scholarly journals Shaping long-term primate development: Telomere length trajectory as an indicator of early maternal maltreatment and predictor of future physiologic regulation

2017 ◽  
Vol 29 (5) ◽  
pp. 1539-1551 ◽  
Author(s):  
Stacy S. Drury ◽  
Brittany R. Howell ◽  
Christopher Jones ◽  
Kyle Esteves ◽  
Elyse Morin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Nonhuman Primate ◽  
Social Rank ◽  
Juvenile Period ◽  
Primate Model ◽  
Causal Pathways ◽  
Biological Mother ◽  
Physiologic Regulation ◽  
Negative Health Outcomes

AbstractThe molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation.

Chemotherapy administration directly into the fourth ventricle in a nonhuman primate model

2012 ◽  
Vol 9 (5) ◽  
pp. 530-541 ◽  
Author(s):  
David I. Sandberg ◽  
M. Melissa Peet ◽  
Mark D. Johnson ◽  
Phaedra Cole ◽  
Tulay Koru-Sengul ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Fourth Ventricle ◽  
Magnetic Resonance Images ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
The Third ◽  
Group I ◽  
Ventricular Tumors ◽  
Group Ii

Object The authors hypothesized that chemotherapy infusions directly into the fourth ventricle might potentially play a role in treating malignant fourth ventricular tumors. The study tested the safety and pharmacokinetics of short- and long-term infusions of methotrexate into the fourth ventricle in a new nonhuman primate model. Methods Six rhesus monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (3 animals), catheters were externalized, and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term methotrexate infusions. In 2 animals, methotrexate (0.5 mg) was infused into the fourth ventricle daily for 5 days. Serial CSF and serum methotrexate levels were measured. The third animal had a postoperative neurological deficit, and the experiment was aborted prior to methotrexate administration. In Group II (3 animals), catheters were connected to a subcutaneously placed port for subsequent long-term methotrexate infusions. In 2 animals, 4 cycles of intraventricular methotrexate, each consisting of 4 daily infusions (0.5 mg), were administered over 8 weeks. The third animal received 3 cycles, and then the experiment was terminated due to self-inflicted wound breakdown. All animals underwent detailed neurological evaluations, MRI, and postmortem histological analysis. Results No neurological deficits were noted after intraventricular methotrexate infusions. Magnetic resonance images demonstrated catheter placement within the fourth ventricle and no signal changes in the brainstem or cerebellum. Histologically, two Group I animals, one of which did not receive methotrexate, had several small focal areas of brainstem injury. Two Group II animals had a small (≤ 1-mm) focus of axonal degeneration in the midbrain. Intraventricular and meningeal inflammation was noted in 4 animals after methotrexate infusions (one from Group I and all three from Group II). In all Group II animals, inflammation extended minimally into brainstem parenchyma. Serum methotrexate levels were undetectable or negligible in both groups, ranging from 0.00 to 0.06 μmol/L. In Group I, the mean peak methotrexate level in fourth ventricle CSF exceeded that in the lumbar CSF by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC (area under the concentration-time curve) were detected at peaks (p = 0.04) but not at troughs (p = 0.50) or at all time collection points (p = 0.12). In Group II, peak fourth ventricle CSF methotrexate levels ranged from 84.62 to 167.89 μmol/L (mean 115.53 ± 15.95 μmol/L [SD]). Trough levels ranged from 0.06 to 0.55 μmol/L (mean 0.22 ± 0.13 μmol/L). Conclusions Methotrexate can be infused into the fourth ventricle in nonhuman primates without clinical or radiographic evidence of injury. Observed inflammatory and other histological changes had no clinical correlate. This approach may have pharmacokinetic advantages over current treatment paradigms. Further experiments are warranted to determine if fourth ventricular chemotherapy infusions may benefit patients with malignant fourth ventricular tumors.

scholarly journals Safe, Long-term Hepatic Expression of Anti-HCV shRNA in a Nonhuman Primate Model

2012 ◽  
Vol 20 (9) ◽  
pp. 1737-1749 ◽  
Author(s):  
David A Suhy ◽  
Shih-Chu Kao ◽  
Tin Mao ◽  
Laurence Whiteley ◽  
Hubert Denise ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Hepatic Expression

scholarly journals Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS

2017 ◽  
Vol 13 (12) ◽  
pp. e1006753 ◽  
Author(s):  
Anjie Zhen ◽  
Christopher W. Peterson ◽  
Mayra A. Carrillo ◽  
Sowmya Somashekar Reddy ◽  
Cindy S. Youn ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Chimeric Antigen Receptor ◽  
Nonhuman Primate ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Hematopoietic Stem ◽  
And Function

scholarly journals Tacrolimus, a Potential Neuroprotective Agent, Ameliorates Ischemic Brain Damage and Neurologic Deficits after Focal Cerebral Ischemia in Nonhuman Primates

2003 ◽  
Vol 23 (10) ◽  
pp. 1183-1194 ◽  
Author(s):  
Yasuhisa Furuichi ◽  
Masashi Maeda ◽  
Akira Moriguchi ◽  
Taiji Sawamoto ◽  
Akio Kawamura ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Nonhuman Primate ◽  
Focal Cerebral Ischemia ◽  
Sensory Function ◽  
Neuroprotective Activity ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Neurologic Deficits ◽  
Infarction Volume

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.

Nonhuman Primate Model of Cleft Palate and its Implications for Middle Ear Pathology

1980 ◽  
Vol 89 (3_suppl) ◽  
pp. 41-46 ◽  
Author(s):  
William J. Doyle ◽  
David C. Phillips ◽  
Erdem I. Cantekin ◽  
Kyle K. Kimes ◽  
Charles D. Bluestone ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Middle Ear ◽  
Soft Palate ◽  
Nonhuman Primate ◽  
Otitis Media With Effusion ◽  
Forced Response ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Long Term Follow Up

The present study is a preliminary report on the development of a nonhuman primate model of cleft palate and middle ear (ME) disease. The causal relationship between a surgical cleft of the soft palate only or a cleft of the hard and soft palate and otitis media with effusion (OME) was investigated in rhesus monkeys. Prior to clefting, ME status was documented by pneumatic otoscopy or otomicroscopic examination and tympanometry over a period of at least five months. A minimum of four preoperative eustachian tube (ET) function evaluations were performed employing the inflation-deflation and the forced-response tests. These procedures were repeated following surgery and during a long-term follow-up. Seventeen of the 18 ears developed a recurrent OME. Postoperative ME pressures were initially high negative values. After the first two postoperative months, high positive ME pressures were recorded. The forced-response test showed little to no long-term changes in passive and active tubal resistances or in the efficiency of tubal dilation as a result of surgery. The inflation-deflation test showed higher opening and closing pressures and a limited and more variable ability to equilibrate applied positive and negative ME pressures following surgery. Both ME status and ET function appeared to improve with time. These findings indicated that the pathogenesis of recurrent OME in this animal model may have been due to changes in ET function associated with an abnormal nasopharynx rather than aberrant tensor veli palatini (TVP) muscle function.

scholarly journals Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2334-2341 ◽  
Author(s):  
Federico Mingozzi ◽  
Nicole C. Hasbrouck ◽  
Etiena Basner-Tschakarjan ◽  
Shyrie A. Edmonson ◽  
Daniel J. Hui ◽  
...  
Keyword(s):  
Immune Response ◽  
Gene Transfer ◽  
Nonhuman Primate ◽  
Drug Regimen ◽  
Factor Ix ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Adeno Associated Virus ◽  
Inhibitory Antibodies

Adeno-associated virus (AAV)–mediated gene transfer of factor IX (F.IX) to the liver results in long-term expression of transgene in experimental animals, but only short-term expression in humans. Loss of F.IX expression is likely due to a cytotoxic immune response to the AAV capsid, which results in clearance of transduced hepatocytes. We used a nonhuman primate model to assess the safety of AAV gene transfer coupled with an anti–T-cell regimen designed to block this immune response. Administration of a 3-drug regimen consisting of mycophenolate mofetil (MMF), sirolimus, and the anti–IL-2 receptor antibody daclizumab consistently resulted in formation of inhibitory antibodies to human F.IX following hepatic artery administration of an AAV-hF.IX vector, whereas a 2-drug regimen consisting only of MMF and sirolimus did not. Administration of daclizumab was accompanied by a dramatic drop in the population of CD4+CD25+FoxP3+ regulatory T cells (Tregs). We conclude that choice of immunosuppression (IS) regimen can modulate immune responses to the transgene product upon hepatic gene transfer in subjects not fully tolerant; and that induction of transgene tolerance may depend on a population of antigen-specific Tregs.

scholarly journals Maternal and postnatal high-fat diet consumption programs energy balance and hypothalamic melanocortin signaling in nonhuman primate offspring

2017 ◽  
Vol 313 (2) ◽  
pp. R169-R179 ◽  
Author(s):  
Elinor L. Sullivan ◽  
Heidi M. Rivera ◽  
Cadence A. True ◽  
Juliana G. Franco ◽  
Karalee Baquero ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Nonhuman Primate ◽  
High Fat Diet ◽  
Control Diet ◽  
High Fat ◽  
Melanocortin System ◽  
Juvenile Period ◽  
Primate Model ◽  
Related Peptide

Maternal high-fat-diet (HFD) consumption during pregnancy decreased fetal body weight and impacted development of hypothalamic melanocortin neural circuitry in nonhuman primate offspring. We investigated whether these impairments during gestation persisted in juvenile offspring and examined the interaction between maternal and early postnatal HFD consumption. Adult dams consumed either a control diet (CTR; 15% calories from fat) or a high-saturated-fat diet (HFD; 37% calories from fat) during pregnancy. Offspring were weaned onto a CTR or HFD at ~8 mo of age. Offspring from HFD-fed dams displayed early catch-up growth and elevated body weight at 6 and 13 mo of age. Maternal and postnatal HFD exposure reduced the amount of agouti-related peptide fibers in the paraventricular nucleus of the hypothalamus. Postnatal HFD consumption also decreased the amount of agouti-related peptide fibers in the arcuate nucleus of the hypothalamus. Postnatal HFD was associated with decreased food intake and increased activity. These results support and extend our previous findings of maternal diet effects on fetal development and reveal, for the first time in a nonhuman primate model, that maternal HFD-induced disturbances in offspring body weight regulation extended past gestation into the juvenile period. Maternal HFD consumption increases the risk for offspring developing obesity, with the developmental timing of HFD exposure differentially impacting the melanocortin system and energy balance regulation. The present findings provide translational insight into human clinical populations, suggesting that profound health consequences may await individuals later in life following intrauterine and postnatal HFD exposure.

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