Clinical and histopathological evaluation of 13 cases of adenocarcinoma in aged rhesus macaques (Macaca mulatta).

In recent years, the emphasis on aging research, has led to an increase in the number of aged macaques being maintained in some research facilities with a subsequent increase in the occurrence of age-related diseases. One of the most commonly reported age related diseases is intestinal adenocarcinoma. At the University of Illinois at Chicago (UIC), which maintains a colony of approximately 55 aged rhesus macaques 13 cases of intestinal adenocarcinoma were diagnosed within a 25-month period. This report provides a comprehensive description of the clinical findings for intestinal adenocarcinoma in aged rhesus macaques, including results from physical examinations, laboratory tests, radiographic evaluations, gross and histopathologic findings as well as a comparison with the disease condition in humans. The use of carcinoembryonic antigen as a potential tumor marker was evaluated by immunohistochemical analysis of tissue specimens in 10 cases. Intestinal adenocarcinoma is a disease condition that should be of concern to individuals responsible for the care of aged rhesus macaques.

Novel use of the Elizabethan collar as a "hoop-skirt" for protecting wounds and catheters in nonhuman primates.

This article describes the novel use of an Elizabethan collar, which is attached to a primate jacket to create a tamper-proof "hoop-skirt" for protecting wounds and catheters. We successfully have used this hoop-skirt to manage juvenile male rhesus monkeys with Foley catheters for 10 days post-prostatectomy. In addition, our hoop-skirt has been used to manage wounds on the hindlimbs of both macaques and baboons.

Ex vivo expansion of autologous bone marrow CD34(+) cells with porcine microvascular endothelial cells results in a graft capable of rescuing lethally irradiated baboons.

Hematopoietic stem cell (HSC) self-renewal in vitro has been reported to result in a diminished proliferative capacity or acquisition of a homing defect that might compromise marrow repopulation. Our group has demonstrated that human HSC expanded ex vivo in the presence of porcine microvascular endothelial cells (PMVEC) retain the capacity to competitively repopulate human bone fragments implanted in severe combined immunodeficiency (SCID) mice. To further test the marrow repopulating capacity of expanded stem cells, our laboratory has established a myeloablative, fractionated total body irradiation conditioning protocol for autologous marrow transplantation in baboons. A control animal, which received no transplant, as well as two animals, which received a suboptimal number of marrow mononuclear cells, died 37, 43, and 59 days postirradiation, respectively. Immunomagnetically selected CD34(+) marrow cells from two baboons were placed in PMVEC coculture with exogenous human cytokines. After 10 days of expansion, the grafts represented a 14-fold to 22-fold increase in cell number, a 4-fold to 5-fold expansion of CD34(+) cells, a 3-fold to 4-fold increase of colony-forming unit-granulocyte-macrophage (CFU-GM), and a 12-fold to 17-fold increase of cobblestone area-forming cells (CAFC) over input. Both baboons became transfusion independent by day 23 posttransplant and achieved absolute neutrophil count (ANC) >500/microL by day 25 +/- 1 and platelets >20,000/microL by day 29 +/- 2. This hematopoietic recovery was delayed in comparison to two animals that received either a graft consisting of freshly isolated, unexpanded CD34(+) cells or 175 x 10(6)/kg unfractionated marrow mononuclear cells. Analysis of the proliferative status of cells in PMVEC expansion cultures demonstrated that by 10 days, 99.8% of CD34(+) cells present in the cultures had undergone cycling, and that the population of cells expressing a CD34(+) CD38(-) phenotype in the cultures was also the result of active cell division. These data indicate that isolated bone marrow CD34(+) cells may undergo cell division during ex vivo expansion in the presence of endothelial cells to provide a graft capable of rescuing a myeloablated autologous host.

Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity.

This study was undertaken to determine the modulation of uterine function by chorionic gonadotrophin (CG) in a nonhuman primate. Infusion of recombinant human CG (hCG) between days 6 and 10 post ovulation initiated the endoreplication of the uterine surface epithelium to form distinct epithelial plaques. These plaque cells stained intensely for cytokeratin and the proliferating cell nuclear antigen. The stromal fibroblasts below the epithelial plaques stained positively for alpha-smooth muscle actin (alphaSMA). Expression of alphaSMA is associated with the initiation of decidualization in the baboon endometrium. Synthesis of the glandular secretory protein glycodelin, as assessed by Western blot analysis, was markedly up-regulated by hCG, and this increase was confirmed by immunocytochemistry, Northern blot analysis, and reverse transcriptase-PCR. To determine whether hCG directly modulated these uterine responses, we treated ovariectomized baboons sequentially with estradiol and progesterone to mimic the hormonal profile of the normal menstrual cycle. Infusion of hCG into the oviduct of steroid-hormone-treated ovariectomized baboons induced the expression of alphaSMA in the stromal cells and glycodelin in the glandular epithelium. The epithelial plaque reaction, however, was not readily evident. These studies demonstrate a physiological effect of CG on the uterine endometrium in vivo and suggest that the primate blastocyst signal, like the blastocyst signals of other species, modulates the uterine environment prior to implantation.

Chorionic gonadotropin, estradiol, and progesterone levels in baboons (Papio anubis) during early pregnancy and spontaneous abortion.

The purpose of this study was to sequentially characterize peripheral chorionic gonadotropin (CG), estradiol (E2), and progesterone (P) profiles during early pregnancy in the baboon (Papio anubis). Ten pregnant baboons were bled sequentially at eighteen time points between Days 8 and 128 of gestation. In addition, blood was obtained at corresponding time points from 5 spontaneously aborting baboons. CG levels were assessed in a mouse Leydig cell bioassay using rhesus pituitary LH as the standard E2 and P levels were measured by RIA. Pregnancy-associated CG activity was detectable by Day 15 (901.4 +/- 275.6 ng/ml), peaked at Day 27 (53,494.1 +/- 14,995.6 ng/ml), and then returned to baseline values by Day 51 (45.4 +/- 8.9 ng/ml). Mean E2 concentrations rose from 28.9 +/- 4.3 pg/ml on Day 8 to 280.6 +/- 145.5 pg/ml on Day 58 and then increased 9-fold to a level of 2436.4 +/- 928.0 pg/ml on Day 72. Mean E2 concentrations ranged between 2065.9 and 3830.9 pg/ml from Day 72 through Day 128. Mean P concentrations ranged from 7.5 to 10.2 ng/ml between Days 8 and 21, rising dramatically to 38.6 +/- 4.6 ng/ml on Day 37 prior to declining to levels that ranged from 11.1 to 17.1 ng/ml between Days 51 and 128. CG levels were low in 3 of 5 animals prior to spontaneous abortion E2 and P concentrations preceding spontaneous abortion were similar to values in uncomplicated pregnancy; however, at the time abortion was detected P concentrations in all 5 animals were 1.3 ng/ml or less.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma corticotropin-releasing factor concentrations in the baboon during pregnancy.

We have studied the secretion of placental CRF during pregnancy in the baboon, an animal model with many similarities to human pregnancy. Plasma CRF was measured in two groups of animals. In group 1, studies were performed in six anesthetized animals beginning 8 days postconception. In group 2, studies were performed in five unanesthetized chronically catheterized maternal and five fetal animals in the latter third of pregnancy. In the first study beginning early in pregnancy, CRF was undetectable in all animals on days 8 and 15 postconception. Plasma CRF became detectable in two animals on day 24 and in the remaining four on day 30. Plasma CRF rose significantly to a mean of 810 +/- 160 pg/ml at 37 days gestation (F = 4.20; P < 0.001). Mean maternal plasma CRF was 2452 +/- 1120 pg/ml on day 44 and remained elevated, with a great deal of variability between subjects, until the end of the study period (128 days of gestation). Samples in this group were obtained after ketamine sedation. The effect of ketamine on CRF was studied in three chronically catheterized animals. Samples were obtained before and 2, 4, 6, and 24 h after ketamine administration (40 mg, iv). The baseline CRF concentration was 1168 +/- 131 pg/ml and did not change significantly over the time period studied. In the second study in the chronically catheterized animals, maternal plasma CRF was 1990 +/- 680 pg/ml at 131-140 days gestation and remained elevated until near term at 170 days (term = 175-180 days). Within 24 h after birth, plasma CRF became undetectable (< 60 pg/ml). CRF was also measured in chronically catheterized fetal baboons. The mean CRF concentration was 614 +/- 224 pg/ml at 131-140 days and remained in this range until the end of the period studied (151-160 days gestation). To characterize the CRF immunoactivity in maternal baboon plasma, Sephadex chromatography was performed on an 8.4-ml plasma sample obtained at 160 days gestation. The majority of the CRF immunoactivity eluted in the same position as synthetic human CRF. We conclude that high levels of placental CRF are present in the systemic circulation of the maternal and fetal baboon during pregnancy. In contrast to human pregnancy, which is characterized by an exponential rise in maternal CRF concentrations in the final weeks before delivery, an exponential rise in maternal baboon CRF concentrations occurs early in pregnancy.

Ultrasonic determination of fetal parameters in baboons (Papio anubis)

The use of nonhuman primates to study reproductive physiology, fetal development, and neonatal management often depends on the availability of pregnant and fetal animals of known gestational history. The purpose of this study was to establish and correlate normal fetal growth parameters with gestational age in olive baboons (Papio anubis). Normal cycling females were bred to proven males by using the degree of perineal swelling and vaginal cytology to determine onset of ovulation. The subjects were evaluated to determine pregnancy beginning 18 days postmating, using an Aloka-650 diagnostic ultrasound unit, equipped with a 7.5 mHz prostate probe and a 5 mHz transabdominal probe. Ten pregnant animals were then evaluated sonographically every 3 days through day 30 and weekly through day 135 (average gestation 184 days). Measurements included gestational sac, greatest-length, biparietal diameter, femur length, head circumference, and abdominal circumference. Using the means and standard deviations, growth curves were constructed, and the data used to develop predicted value charts for gestational age estimation. Using the predicted value charts established in our study, subsequent evaluation of pregnant baboons in our colony disclosed concordance with actual gestational age.

Induction of multiple follicular development and superovulation in the olive baboon, Papio anubis.

The objective of this study was to induce multiple follicular development and superovulation in the olive baboon. Beginning at menses, adult female baboons were treated with hMG for 10 days followed by hCG on day 11. Multiple follicular development was seen in all 19 animals; superovulation occurred in 11 of these. Serum E2 and P levels were consistent with multiple follicular and corpora lutea development, respectively. Ovulated ova were able to be fertilized. These results indicate that olive baboons can be superovulated using a regimen of hMG and hCG, however, development of antibodies against the human hormones precludes restimulation.