Neonatal intubation with direct laryngoscopy vs videolaryngoscopy: an extremely premature baboon model.

OBJECTIVE: To compare the ability to successfully intubate extremely preterm baboons using conventional direct laryngoscopy (DL) vs videolaryngoscopy. METHODS: A prospective randomized crossover study using experienced and inexperienced neonatal intubators. All participants were shown an educational video on intubation with each device, followed by attempt of the procedure. The time for successful intubation was the primary outcome. RESULTS: Seven subjects comprised the experienced group, while 10 individuals were in the inexperienced group. The overall intubation success rate was comparable between both devices (53% vs 26%, P = 0.09); however, mean time to intubate with the conventional laryngoscope was faster (25.5 vs 39.4 s, P = 0.02). Although both groups intubated faster with DL, it only reached statistical significance in the inexperienced group (27.0 vs 48.7 s, P < 0.05). CONCLUSION: Conventional DL and videolaryngoscopy are suitable modes for intubating extremely preterm baboons. Although experienced intubators prefer DL, intubation success rate and time to intubate with both devices were comparable. In inexperienced intubators, participants preferred and intubated faster with DL.

Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet.

BACKGROUND: Endothelial dysfunction signals the initiation and progression of atherosclerosis. Elevated LDL-cholesterol concentrations have been suggested to induce endothelial dysfunction, but direct in vivo evidence for the relation is still lacking. OBJECTIVE: We examined the hypothesis that a high-cholesterol, high-fat (HCHF) diet can directly cause endothelial dysfunction in vivo. DESIGN: We measured inflammatory and endothelial dysfunctional markers in circulating blood and directly in endothelial cells, which were collected by femoral artery biopsies, in 10 baboons before and after a 7-wk HCHF dietary challenge. RESULTS: We found that the HCHF diet induced a high inflammatory status, as indicated by increased concentrations of interleukin 6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1. Although the concentrations of endothelial dysfunctional markers, such as soluble vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1, were not increased by the HCHF diet, membrane-bound VCAM-1 and membrane-bound E-selectin on endothelial cells were highly increased after 7 wk of the HCHF diet (P < 0.01). In contrast, the concentrations of endothelial nitric oxide synthase in endothelial cells were significantly reduced by the 7-wk HCHF diet (P < 0.01). Furthermore, the dietary challenge attenuated endothelial cell responses to TNF-alpha, lipopolysaccharide, native LDL cholesterol, and oxidized LDL-cholesterol stimulation. CONCLUSIONS: Our results show that an HCHF diet can directly induce inflammation and endothelial dysfunction. Prior in vivo exposure to an HCHF diet attenuates the in vitro responses of endothelial cells to atherogenic risk factors. This preconditioning phenomenon may have significant clinical relevance.

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid.

BACKGROUND: Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology. METHODS: Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites. RESULTS: Each metabolite exhibited significant heritability in baboons (5-HIAA: h(2) =.30 +/-.17; MHPG: h(2) =.36 +/-.16; HVA: h(2) =.50 +/-.19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG. CONCLUSIONS: Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.

Expression patterns of phenotypic markers on lymphocytes from human immunodeficiency virus type 2-infected baboons.

The development of AIDS in HIV-1-infected humans is associated with profound changes in the expression patterns of lymphocyte phenotypic markers associated with increased immune activation and with decreased recall immune responses. In assessing these immunologic changes in an animal model, we characterized the expression patterns of immune activation markers on lymphocyte subsets during the acute, chronic, and end stages of HIV-2 infection in baboons. Using flow cytometry, we identified 21 human-specific monoclonal antibodies that were cross-reactive with baboon lymphocytes; however, expression of only 2 of these markers was altered significantly after HIV-2 infection. We found an increase in baboon class II antigen (as measured by anti-HLA-DR) in the CD4(+) T cell subset within 8 weeks of infection (p = 0.045). Moreover, after 1 year of infection, CD11b was downregulated on CD8(+) T lymphocytes (p = 0.027). This downregulation of CD11b was consistently observed in all of the groups of baboons that were chronically infected with three different HIV-2 isolates. In addition, we found substantial downregulation of the interleukin 2 receptor (CD25) and upregulation of class II antigen on CD8(+) lymphocytes in a baboon with an AIDS-like disease. These and other phenotypic markers of immune activation may facilitate characterization of the immunopathogenesis of AIDS in nonhuman primate animal models.

A novel adenovirus species associated with an acute respiratory outbreak in a baboon colony and evidence of coincident human infection.

Adenoviruses (AdVs) are DNA viruses that infect many vertebrate hosts, including humans and nonhuman primates. Here we identify a novel AdV species, provisionally named "simian adenovirus C (SAdV-C)," associated with a 1997 outbreak of acute respiratory illness in captive baboons (4 of 9) at a primate research facility in Texas. None of the six AdVs recovered from baboons (BaAdVs) during the outbreak, including the two baboons who died from pneumonia, were typeable. Since clinical samples from the two fatal cases were not available, whole-genome sequencing of nasal isolates from one sick baboon and three asymptomatic baboons during the outbreak was performed. Three AdVs were members of species SAdV-C (BaAdV-2 and BaAdV-4 were genetically identical, and BaAdV-3), while one (BaAdV-1) was a member of the recently described SAdV-B species. BaAdV-3 was the only AdV among the 4 isolated from a sick baboon, and thus was deemed to be the cause of the outbreak. Significant divergence (<58% amino acid identity) was found in one of the fiber proteins of BaAdV-3 relative to BaAdV-2 and -4, suggesting that BaAdV-3 may be a rare SAdV-C recombinant. Neutralizing antibodies to the other 3 AdVs, but not BaAdV-3, were detected in healthy baboons from 1996 to 2003 and staff personnel from 1997. These results implicate a novel adenovirus species (SAdV-C) in an acute respiratory outbreak in a baboon colony and underscore the potential for cross-species transmission of AdVs between humans and nonhuman primates. IMPORTANCE Adenoviruses (AdVs) are DNA viruses that infect many animals, including humans and monkeys. In 1997, an outbreak of acute respiratory illness from AdVs occurred in a baboon colony in Texas. Here we use whole-genome sequencing and antibody testing to investigate new AdVs in baboons (BaAdVs) during the outbreak, one of which, BaAdV-3, came from a sick animal. By sequence analysis, BaAdV-3 may be a recombinant strain that arose from a related BaAdV found in baboons nearby in the colony (who were not sick) and yet another unknown AdV. We also found antibodies to these new BaAdVs in baboons and staff personnel at the facility. Taken together, our findings of a new AdV species as the cause of an acute respiratory outbreak in a baboon colony underscore the ongoing threat from emerging viruses that may carry the potential for cross-species transmission between monkeys and humans.

Bone marrow-targeted liposomal carriers: a feasibility study in nonhuman primates.

BACKGROUND & AIMS: Recently, we described a novel surface-modified lipid vesicle formulation (liposome) that had very high targeting to bone marrow in normal rabbits. Because the bone marrow is the site of hematopoiesis, bone marrow-targeted drug-delivery systems have many potential applications. In this study we investigated whether these bone marrow-targeted vesicles are also similarly effective for bone marrow targeting in rhesus monkeys, a primate animal model that is more relevant to humans. MATERIALS & METHODS: The preformed vesicles encapsulating 30 mM glutathione were labeled with technetium-99m ((99m)Tc) for scintigraphic imaging. The vesicles were 216 +/- 21 nm in diameter with a negative surface charge composed of DPPC, cholesterol, anionic amphiphile and poly(ethylene glycol)-DSPE (1:1:0.2:0.013 molar ratio). RESULTS: The whole-body images of rhesus monkeys receiving intravenous (99m)Tc vesicles revealed high uptake of the (99m)Tc vesicles in bone marrow. Based on image analysis, we estimated that approximately 70% of the injected dose of the (99m)Tc vesicles was taken up by the bone marrow. CONCLUSION: This finding increases the feasibility of using this bone marrow-specific drug-delivery system for clinical applications.

Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy.

Helper-dependent adenoviral vectors (HDAds) are attractive for liver-directed gene therapy because they can mediate long-term, high-level transgene expression without chronic toxicity. However, systemic delivery requires high vector doses for efficient hepatic transduction, resulting in dose-dependent acute toxicity. Clearly, strategies to improve hepatic transduction with low vector doses are needed. In this regard, we have previously shown that hydrodynamic injection of helper-dependent adenoviral vectors into mice results in increased hepatic transduction, reduced systemic vector dissemination, and reduced pro-inflammatory cytokines compared with conventional injection and thus has the potential to improve dramatically the therapeutic index of helper-dependent adenoviral vectors. Unfortunately, the rapid, large-volume injection used in this method cannot be applied to larger animals. Therefore, we have developed a novel balloon occlusion catheter-based method to mimic hydrodynamic injection of helper-dependent adenoviral vectors into non-human primates that does not require rapid, large-volume injection. Using a low, clinically relevant vector dose, this minimally invasive method results in high-efficiency hepatic transduction with minimal toxicity and stable long-term transgene expression for at least 413 days.

Fetal and infant head circumference sexual dimorphism in primates.

Studies have shown that after controlling for the effects of body size on brain size, the brains of adult humans, rhesus monkeys, and chimpanzees differ in relative size, where males have a greater volume of cerebral tissue than females. We assess whether head circumference sexual dimorphism is present during early development by evaluating sex differences in relative head circumference in living fetuses and infants within the first year of life. Head circumference is used as a proxy for brain size in the fetus and infant. Femur length is used as a proxy for body length in the fetus. Ultrasonography was used to obtain fetal measures, and anthropometry was used to obtain postnatal measures in humans, rhesus monkeys, baboons, and common marmosets. We show that statistically significant but low levels of head circumference sexual dimorphism are present in humans, rhesus monkeys, and baboons in early life. On average, males have head circumferences about 2% larger than females of comparable femur/body length in humans, rhesus monkeys, and baboons. No evidence for head circumference sexual dimorphism in the common marmoset was found. Dimorphism was present across all body size ranges. We suggest that head circumference sexual dimorphism emerges largely postnatally and increases throughout maturation, particularly in humans who reach adult dimorphism values greater than the monkeys. We suggest that brain dimorphism is not likely to impose an additional energetic burden to the gestating or lactating mother. Finally, some of the problems with ascribing functional significance to brain size sexual dimorphism are discussed, and the energetic implications for brain size sexual dimorphism in infancy are assessed.

Increased virus replication and virulence after serial passage of human immunodeficiency virus type 2 in baboons.

Similar to human immunodeficiency virus type 1 (HIV-1) infection of humans, the natural history of HIV-2 infection in baboons (Papio cynocephalus) is a slow and chronic disease that generally takes several years before an AIDS-like condition develops. To shorten the amount of time to the development of disease, we performed five serial passages of HIV-2(UC2) in baboons by using blood and bone marrow samples during the acute phase of infection when viral loads were at high levels. After these serial passages, virus levels in plasma, peripheral blood mononuclear cells (PBMC) and lymphatic tissues in the acutely infected baboons were increased. Within 1 year of the HIV-2 infection, all of the inoculated baboons showed specific signs of AIDS-related disease progression within the lymphatic tissues, such as vascular proliferation and lymphoid depletion. The HIV-2(UC2) recovered after four serial passages showed increased kinetics of viral replication in baboon PBMC and cytopathicity. This study suggests that the HIV-2 isolate recovered after several serial passages in baboons will be useful in future studies of AIDS pathogenesis and vaccine development by using this animal model.

Blood-sucking lice may disseminate Trypanosoma cruzi infection in baboons

Trypanosoma cruzi (Schyzotrypanum, Chagas, 1909), and Chagas disease are endemic in captive-reared baboons at the Southwest Foundation for Biomedical Research, San Antonio, Texas. We obtained PCR amplification products from DNA extracted from sucking lice collected from the hair and skin of T. cruzi-infected baboons, with specific nested sets of primers for the protozoan kinetoplast DNA, and nuclear DNA. These products were hybridized to their complementary internal sequences. Selected sequences were cloned and sequencing established the presence of T. cruzi nuclear DNA, and minicircle kDNA. Competitive PCR with a kDNA set of primers determined the quantity of approximately 23.9 18.2 T. cruzi per louse. This finding suggests that the louse may be a vector incidentally contributing to the dissemination of T. cruzi infection in the baboon colony