Experimental leprosy in three species of monkeys.

Eleven mangabey monkeys inoculated with Mycobacterium leprae developed lepromatous-type leprosy. Nine of the mangabeys were inoculated with M. leprae isolated from a mangabey with naturally acquired lepromatous leprosy. Immune function was depressed in some of these animals after dissemination of the disease. Two mangabeys developed lepromatous leprosy after inoculation with human M. leprae passaged in an armadillo. Three rhesus and three African green monkeys inoculated with mangabey-derived M. leprae also developed lepromatous leprosy. Mangabeys may be the first reported nonhuman primate model for the study of leprosy. Rhesus and African green monkeys may also prove to be reproducibly susceptible to the disease.

Transmissible lymphoma and simian acquired immunodeficiency syndrome in rhesus monkeys.

Four rhesus monkeys (Macaca mulatta) were inoculated with a homogenate of a cutaneous lepromatous leprosy lesion from a mangabey monkey (Cercocebus atys). One died of B-cell lymphoma, and another died of an immunodeficiency syndrome. Cell suspensions prepared from the tumor and spleen of the monkey with lymphoma induced lymphoma or an immunodeficiency syndrome when inoculated into additional young rhesus monkeys. The immunodeficiency syndrome was similar to simian acquired immunodeficiency syndrome and consisted of opportunistic infections, lymphoid hyperplasia or atrophy, wasting, and syncytial cell formation. Mitogen responses and percentages of T4- and T8-positive lymphocytes were normal until the animals were moribund. Lymphoblastoid cell lines became established in vitro from tumor cell suspensions. These cells were infected with a herpesvirus related to Epstein-Barr virus. In addition, a retrovirus morphologically similar to human T-cell lymphotrophic virus type III (HTLV-III) and simian T-lymphotrophic virus type III (STLV-III) was isolated from one of the lymphoblastoid cell lines (LCL). Type D retroviruses could not be demonstrated in the monkeys in the transmission study; however, a retrovirus similar to that in the LCL was isolated from 4 animals by coculture of peripheral blood lymphocytes with the human cell line H9. These results suggest that this retrovirus, STLV-III/Delta, may be associated with the immunodeficiency syndrome in these macaques and may be of mangabey origin.

Protein deficiency in primates. IV. Pregnant rhesus monkey.

Young adult female rhesus monkeys, maintained in a seminatural environment, when pregnant 30 days were fed a balanced semisynthetic diet containing 15.3 percent casein (13.4 percent protein) or 0.5, or 0.25 that amount for the remainder of thir pregnancy. The diets, made isocaloric by the addition of carbohydrates to replace the missing casein, supplied 4, 2, or 1 g protein/kg per day if the animals ate 120 kcal/kg per day, an assumption that was reasonably accurate. We studied the responses of monkeys delivering normal young at term. All monkeys were clinically healthy during the experiment. All reduced their total plasma protein concentration, principally by decreasing their albumin concentration. Greatest loss occurred in the low-protein group. Albuminuria was a common finding in all groups. Food consumption though varying throughout pregnancy, remained fairly comparable from group to group. Weight gain of the highest protein group was greatest; that for the lowest protein group barely covered the weight of the products of conception. Blood pressure declined during pregnancy while blood glucose rose. There were no morphologic changes in hair bulbs and only suggestive changes in liver cells that pointed to increased vacuolation. Increased metabolic efficiency during pregnancy enables the mother to safely pass through a long pregnancy during most of which she is fed a low-protein diet. Nonpregnant aminals suffer more under the same circumstances.

Variability in blood pressure response to dietary sodium intake among African green monkeys (Cercopithecus aethiops).

Since salt-sensitivity to blood pressure (BP) response is a species-related phenomenon, the response of BP to dietary sodium was examined in 14 adult male African green monkeys (Cercopithecus aethiops). The animals were exposed to graded increase of dietary NaCl at 0 (control), 3.0, 4.5, and 6.0%, respectively for 45, 139, 37, and 90 days. Systolic and diastolic BP and body weights were measured twice weekly. Body weight did not differ significantly between successive diets. The mean (+/- SD) systolic/diastolic BP for control, 3.0, 4.5, and 6.0% NaCl diets were 88.8 +/- 15.4/65.9 +/- 13.7, 101.9 +/- 17.6/72.1 +/- 13.0, 90.5 +/- 20.9/62.2 +/- 16.2, and 115.3 +/- 22.6/81.0 +/- 16.4, respectively. BP changes between successive diets were significant (p less than 0.05). Monkeys with high or low initial mean arterial BP levels on control diet tended to maintain the same order with significantly high correlations between BP levels for successive diet periods (r = 0.88 to 0.95, p less than 0.0001). Thus as a group, this nonhuman primate species responds to increased NaCl intake with elevated mean systolic and diastolic BP. Individual variations in salt sensitivity and consistency in persistence of BP levels in this species has bearing on human hypertension.

The effect of area postrema lesions on hemodynamic responses to systemic methionine-enkephalin in conscious dogs.

In the intact conscious dog, intravenous methionine-enkephalin (ME) increases heart rate and mean arterial blood pressure (MAP). These hemodynamic responses are produced at lower dosages when ME is injected into the vertebral artery, but not the carotid artery, suggesting that ME receptors are localized in the vertebrobasilar artery circulation. The area postrema (AP), a circumventricular organ devoid of a functional blood-brain barrier, represents a likely site for these receptors. We have tested the effects of chronic AP ablation upon hemodynamic responses to ME in conscious dogs. In three dogs with subtotal AP destruction, ME responses were preserved. However, in another dog with complete ablation of both the AP and the area subpostrema, ME responses were eliminated. These results indicate that total destruction of the AP, and perhaps of deeper structures as well, is necessary to abolish hemodynamic responses to ME.

Observations on early and late post-sporozoite tissue stages in primate malaria. IV. Pre-erythrocytic schizonts and/or hypnozoites of Chesson and North Korean strains of Plasmodium vivax in the chimpanzee.

In a continuing reexamination of plasmodial tissue stages within the context of the hypnozoite theory of malarial relapse, 2 strains of Plasmodium vivax with distinct and disparate relapse characteristics in humans were studied in chimpanzees. Following intravenous inoculation of massive numbers of salivary gland sporozoites, both the frequently relapsing Chesson strain and a North Korean strain characterized by predominantly delayed relapses exhibited relapse patterns and antimalarial sensitivity in the splenectomized chimpanzee essentially indistinguishable from those seen in humans. Examination of hepatic biopsies obtained at 7 and 10 days after infection revealed both pre-erythrocytic (pre-e) schizonts and hypnozoites in tissue obtained from the animal infected with the Chesson strain, but only rare hypnozoites (no pre-e schizonts) at 7 days in the animal infected with the North Korean strain. These findings, combined with the comparability of relapse behavior--which indicates the suitability of the chimpanzee as a model for the natural (human) host-parasite relationship--are essentially as predicted by the hypnozoite theory, despite the small numbers of tissue forms seen. Pre-erythrocytic schizogony of the Chesson strain in the liver was essentially indistinguishable from that of other strains studied, also underlining the suitability of this model system for tissue stage studies of P. vivax.

Experimental leprosy in African green monkeys (Cercopithecus aethiops): a model for polyneuritic leprosy.

Three African green monkeys (Cercopithecus aethiops) were inoculated intravenously and intracutaneously with Mycobacterium leprae derived from a naturally infected mangabey monkey. All developed cutaneous lesions at inoculation sites. One developed disseminated cutaneous lesions, while the cutaneous lesions in the other two regressed and eventually disappeared. The animals were examined at necropsy five years after inoculation. All three had active leprosy infection in peripheral nerves with extensive inflammation and fibrosis. The disease histologically resembled borderline-lepromatous leprosy. These findings add a new dimension to animal models of leprosy.

Intestinal absorption, exocrine pancreatic function and response to Vibrio cholerae infection in protein deficient Patas monkeys (Erythrocebus patas).

Six patas monkeys (Erythrocebus patas) were fed a protein-free diet. Sixteen animals of the same species received a standard monkey diet. The protein-depleted patas showed reduced absorption of folic acid but not D-xylose, and 5 out of 6 had a decrease in the exocrine pancreatic function. Animals with reduced folic acid absorption and pancreatic enzyme production developed a longer lasting diarrhoea and excreted the microorganisms for a longer time when challenged with Vibrio cholerae.

Behavioral effects of D-Ala2-beta-endorphin in squirrel monkeys.

The effects of D-Ala2-beta-endorphin administered either intravenously (IV) or intracisternally (IC) in squirrel monkeys were tested using a number of behavioral measures: general activity, eating, social behavior, aggression/distress, analgesia, and startle/escape. There were 10 groups (N = 5) consisting of 4 dose levels administered IC (0.4, 40, 400 microgram/kg) and 6 dose levels injected IV (0, 4, 40, 80, 400, 800 microgram/kg). Every monkey was tested with all tasks on each of 5 identical repeated trials, one pre-injection baseline trial and 4 post-injection trials. After IC administration, the 2 largest doses exerted toxic effects, which were partially reversed with naloxone, producing in 2 cases muscular rigidity and profound sedation. The smaller 4 microgram/kg dose produced significant decreases in activity over trials but increased reactivity to noxious stimulation after the initial post-injection trial. With IV injection reliable changes in activity and approach to food were found. The results demonstrate significant behavioral effects of an endorphin analog in the squirrel monkeys after both central and peripheral injection.

A primate model for acute and recurrent herpetic keratitis.

Twelve squirrel monkeys were inoculated in both eyes with the Rodanus strain of herpes simplex virus type 1 (HSV-1) and were examined for the presence of acute epithelial keratitis. All of the eyes developed dendritic keratitis within 72 hours after inoculation. The twelve monkeys plus two additional similarly infected monkeys were also examined for the presence of clinical recurrences of ocular herpes infections and spontaneous shedding of virus in their tears. Two of the eyes developed stromal disease, and 13 of the monkeys had at least one episode of recurrent clinical epithelial disease. Virus was isolated from two of the eyes with recurrent dendrites.

Phylogenetic variability of serum lipids and lipoproteins in non-human primates fed diets with different contents of dietary cholesterol.

The response of serum lipids and lipoproteins to different levels of dietary cholesterol (0.05% to 1.5% w/w) was measured in six nonhuman primate species. Relative response of serum cholesterol in different species, measured in terms of response, index, varied with dietary cholesterol concentration. The overall response for the different diets allowed ranking of the species as follows: Squirrel is greater than green is greater then spider is approximately thesus is approximately patas is greater than chimpanzee The serum cholesterol response was reflected not only in an increase in beta + pre-beta-lipoprotein cholesterol but also in alpha-lipoprotein cholesterol, with significant differences among species in the amount of cholesterol transported in the lipoprotein classes.

Balantidiosis in a chimpanzee (Pan troglodytes).

A young adult chimpanzee died after a brief gastrointestinal illness characterized by profuse soft stool, vomiting and dyspnoea. Necropsy examination revealed a severe typhlitis and colitis with pseudomembrane formation, and acute aspiration pneumonia. Balantidium coli, a common intestinal parasite, was found in large numbers in the mucosal and submucosal layers of the colon and caecum. The inflammation and degree of invasion associated with Balantidium coli indicates that it was a primary pathogen.

A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.