Biomedical subjects

A F Tarantal

Publications and source records attributed to A F Tarantal.

At least 37 records · Page 2Linked to original sources

PubMed1998

Neuropathogenesis induced by rhesus cytomegalovirus in fetal rhesus monkeys (Macaca mulatta).

Rhesus cytomegalovirus (RhCMV) infection of rhesus macaques offers opportunities to analyze mechanisms of CMV pathogenesis in a primate species. Four fetal rhesus monkeys were inoculated intraperitoneally with RhCMV early in the second trimester, and pregnancies were terminated by hysterotomy during the third trimester. Three fetuses had evidence of severe CMV disease, including intrauterine growth restriction, ventriculomegaly, microcephaly, lissencephaly, and extensive degenerative changes of the cerebral parenchyma. Histopathologic examination revealed polymicrogyria, gliosis, leptomeningitis, periventricular calcifications, and inclusion-bearing cells. These results demonstrate that the developing macaque brain is susceptible to infection with RhCMV early in the second trimester and that intrauterine infection results in neuropathologic outcomes similar to those observed in humans congenitally infected with CMV.

Animals↗

PubMed1998

Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy.

Pregnant women with Plasmodium falciparum infection are at increased risk for complications such as anemia and cerebral malaria. In addition, the infants of these women suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection, and high infant mortality. Although much has been learned from studies of malaria during human pregnancy, progress has been limited by the lack of a suitable animal model. Nonhuman primates are of particular interest because, other than the armadillo, they are the only animals with a discoidal, villous, hemochorial placenta like that of humans. We have established a model of malaria during human pregnancy by inoculating pregnant rhesus monkeys (Macaca mulatta) with Plasmodium coatneyi (a sequestering parasite) during the first trimester. In our initial experiment, four monkeys were inoculated with a fresh inoculum containing 10(8) viable parasites from an infected donor monkey. All four monkeys became parasitemic seven days postinoculation (PI) and three monkeys aborted 7-10 days PI coincident with high peak parasitemias (41,088-374,325 parasites/mm3). Although abortion is one of the outcomes observed in Plasmodium-infected women, the intent of this study was to examine the effects of Plasmodium infection throughout gestation. Since the rapid onset of high parasitemia may have been responsible for the abortions, a decision was made to reduce the size of the effective inoculum. Six additional pregnant monkeys were inoculated with a frozen isolate taken from the same donor containing 10(6) parasites. These six animals became parasitemic by 14 days PI and, along with monkey E412, carried their infants to term. These seven infants weighed significantly less at term than the infants of uninfected mothers (P = 0.0355). Symmetrical IUGR was detected by ultrasound in one fetus with an LBW of 334 g. Another LBW infant (300 g) had asymmetrical growth retardation, which has been associated with uteroplacental insufficiency and was consistent with the lower placental weights found in infected dams compared with controls (P = 0.0455). The infant with symmetric IUGR died at five days of age, while the other is alive but congenitally infected. The IUGR, LBW, congenital infection, postnatal infant mortality, and early abortions observed in these animals suggest that P. coatneyi in pregnant rhesus monkeys is a valid model of malaria in human pregnancy. This model should provide the opportunity to study questions about malaria in pregnancy that have been difficult to study in humans.

Abortion, Veterinary↗

PubMed1997

Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta).

In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring was performed during the course of gestation to monitor viability, growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (i.v.) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least 60-750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities were observed in either male or female fetuses of mothers given iv doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the i.v. formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5 alpha R isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5 alpha R inhibitors administered during pregnancy.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1997

In utero hematopoietic stem cell transplants prolong survival of postnatal kidney transplantation in monkeys.

The authors hypothesized that in utero transplantation of T-cell-depleted paternal marrow into rhesus monkey fetuses would induce tolerance to postnatal kidney grafts from the marrow donor. T-cell-depleted paternal bone marrow was transplanted intraperitoneally into two female fetal rhesus monkeys at 61 +/- 1 days' gestation. Chimeric monkeys (n = 2) received kidney transplants from paternal donors. Control monkeys (n = 2) underwent kidney transplants without prior in utero stem cell transplants. Both chimeric monkeys demonstrated low level (<0.1% donor cells) engraftment in the bone marrow and peripheral blood using the polymerase chain reaction assay for the Y chromosome. The mixed lymphocyte reaction demonstrated hyporeactivity to the donor. Control animals demonstrated severe acute rejection and graft failure 1 week posttransplant. The first chimeric monkey had no significant clinical or sonographic evidence of renal failure until 7 weeks after the transplant. Biopsy findings showed mild rejection 1 week postoperatively, but rejection did not significantly progress until 5 weeks later. The second chimeric monkey had no significant clinical or sonographic changes for 4 weeks, but evidence of moderate rejection was seen on biopsy results. This monkey was given a 10-week course of immunosuppression, and had no clinical or sonographic renal deterioration, although biopsy results showed chronic rejection that was confirmed when electively euthanized 8 months later. Our data suggest that in utero transplantation of hematopoietic stem cells can increase the survival of a kidney allograft in the rhesus monkey.

Animals↗

PubMed1997

The missing link in rhesus monkey amniotic fluid volume regulation: intramembranous absorption.

OBJECTIVE: To investigate whether intramembranous absorption occurs in the rhesus monkey and its role in amniotic fluid (AF) volume regulation as a possible model for the human fetus. MATERIALS AND METHODS: We studied five chronically catheterized rhesus monkey fetuses (Macaca mulatta) at 126 +/- 1 (standard error) days' gestation (term approximately 165 days) with ligated esophagi and catheterized tracheae. Samples (0.5 mL each) of fetal and maternal blood and amniotic and lung fluid were collected at 0, 15, 30, 60, 120, 180, and 240 minutes after injection of 0.1 mCi (3 mL) of technetium-99m (Tc-99m) into the amniotic cavity. RESULTS: In spite of esophageal ligation, there was a rapid absorption of the Tc-99m into the fetal circulation within 15 minutes of injection. The maternal Tc-99m activity increased in parallel to fetal activity but remained lower. The fetal lung fluid Tc-99m activity increased more slowly but was equivalent to the fetal circulating level by 4 hours. CONCLUSIONS: These results suggest that intramembranous absorption occurs and may play an important role in rhesus AF volume regulation and composition. Furthermore, this animal model, which closely resembles the human, may provide valuable insight into abnormalities of human AF volume regulation.

Amniotic Fluid↗

PubMed1997

Detection of Neospora from tissues of experimentally infected rhesus macaques by PCR and specific DNA probe hybridization.

Neospora is a newly recognized Toxoplasma-like cyst-forming coccidian parasite that causes abortion or congenital infections in naturally or experimentally infected animals. In this study, pregnant rhesus macaques were inoculated with culture-derived tachyzoites of a bovine Neospora isolate, and tissue samples from various major organs were collected from dams and fetuses for the detection of parasite DNA by using oligonucleotide primers COC-1 and COC-2 for PCR amplification of a conserved coccidial nuclear small-subunit rRNA gene sequence, and amplification products were confirmed by hybridization with a Neospora-specific DNA probe. PCR products were amplified from DNAs of different fetal monkey tissues, including brain, heart, lung, liver, spleen, skeletal muscle, skin, and placenta. In addition, Neospora DNA was amplified from the brain, heart, and lung tissues of infected rhesus macaque dams. The PCR and probe hybridization system may provide an effective method for the detection of Neospora infection in fetuses and dams from nonhuman primates and may be useful in determining the zoonotic potential of Neospora.

Animals↗

PubMed1997

Direct administration of insulin-like growth factor to fetal rhesus monkeys (Macaca mulatta).

A potential treatment for the amelioration of fetal growth failure is insulin-like growth factor-I (IGF-I). To address concerns of safety and efficacy, IGF-I (80 microg/kg; GroPep Pty.) was administered i.p. to healthy rhesus monkey fetuses via ultrasound guidance every other day between gestational days (GD) 110-120 and 130-140 (third trimester; term = approximately GD 165 +/- 10; n = 6). Pregnancies were monitored sonographically, and fetal/maternal blood samples were collected for complete blood counts, immunophenotyping, and biochemical analyses. Blood samples, external measures of the fetus and newborn, and tissue and organ weights were collected at fetal necropsy (GD 150; n = 2) or at term delivery of neonates (GD 160; n = 4). The results of these investigations have shown no evidence of hypoglycemia in the fetus or dam during the course of treatment. Circulating concentrations of fetal, but not maternal, IGF-I increased with treatment (approximately 80 to approximately 1015 ng/ml), and there was no evidence of a change in serum IGF-II or an increase in IGF binding protein-3 compared with historical control values. Fetal lymphocytes and select red cell parameters increased, and a significant elevation in circulating B cells and CD4/CD8 ratios in fetal lymph nodes was shown. Although no changes were detected in body weights, increases in thymic, splenic, and kidney weights and small intestine lengths occurred. Thus, administration of IGF-I to the fetal monkey is safe and results in 1) transient increases in circulating IGF-I, 2) a significant effect on fetal hematopoietic and lymphoid tissues, and 3) an increase in select fetal organ weights and measures. These data suggest that IGF-I may represent a potential candidate for therapeutic treatment of growth-compromised human fetuses in utero.

Animals↗

PubMed1997

Pregnancy detection by ultrasound and chorionic gonadotropin during the peri-implantation period in the macaque (Macaca fascicularis).

The goal of these studies was to correlate sonographic evidence of pregnancy during the peri-implantation period with the timing of the rise in monkey chorionic gonadotropin (mCG) as measured with an enzyme-linked immunosorbent assay. Animals were time-mated at mid-cycle, and ultrasound examinations were performed on postovulation days 12-15 (n = 77). Pregnancy was sonographically identified in 48 of 77 animals (62.3%), of which 28 had correlative ultrasound/endocrine data collected. For these animals, blood samples were obtained on postovulation days 12-15 for mCG assay. Pregnancy was identified by ultrasound on postovulation days 12 (6/28; 21.4%), 13 (6/28; 21.4%), 14 (8/28; 28.6%) or 15 (8/28; 28.6%). Seven of the 28 (25.0%) were found to have mCG levels consistent with pregnancy (> or = 1 ng/ml) on the same day as ultrasound confirmation, 12 of 28 (42.9%) were sonographically detected as pregnant 1 (n = 6), 2 (n = 3) or 3 (n = 3) days earlier than by mCG, and nine of 28 (32.1%) were found to have elevated mCG levels 1 (n = 7), 2 (n = 1) or 3 (n = 1) days earlier than ultrasound confirmation of pregnancy. The results of these studies have demonstrated (1) the utility of anatomical and endocrine techniques for detecting pregnancy approximately 3 days after the onset of implantation, and (2) the variation in the timing of implantation and the rise in circulating mCG in individual animals.

Animals↗

PubMed1996

Fetal or neonatal infection with attenuated simian immunodeficiency virus results in protective immunity against oral challenge with pathogenic SIVmac251.

We have reported that infection of fetal or neonatal rhesus macaques with attenuated SIVmac1A11 results in transient viremia, anti-SIV antibody responses, weak or absent cytotoxic T-lymphocyte responses, and no clinical disease. In light of these results, we hypothesized that congenital infection with SIVmac1A11 produced immune tolerance to SIV. To test this hypothesis, at approximately 1 year of age, five rhesus macaques infected with SIVmac1A11 as fetuses (n = 3) or newborns (n = 2) and five naive juvenile rhesus macaques were challenged orally with pathogenic SIVmac251. The five naive animals became persistently viremic after oral SIVmac251 inoculation. In contrast, one of three monkeys inoculated with SIVmac1A11 in utero and one of two animals inoculated with SIVmac1A11 at birth were virus culture negative. Virus was isolated from PBMC of the other animals infected with SIVmac1A11 in utero or at birth. However, one animal had a substantially lower viral load than the control animals. These results suggest that SIV-specific immunity rather than tolerance results from congenital infection with attenuated SIVmac and that this immunity is sufficient to provide some protection from pathogenic virus challenge. These results also demonstrate that SIV can be transmitted orally in 6- to 17-month-old rhesus monkeys.

Administration, Oral↗

PubMed1996

Effects of two antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis).

The abortifacient effects of mifepristone and HRP 2000 were compared in gravid long-tailed macaques. Thirty-six animals were studied with treatment administered either by the oral (0.5 or 5.0 mg/kg; N = 5 per antiprogestin per dose) or intramuscular (i.m.) routes (0.5 mg/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; six vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with i.m. administration (3/5 mifepristone, 4/5 HRP 2000) and 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily i.m. treatment, peak levels of 8-16 ng/ml mifepristone were detected whereas 6-10 ng/ ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high dose oral administratation. Results of these studies suggest: (1) both antiprogestins are roughly comparable in terminating early pregnancy although HRP 2000 may be more efficacious when administered i.m. whereas mifepristone may be more effective when administered orally; (2) similar levels of biological activity are seen with the i.m. and high dose oral dosing regimens, with little or no activity with the oral low dose; and (3) infants resulting from surviving pregnancies were not affected by early gestation exposure.

Abortifacient Agents, Steroidal↗

PubMed1996

Identification of bovine Neospora parasites by PCR amplification and specific small-subunit rRNA sequence probe hybridization.

Neospora is a newly recognized genus of pathogenic coccidia, closely related to Toxoplasma gondii, that can cause abortion or congenital disease in a variety of domestic animal hosts. On the basis of the small-subunit rRNA gene sequences of Neospora spp. and other apicomplexa coccidia, oligonucleotide primers COC-1 and COC-2 were used for PCR amplification of conserved sequences of approximately 300 bp in size. A Neospora-specific chemiluminescent probe hybridized to Southern blots of amplification products from Neospora DNA but not to Southern blots with amplified DNA from the other coccidian parasites tested. A Toxoplasma-specific probe whose sequence differed from that of the probe for Neospora spp. by a single base pair was used to distinguish these parasites by specific Southern blot hybridization. The PCR system detected as few as one Neospora tachyzoite in the culture medium or five tachyzoites in samples of whole blood or amniotic fluid spiked with Neospora parasites. In addition, Neospora PCR products were successfully amplified from whole blood and amniotic fluid samples of experimentally infected bovine and rhesus macaque fetuses. These results indicate that this PCR and probe hybridization system could be a valuable adjunct to serology and immunohistochemistry for the diagnosis of Neospora infections in bovine or primate fetuses.

Abortion, Veterinary↗

PubMed1996

A role for epidermal growth factor in the morphological and functional maturation of the adrenal gland in the fetal rhesus monkey in vivo.

We determined the effects of epidermal growth factor (EGF) and beta-methasone on the growth and development of the adrenal gland of the fetal rhesus monkey in vivo between 121-128 days of gestation. The adrenal to body weight ratio was significantly greater (P < 0.05) in EGF-treated fetuses (0.988 +/- 0.046 x 10(-3) g/g) and significantly reduced (P < 0.05) in beta-methasone-treated fetuses (0.401 +/- 0.056 x 10(-3) g/g) compared with that in control fetuses (0.689 +/- 0.050 x 10(-3) g/g). The increase in adrenal weight with EGF administration was due to hypertrophy of definitive zone cells of the adrenal cortex, whereas the reduction in adrenal weight after beta-methasone treatment was due to a decrease in the size of definitive and fetal zone cells of the adrenal cortex. By Western analysis, EGF treatment induced a significant (P < 0.05) 2.8-fold increase in the amount of protein for 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD) in the fetal adrenal. EGF also stimulated the induction of immunocytochemical staining for 3 beta HSD in transitional zone cells of the adrenal cortex. In contrast, beta-methasone resulted in 2.6-, 4.5-, and 6.6-fold significant decreases (P < 0.05) in the amount of protein for cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17,20-lyase, and 3 beta HSD in the fetal adrenal. After beta-methasone treatment. 3 beta HSD staining was detected in some of the definitive zone cells, with no 3 beta HSD staining in the transitional zone. In conclusion, growth and functional differentiation of fetal primate adrenal gland can be accelerated prematurely by EGF and inhibited by glucocorticoid negative feedback.

3-Hydroxysteroid Dehydrogenases↗

PubMed1996

Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys.

A major concern with allogeneic BMT for treating most inherited diseases is the need to overcome graft rejection with conditioning chemotherapy which is associated with a relatively high morbidity and mortality. This can be eliminated if the transplant is done in utero when the fetus is unable to reject donor hematopoietic stem cells (HSC). We studied the efficacy of T cell-depleted (TCD) parental bone marrow as a source of HSC for transplantation into early gestation non-defective fetal rhesus monkeys. Thirteen opposite sexed TCD transplants were done into 44 day fetal recipients and 12 into 61 day recipients (165 day total gestation). The procedure-related mortality was 8%, all in the earlier age group. The overall survival was 60% at birth with a projected survival of 44 +/- 10% at 1.5 years with no difference between the two age groups. We used a PCR assay for the rhesus Y chromosome to detect male donor cells in female recipients (six animals transplanted at 44 days and five at 63 days). The overall engraftment rate was 73% with no difference as a function of gestational age at transplant. In six long-term surviving engrafted females we detected donor cells in the peripheral blood and bone marrow up to 3 years of age. We found a delay in the appearance of donor cells in the peripheral blood in engrafted animals, in some cases for up to 6 months post-BMT. In vitro mixed lymphocyte reaction and cell-mediated lymphocytotoxicity studies between the recipient and donor cells indicate that tolerance was induced to donor cells. Individual and pooled erythroid and myeloid marrow colonies grown in methyl cellulose were collected and analyzed for donor origin by PCR. The amount of donor cells in marrows from long-term engrafted animals was < 0.1%. In a fetal recipient studied at 35 days post-BMT, donor cells were detected in bone marrow and liver in both erythroid and myeloid lineages. These results indicate that TCD parental marrow can durably engraft in utero. While the engraftment rate is similar to that seen with fetal liver as the source of HSC, the degree of peripheral blood engraftment (percent donor cells) in this non-defective primate model is low. It will require increasing the percent pre-or postnatally for this approach to be clinically relevant in those disorders in which there is no selective survival advantage for normal engrafted donor cells.

Animals↗

PubMed1996

Localization of simian immunodeficiency virus nucleic acid and antigen in brains of fetal macaques inoculated in utero.

Neurological dysfunction has been shown to be associated with human immunodeficiency virus (HIV) infection. The incidence of these abnormalities is greater in HIV-infected children when compared with adults, and the patterns of neurological disease are also known to differ from those observed in the adult population. The reasons for these differences are unclear but are most likely related to the immaturity of the host's immune and central nervous systems at the time of infection. This is thought to be particularly true for infants infected with HIV prenatally. To examine these questions, the brains of fetal rhesus macaques that were infected with SIVmac251 at various time points in utero were examined. Direct fetal inoculations were performed on gestational day (GD) 65 (n = 8; early second trimester), GD 110 (n = 4; early third trimester) and GD 130 (n = 2; mid third trimester), with harvest of fetal tissues on GD 80, 100, 130, or 145. Eleven sham controls were included with harvest at correlative time points. Specimens were examined by routine histology, immunohistochemistry, and in situ hybridization to localize viral antigens and SIV nucleic acid. Histologically, scattered glial nodules, spongiosis, and mineralization were found in the basal ganglia and deep white matter in 4 of the 14 fetuses (3 inoculated on GD 65 and one on GD 110). These fetuses and those without histological lesions had viral nucleic acid and SIV antigen in the stroma of the choroid plexus, meninges, and external granular layer of the cerebellum and in columns of cells in the cortical plate. In contrast to juvenile and adult macaques, very few SIV-positive perivascular mononuclear cells were present. These findings suggest that SIV has a different distribution in the brain of fetal macaques after direct infection when compared with adult or juvenile animals. Furthermore, the results of these studies suggest that differences in neurological disease between pediatric and adult patients with acquired immune deficiency syndrome are most likely related to the time of infection.

Animals↗

PubMed1995

Effects of viral virulence on intrauterine growth in SIV-infected fetal rhesus macaques (Macaca mulatta).

Studies with a simian immunodeficiency virus (SIV)-infected fetal monkey model were conducted with a focus on fetal growth and viral pathogenesis. Twenty-six fetuses were inoculated in utero via ultrasound guidance with an uncloned pathogenic strain of SIV or vehicle during the second or third trimesters [gestational day (GD) 65, 110, or 130], sonographically monitored weekly (biometrics, blood flow), then necropsied at incremental time points postinfection. Peripheral blood hematologic (complete blood counts, clinical chemistries), immunologic (immunophenotyping), and endocrine studies [insulin-like growth factor (IGF), IGF-binding proteins (IGFBP)] were conducted. Severe intrauterine growth restriction (IUGR), oligohydramnios, and altered lymphocyte counts were noted for fetuses infected on GD 65. Less severe effects were detected for fetuses inoculated at the later time points, with severity dependent upon the length of SIV infection in utero. IGF studies indicated significant reductions in IGF-I and elevated immunoreactive levels of IGFBP-3 in infected fetuses during the third trimester. Parallel studies conducted with four fetuses infected on GD 65 with a nonpathogenic, molecularly cloned virus (SIVmac1A11) resulted in normal fetal growth, with no effects on hematopoiesis or IGF/IGFBP levels, and no evidence of clinical disease. Taken together, these studies show that (1) infection of fetuses during the early second trimester with an uncloned pathogenic strain of SIV results in severe IUGR and a disruption in the molar ratio of IGF:IGFBP-3, and (2) outcome of fetal SIV infection is determined by the timing of infection and the virulence of the viral inoculum.

Animals↗

PubMed1995

Hematologic and growth-related effects of frequent prenatal ultrasound exposure in the long-tailed macaque (Macaca fascicularis).

Prior investigations have shown that reduced birth weights and transient neutropenias result from frequent exposure of monkey fetuses to ultrasound. To further explore these findings, 26 animals were studied (16 exposed, 10 controls; "triple mode"; ATL Ultramark 9 with HDI; ISPTAd approximately 645 to 714 mW/cm2). Exposures were performed daily for 5 days each week from gestational days (GD) 21 to 35 (5 min), three times weekly from GD 36 to 60 (5 min), then weekly from GD 61 to 153 +/- 1 (10 min). Fetal blood samples (FBS) were collected for complete blood counts (CBCs), hematopoietic progenitor assay, circulating insulin-like growth factors (IGF-I, IGF-II) and binding proteins (IGFBP-3) (GD 120, 140, 153 +/- 1). Animals were delivered by Cesarean section at term (GD 153 +/- 1), and body weights, morphometrics, CBCs, and bone marrow aspirates assessed at delivery and postnatally for 3 months. Fetal neutropenias were noted in exposed animals in addition to reduced circulating progenitors (colony forming unit-granulocyte-macrophage [CFU-GM]). Growth of CFU-GM from bone marrow was exuberant at term, whereas circulating levels were diminished comparable to prenatal samples. Exposed animals were smaller at birth; marked reductions in IGFBP-3 were noted prenatally. These data suggest that frequent prenatal ultrasound exposure can transiently alter the neutrophil lineage, although these findings may be the result of enhanced margination and organ sequestration. Data also suggest that transient, altered growth patterns may be due to perturbations of the IGF axis.

Animals↗

PubMed1995

Comparison of the distinct effects of epidermal growth factor and betamethasone on the morphogenesis of the gas exchange region and differentiation of alveolar type II cells in lungs of fetal rhesus monkeys.

To compare the effects of epidermal growth factor (EGF) and betamethasone on the morphogenesis of the gas exchange region and the differentiation of the alveolar type II cell during fetal lung development, fetal rhesus monkeys (78% gestation) were treated in utero with EGF (5.33 mg/kg total dose), beta-methasone (2.6 mg/kg total dose) or the carrier, saline (control), every other day for 7 days. EGF-treated monkeys had significantly increased body and adrenal weights. Betamethasone-treated monkeys had significantly decreased body and adrenal weights. Exogenous EGF reduced cytoplasmic glycogen and increased the cytoplasmic organelle and SP-A content within alveolar type II cells. In contrast, exogenous betamethasone did not alter alveolar type II cell cytodifferentiation. Neither EGF nor betamethasone treatment significantly altered the structure of the gas exchange region as shown by a lack of change from controls in alveolar airspace size or in the fraction of the gas exchange region that was potential airspace. We conclude that at clinically relevant doses, EGF greatly accelerates the maturation of alveolar type II cells, whereas betamethasone does not. Exogenous EGF may act directly on alveolar type II cells because these cells contain EGF receptor. Neither EGF nor betamethasone had dramatic effects on the morphogenesis of the gas exchange region.

Amniotic Fluid↗

PubMed1995

Characterization of the insulin-like growth factor (IGF) axis in the serum of maternal and fetal macaques (Macaca mulatta and Macaca fascicularis).

The insulin-like growth factors (IGFs) are key effectors of fetal growth and development which are modulated by serum carrier proteins (IGF binding proteins [IGFBPs]). Studies were performed to evaluate the developmental profile of IGFs and IGFBPs in the macaque, an important nonhuman primate model for human development and disease. IGF-I, IGF-II, and IGFBP-3 were studied in the rhesus (Macaca mulatta) and long-tailed (Macaca fascicularis) monkey fetus and dam during the second and third trimesters of pregnancy. Serial fetal blood samples were collected by cardiocentesis every 10 days from gestational day (GD) 90-160, and at 1 month postnatal age; maternal blood samples were collected at similar timepoints. Results indicated that maternal sera IGF-I and IGF-II did not change significantly whereas fetal concentrations of serum IGF-I and IGF-II increased approximately two-fold during the second to the third trimesters. No significant differences were detected between the two species. Western-ligand blot analysis revealed predominant IGFBPs of 45-40 (IGFBP-3) and 28 kDa (IGFBP-1) in both the maternal and fetal compartments, and Western-immunoblot analysis using a specific antisera against IGFBP-3 indicated 45-40 and 28 kDa immunoreactive forms. Thus, although IGF-I, IGF-II, and IGFBP-3 remained relatively unaffected in maternal sera during this period of gestation, fetal concentrations of IGF-I, IGF-II, and IGFBP-3 increased in a developmental profile similar to the human fetus.

Animals↗