Production of premature delivery in pregnant rhesus monkeys by androstenedione infusion.

The endocrine mechanism involved in term and preterm delivery in primates, including pregnant women, are poorly understood. In the term monkey, fetal plasma androgen concentration rises to two hundred times the maternal concentration which remains unchanged. Placental conversion of androgen to estrogen results in increased maternal plasma estrogen concentration at term in both pregnant nonhuman primates and women. In the present study, continuous infusion of androstenedione to 0.8 gestation monkeys resulted in the premature occurrence of labor-type myometrial activity and increases in maternal plasma estrogen, oxytocin and amnion fibronectin concentrations similar to those measured at normal-term labor. Androstenedione induction of these normal-term biochemical and endocrine changes accompanied by fetal membrane rupture, cervical dilatation and live delivery provides a rich opportunity to study the molecular and physiological mechanisms of both term and preterm labor in primates.

Effect of maternal cocaine administration on maternal and fetal glucose, lactate, and insulin in sheep.

Although cocaine use during pregnancy is an important cause of perinatal morbidity and mortality, there are no reports of its effect on maternal and fetal carbohydrate metabolism. Six pregnant ewes and their fetuses were instrumented under halothane general anesthesia at 113-119 days' gestation. Between 124-135 days' gestation, the ewes received a single infusion of vehicle or cocaine (1.0 or 2.0 mg/kg) into the jugular vein. At least 24 hours was allowed between successive injections. Maternal and fetal blood samples were drawn at 30 and 20 minutes before and at 5, 15, 30, and 60 minutes after the injection. Both maternal and fetal glucose and lactate concentrations increased (P less than .05) after injection of cocaine at 2.0 mg/kg. There were no significant changes in maternal or fetal plasma insulin concentrations after vehicle or cocaine administration. Induction of hyperglycemia and lactacidemia could be mechanisms whereby cocaine exerts its adverse effects during pregnancy.

Lack of effect of maternal cocaine administration on myometrial electromyogram and maternal plasma oxytocin concentrations in pregnant sheep at 124-146 days' gestational age.

Although cocaine abuse during human pregnancy is associated with an increased incidence of preterm labor, there are few reports on the effects of cocaine on myometrial activity during pregnancy in experimental animals. Cocaine (0.5, 1, or 2 mg/kg) or vehicle was randomly administered intravenously to 15 pregnant ewes between 124-146 days' gestation (term is 147 days). Neither cocaine nor vehicle administration altered total myometrial electromyographic activity from pre-dose levels 1 or 6 hours after administration. Maternal arterial plasma oxytocin did not change during the study. Using a positive control, we confirmed observations of other investigators that administration of 2 mg/kg cocaine significantly increases maternal arterial blood pressure. The results indicate that cocaine does not stimulate myometrial contractility significantly in late pregnancy in sheep.

Effect of pulsatile intravenous oxytocin administration to pregnant sheep over the last third of gestation on fetal ACTH and cortisol responses to hypotension.

OBJECTIVE: To examine the effect of increasing myometrial contractility in the last third of gestation on ovine fetal response to hypotension. METHODS: Oxytocin (600 microU/kg/minute) or saline was infused via the maternal jugular vein as 5-minute pulses every 20 minutes, starting at 97 +/- 1 days of gestational age (mean +/- standard error of the mean) until labor. Fetal hypotension (10 minutes) was induced by intravenous nitroprusside infusion at 133 +/- 1 days' gestation. RESULTS: Ewes from both groups went into labor at the same gestational age. Total fetal body and adrenal gland weights were higher in controls than in the oxytocin-treated group. Maternal arterial pH and blood gas values were normal throughout the study. At 132-136 days' gestation, fetal arterial oxygen pressure was lower in the oxytocin group than in controls (P < .05). Basal fetal ACTH concentrations did not change between 130 and 136 days in both groups. The mean fetal plasma ACTH concentration was not different between the control (40.6 +/- 4.1 pg/mL) and oxytocin groups (32.6 +/- 4.9 pg/mL). Pre-hypotension fetal plasma ACTH was similar in both groups, whereas cortisol was lower in the oxytocin group. Hypotension significantly increased fetal plasma ACTH and cortisol concentrations; however, both ACTH and cortisol responses were smaller in the oxytocin group (P < .05). CONCLUSIONS: Increased myometrial contractility throughout the last third of gestation modifies the normal ACTH and cortisol relation at the critical time of prepartum increase in adrenocortical activity. In addition, fetal ACTH and cortisol responses to hypotension are diminished in fetuses exposed to such a prolonged increase in myometrial contractility. These observations support the hypothesis that myometrial contractility influences fetal neuroendocrine development.

Leukocytic invasion of the ovine cervix at parturition.

OBJECTIVE: The aim of this study was to use the activity of a leukocyte-specific enzyme, myeloperoxidase, to quantify changes in leukocyte concentration in the ovine cervix during pregnancy. METHODS: Cervical tissue was collected under halothane general anesthesia from 26 sheep at different stages of gestation, in the nonpregnant state, and postpartum. Myeloperoxidase activity was used to assess the degree of leukocytic infiltration of the tissue. RESULTS: Myeloperoxidase activity was low in cervices from nonpregnant ewes and did not increase during pregnancy until the onset of labor. Myeloperoxidase activity decreased after parturition. CONCLUSION: Labor in sheep is associated with leukocytic invasion of the cervix. This observation suggests that leukocytes could participate in cervical connective-tissue reorganization during dilatation at parturition and in postpartum involution of the cervix in the species.

Effect of pulsatile oxytocin administration to the pregnant ewe in the last third of gestation on fetal ACTH and cortisol response to acute hypoxemia.

OBJECTIVE: The aim of this study was to examine the effect of increased myometrial contractility throughout the last third of pregnancy on the ovine fetal response to short-term hypoxemia. METHODS: Oxytocin (600 microU/kg/minute, n = 5) or saline (n = 7) was infused for 5 minutes every 20 minutes into the maternal jugular vein starting at 95-99 days of gestation and continuing throughout the last third of gestation. Fetuses were subjected to a hypoxemic challenge (1 hour) at 131 days of gestation while fetal plasma ACTH and cortisol levels and nuchal muscle electromyogram activity were monitored. RESULTS: The fetal plasma ACTH concentration before and during the hypoxemic challenge was similar in the control and oxytocin groups. The fetal plasma cortisol concentration in the oxytocin group was significantly lower before and during the hypoxemia than in the controls. During hypoxemia, fetal nuchal muscle activity was significantly reduced only in the control group. CONCLUSION: Increased myometrial contracture frequency throughout the last third of pregnancy alters both the neuroendocrine and behavioral responses of fetal sheep to short-term hypoxemia.

Hip dysplasia in rabbits: association with nest box flooring.

PURPOSE: To study etiologic aspects of hip dysplasia in a colony of Dutch-belted rabbits. METHODS: Rabbits used in the study were part of a reproductive toxicologic study. Incidence of hip dysplasia among 296 Dutch-Belted rabbit kits raised on waxed cardboard, smooth Plexiglas, or Plexiglas covered with textured adhesive strips was recorded. All animals were examined at 2 to 4 weeks of age for inability to adduct one or more limbs, then were classified as normal or dysplastic. A subset of 16 juvenile male rabbits (4 normal, 12 affected) raised on Plexiglas flooring were given a physical examination at 12 weeks of age followed by complete necropsy. In four animals (one normal, three affected), pelvic radiography and neurologic examination were performed. RESULTS: Seven percent of the rabbits kits reared on waxed cardboard flooring and 22% of those reared on smooth Plexiglas flooring developed hip dysplasia. Animals reared on Plexiglas floor with traction strips did not have evidence of hip dysplasia. Among the animals selected for detailed analysis, body weight was similar between rabbits with or without splay leg. Affected animals had splaying of one or both hind limbs, various degrees of flattening and reduction of the size of the femoral head, subluxation of the hip, valgus deformity, and patellar luxation. Histologically, there was marked thickening of the hip joint capsule with fibrocartilage formation, mild trabecular bone loss, and bony sclerosis of the proximal portion of the femur and adductor muscle hypoplasia. CONCLUSIONS: Provision of non-slippery flooring during the postnatal period is critical in preventing development of hip dysplasia in rabbits. Hip dysplasia resulted in significant musculoskeletal changes, but not abnormal neurologic development.

Scanning electron microscopy of the wall of the ovine cervix uteri in relation to tensile strength at parturition.

There was a progressive loosening of the collagenous fibre bundles in the stroma of the ovine cervix during spontaneous parturition. The change from an organ with predominantly thick collagen fibre bundles to one with a loose network of collagen fibrils was associated in time with a threefold increase in softness as measured by the Stretch modulus. Infusion of oestradiol 17 beta (E2 beta) for 18 hours elicited similar changes in the structure and mechanical properties of the cervix. Infusion of sodium meclofenamate for 18 hours significantly (P less than 0.005) reduced the effect of E2 beta administered simultaneously.

Cysticercosis in laboratory rabbits.

There are no data on the current incidence of Taenia pisiformis in laboratory rabbits. Two cases of cysticercosis most likely due to T. pisiformis in laboratory rabbits (intermediate host) are presented. Both rabbits had no contact with dogs (final host); their caretakers did not work with dogs, and these caretakers changed into facility scrubs and wore gloves when working with the rabbits. Rabbit 1 may have been infected after being fed hay at our facility. In light of the life cycle of the parasite and the history of rabbit 2, it potentially could have been infected prior to arrival at our facility. There have been only three cases of tapeworm cysts in rabbits in our facility (average daily census, 250) during the last 10 years (incidence, < 1%). This report indicates that although cysticercosis is rare in laboratory rabbits, one should always be aware of such incidental findings. Although it may not produce overt illness in the rabbit, hepatic migration could adversely affect the outcome of some experimental procedures

Cholesterol granulomas in mice deficient in apolipoprotein E.

Three 12- to 16-month-old female B6,129 apolipoprotein E-deficient mice were presented for necropsy because of bilateral masses in the gluteal region. Histopathologic examination revealed cholesterol granulomas extending from the superficial dermis to the underlying gluteal muscles. Microscopic granulomas were found on the face, perivaginal tissues, mesenteric lymph nodes, spleen, joints, kidneys, and choroid plexus. Other lesions included severe atherosclerosis of the aortic valves, aorta, pulmonary artery, and renal artery. Here we show that macroscopic cholesterol granulomas can develop in apolipoprotein E-deficient that receive a normal rodent diet.

Effect of intravaginal application of prostaglandin E2 gel on the mechanical properties of the ovine cervix uteri at term.

The extensibility ("creep" or strain per minute) and the stretch modulus (stress per unit strain) of strips of cervical tissue were measured in vitro. Intravaginal application of prostaglandin E2 gel led to a fourfold increase in the extensibility (mean +/- SE, 15.45 +/- 0.26 versus 4.23 +/- 0.86 min-1; p less than 0.05) and a twofold reduction in the stretch modulus (mean +/- SE, 0.66 +/- 0.03 versus 1.28 +/- 0.12 N.mm2; p less than 0.0005). This marked increase in the degree of softening occurred in the absence of an increase in uterine activity or changes in plasma progesterone concentrations.

Effect of 48-hour infusion of the synthetic oxytocin antagonist, [1-beta-mercapto(beta-(CH2)5)1(OMe)Tyr2,Orn8]-oxytocin, on myometrial activity of pregnant sheep at 139-140 days of gestation.

Currently there is considerable interest in the actions of oxytocin antagonists on the pregnant myometrium. Few studies have been conducted involving long-term infusions of oxytocin antagonists to late-pregnant experimental animals. We set out to determine whether continuous infusion of an oxytocin antagonist ([1-beta-mercapto(beta-(CH2)5)1(OMe)Tyr2,Orn8]-oxytocin) would influence basal levels of myometrial activity of the contracture type and maternal prostaglandins in pregnant sheep. The antagonist was infused into a uterine vein at 80 micrograms.h-1 for 48 h starting at 139 days of gestational age. The antagonist significantly reduced total myometrial electromyogram activity and the frequency of contractures but did not change contracture duration. Antagonist infusion did not produce any significant alterations in maternal carotid or uterine vein 13,14-dihydro-15 keto prostaglandin F2 alpha concentrations. Contractures probably represent an intrinsic instability of the resting membrane potential of uterine muscle and these results suggest that oxytocin may play a role in regulating their frequency in sheep during the last third of gestation.

Lack of effect of fetal administration of cocaine on maternal and fetal plasma adrenocorticotropin, cortisol and lactate concentrations at 127-138 days gestational age.

Few in vivo studies have been done to characterize the effects of cocaine on the maternal and fetal pituitary-adrenal axis during pregnancy. We, therefore, administered cocaine (2 mg.kg-1) intravenously to 6 fetal sheep at 127-138 days of gestation. There was a transient reduction in fetal arterial pO2 with a concomitant increase in pCO2 and a prolonged fall in pH (p less than 0.05) following cocaine injection. No changes were seen in maternal pO2, pCO2 or pH. Maternal adrenocorticotropin (ACTH), cortisol and lactate were not affected by fetal administration of cocaine. Although there was a tendency for fetal plasma ACTH, cortisol and lactate to rise after administering cocaine, the increases were not statistically significant. Previous studies have shown that cocaine administration to the ewe at a similar stage of pregnancy results in increased fetal plasma ACTH concentrations. The results of the present study indicate that cocaine administration to the fetus compromises fetal gas exchange and acid-base balance but the effects on the fetal pituitary-adrenal axis are less pronounced than after maternal administration of cocaine.

Mechanical properties of the ovine cervix during pregnancy, labour and immediately after parturition.

The stretch modulus (stress/strain) of strips of ovine cervical tissue in vitro was measured at different stages of gestation. A decrease in stretch modulus implies softening of the tissue. There was a gradual but progressive reduction in the stretch modulus with advancing pregnancy between 30 and 140 days gestation with a marked increase between 140 days gestation and the onset of labour (P less than 0.005). After the first trimester, the uterine end of the cervix was usually more distensible than the vaginal end. No further reduction in the stretch modulus of the cervix occurred between labour and delivery of the fetus. The results of this study suggest that while there is some softening of the ovine cervix during pregnancy, most of the softening takes place immediately prior to the onset of labour and delivery of the fetus.

Cocaine in pregnancy: the effect of maternal administration of cocaine on the maternal and fetal pituitary-adrenal axes.

The effects of cocaine on the maternal and fetal pituitary-adrenal axis in vivo during pregnancy have not been reported. Six pregnant ewes and their fetuses underwent instrumentation at 113 to 119 days' gestation. Ewes were assigned to receive an intravenous bolus injection of vehicle or cocaine (0.5, 1.0, or 2.0 mg.kg-1) at 124 to 136 days' gestation. Maternal arterial blood gases, fetal pH and fetal PCO2 were unchanged after injection of cocaine or vehicle. After administration of 2.0 mg.kg-1 cocaine, arterial fetal PO2 fell 3.2 +/- 1.72 mm Hg (p less than 0.05) at +5 minutes, returning to baseline by +15 minutes. Maternal and fetal adrenocorticotropin levels rose within 5 minutes after the highest cocaine dose (p less than 0.05). There was a significant (p less than 0.05) increase in maternal cortisol at all doses of cocaine and in fetal cortisol at +15 minutes after the 2.0 mg.kg-1.

Lack of effect of fetal administration of cocaine on maternal and fetal plasma adrenocorticotropin, cortisol and lactate concentrations at 127-138 days gestational age.

Few in vivo studies have attempted to characterize the effects of cocaine on the maternal and fetal pituitary-adrenal axis during pregnancy. We, therefore, administered cocaine (2 mg.kg-1) intravenously to 6 fetal sheep at 127-138 days of gestation. There was a transient reduction in fetal arterial pO2 with a concomitant increase in pCO2 and a prolonged fall in pH (p less than 0.05) following cocaine injection. No changes were seen in maternal pO2, pCO2 or pH. Maternal plasma adrenocorticotropin, cortisol and lactate were not affected by fetal administration of cocaine. Although there was a tendency for fetal plasma adrenocorticotropin, cortisol and lactate to rise after administering cocaine, the increases were not statistically significant. Previous studies have shown that cocaine administration to the ewe at a similar stage of pregnancy results in increased fetal plasma adrenocorticotropin concentrations. The results of the present study indicate that cocaine administration to the fetus compromises fetal gas exchange and acid base balance, but the effects on the fetal pituitary-adrenal axis are less pronounced than after maternal administration of cocaine.