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Biomedical subjects

S Prahalada

Publications and source records attributed to S Prahalada.

52 records · Page 3Linked to original sources
PubMed1984

Clinical features of simian acquired immunodeficiency syndrome (SAIDS) in rhesus monkeys.

A syndrome of acquired immunodeficiency has been identified in a group of rhesus monkeys (Macaca mulatta) which died at the California Primate Research Center. Clinical evaluation of these animals revealed that 50% or more had lymphadenopathy, weight loss, and diarrhea. At least 30% had splenomegaly, fever, cutaneous abscesses and/or arthritis/myositis. Two animals had fibrosarcomas. Anemia was seen in 19 animals, lymphopenia in 14, granulocytopenia in four and thrombocytopenia in three. Hepatitis was diagnosed histopathologically in 13. Electrophoresis revealed hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Numerous bacterial, protozoal, and viral agents were identified including cytomegalovirus and leukocyte-associated herpesvirus. Pathologic lesions included severe post-reactive depletion of lymphocytes in germinal centers and paracortical regions of lymph nodes. Clinical and pathologic changes indicate an acquired immunodeficiency syndrome which has some similarities to AIDS in humans. This disease in monkeys may provide a model for studying that disease.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Calcinosis circumscripta in two rhesus monkeys.

Firm multilobular subcutaneous masses were observed in two female rhesus monkeys (Macaca mulatta). Both masses were excised surgically, but reoccurred within three months. Histologically, multiple loculi of calcified material surrounded by inflammatory cells and fibrous tissue were apparent. A diagnosis of calcinosis circumscripta was made. The gross and histologic appearance of this disease resembles that reported in several species.

Animals↗
PubMed1984

The pathology of an epizootic of acquired immunodeficiency in rhesus macaques.

A syndrome of acquired immunodeficiency within a group of outdoor-housed rhesus macaques (Macaca mulatta) with unusually high mortality has been identified at the California Primate Research Center. The cause of death for most of the affected animals included septicemia and/or chronic diarrhea with wasting, often complicated by other problems. In many cases, multiple or unusual infectious agents were isolated or recognized, including cytomegalovirus, Cryptosporidium spp., and Candida albicans. Septicemias due to usually innocuous agents such as Staphylococcus epidermidis and Alcaligenes faecalis were seen. Two animals developed cutaneous fibrosarcomas. Affected animals had generalized lymphadenopathy and splenomegaly, with depletion of T-cell populations, initially follicular hyperplasia followed by depletion, and absence of plasma cells. This spontaneous disease syndrome in nonhuman primates has similarities to acquired immune deficiency syndrome (AIDS) in humans, providing an animal model for the study of the complex factors modulating the immune system.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Embryotoxicity of Norlestrin, a combined synthetic oral contraceptive, in rhesus macaques (Macaca mulatta).

Thirty timed-mated pregnant rhesus monkeys received Norlestrin (Norethindrone acetate, 2.5 mg, and ethinyl estradiol, 0.05 g per tablet, Parke-Davis) orally at four different dose levels. The dose levels were 5, 10, 25 and 50 mg/day/monkey and the doses were administered during early (days 21-35), late (days 33-46), and throughout (days 21-46) organogenesis, except for the 50-mg-dose-group animals, which were treated only during early organogenesis (days 21-35). All except the animals in the 60-mg-dose group were allowed to go to term (165 days gestation). Pregnancy for the animals in the 50-mg-dose group was terminated by cesarean section on day 50 of gestation and the fetuses were fixed, serially sectioned, and examined histologically. No teratogenicity was observed. However, the prenatal mortality rate (38.5%) was higher for the Norlestrin-treated animals than in the control colony (21%). Eight animals aborted between days 40 and 78 of gestation and two other cases resulted in stillbirths at 139 and 165 days of gestation. There was a higher incidence of abortion (44.4%) in the 25-mg-dose group. Norlestrin treatment during early organogenesis also resulted in a higher abortion rate (37.5%) compared to treatment during late organogenesis (22.2%) abortions). No morphological abnormalities were found in infants observed at birth or in juvenile monkeys which died of natural causes or in those that were sacrificed over a period of two years. No histopathology was observed in the 50-day-old fetuses examined by serial section. Examination of endogenous maternal serum estrogen and progesterone levels in Norlestrin-treated monkeys (25 mg/day, days 21-35) suggested that placental steroidogenesis was not affected; however, the lower levels of estrogen in maternal serum suggested that the ovarian steroidogenesis was affected. Although the precise pathogenesis of this selective embryolethality is not known, several observations in this study suggest a direct generalized embryotoxic effect. Thus, this study for the first time has demonstrated that, while Norlestrin may be embryolethal at 100 times the human contraceptive dose equivalent (25 mg/day) in the rhesus monkey, nevertheless it does not affect the offspring which survive the exposure.

Abortion, Spontaneous↗
PubMed1983

Hyperosmolar non-ketotic diabetic coma in the nonhuman primate: a first report.

Diabetes mellitus was diagnosed in an aged bonnet macaque (Macaca radiata). Six months later the monkey was found comatose. Laboratory findings of extreme hyperglycemia, hyperosmolality, and glycosuria without ketonuria were consistent with a diagnosis of hyperosmolar, non-ketotic diabetic coma (NKC). Further laboratory studies disclosed very low levels of immunoreactive insulin and depressed free fatty acid values. Growth hormone and cortisol levels were within normal limits.

Animals↗
PubMed1983

Arteriovenous malformation in a rhesus monkey (Macaca mulatta).

A developmental arteriovenous malformation of the right arm was recognized in a 1-year-old rhesus monkey. The diagnosis was based on physical findings, ultrasound, and angiography. Treatment consisting of therapeutic transcatheter embolization using polyvinyl alcohol was performed with partial success. Necropsy revealed a lesion that was limited to the skin and subcutis. An abnormal vascular pattern was present leading to and within the lesion.

Animals↗
PubMed1978

Passive immunization with an antibody to the beta-subunit of ovine luteinizing hormone as a method of early abortion--a feasibility study in monkeys (Macaca radiata).

Antiserum to the beta-subunit of ovine luteinizing hormone (oLH-beta) raised in monkeys (Macaca radiata) has been tested by a variety of criteria both in vivo and in vitro to establish its ability to neutralize oLH, hLH, and human chorionic gonadotropin (hCG). Passive administration of this antiserum caused inhibition of ovulation and termination of pregnancy in recipient monkeys as indicated by premature vaginal bleeding and a significant reduction in serum progesterone and estrogen levels. The results suggest that antiserum raised in monkeys against oLH-beta can neutralize monkey LH as well as monkey CG.

Abortion, Induced↗
PubMedDate not supplied

Long-term evaluation of the diethylstilbestrol (DES) syndrome in adult female rhesus monkeys (Macaca mulatta).

This study was designed to examine the transplacental effects of diethylstilbestrol (DES) in rhesus monkeys (Macaca mulatta). Nineteen pregnant females received an approximate human therapeutic dose of 1 mg/day DES beginning on gestational day 21 (Group I), day 100 (Group II), or day 130 (Group III) until term. Colposcopic examination and vaginal biopsies were performed in eight female offspring at 6- and 12-month intervals beginning at 3.5 years of age until death between 5 and 12 years of age. Gross and histological evidence of vaginal adenosis was observed in five of eight (62.5%) females. Adenosis, which occurred in all treatment groups, did not develop into neoplasia; rather, it underwent metaplasia and reversion to squamous epithelium, a frequent observation in human DES cases. The vaginal ridging and/or cervical hooding characteristic of the human syndrome was observed in all exposed females. Although menstrual cyclicity was not impaired, there appeared to be a lower pregnancy rate in treated animals compared to age-matched controls. This long-term evaluation of reproductive morphology and function in the rhesus monkey has provided a useful model for studying the history of benign vaginocervical abnormalities induced by prenatal DES treatment.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Insulin-like growth factor-1 and growth hormone (GH) levels in canine cerebrospinal fluid are unaffected by GH or GH secretagogue (MK-0677) administration.

Elevation in circulating GH levels results in a dose-related increase in serum insulin-like growth factor-1 (IGF-1) levels in dogs. However, it is not known whether elevations in systemic IGF-1 and GH levels contribute to the cerebrospinal fluid (CSF) levels of these hormones. Therefore, a study was designed in dogs to determine if elevated circulating GH levels was a result of a GH secretagogue (MK-0677) or if exogenous GH administration resulted in increased IGF-1 and GH levels in the CSF of dogs. A total of 12 normal, young adult male dogs were randomized to three treatment groups (4 dogs/group) based on body weight. There were 4 vehicle control dogs. A group of 4 dogs were dosed orally with MK-0677 (5 mg/kg/day) dissolved in deionized water. A third group of 4 dogs received subcutaneous injections of porcine GH (pGH) at a dose of 0.1 IU/kg/day. From all dogs, blood and CSF samples were collected prior to the initiation of treatment and on days 7 and 15 of treatment. All samples were assayed using a validated radioimmunoassay. Administration of MK-0677 or pGH resulted in a statistically significant (P < or = 0.05) increased body weight gain and increased serum IGF-1 and GH levels. In contrast, administration of MK-0677 resulted in no significant (P > 0.05) increase in CSF IGF-1 or GH levels on days 7 or 15 of the study. The CSF IGF-1 values ranged from 1.2 to 2.0 ng/ml with minimal variation among three separate samples taken during the course of the study from each dog. Similarly, the CSF GH levels were very low (< 0.98 ng/ml to 2.4 ng/ml) in all dogs irrespective of treatment group. This study has demonstrated that there is no correlation between the circulating levels of IGF-1 or GH and the levels of these hormones in the CSF of normal dogs. An approximately 100-fold difference between serum and CSF IGF-1 levels in vehicle control dogs suggest that there is a blood-brain barrier for the circulating IGF-1. Similarly, failure to see an elevation in CSF GH levels despite increases in serum GH levels shows that there is a blood-brain barrier for GH in normal dogs. These results suggest that the likely source of GH and IGF-1 in the CSF of dogs is from the CNS.

Animals↗
PubMedDate not supplied

Morphological changes in the kidney of dogs chronically exposed to exogenous growth hormone.

Porcine growth hormone was administered subcutaneously to beagle dogs at doses of 0.025, 0.1, and 1 IU/kg/d for 14 weeks, markedly elevating serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. This was accompanied by a significant increase in body weight gain and kidney weights in both male and female dogs. The increase in kidney weight (6 to 54%) was slightly greater than the increase in body weight (6 to 40%). By light microscopy, glomerular deposits, mesangial thickening, and very slight cellular infiltration in glomeruli were seen in mid- and high-dose groups. Based on morphometric evaluation, there was an increase in the renal glomerular area, which was statistically significant (p < or = 0.05) in the mid- and high-dose males and in the high-dose females. This was associated with a statistically significant (p < or = 0.05) increase in the number of total glomerular cells in the mid- and high-dose males. By transmission electron microscopy, thickening of the glomerular basal lamina and diffuse increase of the mesangial matrix were observed in both male and female dogs in the mid- and high-dose groups. Immunohistochemical reactions were negative for IgG, IgM, and C3. The morphological changes in the kidney of dogs resemble the diffuse glomerulosclerosis described in human diabetic nephropathy.

Animals↗
PubMedDate not supplied

Pharmacological and toxicological effects of chronic porcine growth hormone administration in dogs.

The purpose of this study was to evaluate the pharmacological and toxicological effects of exogenous GH administration in normal adult dogs. Because porcine GH (pGH) is structurally identical to canine GH, pGH was selected for a 14-wk study in dogs. Thirty-two dogs (< 2 yr) were randomized to 4 groups (4 dogs/sex/group); 1 group was treated with the vehicle and 3 groups received pGH at 0.025, 0.1, or 1.0 IU/kg/day subcutaneously. Daily clinical signs and weekly body weights were recorded. Hematology, serum biochemistry, urinalyses, electrocardiograms, and ophthalmoscopic examinations were done. Serum GH, insulin-like growth factor-1 (IGF-1), insulin, thyroxine (T4), triiodothyronine (T3), and cortisol levels were determined. Necropsies were performed, organs weighed, and tissues were fixed and processed for light microscopic examination. Porcine GH caused increased body weight gain (p < or = 0.05) through the mid dose; the mean weight gains at study termination in mid- and high-dose groups were 2.8 kg and 4.7 kg, respectively, compared to 0.4 kg and 0.8 kg in control and low-dose groups, respectively. Dose-related increased weights of liver, kidney, thyroid, pituitary gland, skeletal muscle, and adrenal gland were noted. In pGH-treated dogs, increased skin thickness seen grossly correlated histologically with increased dermal collagen. There was no gross or histomorphological evidence of edema. There were dose-related increased serum IGF-1 levels (approximately 2-10-fold; p < or = 0.05) that correlated with the elevated serum GH levels in pGH-treated dogs. Also, increased serum insulin levels (p < or = 0.05) through the mid dose were seen throughout the study. In high-dose dogs, the insulin levels remained elevated over 24 hr postdose. The serum glucose levels in fasted dogs remained within the control range and there was no chronic hyperglycemia based on glycosylated hemoglobin levels. Renal glomerular changes, significant polyuria with decreased urine specific gravity, and increased serum insulin levels suggested that the dogs had early insulin-resistant diabetes. There was minimal or no biologically significant effect of pGH on serum T3, T4, and cortisol levels in dogs. Other serum biochemical changes in pGH-treated dogs included decreased urea nitrogen and creatinine, and increased potassium, cholesterol, and triglycerides. Significant increases in serum calcium and phosphorous levels and alkaline phosphatase activity (bone isozyme) correlated with the histological changes in bone. In pGH-treated dogs, there was a dose-related normochromic, normocytic, nonregenerative anemia. The changes described above, except for the anemia, are related to either anabolic or catabolic effects of high doses of GH. Based on this study, it is concluded that the dog is a good model in which to evaluate the safety of GH secretagogues as well as compounds with GH-like activity.

Anemia↗
PubMedDate not supplied

Morphological changes in the pituitary gland of dogs chronically exposed to exogenous growth hormone.

Growth hormone (GH) synthesis and release from the pituitary is regulated by hypothalamic releasing hormone, insulin-like growth factor-1 (IGF-1), and somatostatin. However, the potential effects of pharmacological doses of exogenous GH on the pituitary are not well studied. To determine the potential chronic effects of exogenous GH on pituitary morphology in dogs, porcine GH (pGH) was administered subcutaneously to 3 groups of dogs (4 animals/sex/group) at doses of 0.025, 0.1, and 1.0 IU/kg/day for 14 wk. A group (4/sex) of dogs served as the vehicle control. The pituitaries from all dogs were weighed and fixed in appropriate fixatives for light and electron microscopic examination; in addition, cells of the pars distalis were quantitated by a point counting method following immunostaining to identify cells containing GH, prolactin (PRL), and adrenocorticotrophic (ACTH) hormones. Administration of pGH resulted in a statistically significant (p < or = 0.05) increased pituitary weight through the high dose. By light microscopy (LM), hypertrophy of pars distalis cells was evident in mid- and high-dose female dogs. The pituitaries of dogs given the lowest dose (0.025 IU/kg/day) of pGH were not remarkable based on weight and LM findings. In addition, transmission electron microscopic (TEM) examination of the pituitary gland of high-dose demonstrated, in both sexes, pituitary cells with variably dilated rough endoplasmic reticulum and decreased numbers of secretory granules; some of these cells reacted positively to GH immunostaining. Quantitative analysis of the pituitary gland of high-dose males and females showed an increase in the absolute volume of all cell populations studied: GH-, PRL-, and ACTH-positive cells. Based on the LM and TEM findings, the increased volume of the cell populations studied is likely related to cellular hypertrophy. The expected elevation in serum GH levels following repeated administration of pGH and an associated elevation in serum IGF-1 levels resulted in morphologic changes in the pituitary gland of dogs given high doses (> or = 0.1 IU/kg/day) of pGH; these observations differed from the reported findings in pituitaries of transgenic mice secreting large quantities of bovine GH.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Effect of chronic growth hormone administration on skeletal muscle in dogs.

Administration of growth hormone (GH) results in increased body weight gain in dogs. Increased body weight gain is believed to be a result of the trophic effect of GH on the musculoskeletal system. However, edema is one of the side effects described in man following exogenous GH administration. Thus, the objective of this study was to determine if the expected increased weight gain in GH-treated dogs is a result of increased muscle mass. Porcine growth hormone (pGH), administered subcutaneously to beagle dogs at doses of 0.025, 0.1, and 1 IU/kg/day for 14 wk, resulted in elevated serum GH and insulin-like growth factor-1 (IGF-1) levels (see accompanying paper, Prahalada et al). This was associated with a significant increase in body weight gain and weights of the cranial tibialis muscle in both male and female dogs. The increased muscle mass likely contributed to the significant increase in body weight gain seen in both sexes. Quantitative analysis of skeletal muscle sections stained for ATPase activity showed increases in type I (slow twitch) and type II (fast twitch) myofiber sizes in mid- and high-dose males and in high-dose females. The ratio of type I and type II muscle fibers remained unchanged. Hypertrophic myofibers were enlarged but had a normal histologic and ultrastructural organization when observed by light and transmission electron microscopy. The results of this study have demonstrated that increased muscle mass in pGH-treated dogs is related to hypertrophy of muscle fibers and not due to edema. Exogenous GH administration has an anabolic effect on skeletal muscle in dogs.

Animals↗
PubMedDate not supplied

Behavioral tests in monkey infants exposed embryonically to an oral contraceptive.

The behavior of rhesus monkey infants exposed to high levels (20 to 100 X the human therapeutic dosage) of an estrogen-progesterone contraceptive (Norlestrin) during embryogenesis was compared to that of untreated controls. No serious deficiencies in regulation of activity, motor maturity, manual dexterity or discrimination learning were recorded in the 3 to 5 month old infants. In addition, age appropriate sex-differentiated behavior was observed in social groups of treated infants at 5 and 11 months of age. On the basis of this information it seems unlikely that accidental use of birth control pills during early pregnancy will seriously affect behavioral competence of offspring during infancy.

Animals↗