Newborn Baboons Research Articles

Planum temporale asymmetry in newborn monkeys predicts the future development of gestural communication’s handedness

The planum temporale (PT), a key language area, is specialized in the left hemisphere in prelinguistic infants and considered as a marker of the pre-wired language-ready brain. However, studies have reported a similar structural PT left-asymmetry not only in various adult non-human primates, but also in newborn baboons. Its shared functional links with language are not fully understood. Here we demonstrate using previously obtained MRI data that early detection of PT left-asymmetry among 27 newborn baboons (Papio anubis, age range of 4 days to 2 months) predicts the future development of right-hand preference for communicative gestures but not for non-communicative actions. Specifically, only newborns with a larger left-than-right PT were more likely to develop a right-handed communication once juvenile, a contralateral brain-gesture link which is maintained in a group of 70 mature baboons. This finding suggests that early PT asymmetry may be a common inherited prewiring of the primate brain for the ontogeny of ancient lateralised properties shared between monkey gesture and human language.

Planum temporale grey matter volume asymmetries in newborn monkeys (Papio anubis).

The Planum temporale (PT) is one of the key hubs of the language network in the human brain. The gross asymmetry of this perisylvian region toward the left brain was considered as the most emblematic marker of hemispheric specialization of language processes in the brain. Interestingly, this neuroanatomical signature was documented also in newborn infants and preterms, suggesting the early brain's readiness for language acquisition. Nevertheless, this latter interpretation was questioned by a recent report in non-human primates of a potential similar signature in newborn baboons Papio anubis based on PT surface measures. Whether this "tip of the iceberg" PT asymmetry is actually reflecting asymmetry of its underlying grey matter volume remains unclear but critical to investigate potential continuities of cortical specialization with human infants. Here we report a population-level leftward asymmetry of the PT grey matter volume in in vivo 34 newborn baboons P. anubis, which showed intra-individual positive correlation with PT surface's asymmetry measures but also a more pronounced degree of leftward asymmetry at the population level. This finding demonstrates that PT leftward structural asymmetry in this Old World monkey species is a robust phenomenon in early primate development, which clearly speaks for a continuity with early human brain specialization. Results also strengthen the hypothesis that early PT asymmetry might be not a human-specific marker for the pre-wired language-ready brain in infants.

Neutralization of pertussis toxin by a single antibody prevents clinical pertussis in neonatal baboons.

Pertussis continues to cause considerable infant mortality world-wide, which could be addressed in part by passive immunization strategies. Antibody hu1B7 is a candidate therapeutic that potently neutralizes pertussis toxin in vitro, prevents leukocytosis in mice and treats established disease in weanling baboons as part of an antibody cocktail. Here, we evaluated the potential for hu1B7 and an extended half-life hu1B7 variant to prevent death, leukocytosis and other clinical symptoms in a newborn baboon model that mimics many aspects of human disease. We administered a single antibody dose to newborn baboons five weeks prior to experimental infection. While all animals were heavily colonized with Bordetella pertussis, prophylaxed animals showed significantly greater survival (P < 0.005), delayed and suppressed leukocytosis (P < 0.01) and enhanced clinical outcomes, including coughing (P < 0.01), as compared to controls. Together, this work demonstrates that a single neutralizing anti-PTx antibody is sufficient to prevent clinical pertussis symptoms.

Maternal Vaccination With a Monocomponent Pertussis Toxoid Vaccine Is Sufficient to Protect Infants in a Baboon Model of Whooping Cough.

Bordetella pertussis is a human pathogen responsible for serious respiratory illness. The disease is most severe in infants too young to be vaccinated with most hospitalizations and deaths occurring within this age group. The Advisory Committee on Immunization Practices recommended immunization of pregnant women to protect infants from birth until their first vaccination at 6-8 weeks of age. We previously demonstrated that maternal vaccination with licensed acellular pertussis vaccines protected newborn baboons from disease. We hypothesized that protection was due to toxin-neutralizing, maternal anti-pertussis toxin antibodies and predicted that maternal vaccination with a pertussis toxoid (PTx)-only vaccine would protect newborns from disease. Infant baboons born to unvaccinated mothers or mothers vaccinated with a PTx-only vaccine were challenged with B. pertussis at 5 weeks of age and followed for infection and signs of disease. Although all challenged infants were heavily colonized, the infant baboons born to mothers vaccinated with PTx-only vaccine were free from clinical disease following exposure to B. pertussis. In contrast, disease was observed in infants born to unvaccinated mothers. Our results demonstrated that maternal vaccination with a PTx-only vaccine is sufficient to protect newborn baboons from disease following exposure to pertussis.

Prematurity disrupts glomeruli development, whereas prematurity and hyperglycemia lead to altered nephron maturation and increased oxidative stress in newborn baboons.

BackgroundPremature birth occurs when nephrogenesis is incomplete and has been linked to increased renal pathologies in the adult. Metabolic factors complicating preterm birth may have additional consequences for kidney development. Here, we evaluated the effects of prematurity and hyperglycemia on nephrogenesis in premature baboons when compared to term animals.MethodsBaboons were delivered prematurely (67% gestation; n=9) or at term (n=7) and survived 2–4 weeks. Preterm animals were classified by glucose control during the first five days of life (DOL): normoglycemic (PtN; serum glucose 50–100mg/dL, n=6) and hyperglycemic (PtH; serum glucose 150–250mg/dL, n=3). Kidneys were assessed histologically for glomeruli relative area, maturity, size, and overall morphology. Kidney lysates were evaluated for oxidative damage with 4-hydroxynonenal (4-HNE) antibody.ResultsHistological examination revealed decreased glomeruli relative area (p<0.05), fewer glomerular generations (p<0.01), and increased renal corpuscle area (p<0.001) in preterm compared to term animals. Numbers of apoptotic glomeruli were similar between groups. PtH kidneys exhibited reduced nephrogenic zone width (p<0.0001), increased numbers of mature glomeruli (p<0.05), and increased 4-HNE staining compared to PtN kidneys.ConclusionPrematurity interrupts normal kidney development, independent of glomerular cell apoptosis. When prematurity is complicated by hyperglycemia; kidney development shifts towards accelerated maturation and increased oxidative stress.

Passive Immunization with Anti-Pertussis Toxin Humanized Monoclonal Antibody Mitigates Clinical Signs of Pertussis Infection in Newborn Baboons

BackgroundPertussis is a significant mortality risk in the developing world, killing up to 200,000 infants annually. Maternal vaccination as a strategy to protect newborns has shown some success, but is unlikely to capture all eligible mothers. Hu1B7 is a monoclonal antibody (mAb) that potently neutralizes pertussis toxin. Hu1B7, when administered as part of a binary mAb cocktail, demonstrated therapeutic efficacy in pertussis-infected weanling baboons. Here, the prophylactic potential of hu1B7 to protect infants during their first few months, when mortality risk is highest, was evaluated.MethodsNeonatal baboons of normal gestational age (180 days ± 10), normal birth weight (~1.0kg), and anti-Fha titer < 5 IU/ml (verifying no prior exposure to Bordetella species) were recruited into the study. At 2 days of age, treated baboons received hu1B7 (40mg/kg, IV), while control animals were untreated. Serum levels of hu1B7 were followed for 5 weeks, at which time the animals were infected with 108 cfu of B. pertussis strain D420. Animals were monitored for clinical signs of disease.ResultsSix controls and seven treated animals were evaluated. All animals were heavily colonized with B. pertussis during the first week after infection. Controls developed significant leukocytosis, most coughed, and three required euthanasia. In contrast, white blood cell counts for all treated animals remained within the normal range, coughing was virtually absent, and all animals maintained normal activity. As expected for a humanized mAb in a nonhuman primate, hu1B7 had an elimination half-life of 11.8±3.4 days.ConclusionProtection of newborn baboons from pertussis was achieved by mAb administration 5 weeks prior to pertussis infection. Hu1B7, when systemically present, mitigated the clinical signs of pertussis, including leukocytosis and coughing, but did not prevent bacterial colonization. Assuming a half-life in humans of 3 weeks, mAb administration at birth could potentially provide 4 months of prophylaxis and is a viable strategy to complement maternal vaccination. Moreover, strategies that extend the mAb half-life and lower the dose could further support developing world application.Disclosures J. Maynard, Synthetic Biologics, Inc.: Collaborator, Research support; A. Nguyen, Synthetic Biologics, Inc.: Collaborator, Research support; R. Wolf, Synthetic Biologics, Inc.: Collaborator, Research support;; J. Papin, Synthetic Biologics, Inc.: Collaborator, Research support; S. Connelly, Synthetic Biologics, Inc.: Employee, Salary; M. Kaleko, Synthetic Biologics, Inc.: Employee and Shareholder, Salary and stock options

Maternal Pertussis Vaccination with a Mono-component Pertussis Toxoid Vaccine is Sufficient to Protect Newborns

Abstract Bordetella pertussis is a highly infectious human pathogen causing serious illness in infants, children and adults. The first pertussis vaccination is administered at two months of age, therefore, infants under two months of age are most vulnerable to infection. Rising incidence of pertussis resulted in the 2012 recommendation by the Advisory Committee on Immunization Practices (ACIP) to immunize all pregnant women to protect infants from birth until their first vaccination. Using a baboon model, we demonstrated that maternal vaccination with the three or four component acellular pertussis vaccines protected newborn baboons from the disease but not from the colonization. We hypothesized this protection was due to the transfer of maternal anti-PT antibodies to the infant. Therefore we evaluated the protection conferred by maternal vaccination with a pertussis toxoid (PTx) only vaccine. Infant baboons born to mothers vaccinated with the PTx-only vaccine were free from disease and had low WBC counts following exposure to B. pertussis at five weeks of age. In contrast, infants born to unvaccinated mothers experienced severe disease with high WBC counts. Our results demonstrate that vaccination of baboons during pregnancy with a PTx-only vaccine is sufficient to protect newborn baboons from disease following exposure to pertussis. Because pertussis toxin is a secreted protein that can be purified from bacterial supernatants, a single-component vaccine comprised of pertussis toxoid is very likely the most cost-effective acellular pertussis vaccine possible. The development and use of mono-component PTx vaccines may enable the extension of maternal vaccine programs to low and middle income countries.

An infant formula toxicity and toxicokinetic feeding study on carrageenan in preweaning piglets with special attention to the immune system and gastrointestinal tract

A toxicity/toxicokinetic swine-adapted infant formula feeding study was conducted in Domestic Yorkshire Crossbred Swine from lactation day 3 for 28 consecutive days during the preweaning period at carrageenan concentrations of 0, 300, 1000 and 2250 ppm under GLP guidelines. This study extends the observations in newborn baboons (McGill et al., 1977) to piglets and evaluates additional parameters: organ weights, clinical chemistry, special gastrointestinal tract stains (toluidine blue, Periodic Acid–Schiff), plasma levels of carrageenan; and evaluation of potential immune system effects. Using validated methods, immunophenotyping of blood cell types (lymphocytes, monocytes, B cells, helper T cells, cytotoxic T cells, mature T cells), sandwich immunoassays for blood cytokine evaluations (IL-6, IL-8, IL1β, TNF-α), and immunohistochemical staining of the gut for IL-8 and TNF-α were conducted. No treatment-related adverse effects at any carrageenan concentration were found on any parameter. Glucosuria in a few animals was not considered treatment-related. The high dose in this study, equivalent to ~430 mg/kg/day, provides an adequate margin of exposure for human infants, as affirmed by JECFA and supports the safe use of carrageenan for infants ages 0–12 weeks and older and infants with special medical needs.

Anatomic Closure of the Premature Patent Ductus Arteriosus: The Role of CD14+/CD163+ Mononuclear Cells and VEGF in Neointimal Mound Formation

Permanent closure of the newborn ductus arteriosus requires the development of neointimal mounds to completely occlude its lumen. VEGF is required for neointimal mound formation. The size of the neointimal mounds (composed of proliferating endothelial and migrating smooth muscle cells) is directly related to the number of VLA4 mononuclear cells that adhere to the ductus lumen after birth. We hypothesized that VEGF plays a crucial role in attracting CD14/CD163 mononuclear cells (expressing VLA4) to the ductus lumen and that CD14/CD163 cell adhesion to the ductus lumen is important for neointimal growth. We used neutralizing antibodies against VEGF and VLA-4 to determine their respective roles in remodeling the ductus of premature newborn baboons. Anti-VEGF treatment blocked CD14/CD163 cell adhesion to the ductus lumen and prevented neointimal growth. Anti-VLA-4 treatment blocked CD14/CD163 cell adhesion to the ductus lumen, decreased the expression of PDGF-B (which promotes smooth muscle migration), and blocked smooth muscle influx into the neointimal subendothelial space (despite the presence of increased VEGF in the ductus wall). We conclude that VEGF is necessary for CD14/CD163 cell adhesion to the ductus lumen and that CD14/CD163 cell adhesion is essential for VEGF-induced expansion of the neointimal subendothelial zone.

Molecular Cloning of the Baboon UDP-Glucuronosyltransferase 2B Gene Family and Their Activity in Conjugating Morphine

Glucuronidation by UDP-glucuronyltransferase 2B enzymes (UGT2Bs) is a major pathway for the elimination of endobiotics and xenobiotics, including therapeutic drugs. Morphine, a probe drug for UGT2B7, is metabolized to morphine-3-beta-glucuronide (M3G) and morphine-6-beta-glucuronide (M6G) in humans. Morphine has been used in a series of experiments in the baboon to characterize developmental changes in fetal glucuronidation. This study identifies the baboon UGT2B family of enzymes, compares them with that of the human and the monkey (Macaca fascicularis), and measures the activity of the individual baboon UGT2Bs toward morphine. UGT2B cDNAs were cloned from the liver of adult and newborn baboons and expressed in human embryonic kidney 293 cells. The UGT activity toward morphine was assessed by the rate of formation of M3G and M6G by high-performance liquid chromatography. Eight baboon UGT2Bs were cloned and identified: UGT2B41 and UGT2B42, which are 90% homologous to human UGT2B4; UGT2B43, which is 93% homologous to human UGT2B15; and UGT2B39, UGT2B40, UGT2B44, UGT2B45, and UGT2B46, which are 89 to 91% homologous to human UGT2B7. Homology between baboon and monkey UGT2B ranged from 92.6 to 99.1%, with the primary protein structure of UGT2B43 being 99.1% identical to monkey UGT2B20, including a unique R96I substitution. Gene conversion interfered with the phylogenetic signal in the baboon UGT2B7-like and the monkey UGT2B4-like groups and led to concerted evolution of these enzymes. All of the baboon UGT2Bs metabolized morphine to both M3G and M6G. This study lays the foundation for investigating the regulation of UGT2B enzymes during fetal and neonatal development in the baboon.

Effects of a patent ductus arteriosus on postprandial mesenteric perfusion in premature baboons.

Superior mesenteric artery flow increases after a feeding to meet the intestines' increased metabolic demands. Although a patent ductus arteriosus can affect superior mesenteric artery perfusion in nonfeeding infants, there is no information about its effects on the hyperemic response that follows a feeding. Our goal was to study the effects of a patent ductus arteriosus on superior mesenteric artery perfusion in preterm baboons. Preterm baboons were delivered at 67% gestation and ventilated for 14 days. Enteral feedings were begun and advanced per protocol. Feeding studies were performed between days 10 and 14. Thirty-one studies were performed in animals with a closed ductus; 21 studies in those with a moderate patent ductus arteriosus shunt (pulmonary-to-systemic blood flow ratio>or=2:1). Two-dimensional echocardiographic and Doppler examinations were performed before and 10 and 30 minutes after a feeding. The groups were similar in birth weights, feeding volumes, and age at time of study. During the preprandial period, baboons with a moderate patent ductus arteriosus had significantly lower blood pressures and systemic blood flows than animals with a closed ductus. Preprandial superior mesenteric artery-blood flow velocities did not differ between the open and closed ductus groups. Animals with a closed ductus increased their superior mesenteric artery-velocities (diastolic and mean) and decreased their superior mesenteric artery relative-vascular-resistance (mean blood pressure/mean superior mesenteric artery-velocity) by 10 minutes after the feeding. By 30 minutes after the feeding, the values were returning to their preprandial values. In contrast, in baboons in the patent ductus arteriosus group, there were no significant changes in superior mesenteric artery-velocity or resistance after the feeding, and superior mesenteric artery-velocities were significantly lower than those in the closed ductus group. A moderate patent ductus arteriosus shunt limits the ability of the preterm newborn baboon to increase its postprandial mesenteric blood flow velocity. We speculate that this may interfere with its ability to meet increased intestinal metabolic demands and may contribute to feeding difficulties.

Ductus Arteriosus Ligation and Alveolar Growth in Preterm Baboons With a Patent Ductus Arteriosus

Premature newborn baboons [125 d (67%) gestation], exposed to a moderate-size patent ductus arteriosus (PDA) [pulmonary-to-systemic blood-flow-ratio (Qp/Qs) = 1.8] for 14 d, have impaired pulmonary function and arrested alveolar development and surface area when compared with age matched fetuses (140 d gestation). Pharmacologic closure of the PDA reduces the detrimental effects of preterm delivery on pulmonary function and surface area. We used preterm baboons (delivered at 125 d gestation and ventilated for 14 d) to study the effects of surgical PDA ligation on pulmonary function and alveolar surface area. After ligation (on day of life 6), ligated animals had lower Qp/Qs ratios [Qp/Qs (ligated, n = 10) = 1.00 +/- 0.04; (nonligated, n = 12) = 2.05 +/- 0.17; mean +/- SD] and higher systemic blood pressures than nonligated control animals. Ventilation and oxygenation indices did not differ between the groups, during either the pre- or postoperative periods. Alveolar surface area measurements were made by digital image analysis and compared with measurements made from fetal lungs at 125 d (n = 6) and 140 d (n = 7) gestation. PDA ligation failed to improve the postnatal arrest in alveolar surface area. In contrast with pharmacologic closure of the PDA, surgical closure failed to improve either pulmonary function or alveolar surface area in baboons with a moderate PDA shunt.

Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age

Stem cells of various tissues are typically defined as multipotent cells with 'self-renewal' properties. Despite the increasing interest in stem cells, surprisingly little is known about the number of times stem cells can or do divide over a lifetime. Based on telomere-length measurements of hematopoietic cells, we previously proposed that the self-renewal capacity of hematopoietic stem cells is limited by progressive telomere attrition and that such cells divide very rapidly during the first year of life. Recent studies of patients with aplastic anemia resulting from inherited mutations in telomerase genes support the notion that the replicative potential of hematopoietic stem cells is directly related to telomere length, which is indirectly related to telomerase levels. To revisit conclusions about stem cell turnover based on cross-sectional studies of telomere length, we performed a longitudinal study of telomere length in leukocytes from newborn baboons. All four individual animals studied showed a rapid decline in telomere length (approximately 2-3 kb) in granulocytes and lymphocytes in the first year after birth. After 50-70 weeks the telomere length appeared to stabilize in all cell types. These observations suggest that hematopoietic stem cells, after an initial phase of rapid expansion, switch at around 1 year of age to a different functional mode characterized by a markedly decreased turnover rate.

The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus Arteriosus Remodeling

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P-selectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68+ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling.

Prenatal glucocorticoid exposure and postnatal adaptation in premature newborn baboons ventilated for six days

Objective Renal and cardiovascular function is improved during the first 24 hours of life in preterm ventilated baboons exposed to prenatal betamethasone (BETA). We hypothesized BETA-induced effects would be sustained through day 6 of life. Study design Pregnant baboons received saline or BETA (6 mg) 48 and 24 hours before preterm delivery at 125 days' gestation. The newborn baboons were ventilated for 6 days, and assessed for renal, cardiovascular, and endocrine function. Results Mean arterial blood pressure (MAP) and glomerular filtration rate (GFR) values 24 hours after delivery were higher in the BETA group. Kidney Na, K-ATPase activity was higher in the BETA group by day 6. All other measures were similar in both groups by day 6. Conclusion Prenatal BETA exposure in the premature baboon: (1) increases MAP and GFR on day 1 without measurable effects by day 6 and (2) increases kidney Na, K-ATPase activity.

Potential role for antiangiogenic proteins in the evolution of bronchopulmonary dysplasia.

Impaired neovascularization is associated with the pathologic presentation of bronchopulmonary dysplasia (BPD). To determine if neovascularization and factors that negatively influence blood vessel formation play a role in the evolution of BPD, we examined the temporospatial distribution of a protein known to inhibit fetal lung neovascularization with associated dysplastic lung formation, endothelial-monocyte activating polypeptide (EMAP) II. Immunohistochemical analysis of EMAP II in lung tissues of human infants with BPD indicated an elevation in EMAP II abundance as compared with control. Utilizing a baboon model, western analysis indicated that EMAP II was increased twofold in those baboons with pathologic signs of BPD as compared with gestational controls. Consistent with our findings in human tissues, immunohistochemistry and in situ hybridization demonstrate that EMAP II is highly expressed in the perivascular stroma and dysplastic lung periphery in neonatal baboons with BPD as compared with controls. Lastly, there is a premature acceleration in EMAP II's perivascular distribution in term newborn baboon as compared with gestational control. The marked increase in EMAP II's temporal expression, its distribution in the perivascular and dysplastic alveolar regions of the lungs, and the interruption in vasculogenesis in BPD suggest that neovascularization and factors that negatively influence blood vessel formation may play a role in BPD evolution.

Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia

Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.

Sex Differences in Captive Olive Baboon Behavior During the First Fourteen Days of Life

I discuss newborn baboon behavioral and proximity sex differences in a population of captive olive baboons (Papio anubis) living in a social group of >500 individuals. The data are based upon 20-min focal observations of 42 mother-newborn pairs (n = 27, n = 15) for infant-days 1–7 and 36 pairs (n = 23, n = 13) for infant-days 8–14 collected late-May through late-November 2001. I examined the first two weeks of infant life via behavioral, proximity, and approach-leave/contact analyses in order to determine whether behavioral sex differences exist during the first few days of life. I examine and analyze these 2 weeks independently due to different sample sizes. I used data from the total available sample population of 57 infants (n = 36, n = 21) to discuss birth, survivorship, and infant weight. Statistically significant age and/or age-sex interactions exist for all of the behavior and proximity measures during either infant-week 1 or 2. Moreover, there is a statistically significant difference in the birth sex ratio in the sample population but no significant difference in infant mortality by sex. There are also relative and significant differences in mothers' treatment of their newborn males and females. There are also some general tendencies for female newborns on average to suckle less and to explore more per focal observation than male infants do as they age. Conversely, male newborns average slightly more time per focal observation 1 m from the mother than do female infants. However, the observed differences may be influenced by maternal behavior in that mothers have higher rates of contact with their female than their male infants.

VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus.

Anatomic remodeling and permanent closure of the newborn ductus arteriosus appears to require the development of intense hypoxia within the constricted vessel wall. Hypoxic ductus smooth muscle cells express vascular endothelial cell growth factor (VEGF). We studied premature baboons and sheep to determine the effects of VEGF inhibition (in baboons) and VEGF stimulation (in sheep) on ductus remodeling in vivo. For study of VEGF inhibition, 13 premature newborn baboons (68% gestation) were treated with inhibitors of both prostaglandin and nitric oxide production to constrict the ductus and induce ductus wall hypoxia. Six received a neutralizing monoclonal antibody against VEGF (A.4.6.1, mAbVEGF), while seven did not. Both groups developed the same degree of ductus constriction, tissue hypoxia, and VEGF expression. The mAbVEGF treatment produced a significant (P < 0.05) reduction in ductus vasa vasorum ingrowth and neointima formation (due to both a decrease in luminal endothelial cell proliferation and a decrease in smooth muscle cell migration into the neointima). For study of VEGF stimulation, nine sheep fetuses (70% gestation) had their ductus wall injected with either VEGF (n = 6) or vehicle (n = 4) in vivo. VEGF administration produced a significant (P < 0.05) increase in vasa vasorum ingrowth and neointima formation. We conclude that VEGF plays an important role in the formation of neointimal mounds and vasa vasorum ingrowth during permanent ductus closure.

Evidence for polyreactive xenoreactive antibodies in the repertoire of human anti-swine antibodies: the ‘next’ humoral barrier to xenotransplantation?

The xenoreactive nature of anti-Galα1–3Gal antibodies, and to a lesser extent, polyreactive antibodies, has been characterized by a number of investigators. With the advent of therapies that avoid hyperacute xenograft rejection due to anti-Galα1–3Gal antibodies coupled with the possible development of Galα1–3Gal deficient swine, the Galα1–3Gal antigen may soon cease to be a barrier to xenotransplantation. With this in mind, the potential xenoreactive nature of polyreactive antibodies was investigated using several approaches. The levels of polyreactive antibodies from the serum of newborn ( n=2) and adult ( n=4) baboons undergoing pulmonary xenotransplantation were evaluated. Depletion of 95% and 94% of total serum IgM, without any decrease in albumin levels, was observed in the newborn baboons. This finding indicates that the IgM present at birth and germ line polyreactive IgM was adsorbed by the xenografts. The depletion of polyreactive antibodies (43–83% reduction of anti-DNP IgM) from adult baboons was also observed following pulmonary xenotransplantation or immunoadsorption therapy plus pulmonary xenotransplantation. Additional experiments using human cord serum indicated that most human polyreactive IgM were adsorbed by pig lung homogenate and that the human polyreactive IgM bound approximately two-fold more to immobilized pig lung antigens than to immobilized human lung antigens. These findings indicate that germline polyreactive antibodies are, for the most part, xenoreactive. These data suggest that polyreactive antibodies, although autoreactive, may be more xenoreactive than autoreactive.