Juvenile Baboons Research Articles

Postnatal persistence of nonhuman primate sex-dependent renal structural and molecular changes programmed by intrauterine growth restriction.

Poor nutrition during fetal development programs postnatal kidney function. Understanding postnatal consequences in nonhuman primates (NHP) is important for translation to our understanding the impact on human kidney function and disease risk. We hypothesized that intrauterine growth restriction (IUGR) in NHP persists postnatally, with potential molecular mechanisms revealed by Western-type diet challenge. IUGR juvenile baboons were fed a 7-week Western diet, with kidney biopsies, blood, and urine collected before and after challenge. Transcriptomics and metabolomics were used to analyze biosamples. Pre-challenge IUGR kidney transcriptome and urine metabolome differed from controls. Post-challenge, sex and diet-specific responses in urine metabolite and renal signaling pathways were observed. Dysregulated mTOR signaling persisted postnatally in female pre-challenge. Post-challenge IUGR male response showed uncoordinated signaling suggesting proximal tubule injury. Fetal undernutrition impacts juvenile offspring kidneys at the molecular level suggesting early-onset blood pressure dysregulation.

Comparison of oral, nebulized and combination antibiotic treatment of Bordetella bronchiseptica in baboons (Papio spp.).

Incidence of Bordetella pertussis, the causative agent of whooping cough, is rising in some global human populations despite high vaccination rates, and significant research is underway to address the issue. Baboons are an established model for pertussis research, but like many mammals, they can be naturally infected with Bordetella bronchiseptica. Because B.bronchiseptica interferes with B.pertussis research, it must be excluded from baboons under consideration for enrollment in pertussis studies. In addition to research-related concerns, B.bronchiseptica can sometimes cause clinical disease in baboons and other nonhuman primates. This study examined the use of antibiotics to clear B.bronchiseptica in naturally infected baboons. Thirty-five juvenile baboons were divided into five treatment groups: oral sulfamethoxazole/trimethoprim (TMS), nebulized gentamicin (gentamicin), combination (TMS+gentamicin) in positive animals, combination (TMS+gentamicin) as a prophylactic in exposed animals and no treatment (control). Combination of oral TMS and nebulized gentamicin given to positive animals was most effective, producing long-term clearance in 11 out of 12 treated animals. To avoid unnecessary use of antibiotics, our primary management strategy is screening and separating to allow natural clearance and limiting exposure to non-infected animals, but this study investigates an antibiotic regimen that could be used in special circumstances.

Assessment of Regenerated Bioscaffold Mitral Valve Annulus Extracellular Matrix Components from a Juvenile Non-human Primate Model

Objective: Critical congenital heart valve disease (CCHVD) in the young has limited treatment options due to sizing options and lack of growth. To assess somatic growth potential, we implanted a bioscaffold mitral valve comprising of porcine small intestinal submucosa (PSIS) in a juvenile baboon model. Methods: Juvenile baboons (n=3) were implanted with a hand-made PSIS (Cormatrix, Roswell, GA) mitral valve. The PSIS valves were excised at 3-, 11- and 20-months post-implantation for histological assessment. In brief, the explants were fixed in 10% Formalin (w/v), paraffin embedded and stained with Movat’s Pentachrome (Movat’s; Alizée Pathology, Inc., Thurmont, MD). These histological images were subsequently thresholded, normalized, color segmented (ImageJ, NIH) and spatially mapped for quantification of ECM components (MATLAB; Mathworks, Natick, MA). Results: We found that PSIS bioscaffold mitral valves annulus integrated with the myocardium and was comprised of collagen, proteoglycans, elastin and fibrin (Figure 1). Interestingly there was no significant difference (p>0.05) between any of the extracellular matrix (ECM) proteins, except proteoglycans; the 3-month explant had a significantly lower (p<0.05) amount of proteoglycans compared to both the 11- and 20-month explants. Conclusions: Our findings suggest that the PSIS bioscaffold mitral valve apparatus can regenerate the annulus of the mitral valve without additional treatment but at an early time point (3-months) could not produce comparable amounts of de novo proteoglycans. Additional treatments to the bioscaffold in vitro (e.g. stem cell incorporation) may enhance the ECM production once implanted

Quantification of microbubble‐induced sonothrombolysis in an ex vivo non‐human primate model

BackgroundIn vitro studies with ultrasound (US) and microbubbles (MB) have reported that sono‐thrombolysis can be achieved at high peak rarefactional acoustic pressure amplitudes (PRAPAs) using 0.25 and 1.05 MHz US frequencies. ObjectiveThe aim of the current study was to determine if these parameters work on an ex vivo physiological model of thrombosis. MethodsA thrombogenic device was placed in an ex vivo chronic arteriovenous shunt in juvenile baboons. Platelet accumulation was measured by dynamic imaging of the device and the 10 cm thrombus tail with 111In‐labeled platelets. After 15 minutes of thrombus formation, treatment with either low‐dose recombinant tissue plasminogen activator (rtPA) or low‐dose rtPA + MB+US was performed for 20 minutes. Four US settings at 0.25% duty cycle were used: 0.25 MHz at PRAPAs of 1.20 and 2.20 MPa, and 1.05 MHz at 1.75 and 4.75 MPa. ResultsPlatelet accumulation was not inhibited by low‐dose rtPA or MB with US alone. Platelet accumulation was significantly reduced with 0.25 MHz US at 2.20 PRAPA (P < .001) and with 1.05 MHz at 1.75 MPa and 4.75 MPa (P < .05) when used with MB and low‐dose rtPA. Although this approach prevented platelet accumulation it did not cause thrombolysis on the device. ConclusionsrtPA + MB + US (0.25 and 1.05 MHz) resulted in inhibition of platelet accumulation on the thrombogenic device when moderately high PRAPAs (≥1.75 MPa) were used. These results taken in context with lytic effects of US on myocardial microthrombi and direct effect on myocardial blood flow and function provide direction for the use of therapeutic US in acute coronary syndromes.

Increased performance in juvenile baboons is consistent with ontogenetic changes in morphology.

In many primates, the greater proportion of climbing and suspensory behaviors in the juvenile repertoire likely necessitates good grasping capacities. Here, we tested whether very young individuals show near-maximal levels of grasping strength, and whether such an early onset of grasping performance could be explained by ontogenetic variability in the morphology of the limbs in baboons. We quantified a performance trait, hand pull strength, at the juvenile and adult stages in a cross-sectional sample of 15 olive baboons (Papio anubis). We also quantified bone dimensions (i.e., lengths, widths, and heights) of the fore- (n = 25) and hind limb (n = 21) elements based on osteological collections covering the whole development of olive baboons. One-year old individuals demonstrated very high pull strengths (i.e., 200% of the adult performance, relative to body mass), that are consistent with relatively wider phalanges and digit joints in juveniles. The mature proportions and shape of the forelimb elements appeared only at full adulthood (i.e., ≥4.5 years), whereas the mature hind limb proportions and shape were observed much earlier during development. These changes in limb performance and morphology across ontogeny may be explained with regard to behavioral transitions that olive baboons experience during their development. Our findings highlight the effect of infant clinging to mother, an often-neglected feature when discussing the origins of grasping in primates. The differences in growth patterns, we found between the forelimb and the hind limb further illustrate their different functional roles, having likely evolved under different ecological pressures (manipulation and locomotion, respectively).

Early Left-Planum Temporale Asymmetry in newborn monkeys (Papio anubis): A longitudinal structural MRI study at two stages of development

The “language-ready” brain theory suggests that the infant brain is pre-wired for language acquisition prior to language exposure. As a potential brain marker of such a language readiness, a leftward structural brain asymmetry was found in human infants for the Planum Temporale (PT), which overlaps with Wernicke's area. In the present longitudinal in vivo MRI study conducted in 35 newborn monkeys (Papio anubis), we found a similar leftward PT surface asymmetry. Follow-up rescanning sessions on 29 juvenile baboons at 7-10 months showed that such an asymmetry increases across the two ages classes. These original findings in non-linguistic primate infants strongly question the idea that the early PT asymmetry constitutes a human infant-specific marker for language development. Such a shared early perisylvian organization provides additional support that PT asymmetry might be related to a lateralized system inherited from our last common ancestor with Old-World monkeys at least 25–35 million years ago.

Abstract 14888: Extracellular Matrix Quantification of Fully Regenerated Neochorade After Bio-scaffold Mitral Valve Implantation in a Juvenile Non-human Primate Model

Introduction: To investigate enhanced treatment options for critical mitral valve disease in children, we implanted a bio-scaffold mitral valve comprising of porcine small intestinal submucosa (PSIS) in a juvenile baboon model. Hypothesis: New tissue formation would be accelerated at physical connections between the replacement bio-scaffold valve and native cardiac tissues, due to direct extracellular matrix (ECM) communications. Methods: Juvenile baboons (n=2) were implanted with a hand-made bicuspid PSIS (Cormatrix, Roswell, GA) mitral valve. The PSIS valves were excised at 11- and 20-months post-implantation. Images of histological stains (Movat’s Pentachrome; Alizée Pathology, Inc., Thurmont, MD) were subsequently spatially mapped for ECM quantification (MATLAB; Mathworks, Natick, MA). Results: PSIS bio-scaffold mitral valves (11- and 20-months post-implantation) facilitated complete regeneration of neochordae. The neochordae seamlessly integrated into the papillary muscles and left ventricular insertion sites ( Figure 1A, E ). We also found that with an increase in implantation duration of ~ 9 months, the collagen, proteoglycan and elastin content (per mm 2 ; Figure 1B-D, F-H ) had a fold-change of 6.96, 18.42 and 4.94, respectively. Conclusions: Our findings suggest that the PSIS bio-scaffold mitral valve apparatus can regenerate neochordae without the need for any biochemical or biomechanical treatment. Nonetheless, other valve spatial areas of importance (e.g. leaflets) will require additional strategies. As a next step, we will produce oscillatory flow-conditioned, stem cell-derived ECM, to accelerate tissue regeneration. The mechanical parameters that we computed to permit physiological oscillatory flow conditions are an oscillatory shear index (OSI) of 0.23 and time averaged bio-scaffold shear stress (TAB-SSS) of 4.6 dynes/cm 2 . Acknowledgements: AHA Award ID: 16GRNT31090009; The Miami Research Heart Institute; FIU-UGS DYF.

Blood Biochemical Reference Intervals for Free-Ranging Olive Baboons (Papio anubis) in Kenya

Biochemical reference intervals are important for assessing the health of target species and populations by identifying abnormalities in key blood parameters. Although reference intervals have been established for baboons in captivity, the lack of data from free-ranging individuals makes it difficult to interpret the results of their blood chemistry panels or to assess and monitor the health of wild baboon populations. The goal of this study was therefore to establish serum biochemical reference intervals for free-ranging olive baboons (Papio anubis) in Kenya. We evaluated 14 biochemical parameters from 28 baboons sampled at the Mpala Research Center, Nanyuki, Kenya. Reference intervals obtained from this wild population were comparable to those from captive baboon populations. Alkaline phosphatase (ALP) and phosphorus levels differed significantly among age classes; both were higher in subadult and juvenile baboons than in adults. However, none of the components of the blood biochemistry panel differed significantly between the sexes. The reference intervals we report provide a baseline for the evaluation and treatment of free-ranging olive baboons and provide context for interpreting the biochemical profiles of captive individuals.

In vivo imaging of bacterial colonization of the lower respiratory tract in a baboon model of Bordetella pertussis infection and transmission

Recent whooping cough (pertussis) outbreaks in many countries highlight the crucial need for a better understanding of the pathogenesis of Bordetella pertussis infection of the respiratory tract. The baboon is a recently described preclinical model for the study of B. pertussis infection and may be ideal for the evaluation of new pertussis vaccines. However, many pathophysiological aspects, including bacterial localization and interactions, have yet to be described in this model. Here, we used a baboon model of infection with a fluorescent GFP-expressing B. pertussis strain, derived from European clinical isolate B1917. Juvenile baboons were used to evaluate susceptibility to infection and transmission. Non-invasive in vivo imaging procedures, using probe-based confocal endomicroscopy coupled with bronchoscopy, were developed to track fluorescent bacterial localization and cellular interactions with host cells in the lower respiratory tract of infected animals. All B1917-GFP-challenged animals developed classical pertussis symptoms, including paroxysmal cough, nasopharyngeal colonization, and leukocytosis. In vivo co-localization with antigen presenting cells and progressive bacterial colonization of the lower airways were also assessed by imaging during the first weeks of infection. Our results demonstrate that in vivo imaging can be used to assess bacterial colonization and to point out interactions in a baboon model of pertussis.

The baboon as a nonhuman primate model for the study of natural Zika virus infection

Background: Zika virus (ZIKV) was first isolated from a sentinel rhesus macaque in the Zika forest of Uganda. Baboons are a nonhuman primate species widely distributed in Africa that could reasonably be a natural reservoir for ZIKV. We characterized the early phases of ZIKV infection in naïve captive baboons and tested immunity induced by primary infection against reinfection with a distant ZIKV strain. Methods & Materials: Four juvenile baboons were injected with 104 or 106 TCID50 of the Puerto Rico strain of ZIKV by the subcutaneous route. Viral loads were determined by RT-PCR in blood, urine, and mucosal swabs. Infection was followed by measuring fever and systemic cytokine changes, and by observing clinical signs. Humoral immune responses were determined by ELISA, and cellular responses by flow cytometry. Transcriptomic analysis was performed on days 0, 3 and 15. Six months after primary infection, the same animals were exposed to 104 TCID50 of the Uganda strain of ZIKV, and virological and immunological outcomes were performed as described before. Results: Viremia was present in all animals and lasted for about 5 days. Virus was transiently present in the urine of some animals. There were no clinical signs of infection, and body temperature was stable during the viremic phase. Cytokine analysis did not show evident peaks of inflammatory cytokines in circulation; however, RNAseq analysis showed a clear inflammatory antiviral response by day 3 PI that resolved by day 15 PI. All animals developed low levels of anti-ZIKV NS1 and crossreactive anti-Dengue GP antibodies, and there was also a detectable cell-mediated immune response to viral antigens. After challenge with ZIKV Uganda strain, there was no detectable viremia and this correlated with a lack of anamnestic humoral and cell-mediated immune response to the viral antigens. Conclusion: Similarl to the majority of human cases, ZIKV infection of baboons resulted in a subclinical infection. However, this infection was able to induce a protective immune response against re-exposure with a distant ZIKV. The baboon may be a useful NHP model of natural ZIKV infection in which to test antivirals and vaccines efficacy.

Nonhuman primate breath volatile organic compounds associate with developmental programming and cardio-metabolic status

Rodent and nonhuman primate studies indicate that developmental programming by reduced perinatal nutrition negatively impacts life course cardio-metabolic health. We have developed a baboon model in which we feed control mothers (CON) ad libitum while nutrient restricted mothers are fed 70% of ad libitum global feed in pregnancy and lactation. Offspring of nutrient restricted mothers are intrauterine growth restricted (IUGR) at term. By 3.5 years IUGR baboons showed signs of insulin resistance, indicating a pre-diabetic phenotype, in contrast to healthy CON offspring. We hypothesized that a novel breath analysis approach would provide markers of the altered cardio-metabolic state in a non-invasive manner. Here we assess whether exhaled breath volatile organic compounds (VOCs) collected from this unique cohort of juvenile baboons with documented cardio-metabolic dysfunction resulting from in utero programming can be detected from their breath signatures. Breath was collected from male and female CON and IUGR baboons at 4.8 ± 0.2 years (human equivalent ∼13 years). Breath VOCs were quantified using a two-dimensional gas chromatography mass spectrometer. Two-way ANOVA, on 76 biologically relevant VOCs identified 27 VOCs (p < 0.05) with altered abundances between groups (sex, birthweight, and sex x birthweight). The 27 VOCs included 2-pentanone, 2-octanone, 2,2,7,7-tetramethyloctane and 3-methyl-1-heptene, which have not previously been associated with cardio-metabolic disease. Unsupervised principal component analysis of these VOCs could discriminate the four clusters defining males, females, CON and IUGR. This study, which is the first to assess quantifiable breath signatures associated with cardio-metabolic programing for any model of IUGR, demonstrates the translational value of this unique model to identify metabolites of programmed cardio-metabolic dysfunction in breath signatures. Future studies are required to validate the translatability of these findings to humans.

Live Attenuated Pertussis Vaccine BPZE1 Protects Baboons Against Bordetella pertussis Disease and Infection.

Evidence suggests that the resurgence of pertussis in many industrialized countries may result from the failure of current vaccines to prevent nasopharyngeal colonization by Bordetella pertussis, the principal causative agent of whooping cough. Here, we used a baboon model to test the protective potential of the novel, live attenuated pertussis vaccine candidate BPZE1. A single intranasal/intratracheal inoculation of juvenile baboons with BPZE1 resulted in transient nasopharyngeal colonization and induction of immunoglobulin G and immunoglobulin A to all antigens tested, while causing no adverse symptoms or leukocytosis. When BPZE1-vaccinated baboons were challenged with a high dose of a highly virulent B. pertussis isolate, they were fully protected against disease, whereas naive baboons developed illness (with 1 death) and leukocytosis. Total postchallenge nasopharyngeal virulent bacterial burden of vaccinated animals was substantially reduced (0.002%) compared to naive controls, providing promising evidence in nonhuman primates that BPZE1 protects against both pertussis disease and B. pertussis infection.

Olive baboons' (Papio anubis) response towards crowned eagles (Stephanoaetus coronatus) at Lake Manyara National Park.

In this paper we report on two encounters between olive baboons (Papio anubis) and crowned eagles (Stephanoaetus coronatus) at Lake Manyara National Park, northern Tanzania. During these encounters olive baboons responded by giving alarm calls and all infants and juveniles rushed down from trees seeking cover under bushes or close proximity to adult conspecifics. In one of the events, alarm calls from banded mongoose (Mungos mungo) and rock hyraxes (Procavia capensis) most likely triggered alarm calling of vervet monkeys (Chlorocebus pygerythrus) which in turn prompted baboons to respond with alarm calls as well. In both observations, adult male baboons took the lead in climbing trees, threatening the eagle (staring, yawning, ground slapping) and chasing it away. The reaction of the baboons suggests that crowned eagles pose a threat at least for juvenile baboons at Lake Manyara National Park.

Distinct Renal Pathology and a Chemotactic Phenotype after Enterohemorrhagic Escherichia coli Shiga Toxins in Non-Human Primate Models of Hemolytic Uremic Syndrome

Enterohemorrhagic Escherichia coli cause approximately 1.5 million infections globally with 176,000 cases occurring in the United States annually from ingesting contaminated food, most frequently E. coli O157:H7 in ground beef or fresh produce. In severe cases, the painful prodromal hemorrhagic colitis is complicated by potentially lethal hemolytic uremic syndrome (HUS), particularly in children. Bacterial Shiga-like toxins (Stx1, Stx2) are primarily responsible for HUS and the kidney and neurologic damage that ensue. Small animal models are hampered by the inability to reproduce HUS with thrombotic microangiopathy, hemolytic anemia, and acute kidney injury. Earlier, we showed that nonhuman primates (Papio) recapitulated clinical HUS after Stx challenge and that novel therapeutic intervention rescued the animals. Here, we present detailed light and electron microscopic pathology examination of the kidneys from these Stx studies. Stx1 challenge resulted in more severe glomerular endothelial injury, whereas the glomerular injury after Stx2 also included prominent mesangiolysis and an eosinophilic inflammatory infiltration. Both toxins induced glomerular platelet-rich thrombi, interstitial hemorrhage, and tubular injury. Analysis of kidney and other organs for inflammation biomarkers showed a striking chemotactic profile, with extremely high mRNA levels for IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1α and elevated urine chemokines at 48hours after challenge. These observations give unique insight into the pathologic consequences of each toxin in a near human setting and present potential pathways for therapeutic intervention.

Rescue from lethal Shiga toxin 2-induced renal failure with a cell-permeable peptide

Intestinal infection with Shiga toxin (Stx)-producing E.coli is a leading cause of hemolytic uremic syndrome and acute renal injury in otherwise healthy children in the US. Antibiotics are contraindicated and a therapeutic priority is agents that act intracellularly against the bacterial toxins that drive kidney injury. Our aim was to evaluate whether intravenous administration of a cell-permeable peptide (TVP) that binds to Stx2 will reduce disease severity and rescue juvenile baboons from a lethal Stx2 dose (50 ng/kg). TVP (5 mg/kg) was delivered i.v. simultaneously with toxin (prevention protocol) or at 6 or 24 h after toxin with daily 1 mg/kg supplements up to day 4 (rescue protocols). Biomarkers were monitored in blood and urine up to 28 days. TVP therapy resulted in either absence of clinical signs of acute kidney injury and normal urine output (prevention), or delayed and reduced BUN and creatinine levels (rescue) with concomitant survival. Delayed peptide administration significantly reduced thrombocytopenia, but surprisingly did not alter anemia even when monitored for 28 days in rescued survivors. This is the first successful cell-permeable therapeutic that counteracts Stx2 lethality in an animal model, which recapitulates many of the human responses to enteric infection.

Prenatal betamethasone exposure has sex specific effects in reversal learning and attention in juvenile baboons

We investigated effects of 3 weekly courses of fetal betamethasone (βM) on motivation and cognition in juvenile baboon offspring utilizing the Cambridge Neuropsychological Test Automated Battery. Pregnant baboons (Papio species) received 2 injections of saline control or 175 μg/kg βM 24 hours apart at 0.6, 0.65, and 0.7 gestation. Offspring (saline control female, n = 7 and saline control male, n = 6; βM female [FβM], n = 7 and βM male [MβM], n = 5) were studied at 2.6-3.2 years with a progressive ratio test for motivation, simple discriminations and reversals for associative learning and rule change plasticity, and an intra/extradimensional set-shifting test for attention allocation. βM exposure decreased motivation in both sexes. In intra/extradimensional testing, FβM made more errors in the simple discrimination reversal (mean difference of errors [FβM - MβM] = 20.2 ± 9.9; P ≤ .05), compound discrimination (mean difference of errors = 36.3 ± 17.4; P ≤ .05), and compound reversal (mean difference of errors = 58 ± 23.6; P < .05) stages as compared to the MβM offspring. This central nervous system developmental programming adds growing concerns of long-term effects of repeated fetal synthetic glucocorticoid exposure. In summary, behavioral effects observed show sex-specific differences in resilience to multiple fetal βM exposures.

CANTAB delayed matching to sample task performance in juvenile baboons

This study reports the administration of the Cambridge Neuropsychological Test Automated Battery system's delayed matching to sample (DMTS) task to juvenile baboons. Nine subjects (female = 5, male = 4) were trained with delay intervals ranging from 0 to 80 s. Trial unique stimuli were utilized in combination with matching to sample, in contrast to non-matching to sample, to more accurately assess components of medial temporal lobe (hippocampal formation) mediated working memory. These parameters force subjects to rely on recognition for matching stimuli and overcome their innate tendency to choose novel stimuli (non-matching), thus increasing task difficulty. Testing with delays intervals of 0–2, 4, 8, and 16 s revealed decreased percent correct responding as delay intervals increased. An effect of 1 vs. 3 distractor stimuli on accuracy was also noted. Increasing the number of distractors resulted in decreased observing response latencies. The increase in choice response latency seen with increasing delay interval was independent of number of distractor stimuli presented. There were no sex differences in task performance. Our laboratory is focused on understanding the functional consequences of suboptimal conditions during pregnancy and early postnatal life in offspring. The ability of juvenile baboons to perform the DMTS task demonstrates the utility of this non-human primate model in examining pre- and post-natal conditions that impact the development of working memory. Evaluation of causes and consequences of impaired working memory in a variety of human diseases will be assisted by the use of this task in nonhuman primate models of human health and disease.

The Relationship of Accentuated Lines in Enamel to Weaning Stress in Juvenile Baboons (Papio hamadryas anubis)

Weaning conflict may represent an evolutionary conflict of interest between parent and offspring, an honest signal of need on the part of a weanling, or both. Accentuated lines visible in histological sections of teeth are indicators of stress during enamel formation and have been hypothesised to form in baboon teeth during weaning. We analysed growth increments in 5 tooth sections from 2 Ugandan baboons (Papio hamadryas anubis), using polarised light microscopy, to determine when stresses occurred during the weaning process. Dietary transitions were reconstructed using normalised strontium intensities (Sr/Ca) in enamel. Accentuated lines were cross-matched between teeth from the same animal and plotted by month. The highest frequency of stress was experienced at around 6 months in 1 baboon, coinciding with an inferred reduction in suckling frequency, and at 11 months in another, coinciding with the inferred cessation of suckling. Because accentuated lines appear to indicate weaning stress at dietary transitions, weaning conflict may represent an honest signal of need on the part of the weanling.

Performance of juvenile baboons on neuropsychological tests assessing associative learning, motivation and attention

The CANTAB (Cambridge Neuropsychological Test Automated Battery), a system developed for human neuropsychological testing, has previously been used to assess cognitive function in two species of nonhuman primates, common marmoset monkeys and rhesus macaques. We describe the application of the system to the juvenile baboon, a nonhuman primate species offering specific investigative advantages. Juvenile baboons were trained and tested on a progressive ratio task to assess motivation, simple discrimination and simple reversal tasks to assess associative learning, and intra- and extra-dimensional set-shifting tasks to assess selective attention and attentional set-shifting, respectively. Study subjects were 8 juvenile baboons ( Papio sp.), 4 females and 4 males aged 3.0 ± 0.1 (mean + SEM) years and weight 8.2 ± 0.4 kg. All baboons were easily trained, readily learned the neuropsychological tests and exhibited a stable performance. Applying a method such as the CANTAB has significant implications for expanding on the translational utility of the baboon in studies of neurodevelopment.

A Multi-Lineage Oral Hemokine™ HQK-1002 Enhances Neutrophil Recovery in Sub-Lethally Irradiated Mice and in Baboons.

Abstract 2509Poster Board II-486Acute radiation syndrome and therapeutic radiation are associated with cytopenias, notably severe neutropenia, particularly when large regions of bone marrow are exposed. An orally-active neutrophil stimulant which reduces the duration or magnitude of neutropenia would offer therapeutic benefit in radiation therapy and would be useful for acute radiation exposure. Orally-bioavailable short-chain fatty acid derivatives (SCFAD, HemokinesTM HQK-1002 and its S-enantiomer HQK-1002S), which stimulate proliferation of growth factor-dependent hematopoietic cell lines and CFU-GM cultures, were evaluated for in vivo activity in irradiated and 5-FU-treated mice and in normal baboons. In sub-lethal irradiation studies, mice were irradiated (6 Gy single dose) and then treated with saline or HQK-1002 once daily, 5 days/week for 2 weeks, beginning on day 1 after irradiation, and absolute neutrophil counts (ANC) were determined. The mean nadir of absolute neutrophil counts (ANC) <500/mm3 was 6 days in sub-lethally-irradiated mice treated with HQK-1002, and 18 days in the saline treated controls. In HQK-1002 treated mice, ANC did not decline below 200/mm3, while saline-treated animals experienced 10 days of severe neutropenia with ANC <200/mm3. In lethally-irradiated (LD90) mice, either saline or the (S) enantiomer of HQK-1002 was administered daily. ANC and marrow pathology were compared between saline and HQK-1002S-treated animals. The duration of peripheral neutropenia was similar in controls and HQK-1002S-treated animals, but bone marrow pathology demonstrated profound ablation of all mature myeloid series (10-20% cellularity) in the saline controls, while HQK-1002S-treated animals had normal bone marrow cellularity (55–75%) with complete neutrophil maturation within 2 weeks following radiation. In 5FU-treated mice, neutrophil recovery was compared between HQK-1002, saline, or G-CSF treatment for 3 weeks. Recovery from profound neutropenia (nadir at Day 9) occurred by Day 13 in G-CSF- and HQK-1002 treated animals, 5 days before recovery was observed in saline controls. HQK-1002 and HQK-1002S were also administered to non-irradiated, normal juvenile baboons, once daily for 5 days, and CBCs and neutrophil counts were assayed. HQK-1002 or HQK-1002S treatment in 3 unchallenged baboons resulted in a two-fold to three-fold rises in ANC within 7 days. Collectively, these studies strongly suggest that HQK-1002 and HQK-1002S, orally-bioavailable SCFADs, stimulate myelopoiesis in vivo in normal animals and during sub-lethal radiation-induced bone marrow suppression, and merit further evaluation in neutropenia associated with marrow suppression. Disclosures:Perrine:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Boosalis:HemaQuest Pharmaceuticals: Equity Ownership. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:hemaQuest Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Faller:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.