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1.
Horm Behav ; 158: 105468, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38101144

RESUMO

Hormonal contraceptives are utilized by millions of women worldwide. However, it remains unclear if these powerful endocrine modulators may alter cognitive function. Habit formation involves the progression of instrumental learning as it goes from being a conscious goal-directed process to a cue-driven automatic habitual motor response. Dysregulated goal and/or habit is implicated in numerous psychopathologies, underscoring the relevance of examining the effect of hormonal contraceptives on goal-directed and habitual behavior. This study examined the effect of levonorgestrel (LNG), a widely used progestin-type contraceptive, on the development of habit in intact female rats. Rats were implanted with subcutaneous capsules that slowly released LNG over the course of the experiment or cholesterol-filled capsules. All female rats underwent operant training followed by reward devaluation to test for habit. One group of females was trained at a level that is sub-threshold to habit, while another group of females was trained to a level well over the habit threshold observed in intact females. The results reveal that all sub-threshold trained rats remained goal-directed irrespective of LGN treatment, suggesting LNG is not advancing habit formation in female rats at this level of reinforcement. However, in rats that were overtrained well above the threshold, cholesterol females showed habitual behavior, thus replicating a portion of our original studies. In contrast, LNG-treated habit-trained rats remained goal-directed, indicating that LNG impedes the development and/or expression of habit following this level of supra-threshold to habit training. Thus, LNG may offset habit formation by sustaining attentional or motivational processes during learning in intact female rats. These results may be clinically relevant to women using this type of hormonal contraceptive as well as in other progestin-based hormone therapies.


Assuntos
Objetivos , Levanogestrel , Humanos , Ratos , Feminino , Animais , Levanogestrel/farmacologia , Progestinas/farmacologia , Condicionamento Operante/fisiologia , Hábitos , Colesterol/farmacologia , Anticoncepcionais/farmacologia
2.
Mol Psychiatry ; 27(4): 2225-2246, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35177824

RESUMO

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.


Assuntos
Ataques Terroristas de 11 de Setembro , Transtornos de Estresse Pós-Traumáticos , Ansiedade , Canais de Cloreto , Expressão Gênica , Humanos , Proteínas de Ligação a RNA , Autorrelato , Ataques Terroristas de 11 de Setembro/psicologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico
3.
Prev Sci ; 23(6): 1029-1040, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35107694

RESUMO

Children with developmental delays or disabilities (DD) are at risk for self-regulation difficulties and behaviour problems compared to typically developing children. Intervening early is crucial to prevent long-term adjustment challenges across home and school contexts. Parenting has been identified as a malleable target of intervention for improving children's adaptive functioning across behavioural, emotional and cognitive domains. Although parent management training (PMT) is an identified best-practice, key questions remain about the critical components of interventions and how novel approaches like video feedback may offer additional benefits. Using a pre-test-post-test one group and superiority design, we evaluated the efficacy of two models of the Keeping Parents Trained and Supported (KEEP) preschool program with parent-only components among 175 families with children diagnosed or at-risk for DD. KEEP-P included core PMT (Oregon Model) methods and KEEP-V integrated KEEP with Filming Interactions to Nurture Development video coaching methods for enhancing developmentally supportive interactions. Intervention outcomes on children's behaviour problems and executive functioning, parenting stress and parent-child relationship quality were compared between groups. Both groups demonstrated significant reductions over time in child behavioural problems, developmental problems and parenting stress. Significant improvements were observed in children's executive functioning, parents' sense of competence and mindfulness in parenting. Group differences were observed in parent's sense of competence, with individuals receiving KEEP-P displaying greater increases over time. Higher intervention dosage predicted a greater reduction in stressful child behaviours and greater improvements in children's inhibitory control.


Assuntos
Tutoria , Comportamento Problema , Pré-Escolar , Humanos , Relações Pais-Filho , Poder Familiar/psicologia , Pais/educação
4.
Brain Behav Immun ; 91: 393-403, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33342465

RESUMO

Increasingly, it has been recognized that analysis at the symptom, rather than diagnostic, level will drive progress in the field of immunopsychiatry. Network analysis offers a useful tool in this pursuit with the ability to identify associations between immune markers and individual symptoms, independent of all other variables modeled. However, investigation into how methodological decisions (i.e., including vs. excluding participants with C-reactive protein (CRP) >10 mg/L, regularized vs. nonregularized networks) influence results is necessary to establish best practices for the use of network analysis in immunopsychiatry. In a sample of 3,464 adult participants from the 2015-2016 National Health and Nutrition Examination Survey dataset, this study found consistent support for associations between CRP and fatigue and changes in appetite and some support for additional CRP-criterion associations. Methodologically, results consistently demonstrated that including individuals with CRP >10 mg/L and estimating nonregularized networks provided better estimates of these associations. Thus, we recommend considering the use of nonregularized networks in immunopsychiatry and inclusion of cases with CRP values >10 mg/L when testing the association between CRP and depression criteria, unless contraindicated by the research question being tested. Additionally, results most consistently suggest that CRP is uniquely related to fatigue and changes in appetite, supporting their inclusion in an immunometabolic phenotype of depression. Finally, these associations suggest that fatigue and changes in appetite might be particularly receptive to anti-inflammatory treatments. However, future research with more nuanced measures is necessary to parse out whether appetite increases or decreases drive this association. Further, longitudinal research is an important next step to test how these relationships manifest over time.


Assuntos
Proteína C-Reativa , Depressão , Adulto , Biomarcadores , Proteína C-Reativa/análise , Humanos , Inflamação , Inquéritos Nutricionais
5.
J Gen Intern Med ; 35(1): 326-330, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31659667

RESUMO

BACKGROUND: Programs for high-need, high-cost (HNHC) patients can improve care and reduce costs. However, it may be challenging to implement these programs in rural and underserved areas, in part due to limited access to specialty consultation. AIM: Evaluate the feasibility of using the Extension for Community Health Outcomes (ECHO) model to provide specialist input to outpatient intensivist teams (OITs) dedicated to caring for HNHC patients. SETTING: Weekly group videoconferencing sessions that connect multidisciplinary specialists with OITs. PARTICIPANTS: Six OITs across New Mexico, typically consisting of a nurse practitioner or physician assistant, a registered nurse, a counselor or social worker, and at least one community health worker. PROGRAM DESCRIPTION: OITs and specialists participated in weekly teleECHO sessions focused on providing the OITs with case-based mentoring and support. PROGRAM EVALUATION: OITs and specialists discussed 427 highly complex patient cases, many of which had social or behavioral health components to address. In 70% of presented cases, the teams changed their care plan for the patient, and 87% reported that they applied what they learned in hearing case presentations to other HNHC patients. DISCUSSION: Pairing the ECHO model with intensive outpatient care is a feasible strategy to support OITs to provide high-quality care for HNHC patients.


Assuntos
Tutoria , Profissionais de Enfermagem , Humanos , Atenção Primária à Saúde , População Rural , Comunicação por Videoconferência
6.
J Gen Intern Med ; 35(1): 21-27, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31667743

RESUMO

BACKGROUND: A small number of high-need patients account for a disproportionate amount of Medicaid spending, yet typically engage little in outpatient care and have poor outcomes. OBJECTIVE: To address this issue, we developed ECHO (Extension for Community Health Outcomes) Care™, a complex care intervention in which outpatient intensivist teams (OITs) provided care to high-need high-cost (HNHC) Medicaid patients. Teams were supported using the ECHO model™, a continuing medical education approach that connects specialists with primary care providers for case-based mentoring to treat complex diseases. DESIGN: Using an interrupted time series analysis of Medicaid claims data, we measured healthcare utilization and expenditures before and after ECHO Care. PARTICIPANTS: ECHO Care served 770 patients in New Mexico between September 2013 and June 2016. Nearly all had a chronic mental illness, and over three-quarters had a chronic substance use disorder. INTERVENTION: ECHO Care patients received care from an OIT, which typically included a nurse practitioner or physician assistant, a registered nurse, a licensed mental health provider, and at least one community health worker. Teams focused on addressing patients' physical, behavioral, and social issues. MAIN MEASURES: We assessed the effect of ECHO Care on Medicaid costs and utilization (inpatient admissions, emergency department (ED) visits, other outpatient visits, and dispensed prescriptions. KEY RESULTS: ECHO Care was associated with significant changes in patients' use of the healthcare system. At 12 months post-enrollment, the odds of a patient having an inpatient admission and an ED visit were each reduced by approximately 50%, while outpatient visits and prescriptions increased by 23% and 8%, respectively. We found no significant change in overall Medicaid costs associated with ECHO Care. CONCLUSIONS: ECHO Care shifts healthcare utilization from inpatient to outpatient settings, which suggests decreased patient suffering and greater access to care, including more effective prevention and early intervention for chronic conditions.


Assuntos
Hospitalização , Medicaid , Serviço Hospitalar de Emergência , Gastos em Saúde , Humanos , Aceitação pelo Paciente de Cuidados de Saúde , Estados Unidos
7.
Brain Behav Immun ; 86: 30-42, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30999015

RESUMO

This study provides a comprehensive review of the published research on the association between early life adversity and markers of inflammation in children and adolescents. We conducted a systematic review of the published literature on the association between early life adversity and markers of inflammation in pediatric populations. To date, 27 studies have been published in this area representing a wide range of global populations and diverse methods of which nearly half were prospective, longitudinal studies. Of these 27, only 12 studies shared an inflammatory outcome with 4 or more other studies; 9 for CRP, and 6 for IL-6. The association between early life adversity and both CRP, z = .07 [.04, .10], and IL-6, z = .17 [-.07, .42], were small and only significant for CRP although comparable in magnitude to the effects observed in adult samples. Descriptively, the association between early life adversity and CRP appeared to be stronger in studies conducted in infants and adolescents compared with middle childhood. There was minimal evidence of publication bias for studies measuring CRP, but evidence of publication bias for studies using IL-6. Eight studies have looked at the association between early life adversity and stimulated inflammatory cytokines in vitro, and both the methods and results of these studies were mixed; the majority observed exaggerated production of inflammatory cytokines despite mixed methodological approaches that make comparisons across studies difficult. In summary, the evidence supporting an association between early life adversity and inflammation in pediatric samples is limited so far by the number of studies and their heterogeneous methodological approaches. More research that is grounded in a developmental framework and informed by the complexity of the innate immune system is needed in this area.


Assuntos
Experiências Adversas da Infância , Biomarcadores/sangue , Inflamação/sangue , Inflamação/etiologia , Adolescente , Proteína C-Reativa/análise , Criança , Citocinas/sangue , Humanos , Estudos Prospectivos
8.
Matern Child Health J ; 23(3): 377-385, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30600511

RESUMO

Objectives To determine the effect of an enhanced information package, the Welcome to Parenthood® (W2P) Kit, given at birth on (a) early parenting experiences and (b) use of educational resources and community services. Methods Two-group, post-test only design, with parents (mothers and fathers) in comparison group (n = 186; received standard discharge information) recruited prior to intervention group (n = 195; received W2P Kit); most were Canadian-born and highly educated. Participants completed an investigator-designed, online or telephone survey at 3 months postpartum, which generated quantitative and qualitative data. The W2P Kit included evidence-based, educational resources about infant feeding, child development, and parenting skills that targeted mothers and fathers, information about community services for new parents, infant board book, and small gifts. Results At 3 months postpartum the intervention group was significantly more likely to be aware of, and to have used, the educational resources than the comparison group. The intervention group was also more likely to have made an unplanned visit to the doctor for their infant, but groups did not differ in early parenting experiences or use of community services. Parents who received the W2P Kit reported that it was helpful to learn about various aspects of child development and parenting. Conclusions for Practice Parents who received the W2P Kit reported increased awareness and use of educational resources, but participants in both groups reported similar experiences as a new parent and use of community services. An enhanced information package given at birth may be a useful health promotion strategy.


Assuntos
Poder Familiar/psicologia , Educação de Pacientes como Assunto/métodos , Adulto , Feminino , Humanos , Lactente , Comportamento de Busca de Informação , Masculino , Educação de Pacientes como Assunto/normas , Cuidado Pós-Natal , Pesquisa Qualitativa , Apoio Social , Seguridade Social , Inquéritos e Questionários
9.
Genet Med ; 20(4): 464-469, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28914269

RESUMO

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.


Assuntos
Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Diagnóstico Molecular , Alelos , Biópsia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genótipo , Humanos , Lactente , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Fenótipo , Polimorfismo de Nucleotídeo Único , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento do Exoma , Sequenciamento Completo do Genoma
10.
Int J Neuropsychopharmacol ; 21(1): 3-11, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186416

RESUMO

Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).


Assuntos
Neuropeptídeo Y/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adulto , Ansiedade/tratamento farmacológico , Estudos de Coortes , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
11.
Brain Behav Immun ; 73: 85-114, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29928963

RESUMO

One of the most common inflammatory markers examined in depression is C-reactive protein (CRP). However, the magnitude of the association between CRP and depression when controlling for potentially confounding factors such as age, sex, socio-economic status, body mass index, medication and other substance use, and medical illness, is unclear. Inconsistencies in other methodological practices, such as sample collection, assaying, and data cleaning and transformation, may contribute to variations in results. We aggregate studies that examined the association between CRP and depression in two ways. First, a systematic review summarizes how studies of CRP and depression have reported on methodological issues. Second, a tiered meta-analysis aggregates studies that have adhered to various levels of methodological rigor. Findings from the systematic review indicate a lack of protocol detail provided. The effect between depression and CRP was small, but highly significant across all stages of the meta-analysis (p < 0.01). The effect size in the most methodologically rigorous stage of the meta-analysis, which included studies controlling for age, sex, obesity, medical conditions and substance, medication, or psychosocial factors, was small (r = 0.05). There were also only 26 articles in this stage (13% of studies from the systematic review), suggesting that more studies that consistently account for these confounding factors are needed. Additionally, an a priori quality score of methodological rigor was a significant moderator in this stage of the meta-analysis. The effect size was strikingly attenuated (r = 0.005) and non-significant in studies with higher quality scores. We describe a set of recommended guidelines for future research to consider, including sample collection and assaying procedures, data cleaning and statistical methods, and control variables to assess.


Assuntos
Proteína C-Reativa/metabolismo , Proteína C-Reativa/fisiologia , Depressão/metabolismo , Biomarcadores/sangue , Proteína C-Reativa/análise , Comorbidade , Fatores de Confusão Epidemiológicos , Transtorno Depressivo/metabolismo , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Reprodutibilidade dos Testes
12.
BMC Med Inform Decis Mak ; 18(Suppl 2): 48, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-30066653

RESUMO

BACKGROUND: Cardiac Resynchronization Therapy (CRT) is an established pacing therapy for heart failure patients. The New York Heart Association (NYHA) class is often used as a measure of a patient's response to CRT. Identifying NYHA class for heart failure (HF) patients in an electronic health record (EHR) consistently, over time, can provide better understanding of the progression of heart failure and assessment of CRT response and effectiveness. Though NYHA is rarely stored in EHR structured data, such information is often documented in unstructured clinical notes. METHODS: We accessed HF patients' data in a local EHR system and identified potential sources of NYHA, including local diagnosis codes, procedures, and clinical notes. We further investigated and compared the performances of rule-based versus machine learning-based natural language processing (NLP) methods to identify NYHA class from clinical notes. RESULTS: Of the 36,276 patients with a diagnosis of HF or a CRT implant, 19.2% had NYHA class mentioned at least once in their EHR. While NYHA class existed in descriptive fields association with diagnosis codes (31%) or procedure codes (2%), the richest source of NYHA class was clinical notes (95%). A total of 6174 clinical notes were matched with hospital-specific custom NYHA class diagnosis codes. Machine learning-based methods outperformed a rule-based method. The best machine-learning method was a random forest with n-gram features (F-measure: 93.78%). CONCLUSIONS: NYHA class is documented in different parts in EHR for HF patients and the documentation rate is lower than expected. NLP methods are a feasible way to extract NYHA class information from clinical notes.


Assuntos
Registros Eletrônicos de Saúde , Insuficiência Cardíaca/classificação , Processamento de Linguagem Natural , Idoso , Terapia de Ressincronização Cardíaca , Progressão da Doença , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , New York , Resultado do Tratamento
13.
J Trauma Dissociation ; 19(3): 307-324, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29547079

RESUMO

Prior research has identified the role of childhood maltreatment in externalizing problems and executive function (EF) deficits, but minimal work has been done to characterize the effects of co-occurring maltreatment types, defined as polyvictimization. Here, we sought to characterize the association between polyvictimization and externalizing problems in a sample of foster care children aged 3-4 years (N = 84) and examine how EF may mediate or moderate that relationship. A moderation model was supported in that only polyvictimized children with EF scores 1.62 or more standard deviations below the mean were at heightened risk for clinically severe externalizing problems, while no association between polyvictimization and externalizing problems were observed for children who scored at the mean or above on the EF measure. Findings highlight that EF may serve as a resilience factor indicating that individual differences in polyvictimized children's EF skills help to predict variability in externalizing problems. Future research on designing and optimizing intervention programs that target EF skills may mitigate the development of maladaptive outcomes for polyvictimized children.


Assuntos
Maus-Tratos Infantis/psicologia , Transtornos do Comportamento Infantil/psicologia , Criança Acolhida/psicologia , Vítimas de Crime/psicologia , Função Executiva , Emoções Manifestas , Pré-Escolar , Feminino , Humanos , Controle Interno-Externo , Masculino
14.
Eur J Immunol ; 46(6): 1504-10, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26990433

RESUMO

Type I interferon (IFN-α/ß) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-α/ß-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-α/ß signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-α/ß-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-α/ß signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.


Assuntos
Regulação da Expressão Gênica , Memória Imunológica , Interleucina-5/genética , Fator de Transcrição STAT4/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Transcrição Gênica , Biomarcadores , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Interferon beta/metabolismo , Interferon beta/farmacologia , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais
15.
Proc Natl Acad Sci U S A ; 111(45): 16136-41, 2014 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-25331895

RESUMO

Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.


Assuntos
Transtornos de Ansiedade/imunologia , Comportamento Animal , Interleucina-6/imunologia , Estresse Psicológico/imunologia , Aloenxertos , Animais , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Transplante de Medula Óssea , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/patologia , Interleucina-6/genética , Camundongos , Camundongos Knockout , Estresse Psicológico/genética , Estresse Psicológico/patologia , Fatores de Tempo , Quimeras de Transplante/genética , Quimeras de Transplante/imunologia
16.
J Immunol ; 192(12): 5687-94, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24813204

RESUMO

CD4(+) Th2 development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive-feedback loop that maintains elevated GATA3 expression. Type I IFN (IFN-α/ß) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we uncovered a unique mechanism by which IFN-α/ß signaling represses the GATA3 gene in human Th2 cells. IFN-α/ß suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved noncoding sequence (CNS-1) upstream of exon 1A. IFN-α/ß treatment led to a closed conformation of CNS-1, as assessed by DNase I hypersensitivity, along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-α/ß signaling, even in the presence of IL-4. Thus, IFN-α/ß disrupts the GATA3-autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.


Assuntos
Metilação de DNA/imunologia , Elementos Facilitadores Genéticos/imunologia , Fator de Transcrição GATA3/imunologia , Interferon-alfa/imunologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Transcrição Gênica/imunologia , Adulto , Metilação de DNA/genética , Éxons/imunologia , Feminino , Fator de Transcrição GATA3/genética , Humanos , Interferon-alfa/genética , Interferon beta/genética , Interferon beta/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Masculino , Transdução de Sinais/genética , Células Th2/citologia , Transcrição Gênica/genética
17.
Public Health Nurs ; 33(5): 440-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27145885

RESUMO

OBJECTIVES: To evaluate a new prenatal education program evaluation tool, the UpStart Parent Survey - Prenatal, in terms of: (a) reliability and validity; (b) sensitivity to change over time; (c) whether results differed for mothers versus fathers; and (d) whether results differed when using an electronic tablet-computer versus a paper survey. DESIGN AND SAMPLE: Psychometric study. Participants were 277 expectant mothers (n = 161) and fathers (n = 106) enrolled in Childbirth Essentials, a 6-week prenatal education program. MEASURES: The UpStart Parent Survey - Prenatal is a retrospective pretest/posttest survey with three scales: Parenting Knowledge, Parenting Experience, and Program Satisfaction, and three open-ended questions. RESULTS: The UpStart Parent Survey - Prenatal is sensitive to change and demonstrated significant positive differences in parenting knowledge and parenting experience. There was no difference in results whether the survey was completed by mothers or fathers. Results were similar whether paper or electronic formats were used. The survey was easy to complete. CONCLUSION: The UpStart Parent Survey - Prenatal holds promise as a reliable and valid evaluation tool to capture outcomes of brief prenatal education programs that target the general population of expectant parents.


Assuntos
Pais/educação , Educação Pré-Natal , Avaliação de Programas e Projetos de Saúde/métodos , Inquéritos e Questionários , Adolescente , Adulto , Feminino , Humanos , Masculino , Poder Familiar/psicologia , Pais/psicologia , Satisfação Pessoal , Psicometria , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
19.
Physiol Behav ; 275: 114456, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38181831

RESUMO

Instrumental behavior can reflect the influence of goal-directed and habitual systems. Contemporary research suggests that stress may facilitate control by the habitual system under conditions where the behavior would otherwise reflect control by the goal-directed system. However, it is unclear how stress modulates the influence of these systems on instrumental responding to achieve this effect, particularly in females. Here, we examine whether a mild psychogenic stressor experienced before acquisition training (Experiment 1), or prior to the test of expression (Experiment 2) would influence goal-directed and habitual control of instrumental responding in female rats. In both experiments, rats acquired an instrumental nose-poke response for a sucrose reward. This was followed by a reinforcer devaluation phase in which half the rats in Stressed and Non-Stressed conditions received pairings of the sucrose pellet with illness induced by lithium chloride until they rejected the pellet when offered. The remaining rats received a control treatment consisting of pellets and illness on separate days (Unpaired). Control by goal-directed and habitual systems was evaluated in a subsequent nonreinforced test of nose poking. The results of Experiment 1 indicated that the Non-Stressed Paired group reduced nose-poking compared to the Unpaired controls, identifying the response as goal directed, whereas the Stressed Paired and Unpaired groups made a similar number of nose pokes identifying the response as habitual despite a similar amount of training. Results from Experiment 2 indicated habitual control of nose-poke responding was present when stress was experienced just prior to the test. Collectively, these data suggest that stress may facilitate habitual control by altering the relative influence of goal-directed and habitual processes underpinning instrumental behavior. These results may be clinically relevant for understanding the contributions of stress to dysregulated instrumental behavior in compulsive pathologies.


Assuntos
Condicionamento Operante , Objetivos , Ratos , Feminino , Animais , Motivação , Recompensa , Sacarose/farmacologia , Hábitos
20.
Sleep Health ; 10(1): 24-30, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38151377

RESUMO

GOAL AND AIMS: To pilot the feasibility and evaluate the performance of an EEG wearable for measuring sleep in individuals with Parkinson's disease. FOCUS TECHNOLOGY: Dreem Headband, Version 2. REFERENCE TECHNOLOGY: Polysomnography. SAMPLE: Ten individuals with Parkinson's disease. DESIGN: Individuals wore Dreem Headband during a single night of polysomnography. CORE ANALYTICS: Comparison of summary metrics, bias, and epoch-by-epoch analysis. ADDITIONAL ANALYTICS AND EXPLORATORY ANALYSES: Correlation of summary metrics with demographic and Parkinson's disease characteristics. CORE OUTCOMES: Summary statistics showed Dreem Headband overestimated several sleep metrics, including total sleep, efficiency, deep sleep, and rapid eye movement sleep, with an exception in light sleep. Epoch-by-epoch analysis showed greater specificity than sensitivity, with adequate accuracy across sleep stages (0.55-0.82). IMPORTANT SUPPLEMENTAL OUTCOMES: Greater Parkinson's disease duration and rapid eye movement behavior were associated with more wakefulness, and worse Parkinson's disease motor symptoms were associated with less deep sleep. CORE CONCLUSION: The Dreem Headband performs similarly in Parkinson's disease as it did in non-Parkinson's disease samples and shows promise for improving access to sleep assessment in people with Parkinson's disease.


Assuntos
Doença de Parkinson , Humanos , Polissonografia , Doença de Parkinson/complicações , Sono , Fases do Sono , Eletroencefalografia
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