmembrane domain which is not present in rodents. Furthermore, the MR1 cytoplasmic region is longer in rodents, with a conserved serine-containing motif that could be involved in endocytosis; remarkably, this motif is absent in the three primate species. We also describe the presence in the chimpanzee of a sequence homologous to the MR1P1 pseudogene previously found in humans.

Amino Acid Sequence↗

The T-cell receptor beta chain-encoding gene repertoire of a New World primate species, the cotton-top tamarin.

The New World primate, the cotton-top tamarin (Saguinus oedipus), expresses major histocompatibility complex (MHC) class I molecules with limited diversity. The uniqueness of the cotton-top tamarin MHC class I loci may contribute to this species' unusual susceptibility to viral infections and high incidence of ulcerative colitis. As a prelude to examining the effect of this limited MHC class I diversity on the tamarin CD8(+) T-cell receptor (TCR) repertoire, we identified expressed tamarin TCR beta chain (TCRB) cDNAs by anchored and inverse polymerase chain reaction. Sequence alignments and phylogenetic comparisons with human and rhesus macaque sequences identified homologues of 21 human variable (V) gene families. Only single variable region genes were identified in each of these tamarin VB families, with the exception of the VB 5, 9, and 13 families which were comprised of two or three distinct members. The multiple genes within these three VB families do not appear to have separate human homologues, but rather aligned equally well to a single human gene from their respective VB families. These genes appear to have arisen, therefore, by duplication of certain VB genes in the tamarin ancestors following their divergence from the lineage leading to Old World primates and hominoids. Homologues of 12 of the 13 human joining (J) region genes were also identified in the tamarin. Comparison of the proportion of nonsynonymous (pN) and synonymous (pS) substitutions occurring per site within tamarin variable region genes demonstrated a reduction in pN in the framework regions compared with pN in the presumed MHC contact regions (CDR1 and CDR2). Taken together, these findings illustrate that the TCR beta chain-encoding genes of the cotton-top tamarin are similar in structure and degree of complexity compared with their Old World primate and human counterparts.

Amino Acid Sequence↗

Chromosome painting in Callicebus lugens, the species with the lowest diploid number (2n=16) known in primates.

Cytogenetic studies have shown that New World primates are karyologically diverse and highly derived. The genus Callicebus is the best example of this karyological diversity, with diploid numbers ranging from 2n=50 to 2n=16. We report on Callicebus lugens, which has the lowest diploid number (2n=16) yet found in the primate order and represents a striking example of extreme karyotypic shuffling. To better understand the genomic rearrangements that have resulted in this extremely low diploid number, we mapped chromosome homologies between C. lugens and humans by in situ hybridization. The total number of hybridization signals was 42, excluding the Y chromosome, with a total of 34 syntenic associations not found in humans. This species has one of the most derived karyotypes among the Platyrrhini. Fusion has been the predominant mode of karyological evolution, although fissions and inversions have also transformed the C. lugens karyotype. Remarkably in such a highly rearranged karyotype, the synteny of 11 human chromosomes (4, 5, 9, 12, 13, 14, 17, 18, 20, 21, and X) was maintained intact, even if most of these human-homologous gene clusters were translocated. Other human syntenies, such as homologues to human chromosomes 10 and 16, were highly fragmented. Comparisons of the C. lugens-human homology map with those of other New World primates have not yet helped establish a phylogenic arrangement between congeneric species or link Callicebus with any other genus.

Animals↗

Estimation of the duration of the cycle of the seminiferous epithelium in the non-human primate Macaca mulatta using the 5-bromodeoxyuridine technique.

A comparatively low yield of germ cells has been reported for the spermatogenic process in primates. Kinetic studies of spermatogenesis and the spermatogenic cycle are needed to investigate this phenomenon but require the application of radioactively labeled compounds or irradiation. We have therefore investigated the suitability of a non-radioactive approach, viz., administration of 5-bromodeoxyuridine, for the determination of the kinetics of the spermatogenic cycle in a non-human primate, the rhesus monkey (Macaca mulatta). Four adult in-season animals received a bolus of 33 mg/kg 5-bromodeoxyuridine, one testis from each monkey was removed 3 h later and the other testis after 10 days and 11 h. Tissue was fixed in Bouin's solution and embedded in Paraplast. 5-Bromodeoxyuridine was localized by immunogold-silver staining with a monoclonal antibody. PAS-hematoxylin counterstaining was used for spermatogenic stage identification. At 3 h, the leptotene and zygotene spermatocytes in stages VII-IX were the most advanced 5-bromodeoxyuridine-positive cells. At 10 days 11 h, the label had advanced and pachytene spermatocytes in stages VI-IX contained 5-bromodeoxyuridine. The duration of the spermatogenic cycle was 10.42+/-0.07 days (range: 10.25-10.62 days). Peritubular cells and interstitial cells were rarely 5-bromodeoxyuridine-positive, and Sertoli cells were consistently negative for 5-bromodeoxyuridine. Importantly, our kinetic data closely resemble those obtained by means of the application of irradiation for this macaque species. We conclude that administration of 5-bromodeoxyuridine represents a non-radioactive reliable approach for studying kinetic aspects of the spermatogenic process in primates.

Animals↗

Intradiscal application of hyaluronic acid in the non-human primate lumbar spine: radiological results.

Prospectively, with randomized segment-treatment assignment, and with blinded evaluators, lumbar motion segments in Cercopithecus monkeys were analyzed for macroscopic and radiological changes 24 weeks after nucleotomy and nucleotomy with additional intradiscal application of different hyaluronic acid formulations versus untreated control segments. The objective was to find out whether hyaluronic acid is able to influence the degenerative cascade in nonhuman primates after nucleotomy. In a similar procedure, hyaluronic acid has proven to decrease degeneration after nucleotomy in a Minipig model. This is the first such study ever undertaken in primates, thus trying to overcome the known limitations of non-primate spine models. Twenty monkeys with four segments each obtained nucleotomy in three segments and solely exposure of another control segment. Nucleotomy was performed from a transpsoatic retroperitoneal approach. Preoperative radiographs and follow-up radiographs, magnetic resonance imaging (MRI), computed tomography (CT), Q-CT with bone mineral density measurements and three-dimensional reconstruction were obtained and analyzed qualitatively and quantitatively. Segments with high-molecular-weight hyaluronic acid (Hylan G-F 20) application proved to be significantly superior over those with a standard nucleotomy in radiographs, MR images, CT scans, and macroscopic appearance at follow-up. Control segments remained unaffected. Interdependence between the different methods validated the utilized methods of quantitative radiological assessment of degeneration. Hylan G-F 20 appears to be a possible adjunct in reducing postoperative degeneration in an animal nucleotomy model. It deserves further evaluation, despite the fact that the mechanisms of its effects are still speculative.

Animals↗

Laser Doppler flowmetry in non-human primate stroke studies: model refinement for pre-clinical development of cerebroprotective strategies.

BACKGROUND: Safety, feasibility, and efficacy trials in non-human primate stroke models are essential to the evaluation of experimental therapies and their translation to humans. Although Laser Doppler Flowmetry has been successfully employed in rodent stroke to continuously monitor cerebral blood flow, it has not been applied in primate studies. This investigation examined the utility of Laser Doppler Flowmetry in refining an existing baboon model of cerebral ischemia/reperfusion. METHOD: Continuous Laser Doppler Flowmetry monitoring was used, in non-human primates, to document local cerebral blood flow before, during, and after middle cerebral artery territory occlusion. In each baboon (n = 7) a single Doppler probe was placed into the left frontal cortex through a precoronal burr hole. Correlations between Laser Doppler Flowmetry values and latencies to Motor Evoked Potential dropout were compared using a linear regression model. FINDINGS: Placement of the Laser Doppler probe was easily accomplished in all animals. Laser Doppler Flowmetry tracings accurately documented blood flow changes that occurred with each technical manipulation during the procedure. Laser Doppler confirmed decreased perfusion that coincided both regionally and temporally with vessel occlusion. Depth of ischemia as measured by Laser Doppler Flowmetry was associated with Motor Evoked Potential dropout latencies for individual animals. CONCLUSIONS: Continuous, single probe Laser Doppler Flowmetry is a reliable method of documenting perfusion changes following middle cerebral artery territory occlusion in a baboon model of reperfused stroke. This advanced intraoperative monitoring technique may lead to more accurate evaluation of acute stroke therapies in pre-clinical trials.

Animals↗

Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.

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

Non-invasive blood sampling from primates using laboratory-bred blood-sucking bugs (Dipetalogaster maximus; Reduviidae, Heteroptera).

Primates are easily stressed by the conventional veterinary blood sampling routine and consequently, measured blood parameters may be biased. In this study, we tested blood-sucking bugs (Dipetalogaster maximus) on one lemur and two ape species (Microcebus murinus, Pongo abelii, Pan paniscus) as an alternative, non-invasive technique for bleeding primates. Within time periods of between 6 and 62 min we obtained blood volumes of 0.01-2.4 ml in 11 out of 12 trials from all three species. Therefore, we conclude that these bugs represent a new, gentle and effective tool for bleeding captive primates without stress.

Animals↗

Nutrition and biogenesis of plasma lipoproteins in nonhuman primates.

In this article we examine the production of very low-density lipoprotein (VLDL) by perfused livers obtained from chow- and cholesterol-fed nonhuman primates. These data illustrate two important features of VLDL production. First, VLDL is secreted from the liver in a form very close to that of its plasma counterpart. Thus for chow-fed animals, plasma VLDL and liver perfusate VLDL have similar lipid compositions. Second, the composition of VLDL can be modified significantly by diet in each of two primate species, the Rhesus monkey and the baboon. Rhesus monkey livers uniformly secrete larger quantities of VLDL and show more dramatic dietary effects than do baboon livers. Nevertheless, perfused livers from both species reveal qualitatively similar responses to dietary peanut oil and to lard fed in combination with cholesterol. Both fat-containing diets induce the livers to secrete VLDL enriched in cholesteryl ester compared with control perfusates yet still cholesteryl ester deficient compared with the animals' plasma VLDL. Peanut oil diet reduces the hepatic output of VLDL-associated apoprotein B and triglyceride, whereas lard increases hepatic secretion of VLDL-associated lipids and apoprotein E. We conclude that the nature of dietary fat plays an important role in determining the profile and composition of lipoproteins formed and secreted by the primate liver. We have also briefly reviewed the production of high-density lipoprotein, which is probably formed in the plasma from many sources, with special emphasis on the possible role of newly secreted lipid-poor apolipoprotein A-I and A-II.

Animals↗

Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus.

Lithium lengthens the period of free-running circadian rhythms in a variety of species, but this effect has not been demonstrated unequivocally in primates. Because of the possible link between lithium's action on the circadian clock and its therapeutic action in human mood disorders, we tested the ability of lithium to lengthen circadian period in a diurnal primate with circadian properties similar to those of humans. Lithium carbonate was administered in food pellets to 8 adult male squirrel monkeys (Saimiri sciureus) for at least 27 consecutive days. Serum lithium levels on the last day of lithium administration ranged from 0.76 to 2.02 mEq/liter, comparable to the therapeutic range for treatment of bipolar disorder in humans (0.6-1.2 mEq/liter). Circadian periods of perch-hopping activity were longer during lithium treatment than during baseline in 7 of the 8 monkeys (changes of -0.08 to +1.41 hr, mean +0.55 hr, p = 0.01), and returned toward baseline values when lithium was discontinued. In most cases, the period change was evident within a few days after beginning full lithium dose, and was not accompanied by changes in level or pattern of activity, nor in amplitude of the circadian rhythm. Food consumption and body weight were reduced during lithium treatment, and rebounded on return to lithium-free diet. Period change was related to lithium dose (p less than 0.05), but did not correlate with food consumption, body weight, or baseline circadian period. These results, by establishing that lithium lengthens circadian period in primates, suggest that studying the cellular mechanisms of this circadian effect may be relevant to understanding lithium's therapeutic effect on mood in humans.

Animals↗

Neuroactive amino acids influence gonadotrophin output by a suprapituitary mechanism in either rodents or primates.

Systemic administration of excitatory amino acids (Glu or NMA) rapidly enhances LH release (rodents or primates) and GABA blocks this action (rodents). In the present study rodent and primate pituitaries were incubated with NMA, Glu and/or GABA, with or without added LH-RH. Only LH-RH affected LH release. Therefore the probable site of NMA, Glu or GABA action on LH release in both rodents and primates is suprapituitary.

Amino Acids↗

W-like response properties of interlaminar zone cells in the lateral geniculate nucleus of a primate (Galago crassicaudatus).

Recent anatomical studies have suggested that the cells located in the interlaminar zones (ILZs) of the primate dorsal lateral geniculate nucleus (LGN) relay visual information from the retina to the striate cortex in a manner similar to that of W-cells in the LGN of cat. In the present study, we examined this idea directly by recording the response properties of single cells localized to the ILZs in the prosimian primate, Galago crassicaudatus. The properties of the cells in the ILZs were found to be physiologically distinct from the X-like and Y-like properties of the parvocellular and magnocellular LGN layers. Moreover, the small cells located in the interlaminar zones were physiologically similar to the W-like cells found in the specialized small-celled koniocellular layers in these primates. As is the case with the koniocellular layer cells, the ILZ cells exhibited a broad range of properties which, as a group, were distinguished by the following characteristics: the ILZ cells had long latencies to stimulation of the optic chiasm (mean, 3.95 ms) and to antidromic stimulation from striate cortex (mean, 3.31 ms) and had relatively large receptive-field centers (mean, 1.79 degrees). They also had low maintained discharge rates (5.5 spikes/s), relatively long response latencies to light (mean onset, 82 ms; peak, 112 ms) and low peak firing rates (59 spikes/s). Few (25%) had standard receptive-field organization (ON-center, OFF-surround, or vice versa). Only 29% responded well to sine-wave gratings and all were influenced by non-visual (auditory and tactile) stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography.

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.

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

Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates.

The distribution of histamine H1, H2 and H3 receptors in postmortem human and rhesus monkey brain was examined using receptor autoradiography. [125I]Iodobolpyramine, [125I]iodoaminopotentine and [3H](R) alpha-methylhistamine were used as ligands to label H1, H2 and H3 receptors respectively. The 3 receptor subtypes were identified in the human and monkey brains. Each receptor presented comparable distribution in the two primate brains. H1 and H2 receptors were particularly enriched in the caudate and putamen and observed in other brain areas such as the neocortex and hippocampus. H3-receptors were found to predominate in the basal ganglia where the highest densities were localized in the two segments of the globus pallidus. They were also observed in the hippocampus and cortical areas. The distribution of these 3 histamine receptors in the primate brain suggests the involvement of histaminergic mechanism in the functions of many brain areas. In particular, H2 and H3 receptors could play a role in the regulation of the basal ganglia functions in primates.

Adult↗

Descending adrenergic input to the primate spinal cord and its possible role in modulation of spinothalamic cells.

The present study focuses on 3 different aspects of the descending adrenergic system in the primate: (1) the distribution of adrenergic fibers and terminals in the spinal cord, (2) the source of this input and (3) the possible physiological effects of this system on spinal nociceptive processing. Antibodies to the enzyme phenylethanolamine-N-methyltransferase (PNMT) were employed to map the distribution of epinephrine-containing axonal profiles in the primate spinal cord. Smooth longitudinally oriented fibers were localized to the outer edge of the lateral funiculus. PNMT-containing axonal enlargements were distributed to the superficial dorsal horn, intermediate gray matter and the region surrounding the central canal at all spinal cord levels. PNMT-immunostained profiles were also observed in the intermediolateral cell column. A double labeling study employing retrograde transport of HRP from the spinal cord and PNMT immunohistochemistry identified a small population of HRP-PNMT-labeled neurons in the 'C1' region at the levels of the medulla and ponto-medullary junction. Thus, these cells are a probable source of adrenergic input to the spinal cord. Electrophysiological studies demonstrated that iontophoresis of epinephrine onto identified primate spinothalamic tract neurons in the lumbar dorsal horn resulted in inhibition of the glutamate-induced firing of these cells. The data from these studies support the hypothesis that adrenergic (PNMT-containing) cells in the caudal brainstem project to all levels of the cord and may contribute to descending modulation of nociceptive processing at these levels.

Animals↗

Effects of d-norgestrel-releasing intracervical devices in the nonhuman primate, Erythrocebus patas.

Primates (Erythrocebus patas) were implanted with intracervical devices which slowly released d-norgestrel at either of two rates: 38 +/- 12 microgram/day (high dose, 4 animals) or 14 +/- 10 microgram/day (low dose, 3 animals). An additional 8 animals received placebo devices or were untreated controls. All animals were studied for 3 months of exposure, at which time they were necropsied and evaluated. The uterus in all of the high dose primates had endometrial stromal and epithelial hyperplasia and, in two primates, suppurative endometritis. Similar, but less severe, uterine changes were present in animals of the low dose group. Systemic effects included evidence of diminished menstrual cycling and an absence of corpora lutea at both dose levels. Our results indicate that local application of these levels of d-norgestrel for contraception produces effects similar to those from systemically administered d-norgestrel.

Animals↗

Connective tissue composition of aortas from non-human primates. A comparative study.

Connective tissue composition of aortas from several non-human primate species has been studied in an effort to relate collagen, elastin, ang glycosaminoglycan (GAG) content to species susceptibility to atherosclerosis. Among the species studied the baboon contained the highest content of GAG in the aorta. While the distribution of individual GAG varied from species to species, heparan sulfate (HS) was the highest GAG in aortas from most of the species. The ratio of HS to chondroitin sulfates (CS) plus dermatan sulfate (DS) was lowest in the baboon, a species relatively less susceptible to atherosclerosis, and highest in the squirrel monkey, a very susceptible primate. If a relationship exists between HS to CS + DS ratio in the aorta and atherosclerosis, the primates can be arranged in the following decreasing order of susceptibility: squirrel, chimpanzee, stump-tailed, rhesus, African green, patas, baboon. In studies of other connective tissue components, the proportion of total collagen to elastin was found lowest in the baboon. Such observations emphasize the importance of connective tissue in the pathogenesis of atherosclerosis.

Animals↗