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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360852

RESUMO

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.


Assuntos
Antidepressivos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Ácidos Graxos Insaturados/metabolismo , Macaca mulatta , Masculino
3.
Neurotoxicol Teratol ; 77: 106841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31863841

RESUMO

"Intralitter likeness," the possibility that the shared genetics and/or maternal environment in multiparous species causes strong similarity for outcome variables in littermates, violates a core statistical assumption, that of observation independence, when littermate outcomes are analyzed. Intralitter likeness has been of major concern to investigators for several decades. Despite consensus and guidance, many research reports in the rodent literature continue to ignore intralitter likeness. A historical review of the literature revealed that the long-preferred solution was to include litter as an effect in statistical models. Limitations in software development and computing capacity prior to 1990, however, appear to have led researchers and guidance authorities to endorse instead the method of using one value per litter. Here, the history of discussions regarding intralitter likeness in developmental neurotoxicological research is reviewed; growing knowledge regarding the biological bases and significance of intralitter likeness is discussed; principles underlying the use of litter as a random effect in mixed models are presented; statistical examples are provided illustrating the advantages and critical importance of including litter as a random effect in mixed models; and results using all data points (all pups from all litters) with litter as a random effect, are compared to results based on random selections of representative littermates. Mixed models with litter included as a random effect have distinct advantages for the analysis of clustered data. Modern computing capacity provides ready accessibility to mixed models for all researchers. Accessibility however does not preclude the need for appropriate expertise and consultation in the use of mixed (hierarchical) models.


Assuntos
Interpretação Estatística de Dados , Tamanho da Ninhada de Vivíparos , Modelos Estatísticos , Animais
4.
Artigo em Inglês | MEDLINE | ID: mdl-31471184

RESUMO

BACKGROUND: The potential long-term effects of childhood fluoxetine therapy on brain serotonin systems were studied using a nonhuman primate model, the rhesus monkey. METHODS: Juvenile male rhesus (1-4 years of age, corresponding to 4-11 years of age in children) were treated orally with fluoxetine (2 mg/kg) or vehicle daily for 2 years and removed from treatment during the third year. Each treatment group was assigned an equal number of subjects with low and high transcription polymorphisms of MAOA. One year after discontinuation of treatment, positron emission tomography scans were conducted (n = 8 treated monkeys, n = 8 control monkeys) using [11C]DASB to quantify serotonin transporter in 16 cortical and subcortical regions. RESULTS: Fluoxetine-treated monkeys with MAOA low transcription polymorphism had significantly lower [11C]DASB binding potentials than control monkeys. This finding was seen throughout the brain but was strongest in prefrontal and cingulate cortices. The MAOA × fluoxetine interaction was enhanced by binding potentials that were nonsignificantly higher in monkeys with high transcription polymorphism. CONCLUSIONS: Juvenile fluoxetine treatment has residual posttreatment effects on brain serotonin transporter that depend on MAOA genotype. MAOA genotype may be important to consider when treating children with fluoxetine.


Assuntos
Encéfalo/efeitos dos fármacos , Fluoxetina/farmacologia , Monoaminoxidase/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Fatores Etários , Compostos de Anilina/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Feminino , Fluoxetina/administração & dosagem , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Ligação Proteica , Inibidores de Captação de Serotonina/administração & dosagem , Sulfetos/farmacocinética , Fatores de Tempo
5.
PLoS One ; 13(2): e0191909, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29444171

RESUMO

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and ß-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways.


Assuntos
Barreira Hematoencefálica , Encéfalo/metabolismo , Cognição , Dieta Ocidental , Receptores de LDL/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Front Pediatr ; 6: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29473029

RESUMO

Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years) prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.

7.
Dev Cogn Neurosci ; 26: 52-61, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28521247

RESUMO

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.


Assuntos
Cognição/efeitos dos fármacos , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Animais , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Macaca mulatta , Masculino , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia
9.
Behav Neurol ; 2017: 5238402, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29358844

RESUMO

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV's beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms.


Assuntos
Aciclovir/farmacologia , Encefalite por Herpes Simples/tratamento farmacológico , Imunoglobulinas Intravenosas/farmacologia , Animais , Feminino , Herpesvirus Humano 1/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Eur Neuropsychopharmacol ; 26(7): 1110-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27084303

RESUMO

We report on biochemical pathways perturbed upon chronic fluoxetine administration to juvenile macaques using global metabolomics analyses of fibroblasts derived from skin biopsies. After exposure to tissue culture conditions confounding environmental factors are eliminated and identification of metabolites whose levels are affected by the drug become apparent with a better signal-to-noise ratio compared to data obtained from plasma and cerebrospinal fluid (CSF). Levels of more than 200 metabolites were analyzed to interrogate affected molecular pathways and identify biomarkers of drug response. In addition, we have correlated the metabolomics results with monoamine oxidase (MAOA) genotype and impulsivity behavioral data. Affected pathways include Purine and Pyrimidine metabolisms that have been previously implicated to contribute to neuropsychiatric disorders.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fluoxetina/farmacologia , Metaboloma/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Biomarcadores Farmacológicos/metabolismo , Células Cultivadas , Estudos de Coortes , Comportamento Impulsivo/fisiologia , Macaca mulatta , Masculino , Metabolômica , Monoaminoxidase/genética , Pele/efeitos dos fármacos , Pele/metabolismo
11.
Neurotoxicol Teratol ; 55: 1-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26956991

RESUMO

Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey's genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children.


Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Fluoxetina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Privação do Sono/induzido quimicamente , Actigrafia , Animais , Genótipo , Macaca mulatta , Masculino , Monoaminoxidase/genética , Polimorfismo Genético , Sono/efeitos dos fármacos
12.
Neuropharmacology ; 105: 553-560, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26905291

RESUMO

Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n = 16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitation and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Psicotrópicos/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Comportamento Social , Animais , Comportamento Animal/fisiologia , Abrigo para Animais , Macaca mulatta , Masculino , Repetições Minissatélites , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Grupo Associado , Variantes Farmacogenômicos , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Transcrição Genética
13.
Bone ; 79: 162-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26067181

RESUMO

Male rhesus monkeys received a therapeutic oral dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine daily from 1 to 3 years of age. Puberty is typically initiated between 2 and 3 years of age in male rhesus and reproductive maturity is reached at 4 years. The study group was genotyped for polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (SERT) genes that affect serotonin neurotransmission. Growth was assessed with morphometrics at 4 month intervals and radiographs of long bones were taken at 12 month intervals to evaluate skeletal growth and maturation. No effects of fluoxetine, or MAOA or SERT genotype were found for growth during the first year of the study. Linear growth began to slow during the second year of the study and serotonin reuptake transporter (SERT) long polymorphic region (5HTTLPR) polymorphism effects with drug interactions emerged. Monkeys with two SERT 5HTTLPR L alleles (LL, putative greater transcription) had 25-39% less long bone growth, depending on the bone, than monkeys with one S and one L allele (SL). More advanced skeletal maturity was also seen in the LL group, suggesting earlier onset of puberty. An interaction between 5HTTLPR polymorphisms and fluoxetine was identified for femur and tibia growth; the 5HTTLPR effect was seen in controls (40% less growth for LL) but not in the fluoxetine treated group (10% less growth for LL). A role for serotonin in peripubertal skeletal growth and maturation has not previously been investigated but may be relevant to treatment of children with SSRIs.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Fluoxetina/efeitos adversos , Polimorfismo de Nucleotídeo Único , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/efeitos adversos , Animais , Genótipo , Macaca mulatta , Masculino
14.
J Nutr ; 145(3): 647-53, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25733484

RESUMO

BACKGROUND: Anemia during the third trimester of fetal development affects one-third of the pregnancies in the United States and has been associated with postnatal behavioral outcomes. This study examines how fetal iron deficiency (ID) interacts with the fetal monoamine oxidase A (MAOA) genotype. MAOA metabolizes monoamine neurotransmitters. MAOA polymorphisms in humans affect temperament and modify the influence of early adverse environments on later behavior. OBJECTIVE: The aim of the study was to advance translation of developmental ID research in animal models by taking into account genetic factors that influence outcomes in human populations. METHODS: Male infant rhesus monkeys 3-4 mo old born to mothers fed an ID (10 ppm iron) diet were compared with controls (100 ppm iron). Infant monkeys with high- or low-transcription rate MAOA polymorphisms were equally distributed between diet groups. Behavioral responses to a series of structured experiences were recorded during a 25-h separation of the infants from their mothers. RESULTS: Infant monkeys with low-transcription MAOA polymorphisms more clearly demonstrated the following ID effects suggested in earlier studies: a 4% smaller head circumference, a 39% lower cortisol response to social separation, a 129% longer engagement with novel visual stimuli, and 33% lesser withdrawal in response to a human intruder. The high MAOA genotype ID monkeys demonstrated other ID effects: less withdrawal and emotionality after social separation and lower "fearful" ratings. CONCLUSION: MAOA × ID interactions support the role of monoamine neurotransmitters in prenatal ID effects in rhesus monkeys and the potential involvement of common human polymorphisms in determining the pattern of neurobehavioral effects produced by inadequate prenatal nutrition.


Assuntos
Anemia Ferropriva/genética , Emoções/fisiologia , Transtornos da Nutrição Fetal/genética , Feto/enzimologia , Genótipo , Anemia Ferropriva/enzimologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Transtornos da Nutrição Fetal/enzimologia , Hidrocortisona/metabolismo , Macaca mulatta , Masculino , Monoaminoxidase/genética , Monoaminoxidase/metabolismo
15.
Br J Nutr ; 112(9): 1478-83, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25351859

RESUMO

Individual differences in sleep patterns of children may have developmental origins. In the present study, two factors known to influence behavioural development, monoamine oxidase A (MAOA) genotype and prenatal Fe-deficient (ID) diet, were examined for their influences on sleep patterns in juvenile rhesus monkeys. Sleep patterns were assessed based on a threshold for inactivity as recorded by activity monitors. Pregnant monkeys were fed diets containing either 100 parts per million (ppm) Fe (Fe sufficient, IS) or 10 ppm Fe (ID). At 3-4 months of age, male offspring were genotyped for polymorphisms of the MAOA gene that lead to high or low transcription. At 1 and 2 years of age, sleep patterns were assessed. Several parameters of sleep architecture changed with age. At 1 year of age, monkeys with the low-MAOA genotype demonstrated a trend towards more sleep episodes at night compared with those with the high-MAOA genotype. When monkeys reached 2 years of age, prenatal ID reversed this trend; ID in the low-MAOA group resulted in sleep fragmentation, more awakenings at night and more sleep episodes during the day when compared with prenatal IS in this genotype. The ability to consolidate sleep during the dark cycle was disrupted by prenatal ID, specifically in monkeys with the low-MAOA genotype.


Assuntos
Ferro/deficiência , Macaca mulatta/fisiologia , Monoaminoxidase/genética , Sono/fisiologia , Anemia Ferropriva/complicações , Animais , Feminino , Genótipo , Ferro na Dieta/administração & dosagem , Macaca mulatta/genética , Masculino , Repetições Minissatélites , Modelos Animais , Polimorfismo Genético , Gravidez , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Sono/genética
16.
Psychopharmacology (Berl) ; 231(20): 4041-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24700388

RESUMO

RATIONALE: The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only psychopharmacological agent approved for use in children. While short-term studies of side effects have been performed, long-term consequences for brain development are not known. Such studies can be performed in appropriate animal models if doses modeling therapeutic use in children are known. OBJECTIVES: The goal of this study was to identify a daily dose of fluoxetine in juvenile monkeys which would result in serum fluoxetine and norfluoxetine concentrations in the therapeutic range for children. METHODS: Juvenile (2.5-year-old rhesus monkeys, n = 6) received single administration of doses of 1, 2, and 4 mg/kg day fluoxetine on a background of chronic dosing at an intermediate level to provide steady-state conditions to model therapeutic administration. Using nonlinear modeling, standard pharmacokinetic parameters were derived. Cerebrospinal fluid monoamine neurotransmitters were assayed to confirm the pharmacological effects. RESULTS: Dose-dependent area under the curve (AUC) and C max values were seen, while T max and absorption/elimination half-lives were minimally influenced by dose. A dosage of 2 mg/kg day given over a 14-week period led to steady-state serum concentrations of active agent (fluoxetine + norfluoxetine) similar to those recorded from drug monitoring studies in children. Cisternal cerebrospinal fluid concentrations of serotonin increased significantly over the 14-week period, while concentrations of the serotonin metabolite (5-HIAA) were lower but not significantly different. CONCLUSIONS: A dose of 2 mg/kg day fluoxetine in juvenile rhesus monkeys provides an internal dose similar to therapeutic use in children and will help establish a valuable animal model for understanding fluoxetine's therapeutic and potential adverse effects in children.


Assuntos
Fluoxetina/farmacocinética , Inibidores de Captação de Serotonina/farmacocinética , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Animais , Relação Dose-Resposta a Droga , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Macaca mulatta , Masculino , Modelos Animais , Serotonina/líquido cefalorraquidiano
17.
Am J Hematol ; 89(5): 459-66, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24415575

RESUMO

Most human physiologic set points like body temperature are tightly regulated and show little variation between healthy individuals. Red blood cell (RBC) characteristics such as hematocrit and mean cell volume are stable within individuals but can vary by 20% from one healthy person to the next. The mechanisms for the majority of this inter-individual variation are unknown and do not appear to involve common genetic variation. Here, we show that environmental conditions present during development, namely in utero iron availability, can exert long-term influence on a set point related to the RBC life cycle. In a controlled study of rhesus monkeys and a retrospective study of humans, we use a mathematical model of in vivo RBC population dynamics to show that in utero iron deficiency is associated with a lowered threshold for RBC clearance and turnover. This in utero effect is plastic, persisting at least 2 years after birth and after the cessation of iron deficiency. Our study reports a rare instance of developmental plasticity in the human hematologic system and also shows how mathematical modeling can be used to identify cellular mechanisms involved in the adaptive control of homeostatic set points.


Assuntos
Anemia Ferropriva/sangue , Eritrócitos Anormais/citologia , Eritrócitos/citologia , Complicações Hematológicas na Gravidez/sangue , Animais , Eritrócitos/patologia , Eritrócitos Anormais/patologia , Feminino , Hematócrito/métodos , Homeostase , Humanos , Macaca mulatta , Masculino , Modelos Biológicos , Gravidez , Estudos Retrospectivos
18.
Hum Mol Genet ; 23(9): 2447-58, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24352790

RESUMO

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity prior to death between 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.


Assuntos
Éxons/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Animais , Western Blotting , Feminino , Imunofluorescência , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética
19.
Alcohol Clin Exp Res ; 38(2): 551-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24164332

RESUMO

BACKGROUND: Minimal scientific information is available to inform public health policy on binge drinking prior to pregnancy detection. The nonhuman primate provides a valuable animal model for examining consequences to reproduction and offspring function that may result from this common pattern of alcohol abuse. METHODS: Adult female rhesus monkeys were dosed with 1.5 g/kg per day ethanol (EtOH) by gavage 2 d/wk beginning 7 months prior to mating and continuing to pregnancy detection at 19 to 20 days gestation. Postnatal evaluation of control (n = 6) and EtOH-treated (n = 4) infants included a neonatal neurobehavioral assessment, a visual paired comparison (cognitive) test at 35 days of age, and mother-infant interaction at 100 to 112 days of age. RESULTS: Alcohol-exposed neonates did not differ from controls in posture and reflex measures. Longer durations of visual fixation, suggesting slower visual processing, and greater novelty preference were seen in the alcohol group. At early weaning age, as infants spent more time away from their dams, more of the reunions between mother and infant were initiated by the mothers in the alcohol-exposed group, suggesting a more immature mother-infant interaction. CONCLUSIONS: Intermittent high-dose alcohol exposure (binge drinking) discontinued at early pregnancy detection in rhesus monkey can result in altered behavioral function in the infant. Mediating effects on ovum, reproductive tract, and early embryo can be explored in this model. Studies of longer-term consequences in human populations and animal models are needed.


Assuntos
Comportamento Animal/efeitos dos fármacos , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Idade Gestacional , Macaca mulatta , Comportamento Materno/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Gravidez , Reflexo/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos
20.
Am J Primatol ; 75(11): 1139-46, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23824639

RESUMO

Sources of variability in hemoglobin concentration in blood were examined in over 600 rhesus infants at the California National Primate Research Center who had complete blood counts (CBCs) conducted at 3-4 months of age. These infants were born and raised in outdoor social housing. Hemoglobin values ranged from 8.5 to 15.3 µg/dl with a mean and standard deviation of 12.2±0.8 µg/dl. As expected, hemoglobin was strongly associated with the number of red blood cells (RBCs). Plasma protein concentration, an indicator of blood volume, was not a predictor. Associations with infant age, weight and sex, infant serum cortisol, dam's reproductive history, and birth year, month and location were evaluated in regression analyses. Cage of origin, maternal age at delivery and infant weight were associated with hemoglobin concentrations. Unexpectedly, serum cortisol, determined at the same time as CBC samples were taken, was the strongest predictor of hemoglobin concentration. The basis, as well as the functional significance, of the variation in infant hemoglobin and its association with serum cortisol in this population of rhesus fed a nutritionally optimized diet and housed under standard conditions is relevant to the development of both nonhuman and human primate infants.


Assuntos
Hemoglobinas/análise , Macaca mulatta/sangue , Idade Materna , Desmame , Animais , Contagem de Células Sanguíneas , Peso Corporal , California , Dieta/veterinária , Meio Ambiente , Contagem de Eritrócitos , Feminino , Abrigo para Animais , Hidrocortisona/sangue , Masculino
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