RESUMO
Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.
Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Proteína Vermelha Fluorescente , Camundongos , Masculino , Feminino , Animais , Acetato de Desoxicorticosterona/farmacologia , Núcleo Solitário/fisiologia , Células Receptoras Sensoriais , Pressão Sanguínea/fisiologia , Fenilefrina/farmacologia , Canais IônicosRESUMO
PURPOSE: We undertook a study to assess whether presence of community support persons (CSPs), with no hospital affiliation or alignment, mitigates acts of obstetric racism during hospitalization for labor, birth, and immediate postpartum care. METHODS: We conducted a cross-sectional cohort study, measuring 3 domains of obstetric racism as defined for, by, and with Black birthing people: humanity (violation of safety and accountability, autonomy, communication and information exchange, and empathy); kinship (denial or disruption of community and familial bonds that support Black birthing people); and racism in the form of anti-Black racism and misogynoir (weaponization of societal stereotypes and scripts in service provision that reproduce gendered anti-Black racism in the hospital). We used a novel, validated instrument, the Patient-Reported Experience Measure of Obstetric Racism (the PREM-OB Scale suite), and linear regression analysis to determine the association between CSP presence during hospital births and obstetric racism. RESULTS: Analyses were based on 806 Black birthing people, 720 (89.3%) of whom had at least 1 CSP present throughout their labor, birth, and immediate postpartum care. The presence of CSPs was associated with fewer acts of obstetric racism across all 3 domains, with statistically significant reductions in scores in the CSP group of one-third to two-third SD units relative to the no-CSP group. CONCLUSIONS: Our findings suggest that CSPs may be an effective way to reduce obstetric racism as part of quality improvement initiatives, emphasizing the need for democratizing the birthing experience and birth space, and incorporating community members as a way to promote the safety of Black birthing people in hospital settings.Annals "Online First" article.
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Trabalho de Parto , Racismo , Gravidez , Feminino , Humanos , Racismo/prevenção & controle , Estudos Transversais , Apoio Comunitário , Parto ObstétricoRESUMO
BACKGROUND: Many pregnant and parenting people with substance use disorders (SUD) refrain from seeking perinatal care or treatment for their SUD for fear of being treated poorly by health care providers and/or triggering a child welfare investigation. For those who do seek treatment, there are relatively few clinicians willing and able to prescribe medications for opioid use disorder (MOUD) to pregnant people. Both stigma and lack of access to treatment put many pregnant and parenting people at risk. Drug-related deaths contribute significantly to U.S. maternal mortality rates, with people at especially high risk of drug overdose in the months following delivery. METHODS: The Foundation for Opioid Response Efforts (FORE) is a national philanthropy focused on finding and fostering solutions to the opioid crisis. We draw lessons from our grantees' efforts to expand access to substance use treatment and recovery supports for pregnant and parenting people. RESULTS: To build systems of care that ensure more pregnant people get timely perinatal care, we need to expand training for perinatal providers on how to provide OUD treatment, clarify child welfare reporting rules, and engage and support trusted organizations and community-based services. CONCLUSIONS: In addition to changes to our systems of SUD treatment and recovery, we need greater philanthropic investment in efforts to combat the public health crisis of substance use and overdose among pregnant and parenting people. Private funders have the leeway to act quickly, take risks, and demonstrate the effectiveness of new approaches, building the case for investment of public resources in such initiatives.
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Medo , Transtornos Relacionados ao Uso de Opioides , Criança , Feminino , Gravidez , Humanos , Analgésicos Opioides , Proteção da Criança , Saúde da Família , Transtornos Relacionados ao Uso de Opioides/terapiaRESUMO
The hypothalamic paraventricular nucleus (PVN) controls neuroendocrine axes and the autonomic nervous system to mount responses that cope with the energetic burdens of psychological or physiological stress. Neurons in the PVN that express the angiotensin Type 1a receptor (PVNAgtr1a) are implicated in neuroendocrine and autonomic stress responses; however, the mechanism by which these neurons coordinate activation of neuroendocrine axes with sympathetic outflow remains unknown. Here, we use a multidisciplinary approach to investigate intra-PVN signaling mechanisms that couple the activity of neurons synthesizing corticotropin-releasing-hormone (CRH) to blood pressure. We used the Cre-Lox system in male mice with in vivo optogenetics and cardiovascular recordings to demonstrate that excitation of PVNAgtr1a promotes elevated blood pressure that is dependent on the sympathetic nervous system. Next, neuroanatomical experiments found that PVNAgtr1a synthesize CRH, and intriguingly, fibers originating from PVNAgtr1a make appositions onto neighboring neurons that send projections to the rostral ventrolateral medulla and express CRH type 1 receptor (CRHR1) mRNA. We then used an ex vivo preparation that combined optogenetics, patch-clamp electrophysiology, and Ca2+ imaging to discover that excitation of PVNAgtr1a drives the local, intra-PVN release of CRH, which activates rostral ventrolateral medulla-projecting neurons via stimulation of CRHR1(s). Finally, we returned to our in vivo preparation and found that CRH receptor antagonism specifically within the PVN lowered blood pressure basally and during optogenetic activation of PVNAgtr1a Collectively, these results demonstrate that angiotensin II acts on PVNAgtr1a to conjoin hypothalamic-pituitary-adrenal axis activity with sympathetically mediated vasoconstriction in male mice.SIGNIFICANCE STATEMENT The survival of an organism is dependent on meeting the energetic demands imposed by stressors. This critical function is accomplished by the CNS's ability to orchestrate simultaneous activities of neurosecretory and autonomic axes. Here, we unveil a novel signaling mechanism within the paraventricular nucleus of the hypothalamus that links excitation of neurons producing corticotropin-releasing-hormone with excitation of neurons controlling sympathetic nervous system activity and blood pressure. The implication is that chronic stress exposure may promote cardiometabolic disease by dysregulating the interneuronal cross-talk revealed by our experiments.
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Pressão Sanguínea/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Vasoconstrição/fisiologia , Animais , Sistema Nervoso Autônomo/fisiologia , Masculino , Camundongos , Neurônios/fisiologiaRESUMO
Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.
Assuntos
Angiotensinas/farmacologia , Arginina Vasopressina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Optogenética , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Sódio na DietaRESUMO
OBJECTIVE: Evaluate the risk of preterm (<37 weeks) or early term birth (37 or 38 weeks) by body mass index (BMI) in a propensity score-matched sample. DESIGN: Retrospective cohort analysis. SETTING: California, USA. POPULATION: Singleton live births from 2011-2017. METHODS: Propensity scores were calculated for BMI groups using maternal factors. A referent sample of women with a BMI between 18.5 and <25.0 kg/m2 was selected using exact propensity score matching. Risk ratios for preterm and early term birth were calculated. MAIN OUTCOME MEASURES: Early birth. RESULTS: Women with a BMI <18.5 kg/m2 were at elevated risk of birth of 28-31 weeks (relative risk [RR] 1.2, 95% CI 1.1-1.4), 32-36 weeks (RR 1.3, 95% CI 1.2-1.3), and 37 or 38 weeks (RR 1.1, 95% CI 1.1-1.1). Women with BMI ≥25.0 kg/m2 were at 1.2-1.4-times higher risk of a birth <28 weeks and were at reduced risk of a birth between 32 and 36 weeks (RR 0.8-0.9) and birth during the 37th or 38th week (RR 0.9). CONCLUSION: Women with a BMI <18.5 kg/m2 were at elevated risk of a preterm or early term birth. Women with BMI ≥25.0 kg/m2 were at elevated risk of a birth <28 weeks. Propensity score-matched women with BMI ≥30.0 kg/m2 were at decreased risk of a spontaneous preterm birth with intact membranes between 32 and 36 weeks, supporting the complexity of BMI as a risk factor for preterm birth. TWEETABLE ABSTRACT: Propensity score-matched women with BMI ≥30 kg/m2 were at decreased risk of a late spontaneous preterm birth.
Assuntos
Nascimento Prematuro , Índice de Massa Corporal , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Perinatal quality improvement lacks valid tools to measure adverse hospital experiences disproportionately impacting Black mothers and birthing people. Measuring and mitigating harm requires using a framework that centers the lived experiences of Black birthing people in evaluating inequitable care, namely, obstetric racism. We sought to develop a valid patient-reported experience measure (PREM) of Obstetric Racism© in hospital-based intrapartum care designed for, by, and with Black women as patient, community, and content experts. METHODS: PROMIS© instrument development standards adapted with cultural rigor methodology. Phase 1 included item pool generation, modified Delphi method, and cognitive interviews. Phase 2 evaluated the item pool using factor analysis and item response theory. RESULTS: Items were identified or written to cover 7 previously identified theoretical domains. 806 Black mothers and birthing people completed the pilot test. Factor analysis concluded a 3 factor structure with good fit indices (CFI = 0.931-0.977, RMSEA = 0.087-0.10, R2 > .3, residual correlation < 0.15). All items in each factor fit the IRT model and were able to be calibrated. Factor 1, "Humanity," had 31 items measuring experiences of safety and accountability, autonomy, communication, and empathy. A 12-item short form was created to ease respondent burden. Factor 2, "Racism," had 12 items measuring experiences of neglect and mistreatment. Factor 3, "Kinship," had 7 items measuring hospital denial and disruption of relationships between Black mothers and their child or support system. CONCLUSIONS: The PREM-OB Scale™ suite is a valid tool to characterize and quantify obstetric racism for use in perinatal improvement initiatives.
Assuntos
Racismo , Feminino , Humanos , Medidas de Resultados Relatados pelo Paciente , Psicometria/métodos , Inquéritos e QuestionáriosRESUMO
Maintaining homeostasis while navigating one's environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.
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Optimizing postpartum care highlights the need for care coordination, enhancement, and expansion of health care services after childbirth. Yet the prioritization of disease surveillance, management, and mitigation during birth and beyond within the American College of Obstetrics and Gynecology facilitates the medicalization and pathologization of Black bodies, voices, and power. Thus, we offer the Building and Bridging Black Futures Beyond Birth Model: A 12-Step Black Woman-Person First Approach, as a more humane and holistic model of culturally affirming and clinically responsive care. Destigmatizing and democratizing care bridges the gap between intent and impact in postpartum care optimization, particularly for Black women, girls, and gender expansive people and their communities.
Assuntos
Ginecologia , Obstetrícia , Parto Obstétrico , Feminino , Humanos , Cuidado Pós-Natal , GravidezRESUMO
The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.
Assuntos
Encéfalo/metabolismo , Fármacos Neuroprotetores , Canais de Potássio Shab/metabolismo , Sintaxina 1/metabolismo , Animais , Proteínas Munc18/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos , Proteínas SNARE/metabolismoRESUMO
Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.
Assuntos
Envelhecimento/imunologia , Encéfalo/imunologia , Microbioma Gastrointestinal/fisiologia , Prebióticos , Animais , Fezes/química , Fezes/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologiaRESUMO
BACKGROUND: Exposures to structural racism has been identified as one of the leading risk factors for adverse maternal and infant health outcomes among Black women; yet current measures of structural racism do not fully account for inequities seen in adverse maternal and infant health outcomes between Black and white women and infants. In response, the purpose of this study was to conceptualize structural racism from the perspectives of Black women across the reproductive lifespan and its potential impact on adverse maternal and infant health outcomes. METHODS: We conducted a series of focus groups with 32 Black women across the reproductive lifespan (5 preconception, 13 pregnant, and 14 postpartum). Study criteria including self-identifying as Black, residing in Oakland or Fresno, California and representing one of three reproductive life tracks (preconception, pregnant, postpartum). We consulted with study participants and an expert advisory board to validate emergent domains of structural racism. RESULTS: Nine domains of structural racism emerged from a ground theory constant comparative analysis: Negative Societal Views; Housing; Medical Care; Law Enforcement; Hidden Resources; Employment; Education, Community Infrastructure; and Policing Black Families. CONCLUSIONS FOR PRACTICE: Findings from this study suggest that there is an interplay among structural racism, and social and structural determinants of health which has negative impacts on Black women's sexual and reproductive health. Furthermore, findings from this study can be used to develop more comprehensive medical assessments and policies to address structural racism experienced by Black women across the reproductive lifespan.
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Racismo , Negro ou Afro-Americano , Feminino , Humanos , Lactente , Longevidade , Período Pós-Parto , Gravidez , ReproduçãoRESUMO
BACKGROUND: Despite the disproportionate prevalence of gestational diabetes (GDM) and preterm birth (PTB) and their associated adverse perinatal outcomes among Black women, little is known about PTB among Black women with GDM. Specifically, the relationship between PTB by subtype (defined as indicated PTB and spontaneous PT labor) and severity, GDM, and nativity has not been well characterized. Here we examine the risk of PTB by severity (early < 34 weeks, late 34 to 36 weeks) and early term birth (37 to 38 weeks) by nativity among Black women with GDM in California. METHODS: This retrospective cohort study used linked birth certificate and hospital discharge data for 8609 of the 100,691 self-identifying non-Hispanic Black women with GDM who had a singleton live birth between 20 and 44 weeks gestation in California in 2013-2017. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were examine risks for PTB, by severity and subtype, and early term birth using multivariate regression modeling. RESULTS: Approximately, 83.9% of Black women with GDM were US-born and 16.1% were foreign-born. The overall prevalence of early PTB, late PTB, and early term birth was 3.8, 9.5, and 29.9%, respectively. Excluding history of prior PTB, preeclampsia was the greatest overall risk factor for early PTB (cOR = 6.7, 95%, CI 5.3 to 8.3), late PTB (cOR = 4.3, 95%, CI 3.8 to 5.0), and early term birth (cOR = 1.8, 95%, CI 1.6 to 2.0). There was no significant difference in the prevalence of PTB by subtypes and nativity (p = 0.5963). Overall, 14.2% of US- compared to 8.9% of foreign-born women had a PTB (early PTB: aOR = 0.56, 95%, CI 0.38 to 0.82; late PTB: aOR = 0.57, 95%, CI 0.45 to 0.73; early term birth: aOR = 0.67, 95%, CI 0.58 to 0.77). CONCLUSIONS: Foreign-born status remained protective of PTB, irrespective of severity and subtype. Preeclampsia, PTB, and GDM share pathophysiologic mechanisms suggesting a need to better understand differences in perinatal stress, chronic disease, and vascular dysfunction based on nativity in future epidemiologic studies and health services research.
Assuntos
Negro ou Afro-Americano/etnologia , Diabetes Gestacional/diagnóstico , Emigrantes e Imigrantes/estatística & dados numéricos , Pré-Eclâmpsia/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , California , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/etnologia , Feminino , Idade Gestacional , Disparidades nos Níveis de Saúde , Humanos , Recém-Nascido , Idade Materna , Gravidez , Nascimento Prematuro/etnologia , Prevalência , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Pre-treatment with the corticotropin-releasing factor antagonist α-helical CRF9-41 prevents inhibition of gastric emptying by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level, but its inhibition of sucrose intake is not affected. This is suggestive of separable underlying mechanisms of action in the caudal brainstem for cocaine-and amphetamine-regulated transcript peptide with regard to food intake and gastrointestinal functions. Here we further examine cocaine-and amphetamine-regulated transcript peptide-corticotropin-releasing factor receptor interactions in caudal brainstem controls of solid food intake. Injections of combinations of vehicle, cocaine-and amphetamine-regulated transcript peptide (0.5 µg or 1 µg) or α-helical CRF9-41 were given into the fourth cerebral ventricle of rats. Nocturnal solid food intake was recorded over 22 h. RESULTS: Pre-treatment with α-helical CRF9-41 into the fourth ventricle significantly increased the responsivity to cocaine-and amphetamine-regulated transcript peptide on hypophagia. In a separate control experiment, α-helical CRF9-41 pre-treatment blocked CRF-induced food intake inhibition indicative of its antagonistic effectiveness. CONCLUSIONS: We conclude that an endogenous Corticotropin-releasing factor agonist may modulate suppression of food intake caused by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level in the absence of stress. A potential caudal brainstem mechanism whereby cocaine-and amphetamine-regulated transcript peptide effects on food intake is attenuated via corticotropin-releasing factor receptor activity causing tonic inhibition, is suggested.
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Fármacos do Sistema Nervoso Central/farmacologia , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ingestão de Alimentos/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Fragmentos de Peptídeos/farmacologia , Rombencéfalo/efeitos dos fármacos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Alimentos/fisiologia , Quarto Ventrículo , Injeções Intraventriculares , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Rombencéfalo/metabolismoRESUMO
Perinatal and neonatal nurses have a critical role to play in effectively addressing the disproportionate prevalence of adverse pregnancy outcomes experienced by black childbearing families. Upstream inequities in maternal health must be better understood and addressed to achieve this goal. The importance of maternal health before, during, and after pregnancy is illustrated with the growing and inequitable prevalence of 2 common illnesses, pregestational diabetes and chronic hypertension, and 2 common conditions during and after pregnancy, gestational diabetes and preterm birth. New care models are needed and must be structured on appropriate ethical principles for serving black families in partnership with nurses. The overarching purpose of this article is to describe the ethics of perinatal care for black women; to discuss how social determinants of health, health disparities, and health inequities affecting women contribute to poor outcomes among their children; and to provide tools to dismantle structural racism specific to "mother blame" narratives." Finally, strategies are presented to enhance the provision of ethical perinatal care for black women by nurses.
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Negro ou Afro-Americano/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Saúde Materna , Assistência Perinatal/ética , Racismo/etnologia , Feminino , Equidade em Saúde , Humanos , Recém-Nascido , Terapia Narrativa , Avaliação das Necessidades , Enfermagem Neonatal/organização & administração , Papel do Profissional de Enfermagem , Cuidado Pós-Natal/ética , Gravidez , Racismo/economia , Estados UnidosRESUMO
We present the design of an innovative molecular neuroprotective strategy and provide proof-of-concept for its implementation, relying on the injury-mediated activation of an ectopic gene construct. As oxidative injury leads to the intracellular liberation of zinc, we hypothesize that tapping onto the zinc-activated metal regulatory element (MRE) transcription factor 1 system to drive expression of the Kv2.1-targeted hepatitis C protein NS5A (hepatitis C nonstructural protein 5A) will provide neuroprotection by preventing cell death-enabling cellular potassium loss in rat cortical neurons in vitro. Indeed, using biochemical and morphologic assays, we demonstrate rapid expression of MRE-driven products in neurons. Further, we report that MRE-driven NS5A expression, induced by a slowly evolving excitotoxic stimulus, functionally blocks injurious, enhanced Kv2.1 potassium whole-cell currents and improves neuronal viability. We suggest this form of "on-demand" neuroprotection could provide the basis for a tenable therapeutic strategy to prevent neuronal cell death in neurodegeneration.
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Hepacivirus/metabolismo , Hepatite C/metabolismo , Neuroproteção/efeitos dos fármacos , Canais de Potássio Shab/metabolismo , Proteínas não Estruturais Virais/metabolismo , Zinco/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Hepatite C/virologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Potássio/metabolismo , Transporte Proteico/efeitos dos fármacos , RatosRESUMO
Besides its well-known action to stimulate thyroid hormone release, thyrotropin mRNA is expressed within the brain, and thyrotropin and its receptor have been shown to be present in brain areas that control feeding and gastrointestinal function. Here, the hypothesis that thyrotropin acts on receptors in the hindbrain to alter food intake and/or gastric function was tested. Fourth ventricular injections of thyrotropin (0.06, 0.60, and 6.00 µg) were given to rats with chronic intracerebroventricular cannulas aimed at the fourth ventricle. Thyrotropin produced an acute reduction of sucrose intake (30 min). The highest dose of thyrotropin caused inhibition of overnight solid food intake (22 h). In contrast, subcutaneous administration of corresponding thyrotropin doses had no effect on nutrient intake. The highest effective dose of fourth ventricular thyrotropin (6 µg) did not produce a conditioned flavor avoidance in a standardized two-bottle test, nor did it affect water intake or gastric emptying of glucose. Thyrotropin injected in the fourth ventricle produced a small but significant increase in rectal temperature and lowered plasma levels of tri-iodothyronin but did not affect plasma levels of thyroxine. In addition, there was a tendency toward a reduction in blood glucose 2 h after fourth ventricular thyrotropin injection ( P = 0.056). In conclusion, fourth ventricular thyrotropin specifically inhibits food intake, increases core temperature, and lowers plasma levels of tri-iodothyronin but does not affect gastromotor function.
Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Rombencéfalo/efeitos dos fármacos , Resposta de Saciedade/efeitos dos fármacos , Tireotropina/administração & dosagem , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Ratos Sprague-Dawley , Receptores da Tireotropina/agonistas , Receptores da Tireotropina/metabolismo , Rombencéfalo/metabolismo , Fatores de Tempo , Tri-Iodotironina/sangueRESUMO
Over the last decade, there has been increased interest in the role of the gut microbiome in health including brain health. This is by no means a new theory; Elie Metchnikoff proposed over a century ago that targeting the gut by consuming lactic acid bacteria such as those in yogurt, could improve or delay the onset of cognitive decline associated with ageing. However, there is limited information characterising the relationship between the behavioural and physiological sequelae of ageing and alterations in the gut microbiome. To this end, we assessed the behavioural, physiological and caecal microbiota profile of aged male mice. Older mice (20-21months old) exhibited deficits in spatial memory and increases in anxiety-like behaviours compared to younger mice (2-3months old). They also exhibited increased gut permeability, which was directly correlated with elevations in peripheral pro-inflammatory cytokines. Furthermore, stress exacerbated the gut permeability of aged mice. Examination of the caecal microbiota revealed significant increases in phylum TM7, family Porphyromonadaceae and genus Odoribacter of aged mice. This represents a shift of aged microbiota towards a profile previously associated with inflammatory disease, particularly gastrointestinal and liver disorders. Furthermore, Porphyromonadaceae, which has also been associated with cognitive decline and affective disorders, was directly correlated with anxiety-like behaviour in aged mice. These changes suggest that changes in the gut microbiota and associated increases in gut permeability and peripheral inflammation may be important mediators of the impairments in behavioural, affective and cognitive functions seen in ageing.
Assuntos
Fatores Etários , Encéfalo/microbiologia , Microbioma Gastrointestinal/fisiologia , Animais , Ansiedade/microbiologia , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Cognição/fisiologia , Citocinas/sangue , Trato Gastrointestinal/microbiologia , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL/microbiologia , Microbiota/fisiologia , Porphyromonas/metabolismo , Porphyromonas/patogenicidadeRESUMO
The Centering Equality, Race, and Cultural Literacy in Family Planning (CERCL-FP) program aims to break racial silence and dismantle structural racism in the field of family planning, by providing racial equity workshops and trainings. OBJECTIVE: The objective of this study was to begin a multi-phased, rigorous evaluation to determine the impact and outcomes of the work of CERCL-FP. STUDY DESIGN: A needs assessment with former graduates and current directors of fellowships in family planning was conducted using qualitative interviews. The focus of these interviews was to determine the ability, readiness, and willingness of the field of family planning to retrofit new curricula grounded in equity, race, and cultural literacy. RESULTS: Nine (N = 9) interviews were completed with seven board certified obstetrician-gynecologists and two board certified family medicine physicians. Three themes were identified: (1) Establishing the Distribution of Work; (2) The Push/Pull of Change from Inside and Outside: Curricula and Faculty Responsibilities; and (3) Reproductive Justice and Fellowships in Family Planning. Despite acknowledging the need to retrofit the field of family planning with content grounded in equity, race, and cultural literacy, there are structural, institutional, and individual level barriers that have limited the adoption of CERCL-FP curricula within family planning curriculum nationwide. CONCLUSION: Findings from this study illuminate multiple barriers that should be considered when expanding foundational knowledge of clinicians and researchers. IMPLICATIONS: Similar to the slow integration of research findings into clinical practice, this study shows that integration of social science and new curricula within the field of family planning faces significant barriers. Strategies to address these barriers are crucial to ensuring successful integration of equity, race, and cultural literacy within family planning.
RESUMO
Racism pervades the US criminal legal and family policing systems, particularly impacting cases involving women with a history of a substance use disorder (SUD). Laws criminalizing SUD during pregnancy disproportionately harm Black women, as do family policing policies around family separation. Discrimination within intersecting systems may deter Black pregnant women with a SUD from seeking evidence-based pregnancy and substance use care. This convergent parallel mixed-methods study aimed to illuminate how systemic oppression influenced the lived experiences of Black mothers with a SUD, facing dual involvement in the criminal legal and family policing systems. Using convenience and snowball sampling techniques, we recruited 15 Black mothers who were incarcerated, used substances while pregnant, and had a history with family policing systems. We conducted semi-structured interviews and developed and distributed a scale questionnaire to describe participants' experiences navigating overlapping systems of surveillance and control. Drawing on models of systemic anti-Black racism and sexism and reproductive justice, we assessed participants' experiences of racism and gender-based violence within these oppressive systems. Participants described how intersecting systems of surveillance and control impeded their prenatal care, recovery, and abilities to parent their children in gender and racially specific ways. Although they mostly detailed experiences of interpersonal discriminatory treatment, particularly from custody staff while incarcerated and pregnant, participants highlighted instances of systemic anti-Black gendered racism and obstetric racism while accessing prenatal care and substance use treatment in carceral and community settings. Their narratives emphasize the need for action to measure and address the upstream macro-level systems perpetuating inequities.