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1.
FASEB J ; 35(9): e21788, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34425031

RESUMO

Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF-1α, REDD-1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2 ) (n = 3) induced REDD-1, inhibited mTOR complex-1 (mTORC1) activity and increased IGFBP-1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF-1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia-mediated inhibition of mTORC1 and induction of IGFBP-1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF-1α and also REDD-1 expression, inhibited mTORC1 and increased IGFBP-1 secretion/phosphorylation. Induction of HIF-1α (DMOG) and REDD-1 by Compound 3 inhibited mTORC1, increased IGFBP-1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF-1α induction, increased REDD-1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP-1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia-responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.


Assuntos
Técnicas de Cultura de Células , Modelos Animais de Doenças , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Hipóxia/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Eritropoetina/metabolismo , Peso Fetal , Feto/química , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/química , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Microscopia de Fluorescência , Tamanho do Órgão , Papio , Fosforilação , Proteína Quinase C-alfa/metabolismo , Receptores da Eritropoetina/metabolismo , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Am J Primatol ; 83(9): e23315, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339526

RESUMO

This study was designed to (1) characterize the macronutrient composition of olive baboon (Papio anubis) milk, (2) compare baboon milk composition to that of rhesus macaques (Macaca mulatta), and (3) evaluate the association between the proportion of milk energy derived from protein and relative growth rate within anthropoid primates. A single milk sample was collected from each of eight lactating olive baboons ranging between 47- and 129-days postparturition and six rhesus macaques from 15- to 92-days living at the same institution under identical management conditions. Macronutrient composition (water, fat, protein sugar, and ash) was determined using standard techniques developed at the Nutrition Laboratory at the Smithsonian National Zoological Park. Baboon milk on average contained 86.0% ± 0.6% water, 4.7% ± 0.5% fat, 1.6% ± 0.04% protein, 7.3% ± 0.07% sugar, and 0.165% ± 0.007% ash. Baboon milk gross energy (GE) averaged 0.81 ± 0.04 kcal/g with 51.9% ± 2.6% from fat, 11.8% ± 0.7% from protein, and 36.2% ± 2.0% from sugar. Baboon milk demonstrated strong similarity to milk composition of the closely phylogenetically related rhesus macaque (86.1% ± 0.3% water, 4.1% ± 0.4% fat, 1.69% ± 0.05% protein, 7.71% ± 0.08% sugar, 0.19% ± 0.01% ash, and 0.78 kcal/g). There was no statistical difference between baboon and macaque milk in the proportions of energy from fat, sugar, and protein. Baboon milk can be described as a high sugar, moderate fat, and low protein milk with moderate energy density, which is consistent with their lactation strategy characterized by frequent, on-demand nursing and relatively slow life history compared to nonprimate mammal taxa. The milk energy from protein of both baboon and macaque (12.8% ± 0.3%) milk was intermediate between the protein milk energy of platyrrhine (19.3%-23.2%) and hominoid (8.9%-12.6%) primates, consistent with their relative growth rates also being intermediate. Compared to these cercopithecid monkeys, platyrrhine primates have both higher relative growth rates and higher milk energy from protein, while apes tend to be lower in both.


Assuntos
Leite , Papio anubis , Animais , Feminino , Lactação , Macaca mulatta , Nutrientes , Papio
3.
J Med Primatol ; 50(5): 273-275, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34378228

RESUMO

We measured walking speed in baboons (67 female, 36 male; 5-22 years) to develop regression formulas to predict biological age. The final model strongly predicted age from just speed and sex. Walking speed is a valuable baboon aging biomarker. We present the first male speed data in a nonhuman primate.


Assuntos
Envelhecimento , Velocidade de Caminhada , Animais , Feminino , Masculino , Papio
4.
Horm Behav ; 134: 105020, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34391183

RESUMO

Environmental challenges in the form of temperature extremes and unusual precipitation, which may lead to prolonged periods outside the thermoneutral zone, can be detrimental to animal physiology. Chacma baboons in the Cape Peninsula of South Africa, one of the highest latitudes at which nonhuman primates are found, experience extremes of both temperature and rainfall, as well as seasonal differences in day length that require animals to condense their daily routine into dramatically reduced daylight hours. Here we examine the effects of these climatic factors on the behavior (activity budgets and foraging patterns) and physiology (fecal glucocorticoid concentrations) of adult females (N = 33) in three groups of chacma baboons (Papio ursinus) inhabiting the Cape Peninsula, where temperatures ranged from 7 to 39 °C, monthly rainfall ranged from 2 to 158 mm, and day length varied by 4.5 h across seasons. Climatic variables showed a clear relationship to female baboon glucocorticoid concentrations, which significantly increased with lower temperatures, higher rainfall and shorter day lengths. Activity budgets also differed between summer and winter, with females generally spending less time socializing, moving and resting in the winter compared to summer, with some differences between troops in their feeding-related activities. Cold temperatures accompanied by rainfall and short day lengths may thus represent an ecological constraint for this population. This study highlights the potential impact of anthropogenic climate change on the physiology, behavior, and, ultimately, survival of wildlife populations.


Assuntos
Comportamento Alimentar , Papio ursinus , Animais , Feminino , Papio , Estações do Ano , África do Sul
5.
Nutrients ; 13(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445051

RESUMO

Intrauterine growth restriction (IUGR) is associated with reduced placental amino acid transport (AAT). However, it remains to be established if changes in AAT contribute to restricted fetal growth. We hypothesized that reduced in vivo placental AAT precedes the development of IUGR in baboons with maternal nutrient restriction (MNR). Baboons were fed either a control (ad libitum) or MNR diet (70% of control diet) from gestational day (GD) 30. At GD 140, in vivo transplacental AA transport was measured by infusing nine (13)C- or (2)H-labeled essential amino acids (EAAs) as a bolus into the maternal circulation at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each EAA was measured. Microvillous plasma membrane (MVM) system A and system L transport activity were determined. Fetal and placental weights were not significantly different between MNR and control. In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly decreased for tryptophan in MNR. MVM system A and system L activity was markedly reduced in MNR. Reduction of in vivo placental amino acid transport precedes fetal growth restriction in the non-human primate, suggesting that reduced placental amino acid transfer may contribute to IUGR.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Dieta com Restrição de Proteínas , Retardo do Crescimento Fetal/etiologia , Troca Materno-Fetal , Placenta/metabolismo , Animais , Transporte Biológico , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/fisiopatologia , Idade Gestacional , Fenômenos Fisiológicos da Nutrição Materna , Papio , Gravidez
6.
Proc Biol Sci ; 288(1955): 20210839, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34315256

RESUMO

When members of a group differ in locomotor capacity, coordinating collective movement poses a challenge: some individuals may have to move faster (or slower) than their preferred speed to remain together. Such compromises have energetic repercussions, yet research in collective behaviour has largely neglected locomotor consensus costs. Here, we integrate high-resolution tracking of wild baboon locomotion and movement with simulations to demonstrate that size-based variation in locomotor capacity poses an obstacle to the collective movement. While all baboons modulate their gait and move-pause dynamics during collective movement, the costs of maintaining cohesion are disproportionately borne by smaller group members. Although consensus costs are not distributed equally, all group-mates do make locomotor compromises, suggesting a shared decision-making process drives the pace of collective movement in this highly despotic species. These results highlight the importance of considering how social dynamics and locomotor capacity interact to shape the movement ecology of group-living species.


Assuntos
Comportamento Cooperativo , Comportamento Social , Animais , Humanos , Locomoção , Papio
7.
J Am Assoc Lab Anim Sci ; 60(4): 484-488, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34193333

RESUMO

Alopecia occurs frequently in captive populations of nonhuman primates. Because multiple factors can play a role in alopecia, a better understanding of its etiology will help identify potential welfare concerns. The purpose of this study was to investigate risk factors for alopecia in a breeding colony of baboons with a focus on pregnancy and age. Alopecia was scored on a scale of 0 (no alopecia) to 5 (severe alopecia) in 253 female baboons during routine physicals. The subjects ranged in age from 4 to 23 y (Mean = 9.6) and were categorized as pregnant (n = 83), nursing (n = 60) or control (n = 110). Resulting alopecia scores were combined into 2 categories (mild = 0 or 1; moderate = 2 or 3); no animals scored a 4 or 5. Significantly more pregnant females had moderate alopecia than did control females. There was no effect of age on alopecia. An unexpected outcome was that among nursing females, more of those with female infants had moderate alopecia than did those with male infants. The impact of the infant's sex on alopecia may be due to sex differences in maternal contact or maternal investment. This information adds to our understanding of alopecia risk factors in captive nonhuman primates.


Assuntos
Alopecia , Papio hamadryas , Alopecia/epidemiologia , Alopecia/veterinária , Animais , Feminino , Masculino , Papio , Gravidez
9.
Science ; 373(6551): 181-186, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244407

RESUMO

Relatives have more similar gut microbiomes than nonrelatives, but the degree to which this similarity results from shared genotypes versus shared environments has been controversial. Here, we leveraged 16,234 gut microbiome profiles, collected over 14 years from 585 wild baboons, to reveal that host genetic effects on the gut microbiome are nearly universal. Controlling for diet, age, and socioecological variation, 97% of microbiome phenotypes were significantly heritable, including several reported as heritable in humans. Heritability was typically low (mean = 0.068) but was systematically greater in the dry season, with low diet diversity, and in older hosts. We show that longitudinal profiles and large sample sizes are crucial to quantifying microbiome heritability, and indicate scope for selection on microbiome characteristics as a host phenotype.


Assuntos
Bactérias/classificação , Meio Ambiente , Microbioma Gastrointestinal/genética , Papio/microbiologia , Actinobacteria/classificação , Actinobacteria/genética , Actinobacteria/crescimento & desenvolvimento , Actinobacteria/isolamento & purificação , Envelhecimento , Animais , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bacteroidetes/classificação , Bacteroidetes/genética , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/isolamento & purificação , Dieta , Fezes/microbiologia , Feminino , Firmicutes/classificação , Firmicutes/genética , Firmicutes/crescimento & desenvolvimento , Firmicutes/isolamento & purificação , Genótipo , Humanos , Masculino , Papio/genética , Fenótipo , Estações do Ano , Comportamento Social
10.
Vaccine ; 39(30): 4063-4071, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34140172

RESUMO

Respiratory syncytial virus (RSV) is the major viral respiratory pathogen for human infants and children. Despite a severe global burden incurred by annual RSV epidemics, there is no licensed RSV vaccine. We have developed an RSV vaccine from a human RSV strain from which the gene for the viral M protein has been deleted ("Mnull RSV"). RSV infects airway cells and produces each of its proteins. The M protein is responsible for reassembling the various other synthesized viral proteins into new, intact virus. In the absence of the M protein, therefore, reassembly does not occur, and the Mnull RSV does not replicate. We vaccinated 2-week old infant baboons with Mnull RSV either intranasally (IN) or directly into the lung (intratracheal, or IT), then infected these animals by inoculating human RSV directly into the lung. IN vaccination induced inconsistent serum RSV neutralizing antibody (NA) responses, but provided moderate reductions in respiratory rates, overall signs of illness and viral replication in bronchoalveolar lavage (BAL) fluid following infection. Intratracheal vaccination induced much stronger RSV NA responses, which persisted for at least 4-6 months. Following RSV infection, animals vaccinated by the IT route had much greater reductions in tachypnea and work of breathing than animals vaccinated IN, and had undetectable amounts of virus in BAL fluids. These results support the further development of IT Mnull RSV vaccination to reduce the impact of RSV infection in humans.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Criança , Humanos , Lactente , Papio , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinação , Replicação Viral
11.
Geroscience ; 43(4): 2067-2085, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089175

RESUMO

Aging is associated with progressive loss of cellular homeostasis resulting from intrinsic and extrinsic challenges. Lack of a carefully designed, well-characterized, precise, translational experimental model is a major limitation to understanding the cellular perturbations that characterize aging. Here, we tested the feasibility of primary fibroblasts isolated from nonhuman primates (baboons) as a model of cellular resilience in response to homeostatic challenge. Using a real-time live-cell imaging system, we precisely defined a protocol for testing effects of prooxidant compounds (e.g., hydrogen peroxide (H2O2), paraquat), thapsigargin, dexamethasone, and a low glucose environment on cell proliferation in fibroblasts derived from baboons across the life course (n = 11/sex). Linear regression analysis indicated that donor age significantly reduced the ability of cells to proliferate following exposure to H2O2 (50 and 100 µM) and paraquat (100 and 200 µM) challenges in cells from males (6.4-21.3 years; average lifespan 21 years) but not cells from females (4.3-15.9 years). Inhibitory effects of thapsigargin on cell proliferation were dependent on challenge duration (2 vs 24 h) and concentration (0.1 and 1 µM). Cells from older females (14.4-15.9 years) exhibited greater resilience to thapsigargin (1 µM; 24 h) and dexamethasone (500 µM) challenges than did those from younger females (4.3-6.7 years). The cell proliferation response to low glucose (1 mM) was reduced with age in both sexes. These data indicate that donor's chronological age and sex are important variables in determining fibroblast responses to metabolite and other challenges.


Assuntos
Glucocorticoides , Peróxido de Hidrogênio , Animais , Proliferação de Células , Feminino , Glucocorticoides/farmacologia , Masculino , Estresse Oxidativo , Papio
12.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L321-L335, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34105359

RESUMO

Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with Streptococcus pneumoniae [5 × 109 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n = 6) or sham treatment (n = 6) for 4 h at 30 h after inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 h, necropsy was performed. Inoculated animals developed severe pneumonia and septic shock. Compared with sham-treated animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P < 0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated bronchoalveolar lavage (BAL) CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3 inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines and is renal protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.


Assuntos
Hemofiltração , Heparina/química , Pneumonia Pneumocócica/terapia , Choque Séptico/terapia , Streptococcus pneumoniae/metabolismo , Animais , Citocinas/metabolismo , Masculino , Papio , Projetos Piloto , Pneumonia Pneumocócica/sangue , Choque Séptico/sangue
13.
Parasit Vectors ; 14(1): 316, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112218

RESUMO

BACKGROUND: Cryptosporidiosis causes high morbidity and mortality in children under 2 years of age globally. The lack of an appropriate animal model that mimics the pathogenesis of disease in humans has hampered the development and testing of potential therapeutic options. This study aimed to develop and validate an infant baboon infection model of cryptosporidiosis. METHODS: Eighteen immunocompetent weaned infant baboons aged 12 to 16 months were used. The animals were n = 3 controls and three experimental groups of n = 5 animals each inoculated with Cryptosporidium parvum oocysts as follows: group 1: 2 × 104, group 2: 2 × 105, group 3: 2 × 106 followed by daily fecal sampling for oocyst evaluation. Blood sampling for immunological assay was done on the day of infection and weekly thereafter until the end of the experiment, followed by necropsy and histopathology. Statistical analysis was performed using R, SPSS, and GraphPad Prism software. Analysis of variance (ANOVA) and Bonferroni post hoc tests were used for comparison of the means, with p < 0.05 considered as a significant difference. Correlation coefficient and probit analysis were also performed. RESULTS: In all experimental animals but not controls, the onset of oocyst shedding occurred between days 2 and 4, with the highest oocyst shedding occurring between days 6 and 28. Histological analysis revealed parasite establishment only in infected animals. Levels of cytokines (TNF-α, IFN-γ, and IL-10) increased significantly in experimental groups compared to controls. CONCLUSION: For developing a reproducible infant baboon model, 2 × 104 oocysts were an effective minimum quantifiable experimental infection dose.


Assuntos
Criptosporidiose/parasitologia , Cryptosporidium parvum/crescimento & desenvolvimento , Modelos Animais de Doenças , Papio , Fatores Etários , Animais , Criptosporidiose/fisiopatologia , Fezes/parasitologia , Feminino , Masculino , Oocistos/patogenicidade , Contagem de Ovos de Parasitas , Desmame
14.
Front Immunol ; 12: 667093, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177906

RESUMO

Background: Perioperative cardiac xenograft dysfunction (PCXD) describes a rapidly developing loss of cardiac function after xenotransplantation. PCXD occurs despite genetic modifications to increase compatibility of the heart. We report on the incidence of PCXD using static preservation in ice slush following crystalloid or blood-based cardioplegia versus continuous cold perfusion with XVIVO© heart solution (XHS) based cardioplegia. Methods: Baboons were weight matched to genetically engineered swine heart donors. Cardioplegia volume was 30 cc/kg by donor weight, with del Nido cardioplegia and the addition of 25% by volume of donor whole blood. Continuous perfusion was performed using an XVIVO © Perfusion system with XHS to which baboon RBCs were added. Results: PCXD was observed in 5/8 that were preserved with crystalloid cardioplegia followed by traditional cold, static storage on ice. By comparison, when blood cardioplegia was used followed by cold, static storage, PCXD occurred in 1/3 hearts and only in 1/5 hearts that were induced with XHS blood cardioplegia followed by continuous perfusion. Survival averaged 17 hours in those with traditional preservation and storage, followed by 11.47 days and 15.03 days using blood cardioplegia and XHS+continuous preservation, respectively. Traditional preservation resulted in more inotropic support and higher average peak serum lactate 14.3±1.7 mmol/L compared to blood cardioplegia 3.6±3.0 mmol/L and continuous perfusion 3.5±1.5 mmol/L. Conclusion: Blood cardioplegia induction, alone or followed by XHS perfusion storage, reduced the incidence of PCXD and improved graft function and survival, relative to traditional crystalloid cardioplegia-slush storage alone.


Assuntos
Transplante de Coração , Animais , Parada Cardíaca Induzida/métodos , Xenoenxertos , Papio , Perfusão , Suínos , Transplante Heterólogo
15.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071951

RESUMO

Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Inflamação/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Celecoxib/farmacologia , Química Farmacêutica/métodos , Feminino , Humanos , Cinética , Ligantes , Imageamento por Ressonância Magnética , Masculino , Camundongos , Papio , Permeabilidade , Ratos
16.
Xenotransplantation ; 28(4): e12701, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34053125

RESUMO

The current evidence is that sensitization to a pig xenograft does not result in the development of antibodies that cross-react with alloantigens, and therefore, sensitization to a pig xenograft would not be detrimental to the outcome of a subsequent allograft. This evidence relates almost entirely to the transplantation of cells or organs from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. However, it is not known whether recipients of triple-knockout (TKO) pig grafts who become sensitized to TKO pig antigens develop antibodies that cross-react with alloantigens and thus be detrimental to a subsequent organ allotransplant. We identified a single baboon (B1317) in which no (or minimal) serum anti-TKO pig antibodies could be measured-in our experience unique among baboons. We sensitized it by repeated subcutaneous injections of TKO pig peripheral blood mononuclear cells (PBMCs) in the absence of any immunosuppressive therapy. After TKO pig PBMC injection, there was a transient increase in anti-TKO pig IgM, followed by a sustained increase in IgG binding to TKO cells. In contrast, there was no serum IgM or IgG binding to PBMCs from any of a panel of baboon PBMCs (n = 8). We conclude that sensitization to TKO pig PBMCs in the baboon did not result in the development of antibodies that also bound to baboon cells, suggesting that there would be no detrimental effect of sensitization on a subsequent organ allotransplant.


Assuntos
Leucócitos Mononucleares , Animais , Animais Geneticamente Modificados , Xenoenxertos , Papio , Suínos , Transplante Heterólogo
17.
Epilepsy Behav ; 120: 107973, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962250

RESUMO

OBJECTIVE: To evaluate the efficacy of cortical responsive neurostimulation (CRN) in a male baboon with epilepsy and with genetic generalized epilepsy (GGE), as well as the alteration of seizure patterns and their circadian rhythms due to treatment. METHODS: The baboon was implanted with two subdural frontoparietal strips, bridging the medial central sulci bilaterally. Electrocorticography (ECoG) data were downloaded daily during a three-month baseline, then every 2-3 days over a five-month treatment period. Long episodes, reflecting ictal or interictal epileptic discharges, were also quantified. RESULTS: Twenty-three generalized tonic-clonic seizures (GTCS) and 2 episodes of nonconvulsive status epilepticus (NCSE) were recorded at baseline (median 8 events/month), whereas 26 GTCS were recorded under treatment (median 5/month). Similarly, daily indices of long episodes decreased from 0.46 at baseline to 0.29 with treatment. Ictal ECoG patterns and the circadian distribution of GTCS were also altered by RNS therapy. SIGNIFICANCE: This case study provides the proof-of-concept for RNS therapy in the baboon model of GGE. Cortical responsive neurostimulation (CRN) demonstrated a 38% median reduction in GTCS. Distinct ictal patterns were identified, which changed over the treatment period; the circadian pattern of his GTCS also shifted gradually from night to daytime with treatment. Future studies targeting the thalamic nuclei, or combining cortical and subcortical sites, may further improve detection and control of GTCS as well as other generalized seizure types. More broadly, this study demonstrates opportunities for evaluating seizure detection as well as chronic therapeutic interventions over long term in the baboon.


Assuntos
Epilepsia Generalizada , Epilepsia , Estado Epiléptico , Animais , Eletroencefalografia , Humanos , Masculino , Papio , Convulsões
18.
J Vet Pharmacol Ther ; 44(5): 836-841, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33963570

RESUMO

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.


Assuntos
Bordetella bronchiseptica , Animais , Antibacterianos/uso terapêutico , Bordetella pertussis , Papio
19.
Epilepsy Behav ; 121(Pt A): 108012, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022622

RESUMO

The baboon offers a natural model for genetic generalized epilepsy with photosensitivity. In this review, we will summarize some of the more important clinical, neuroimaging, and elctrophysiological findings form recent work performed at the Southwest National Primate Research Center (SNPRC, Texas Biomedical Research Institute, San Antonio, Texas), which houses the world's largest captive baboon pedigree. Due to the phylogenetic proximity of the baboon to humans, many of the findings are readily translatable, but there may be some important differences, such as the mutlifocality of the ictal and interictal epileptic discharges (IEDs) on intracranial electroencephalography (EEG) and greater parieto-occipital connectivity of baboon brain networks compared to juvenile myoclonic epilepsy in humans. Furthermore, there is still limited knowledge of the natural history of the epilepsy, which could be transformative for research into epileptogenesis in genetic generalized epilepsy (GGE) and sudden unexpected death in epilepsy (SUDEP).


Assuntos
Eletroencefalografia , Epilepsia Generalizada , Animais , Papio , Filogenia , Texas
20.
Xenotransplantation ; 28(4): e12700, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036638

RESUMO

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs) and expressing "protective" human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n = 5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n = 5). An anti-CD40mAb-based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90-260 days (median 237, mean 196 days), with histopathological features of antibody-mediated rejection in two kidneys. Group2 kidneys functioned for 0-183 days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody-mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.


Assuntos
Transplante de Rim , Animais , Animais Geneticamente Modificados , Rejeição de Enxerto , Leucócitos Mononucleares , Ácidos Neuramínicos , Papio , Suínos , Transplante Heterólogo
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