Baboon Neonates Research Articles

Dietary DHA and ARA alter the expression of 1700 hepatic genes including the tumor suppressor TOB1 in baboon neonates

Background. We have recently shown that 1100 cerebral genes are differentially expressed in 12 week old baboon neonates consuming medium and high levels of DHA, with ARA. Here we report on differential hepatic gene expression induced by these diets.Methods. Baboon neonates were randomized at birth to three formulas: C, 0/0 DHA/ARA; L, 0.33/0.67%w/w; L3, 1.0/0.67. At 12 weeks, liver was collected and Affymetrix Gene chips assessed gene expression. Significance was determined by t‐tests, and Ingenuity® pathway analysis detected gene relationships.Results. More than 1700 of 54,000 probe sets (ps) were differentially expressed. Most significantly upregulated was TOB1, hepatic tumor suppressor associated with ERBB2. SCD (9‐desaturase) and FADS1 (5‐desaturase) were downregulated. ELOVL6, a PUFA elongase and BHMT (one carbon metabolism) were upregulated with increasing DHA. Ingenuity pathway analysis identified network TOB1 and SCD with many genes interacting with CTNNB1 and ERBB2. A number of (n = 52) transcripts with predicted peroxisome proliferator response elements were differentially expressed, including TOB1.Conclusions. Dietary DHA/ARA within the normal range found in breastmilk had widespread influence on gene expression, including TOB1 and many genes associated with PUFA metabolism. Funding: Mead Johnson Nutritionals, Evansville, IN.

The low density lipoprotein receptor is not necessary for maintaining mouse brain polyunsaturated fatty acid concentrations

The brain cannot synthesize n-6 or n-3 PUFAs de novo and requires their transport from the blood. Two models of brain fatty acid uptake have been proposed. One requires the passive diffusion of unesterified fatty acids through endothelial cells of the blood-brain barrier, and the other requires the uptake of lipoproteins via a lipoprotein receptor on the luminal membrane of endothelial cells. This study tested whether the low density lipoprotein receptor (LDLr) is necessary for maintaining brain PUFA concentrations. Because the cortex has a low basal expression of LDLr and the anterior brain stem has a relatively high expression, we analyzed these regions separately. LDLr knockout (LDLr(-/-)) and wild-type mice consumed an AIN-93G diet ad libitum until 7 weeks of age. After microwaving, the cortex and anterior brain stem (pons and medulla) were isolated for phospholipid fatty acid analyses. There were no differences in phosphatidylserine, phosphatidylinositol, ethanolamine, or choline glycerophospholipid esterified PUFA or saturated or monounsaturated fatty acid concentrations in the cortex or brain stem between LDLr(-/-) and wild-type mice. These findings demonstrate that the LDLr is not necessary for maintaining brain PUFA concentrations and suggest that other mechanisms to transport PUFAs into the brain must exist.

Biochemical and white blood cell profiles of baboon neonates consuming formulas with moderate and high dietary long‐chain polyunsaturated fatty acids

Clinical chemistry and complete blood count (CBC) values were determined in 14 term baboons (Papio species) consuming formula with moderate or high levels of dietary long-chain polyunsaturated fatty acids (LCPUFA) from 2-12 weeks of age. Neonates were randomized to three groups: C: Control, no LCPUFA; L: 0.33% docosahexaenoic acid (DHA)/0.67% arachidonic acid (ARA) (w/w); L3:1.00% DHA/0.67% ARA (w/w). Blood chemistries were assessed at 6 and 12 weeks and CBC parameters were measured at 2, 4, 8, 10, 12 weeks of age. Dietary LCPUFA had significant effects on serum triglyceride (C > L,L3) and calcium (L > C,L3). No other significant effects of diet were detected; pooled values are presented for all other parameters. These data provide longitudinal biochemical and white cell/platelet/immunological data on LCPUFA-fed baboons over the first 12 weeks of life. Data ranges are similar to reference data in cases for which values exist and hematological changes reflect trends observed during human neonatal development.

The Influence of Moderate and High Dietary Long Chain Polyunsaturated Fatty Acids (LCPUFA) on Baboon Neonate Tissue Fatty Acids

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now common ingredients in commercial infant formulas, however, the optimal levels have not been established. Our previous data showed that the current amount of DHA in U.S. term formulas, 0.3%w/w, is insufficient to normalize cerebral cortex DHA to levels in breastfed baboon neonate controls (Diau et al.: BMC Medicine 3: 11, 2005). Here, we report on the influence of higher formula DHA levels on 12-wk-old full-term baboon CNS and visceral organs. Fourteen nursery-reared baboons were randomized to one of three diets: control (C, no DHA-ARA); moderate LCPUFA (L, 0.33%DHA-0.67%ARA); high LCPUFA (L3, 1.00%DHA-0.67%ARA). DHA increased significantly in liver, heart, and plasma (all C < L < L3), RBC (C < L, L3), and CNS regions: precentral gyrus (C < L < L3), frontal cortex, inferior and superior colliculi, globus pallidus, and caudate (all C < L, L3). These data extend previous observations indicating that 1) tissue DHA is more sensitive to diet than ARA; 2) cerebral cortex DHA increases with higher levels of DHA than in present commercial formulas; and 3) basal ganglia and limbic system DHA saturate with levels of DHA currently available in formulas. These results imply that higher levels of DHA are necessary to normalize cortex DHA to those found in breastfed animals.

Differential cerebral cortex transcriptomes of baboon neonates consuming moderate and high docosahexaenoic acid formulas.

BackgroundDocosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system (CNS). These nutrients are present in most infant formulas at modest levels, intended to support visual and neural development. There are no investigations in primates of the biological consequences of dietary DHA at levels above those present in formulas but within normal breastmilk levels.Methods and FindingsTwelve baboons were divided into three formula groups: Control, with no DHA-ARA; “L”, LCPUFA, with 0.33%DHA-0.67%ARA; “L3”, LCPUFA, with 1.00%DHA-0.67%ARA. All the samples are from the precentral gyrus of cerebral cortex brain regions. At 12 weeks of age, changes in gene expression were detected in 1,108 of 54,000 probe sets (2.05%), with most showing <2-fold change. Gene ontology analysis assigns them to diverse biological functions, notably lipid metabolism and transport, G-protein and signal transduction, development, visual perception, cytoskeleton, peptidases, stress response, transcription regulation, and 400 transcripts having no defined function. PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only LCPUFA biosynthetic enzyme that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated by high DHA, while the mitochondrial proton carrier, UCP2, was upregulated. TIMM8A, also known as deafness/dystonia peptide 1, was among several differentially expressed neural development genes. LUM and TIMP3, associated with corneal structure and age-related macular degeneration, respectively, were among visual perception genes influenced by LCPUFA. TIA1, a silencer of COX2 gene translation, is upregulated by high DHA. Ingenuity pathway analysis identified a highly significant nervous system network, with epidermal growth factor receptor (EGFR) as the outstanding interaction partner.ConclusionsThese data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across a wide array of processes, in addition to changes in visual and neural function normally associated with formula LCPUFA.

Dietary DHA but not ARA influences CNS fatty acid status in baboon neonates

Background. The influence of dietary docosahexaenoic acid (DHA) and arachidonic acid (ARA) on infant CNS composition has implications for neural development, including vision, cognition, and motor function. We evaluated CNS tissue response of baboon neonates with concentration and duration of DHA/ARA consumption. Methods. Data from 3 different studies of DHA/ARA-containing formulas or breastfeeding were analyzed together. Neonates (n=43) were born spontaneously at term or preterm by C-section. CNS fatty acids were analyzed at 4 and 12 weeks postpartum for term baboons and 7.5 weeks for preterm neonates, and diet concentrations of DHA-ARA (%, w/w) were none (0,0), moderate, (0.3, 0.6), or high (>0.6, 0.67 or 1.2). Plots and regression analysis was performed for 8 CNS regions and retina. Results. CNS DHA was 5–10% greater in neonates consuming DHA and at the higher end for cortex. Cortex DHA increased with postpartum age, but globus pallidus, putamen, amygdala, and superior and inferior colliculus decreased; retina DHA dropped mildly. CNS ARA was unaffected by dietary ARA and dropped in all structures with age. Conclusions. Dietary DHA supports greater CNS DHA and maintenance of cortex DHA concentration with feeding duration. Regardless of dietary supply, ARA concentrations in the CNS decline postnatally. Funding: NIH DK07158.

Hematological and blood chemistry responses to docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplementation in baboon neonates

We evaluated the response of blood parameters of neonatal baboons consuming infant formulas with differing amounts of DHA/ARA. Nursery reared baboons (Papio cynocephalus) were randomized to one of three diets: Control (C, no DHA-ARA, n=5); 1× LCPUFA (L, 0.32%DHA-0.64%ARA, n=4); 3× LCPUFA (L3, 0.96%DHA-0.64%ARA, n=5), and blood was sampled at biweekly intervals from 2 to 12 weeks of age. Hematology measures were made at 2, 4, 8, 10 and 12 weeks while blood chemistry parameters were assessed at 6 and 12 weeks of age. Statistical analyses were by repeated measures ANOVA and a random coefficient regression model (SAS 9.1, Cary, NC) with p<0.05 cutoff. Hematology: Significant differences due to diet were observed for hemoglobin (HB) (C<L<L3), hematocrit (HCT) (C<L<L3) and red blood cell distribution width (RDW); red blood cell count (RBC) was marginal (p=0.06). RBC values for all diet treatments decreased over time. Blood Chemistry: Significant changes in plasma triglycerides (TG, C>L,L3) and calcium (C<L ; L>L3) were detected. These first hematological data on DHA/ARA supplemented non-human primate neonates reveal HB, HCT, and RDW consistently higher with DHA supplementation at a given time point. Reduction in plasma TG is consistent with similar human adult data. Changes in plasma calcium levels may reflect modifications in mechanisms mediating calcium dynamics, bone turnover and mineralization. Support by Mead Johnson Nutritionals and NIH DK07158.

The influence of moderate and high levels of long chain polyunsaturated fatty acid (LCPUFA) supplementation on 12 week old baboon neonate tissue fatty acids

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are LCPUFA that play a critical role during the perinatal period in CNS and retina development. We evaluated the influence of formula DHA/ARA levels on 12 week old term baboon CNS and visceral organs. Fourteen nursery reared baboons were randomized to one of three diets: Control (C, no DHA-ARA, n=5); 1× LCPUFA (L, 0.32%DHA-0.64%ARA, n=4); 3× LCPUFA (L3, 0.96%DHA-0.64%ARA, n=5). At 12 weeks, animals were euthanized and tissues collected and analyzed for fatty acid profiles using gas chromatography (GC) and GC/mass spectrometry. Results: Supplementation increased DHA in all tissues but did not significantly alter ARA concentrations. DHA increased significantly (p<0.05) in liver (C<L<L3), heart (C<L<L3), plasma (C<L<L3), RBC (C<L,L3) and CNS regions: frontal lobe (C<L,L3), precentralis (C<L<L3), inferior and superior colliculus (C<L,L3), globus pallidus (C<L,L3), caudate (C<L,L3), putamen (C<L.L3), amygdala (C<L,L3), retina (C<L,L3). Conclusion: These data confirm and extend previous observations indicating that 1) tissue DHA is more sensitive to dietary manipulations than ARA, and 2) cerebral cortex DHA increases with higher levels of DHA than are included in present commercial formulas, 3) basal ganglia and limbic system DHA appears to saturate with current levels of formula DHA. Support by Mead Johnson Nutritionals and NIH training grant (DK07158).

Ontogeny of hematological cell and biochemical profiles in maternal and fetal baboons (Papio species)

The normal ranges of hematological cell profiles and biochemistry are documented in adult non-pregnant, pregnant, juvenile, and neonatal baboons. Despite the extensive use of the baboon as a model for the study of various aspects of pregnancy, there is no data from paired mothers and their fetuses at different stages of gestation. Hematologic and biochemical profile data were obtained from eight non-pregnant female baboons, 37 mothers and 38 fetal baboons at 30 +/- 2, 90 +/- 2, 125 +/- 2, and 175 +/- 2 days of gestation (mean +/- range; dGA; term, 180 dGA). Changes observed in fetal and maternal blood during normal baboon pregnancy were similar to those reported in human pregnancy. The level of alkaline phosphatase was two times higher in fetal blood circulation than that reported in human pregnancy.

The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system

BackgroundDocosahexaenoic acid (DHA) and arachidonic acid (ARA) are major components of the cerebral cortex and visual system, where they play a critical role in neural development. We quantitatively mapped fatty acids in 26 regions of the four-week-old breastfed baboon CNS, and studied the influence of dietary DHA and ARA supplementation and prematurity on CNS DHA and ARA concentrations.MethodsBaboons were randomized into a breastfed (B) and four formula-fed groups: term, no DHA/ARA (T-); term, DHA/ARA supplemented (T+); preterm, no DHA/ARA (P-); preterm and DHA/ARA supplemented (P+). At four weeks adjusted age, brains were dissected and total fatty acids analyzed by gas chromatography and mass spectrometry.ResultsDHA and ARA are rich in many more structures than previously reported. They are most concentrated in structures local to the brain stem and diencephalon, particularly the basal ganglia, limbic regions, thalamus and midbrain, and comparatively lower in white matter. Dietary supplementation increased DHA in all structures but had little influence on ARA concentrations. Supplementation restored DHA concentrations to levels of breastfed neonates in all regions except the cerebral cortex and cerebellum. Prematurity per se did not exert a strong influence on DHA or ARA concentrations.Conclusion1) DHA and ARA are found in high concentration throughout the primate CNS, particularly in gray matter such as basal ganglia; 2) DHA concentrations drop across most CNS structures in neonates consuming formulas with no DHA, but ARA levels are relatively immune to ARA in the diet; 3) supplementation of infant formula is effective at restoring DHA concentration in structures other than the cerebral cortex. These results will be useful as a guide to future investigations of CNS function in the absence of dietary DHA and ARA.

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.

Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates

Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 +/- 0.22%wt DHA and 0.62 +/- 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]alpha-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was approximately 3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels.

Docosahexaenoic and Arachidonic Acid Influence on Preterm Baboon Retinal Composition and Function

Dietary n-3 polyunsaturated fatty acid deficiency and prematurity are both associated with suboptimal visual function in nonhuman primates and in humans. This study reports measurements of retinal long chain polyunsaturate (LCP) concentrations and electroretinogram (ERG) parameters for term and preterm neonatal baboons consuming clinically relevant diets. ERGs and retinal fatty acid compositions were obtained from baboon neonates in four groups: term-delivered/breast-fed (B), term/formula-fed (T-), preterm/formula-fed (P-), and preterm/formula (P+) supplemented with long chain polyunsaturates. Initial a-wave slope change (ä), a-wave amplitude (a(amp)) and implicit time (a(i)), and b-wave amplitude (b(amp)) and implicit time (b(i)) were determined and correlations to retinal fatty acid concentrations were evaluated. The P+ group ä and b(amp) significantly improved between 0 and 4 weeks' adjusted age, whereas no P- group parameter improved with age. At four weeks, both a(amp) and b(amp) were significantly greater in group B than in all other groups, and ä and a(i) were greater for P+ than for P-. Concentrations of 22:6n-3, 22:5n-3, and Sigman-3 and the 22:5n-6/22:6n-3 ratio correlated positively with improved retinal response parameters, whereas 22:5n-6, 22:4n-6, 20:4n-6, 20:3n-6, 20:2n-9, 20:1n-9, and 18:1n-9 all correlated negatively (P < 0.05); saturates were uncorrelated. The parameters most linearly related to retinal 22:6n-3 were ä, a(i), and a(amp). Retinal 20:4n-6 concentrations were not influenced by prematurity or supplementation. Breast-feeding optimizes retinal response in 4-week-old baboons. Formula supplemented with 22:6n-3 prevents a decrease in retinal 22:6n-3 and improves preterm ERG parameters compared with unsupplemented formula. Retinal 22:6n-3 status is most closely associated with a-wave parameters.

The influence of prematurity and long chain polyunsaturate supplementation in 4-week adjusted age baboon neonate brain and related tissues.

Clinical studies show that docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplemented formula improve visual function in preterm infants, however improved fatty acid status is known only for plasma and red blood cells (RBC) since target organs cannot be sampled from humans. Baboons were randomized to one of four groups: Term breast-fed (B); Term formula-fed (T-); Preterm formula-fed (P-); and Preterm DHA/ARA-supplemented formula-fed (P+). The P+ contained 0.61 +/- 0.03% DHA and 1.21 +/- 0.09% ARA, and breast milk had 0.68 +/- 0.22% and 0.62 +/- 0.12% as DHA and ARA, respectively. The B and P+ groups had significantly higher DHA concentration in all tissues than T- and P-. The P- group showed dramatically lower DHA content of 35%, 27%, 66%, and 75% in the brain, retina, liver, and plasma, respectively, compared with B. Supplementation prevented declines in DHA levels in the retina, and liver, and attenuated the decline in brain, plasma and RBC of preterm animals. In contrast, ARA was not significantly lower compared with B in any group in any tissue but was significantly elevated in liver and brain. RBC and plasma DHA were correlated with DHA in tissues; RBC/plasma ARA were uncorrelated with tissue ARA. We conclude that 1) DHA drops precipitously in term and preterm primates consuming formula without long chain polyunsaturates, while 22:5n-6 concentration rises; 2) tissue ARA levels are insensitive to dietary LCP supplementation or prematurity, 3) plasma and RBC levels of ARA are uncorrelated with total ARA levels; 4) DHA levels are correlated with group effects and are uncorrelated within groups.

Significant utilization of dietary arachidonic acid is for brain adrenic acid in baboon neonates

Dietary arachidonic acid (20:4n-6) utilization in-vivo for carbon recycling into de-novo lipogenesis and conversion to n-6 long chain polyunsaturates was investigated in baboon neonates using [U-13C]20:4n-6. Neonates consuming a formula typical of human milk received a single oral dose of [13C]arachidonic acid in sn-2 position of either triglyceride or phosphatidylcholine at 18–19 days of postnatal life. Neonate brain, retina, liver, and plasma were obtained 10 days later (28–29 days of life). Low isotopic enrichment (0.27–1.0%Total label) was detected in dihomo-γ-linolenic acid (20:3n-6) in all tissues, but label incorporation into saturates or monounsaturates was not detected. In neonate brain and retina, 16% and 11% of total label was recovered in 22:4n-6, respectively. The relative contribution of dietary fatty acids to postnatal brain 22:4n-6 accretion can be estimated for dietary 20:4n-6 and preformed 22:4n-6 as 17% and 8%, respectively, corresponding to efficiencies of 0.48% and 0.54% of dietary levels, respectively. These results demonstrate in term baboon neonates that in vivo 1) 20:4n-6 was retroconverted to 20:3n-6, 2) 20:4n-6 did not contribute significantly to de novo lipogenesis of saturates and monounsaturates, and 3) the preformed 20:4n-6 contribution to brain 22:4n-6 accumulation was quantitatively a significant metabolic fate for dietary 20:4n-6.—Wijendran, V., P. Lawrence, G-Y. Diau, G. Boehm, P. W. Nathanielsz, and J. T. Brenna. Significant utilization of dietary arachidonic acid is for brain adrenic acid in baboon neonates. J. Lipid Res. 2002. 43: 762–767.

Efficacy of dietary arachidonic acid provided as triglyceride or phospholipid as substrates for brain arachidonic acid accretion in baboon neonates.

Arachidonic acid (AA) is a long-chain polyunsaturate (LCP) present in human breast milk as both triglyceride (TG) and as phospholipid (PL). There has been little attention to the metabolic consequences of lipid form of AA in infant formulas. Our objective was to investigate the efficacy of dietary TG and PL as carriers of AA for accretion in the brain and associated organs of term baboon neonates consuming a formula with LCP composition typical of human milk. TG and phosphatidylcholine (PC) with [U-(13)C]-AA in the sn-2 position and with unlabeled 16:0 in the remaining positions (TG-AA* or PL-AA*, respectively) were used as tracers to study the tissue AA* incorporation. Baboon neonates received a single oral dose of either TG-AA* (n = 3) or PL-AA* (n = 4) at 18-19 d of life. Tissues were obtained 10 d later (28-29 d of life) and isotopic enrichment was measured. In the brain, 4.5% of the PL-AA* dose and 2.1% of the TG-AA* dose were recovered as brain AA*, respectively, indicating that PL was about 2.1-fold more effective than TG as a substrate for brain AA accretion. Preferential incorporation of PL-derived AA* over TG source of AA* was also observed in the liver, lung, plasma, and erythrocytes. Because of the quantitative predominance of TG-AA in formula, total brain AA accretion, expressed as absolute weight, was 5.0-fold greater from TG-AA than from PL-AA. We estimate that about half of postnatal brain AA accretion is derived from dietary preformed AA in term baboon neonates consuming a formula with lipid composition similar to that of human milk.

Growth, neurobehavioral and circadian rhythm development in newborn baboons.

We measured body temperature continuously using telemetry to determine the development of circadian rhythmicity in neonatal baboons after birth. Twelve fetal baboons (nine males and three females) of known gestational age ranging from 167 to 193 d were studied. We eliminated the influence of maternal factors by hand rearing these infants from the moment of birth until 45 d of life. All infants showed steady growth in body weight, head circumference, and crown-rump length. Neurobehavioral responses including visual and auditory orientation, motor maturity, irritability, and consolability increased as a function of age. Circadian rhythms of body temperature were present in the second week of life, and the amplitude of this rhythm increased throughout the developmental period studied. The increase in the amplitude of circadian body temperature rhythm independent of environmental time cues may indicate the maturation of the brain. These neonatal nonhuman primates offer an excellent model for studying neurobehavioral development and maturation of circadian rhythms while controlling external factors in a manner that is not possible with human neonates.

Developmental changes in reactivity of small femoral arteries in the fetal and postnatal baboon

Objective: We evaluated in vitro responsiveness of small arteries (internal diameter, 300 μm) from the femoral vascular bed of normal fetal (0.75-1.0 gestation) and neonatal (43-46 days) baboons to investigate whether the transition from fetal to neonatal life was associated with functional alterations in vasoconstrictor and vasodilator responses. Study Design: The maximum response and sensitivity to potassium and to the constrictor agonists norepinephrine and U46619 (a thromboxane mimetic) were studied by in vitro myography. Vasodilator responses to the endothelium-dependent dilators acetylcholine and bradykinin were also investigated. Results: The maximum response to norepinephrine and U46619 and to potassium increased with gestational age, whereas the sensitivity to these vasoconstrictors was similar in all groups studied. In contrast, acetylcholine- and bradykinin-induced relaxation (median effective concentration and maximum response) did not change with age. Conclusion: Receptor-mediated responses to a catecholamine, a prostanoid, and 2 endotheliumdependent vasodilators are similar in the fetal and neonatal baboon. The increase in maximal constriction with development, which is probably associated with growth or maturation of vascular smooth muscle, is likely to be a functionally important aspect in the development of cardiovascular function. (Am J Obstet Gynecol 2001;184:707-12.)

Deficiencies in lung surfactant proteins A and D are associated with lung infection in very premature neonatal baboons.

Surfactant proteins A (SP-A) and D (SP-D) are important in the innate host defense against pathogenic microorganisms. A deficit in these proteins in premature infants, either because of immaturity or as a consequence of superimposed chronic lung disease (CLD), could increase their susceptibility to infection. The study reported here examined infection in CLD in the premature newborn baboon, and correlated it with the amounts of SP-A and SP-D in lung tissue and lavage fluid. Two groups of baboons were delivered prematurely, at 125 d gestational age (g.a.), and differed principally in whether they developed naturally acquired pulmonary infections and sepsis. Group I animals were ventilated with clinically appropriate oxygen for 6 d and 14 d without clinical incident. Group II animals were ventilated for 5 to 71 d, but differed from those in Group I in that most developed pulmonary infection and/or sepsis. In Group I animals, tissue pools of both SP-A and SP-D were equal to or exceeded those in adults, and lavage pools of SP-A increased progressively with the time of ventilation to about 35% of adult levels after 14 d. In contrast, most Group II animals had concentrations of lavage SP-A that were less than 20% of that in adult animals. A low concentration of lavage SP-A correlated with the release of interleukin-8, and with a high "infection index" based on histopathology, microbiologic cultures, and clinical indications of sepsis. Our data suggest that the amounts of SP-A and SP-D in lavage fluid are indicators of the risk of infection in the evolution of neonatal CLD. Deficits in the amount of lavage SP-A, even after 60 d of ventilation, may have inhibited the resolution of infection and thereby contributed to the developing injury among our Group II animals.

Xenoreactivity of fetal and neonatal baboon intracellular antibody against the pig

Xenoreactivity of fetal and neonatal baboon intracellular antibody against the pig