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OBJECTIVES: To provide an updated systematic review on the use of extracorporeal cardiopulmonary resuscitation (ECPR) compared with manual or mechanical cardiopulmonary resuscitation during cardiac arrest. METHODS: This was an update of a systematic review published in 2018. OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched for randomized trials and observational studies between January 1, 2018, and June 21, 2022. The population included adults and children with out-of-hospital or in-hospital cardiac arrest. Two investigators reviewed studies for relevance, extracted data, and assessed bias. The certainty of evidence was evaluated using GRADE. RESULTS: The search identified 3 trials, 27 observational studies, and 6 cost-effectiveness studies. All trials included adults with out-of-hospital cardiac arrest and were terminated before enrolling the intended number of subjects. One trial found a benefit of ECPR in survival and favorable neurological status, whereas two trials found no statistically significant differences in outcomes. There were 23 observational studies in adults with out-of-hospital cardiac arrest or in combination with in-hospital cardiac arrest, and 4 observational studies in children with in-hospital cardiac arrest. Results of individual studies were inconsistent, although many studies favored ECPR. The risk of bias was intermediate for trials and critical for observational studies. The certainty of evidence was very low to low. Study heterogeneity precluded meta-analyses. The cost-effectiveness varied depending on the setting and the analysis assumptions. CONCLUSIONS: Recent randomized trials suggest potential benefit of ECPR, but the certainty of evidence remains low. It is unclear which patients might benefit from ECPR.
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Reanimación Cardiopulmonar , Oxigenación por Membrana Extracorpórea , Paro Cardíaco Extrahospitalario , Adulto , Niño , Humanos , Paro Cardíaco Extrahospitalario/terapia , Oxigenación por Membrana Extracorpórea/métodos , Reanimación Cardiopulmonar/métodos , Estudios RetrospectivosRESUMEN
Myocardial infarction (MI) triggers an inflammatory response that transitions from pro-inflammatory to reparative over time. Restoring sympathetic nerves in the heart after MI prevents arrhythmias. This study investigated if reinnervation altered the immune response after MI. This study used quantitative multiplex immunohistochemistry to identify the immune cells present in the heart 2 weeks after ischemia-reperfusion. Two therapeutics stimulated reinnervation, preventing arrhythmias and shifting the immune response from inflammatory to reparative, with fewer pro-inflammatory macrophages and more regulatory T cells and reparative macrophages. Treatments did not alter macrophage phenotype in vitro, which suggested reinnervation contributed to the altered immune response.
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Chondroitin sulfate proteoglycans (CSPGs) prevent sympathetic nerve regeneration in the heart after myocardial infarction and prevent central nerve regrowth after traumatic brain injury and spinal cord injury. Currently, there are no small-molecule therapeutics to promote nerve regeneration through CSPG-containing scars. CSPGs bind to monomers of receptor protein tyrosine phosphatase sigma (PTPσ) on the surface of neurons, enhancing the ability of PTPσ to bind and dephosphorylate tropomyosin receptor kinases (Trks), inhibiting their activity and preventing axon outgrowth. Targeting PTPσ-Trk interactions is thus a potential therapeutic target. Here, we describe the development and synthesis of small molecules (HJ-01 and HJ-02) that disrupt PTPσ interactions with Trks, enhance Trk signaling, and promote sympathetic nerve regeneration over CSPGs.
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Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Traumatismos de la Médula Espinal , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Humanos , Regeneración Nerviosa/fisiología , Monoéster Fosfórico Hidrolasas , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Traumatismos de la Médula Espinal/metabolismoRESUMEN
OBJECTIVE: This study evaluated the safety and efficacy of orbital atherectomy (OA) for the treatment of severely calcified coronary artery bifurcation lesions. BACKGROUND: Percutaneous coronary intervention (PCI) of severely calcified coronary artery lesions is associated with lower procedural success and higher rates of target lesion failure compared to non-calcified lesions. OA is an effective treatment for calcified coronary artery lesions prior to stent implantation. However, there is little data regarding the safety and efficacy of OA in patients with coronary artery bifurcation lesions. METHODS: Data were obtained from analysis of patients with severe coronary artery calcification who underwent OA and coronary stent implantation at ten high-volume institutions. Data were pooled and analyzed to assess peri-procedural outcomes and 30-day major adverse cardiac events (MACE). RESULTS: A total of 1156 patients were treated with OA and PCI. 363 lesions were at a coronary artery bifurcation. There were no statistically significant differences in baseline characteristics between the bifurcation and non-bifurcation groups. In the bifurcation group, treatment involved the left anterior descending artery and its branches more frequently and right coronary artery less frequently. After propensity score matching, the 30-day freedom from MACE was not statistically significant between the two groups. CONCLUSION: In this multicenter cohort analysis, patients with severely calcified coronary bifurcation lesions had low rates of MACE and target vessel revascularization at 30 days at rates comparable to non-bifurcation lesions. This analysis demonstrates that OA is safe and effective for complex coronary lesions at both bifurcation and non-bifurcation locations.
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Aterectomía Coronaria , Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Calcificación Vascular , Aterectomía , Aterectomía Coronaria/efectos adversos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/cirugía , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/cirugía , Humanos , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/cirugíaRESUMEN
INTRODUCTION: Vitamin C deficiency has been described in patients with sepsis. The post-cardiac arrest syndrome shares similarities to sepsis, however vitamin C levels in post-arrest patients have been incompletely characterized. We assessed vitamin C levels in a post-arrest population. METHODS: This was a retrospective observational study at a tertiary care center. A convenience sample of post-arrest, sepsis, and healthy control patients was selected from prior studies. Vitamin C levels were measured from samples obtained within 6-h of emergency department admission. A subset of cardiac arrest patients had vitamin C levels additionally measured 24-h later. RESULTS: A total of 84 patients (34 healthy controls, 25 post-arrest, and 25 septic patients) were included. The median baseline vitamin C level in cardiac arrest patients was 0.33â¯mg/dL (0.05-0.83), as compared to 0.91â¯mg/dL (0.69-1.48) in the healthy control group (pâ¯<â¯0.01) and 0.28â¯mg/dL (0.11-0.59) in the septic group (pâ¯=â¯0.36). Vitamin C levels for cardiac arrest patients fell between the two time points, but the change was not statistically significant (median decrease 0.26â¯mg/dL, pâ¯=â¯0.08). CONCLUSIONS: Serum vitamin C levels were lower in post-arrest patients compared to controls and were similar to patients with sepsis. Future studies of vitamin C levels and supplementation following cardiac arrest may be warranted.
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Paro Cardíaco Extrahospitalario , Sepsis , Ácido Ascórbico , Humanos , Estudios Retrospectivos , SobrevivientesRESUMEN
PURPOSE: Many normotensive patients with acute pulmonary embolism (PE) are admitted to an intensive care unit (ICU) to monitor for hemodynamic decompensation. We investigated the incidence and causes of early hemodynamic decompensation in normotensive patients admitted to an ICU with PE. MATERIALS AND METHODS: This was a single-center, retrospective study of normotensive patients admitted to an ICU with primary diagnosis of PE between 2010 and 2017. The primary outcome was hemodynamic decompensation, defined as need for vasopressors within 48â¯h of ICU admission. RESULTS: Of 293 patients included in the study, hemodynamic decompensation occurred in 8 patients (2.7%). The two most common precipitants of hemodynamic decompensation were acute hemorrhage and PE-related right ventricular dysfunction - each contributing to hemodynamic decompensation in 3 patients. CONCLUSIONS: Among patients admitted to the ICU with acute normotensive PE, early hemodynamic decompensation was rare. In patients who experienced decompensation, major bleeding and thrombotic complications were equally likely to have been the precipitant- highlighting the risks of diagnostic anchoring in this population. As our results suggest that ICU-level care may not be necessary for many of these patients, additional tools are needed to assist in the triage of normotensive patients with PE.
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Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Unidades de Cuidados Intensivos , Embolia Pulmonar/fisiopatología , Vasoconstrictores/uso terapéutico , Anciano , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Embolia Pulmonar/complicaciones , Estudios RetrospectivosRESUMEN
INTRODUCTION: There is no standard for categorizing reasons for death in those who achieve return of spontaneous circulation (ROSC) after cardiac arrest but die before hospital discharge. Categorization is important for comparing outcomes across studies, assessing benefits of interventions, and developing quality-improvement initiatives. We developed and tested a method for categorizing reasons for death after cardiac arrest in both in-hospital (IHCA) and out-of-hospital (OHCA) arrests. METHODS: Single-center, retrospective, cohort study of patients with ROSC after IHCA or OHCA between 2008 and 2017 who died before hospital discharge. Traumatic arrests and patients with "do-not-resuscitate" orders prior to their arrest were excluded. Two investigators assigned each patient to one of five predefined reasons for death. Interrater reliability was assessed using Fleiss' kappa. For final categorization, discrepancies were resolved by a third investigator. RESULTS: There were 182 IHCA and 226 OHCA included. There was substantial agreement between raters (kappa of 0.62 and 0.61 for IHCA and OHCA, respectively). Reasons for death for IHCA and OHCA were: neurological withdrawal of care (27% vs 73%), comorbid withdrawal of care (36% vs 4%), refractory hemodynamic shock (25% vs 17%), respiratory failure (1% vs 3%), and sudden cardiac death (11% vs 4%). The differences in reasons for death among the two groups were significant (p-value < 0.001). CONCLUSIONS: Categorizing reasons for death after cardiac arrest with ROSC is feasible using our proposed categories, with substantial inter-rater agreement. Neurologic withdrawal of care is much less common in IHCA than OHCA, which may have implications for further research.
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Causas de Muerte , Mortalidad Hospitalaria , Paro Cardíaco Extrahospitalario/mortalidad , Anciano , Anciano de 80 o más Años , Reanimación Cardiopulmonar/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/terapia , Estudios RetrospectivosRESUMEN
BACKGROUND: Emergency department (ED) crowding is associated with patient safety concerns, increased patients left without being seen (LWBS), low patient satisfaction, and lost ED revenue. The objective was to measure the impact of a revised triage process on ED throughput. METHODS: This study took place at an urban, university-affiliated, adult ED with an annual census of 70,000 and admission rate of 34%. The revised triage approach included: identifying eligible patients at triage based on complaint, comorbidities, and illness acuity; and reallocating a nurse practitioner (NP) into our triage area. We trialed the intervention from 1100-2300 on weekdays from January 13-26, 2016. Adult patients who were not likely to require intensive evaluations were eligible. Primary outcomes were throughput measures including: time to provider, ED length of stay (LOS), and LWBS. Pre- and post-intervention metrics were compared using the Mann-Whitney U test, given the non-normal distribution of the metrics. RESULTS: The NP evaluated 120 patients of which 101 (84%) were discharged, 3 (2.5%) admitted, and 16 (13%) required more intense evaluation. Time to provider decreased from a median (IQR) of 42 (16, 114) to 27 (12.4, 81.5) minutes (p<0.01) and ED LOS from 290 (194.8, 405.6) to 257 (171.2, 363.4) minutes (p<0.01) for all patients not admitted and not requiring a consult. LWBS decreased from a pre-trial 4.6% to 2.2% (p<0.01). CONCLUSION: The revised triage intervention was associated with improvements in several ED throughput metrics and a reduction in LWBS.
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Aglomeración , Servicio de Urgencia en Hospital/normas , Alta del Paciente/estadística & datos numéricos , Satisfacción del Paciente , Triaje/métodos , Adulto , Eficiencia Organizacional , Servicio de Urgencia en Hospital/organización & administración , Femenino , Hospitales Universitarios , Humanos , Masculino , Factores de Tiempo , Estados Unidos , Población UrbanaRESUMEN
BACKGROUND: The risk of sport-related concussion (SRC) has emerged as a major public health concern. In rare instances, sport-related head injuries can be even more severe, such as subdural hemorrhage, epidural hemorrhage, or malignant cerebral edema. Unlike SRCs, sport-related structural brain injury (SRSBI) is rare, may require neurosurgical intervention, and can lead to permanent neurologic deficit or death. Data characterizing SRSBI are limited, and many have recognized the need to better understand these catastrophic brain injuries. The goal of the current series is to describe, in detail, the presentation, management, and outcomes of examples of these rare injuries. CASE DESCRIPTION: During the fall of 2015, three high school football players presented with acute subdural hemorrhages following in-game collisions and were treated at our institution within a span of 2 months. For the 2 athletes who required surgical intervention, a previous SRC was sustained within 4 weeks before the catastrophic event. One year after injury, 2 players have returned to school, though with persistent deficits. One patient remains nonverbal and wheelchair bound. None of the athletes has returned to sports. CONCLUSIONS: Acute subdural hemorrhage resultant from an in-game football collision is rare. The temporal proximity of the reported SRSBIs to recent SRCs emphasizes the importance of return-to-play protocols and raises questions regarding the possibility of second impact syndrome. Although epidemiologic conclusions cannot be drawn from this small sample, these cases provide a unique opportunity to demonstrate the presentation, management, and long-term outcomes of SRSBI in American high school football.
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Atletas , Traumatismos en Atletas/terapia , Lesiones Encefálicas/terapia , Hemorragia Cerebral/terapia , Fútbol Americano/lesiones , Adolescente , Traumatismos en Atletas/diagnóstico , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/diagnóstico , Hemorragia Cerebral/diagnóstico , Humanos , Masculino , EstudiantesRESUMEN
Denervated post-infarct scar is arrhythmogenic. Our aim was to compare QRS frequency content in denervated and innervated left ventricular (LV) scar. In-vivo single lead ECG telemetry device was implanted in 17 heterozygous PTPσ (HET) and 7 lacking PTPσ (KO) transgenic mice. Myocardial infarction (MI) with reperfusion and sham surgery was performed. HET mice developed a denervated scar, whereas KO mice developed innervated scar. The power spectral density was used to assess the QRS frequency content. Denervated as compared to innervated post-MI scar was characterized by the higher relative contribution of 300-500 Hz (14 ± 1 vs. 9 ± 1%; P = 0.001) but reduced relative contribution of 200-300 Hz (86 ± 1 vs. 91 ± 1%; P = 0.001). Norepinephrine concentration in peri-infarct zone correlated with both 1-200 Hz (r = 0.75; P = 0.03) and 200-500 Hz QRS power (r = 0.73; P = 0.04). Sympathetic fiber density within the infarct correlated with 200-300/200-500 Hz QRS power ratio (r = 0.56; P = 0.005). Intracellular sigma peptide injections in post-MI HET mice restored the QRS power.
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Electroencefalografía/métodos , Sistema de Conducción Cardíaco/fisiopatología , Ventrículos Cardíacos/inervación , Ventrículos Cardíacos/fisiopatología , Infarto del Miocardio/fisiopatología , Aturdimiento Miocárdico/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos , Infarto del Miocardio/complicaciones , Aturdimiento Miocárdico/etiología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sistema Nervioso Simpático/patologíaRESUMEN
OBJECTIVES: Baseline and post-concussion neurocognitive testing is useful in managing concussed athletes. Attention deficit hyperactivity disorder (ADHD) and stimulant medications are recognized as potential modifiers of performance on neurocognitive testing by the Concussion in Sport Group. Our goal was to assess whether individuals with ADHD perform differently on post-concussion testing and if this difference is related to the use of stimulants. METHODS: Retrospective case-control study in which 4373 athletes underwent baseline and post-concussion testing using the ImPACT battery. 277 athletes self-reported a history of ADHD, of which, 206 reported no stimulant treatment and 69 reported stimulant treatment. Each group was matched with participants reporting no history of ADHD or stimulant use on several biopsychosocial characteristics. Non-parametric tests were used to assess ImPACT composite score differences between groups. RESULTS: Participants with ADHD had worse verbal memory, visual memory, visual motor speed, and reaction time scores than matched controls at baseline and post-concussion, all with p ≤ .001 and |r|≥ 0.100. Athletes without stimulant treatment had lower verbal memory, visual memory, visual motor speed, and reaction time scores than controls at baseline (p ≤ 0.01, |r|≥ 0.100 [except verbal memory, r = -0.088]) and post-concussion (p = 0.000, |r|> 0.100). Athletes with stimulant treatment had lower verbal memory (Baseline: p = 0.047, r = -0.108; Post-concussion: p = 0.023, r = -0.124) and visual memory scores (Baseline: p = 0.013, r = -0.134; Post-concussion: p = 0.003, r = -0.162) but equivalent visual motor speed and reaction time scores versus controls at baseline and post-concussion. CONCLUSIONS: ADHD-specific baseline and post-concussion neuropsychological profiles, as well as stimulant medication status, may need to be considered when interpreting ImPACT test results. Further investigation into the effects of ADHD and stimulant use on recovery from sport-related concussion (SRC) is warranted.
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Traumatismos en Atletas/complicaciones , Traumatismos en Atletas/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Conmoción Encefálica/complicaciones , Conmoción Encefálica/diagnóstico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Adolescente , Traumatismos en Atletas/psicología , Conmoción Encefálica/psicología , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Memoria , Pruebas Neuropsicológicas , Tiempo de Reacción , Estudios Retrospectivos , Autoinforme , Adulto JovenRESUMEN
cAMP-response element binding protein (CREB) is a nuclear transcription factor activated by multiple extracellular signals including growth factors and hormones. These extracellular cues activate CREB through phosphorylation at Ser133 by various protein serine/threonine kinases. Once phosphorylated, it promotes its association with transcription coactivators CREB-binding protein (CBP) and its paralog p300 to activate CREB-dependent gene transcription. Tumor tissues of different origins have been shown to present overexpression and/or overactivation of CREB, indicating CREB as a potential cancer drug target. We previously identified 666-15 as a potent inhibitor of CREB with efficacious anti-cancer activity both in vitro and in vivo. Herein, we investigated the specificity of 666-15 and evaluated its potential in vivo toxicity. We found that 666-15 was fairly selective in inhibiting CREB. 666-15 was also found to be readily bioavailable to achieve pharmacologically relevant concentrations for CREB inhibition. Furthermore, the mice treated with 666-15 showed no evidence of changes in body weight, complete blood count, blood chemistry profile, cardiac contractility and tissue histologies from liver, kidney and heart. For the first time, these results demonstrate that pharmacological inhibition of CREB is well-tolerated in vivo and indicate that such inhibitors should be promising cancer therapeutics.
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Anilidas , Antineoplásicos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Naftalenos , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Anilidas/efectos adversos , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HEK293 , Humanos , Ratones , Naftalenos/efectos adversos , Naftalenos/farmacocinética , Naftalenos/farmacología , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
OBJECTIVES: Basketball is a physical game played on a hardwood floor among high-jumping athletes at risk for injury. It is currently unknown how sport-related concussion (SRC) affects player performance after injury among professional basketball players. The objective of this study was to explore the impact of SRC on basketball performance among National Basketball Association (NBA) players. METHODS: A retrospective, archival cohort study was performed that compared NBA player performance following concussion to pre-concussive performance. A comprehensive NBA injury database, compiled from publically available sources, was queried for NBA players who suffered concussion from 2005-06 to 2014-15 (10 seasons). Intra-and inter-player analyses were performed against a matched control group of players who missed playing time for personal reasons. RESULTS: Following application of inclusion/exclusion criteria and a matching process, 51 concussed players and 51 control players were included in analysis. There were no statistically significant decrements in baseline to post-concussion performance metrics in intra-player or player vs. controls after 5 return games. CONCLUSIONS: Our findings suggest that at the NBA level, an athlete's performance in the initial 5 games following injury does not suffer from the after-effects of concussive injury. These results may be useful in counseling professional athletes following a concussion.
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Rendimiento Atlético/fisiología , Baloncesto/lesiones , Conmoción Encefálica/fisiopatología , Traumatismos Ocupacionales/fisiopatología , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Masculino , Estudios RetrospectivosRESUMEN
We previously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mass than controls. Here we show, using homozygous knock-in mouse models in which we replace murine Mc3r with wild-type human (MC3R(hWT/hWT)) and double-mutant (C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice do not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin levels are increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signalling in human metabolism and suggest a previously-unrecognized role for the MC3R in adipose tissue development.
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Obesidad/metabolismo , Receptor de Melanocortina Tipo 3/metabolismo , Adipocitos/metabolismo , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Animales , Modelos Animales de Enfermedad , Ingestión de Alimentos , Metabolismo Energético , Grasas/metabolismo , Técnicas de Sustitución del Gen , Humanos , Leptina/metabolismo , Ratones , Obesidad/genética , Obesidad/fisiopatología , Receptor de Melanocortina Tipo 3/genéticaRESUMEN
Sympathetic and parasympathetic control of the heart is a classic example of norepinephrine (NE) and acetylcholine (ACh) triggering opposing actions. Sympathetic NE increases heart rate and contractility through activation of ß receptors, whereas parasympathetic ACh slows the heart through muscarinic receptors. Sympathetic neurons can undergo a developmental transition from production of NE to ACh and we provide evidence that mouse cardiac sympathetic nerves transiently produce ACh after myocardial infarction (MI). ACh levels increased in viable heart tissue 10-14 d after MI, returning to control levels at 21 d, whereas NE levels were stable. At the same time, the genes required for ACh synthesis increased in stellate ganglia, which contain most of the sympathetic neurons projecting to the heart. Immunohistochemistry 14 d after MI revealed choline acetyltransferase (ChAT) in stellate sympathetic neurons and vesicular ACh transporter immunoreactivity in tyrosine hydroxylase-positive cardiac sympathetic fibers. Finally, selective deletion of the ChAT gene from adult sympathetic neurons prevented the infarction-induced increase in cardiac ACh. Deletion of the gp130 cytokine receptor from sympathetic neurons prevented the induction of cholinergic genes after MI, suggesting that inflammatory cytokines induce the transient acquisition of a cholinergic phenotype in cardiac sympathetic neurons. Ex vivo experiments examining the effect of NE and ACh on rabbit cardiac action potential duration revealed that ACh blunted both the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. This raises the possibility that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility. SIGNIFICANCE STATEMENT: Sympathetic neurons normally make norepinephrine (NE), which increases heart rate and the contractility of cardiac myocytes. We found that, after myocardial infarction, the sympathetic neurons innervating the heart begin to make acetylcholine (ACh), which slows heart rate and decreases contractility. Several lines of evidence confirmed that the source of ACh was sympathetic nerves rather than parasympathetic nerves that are the normal source of ACh in the heart. Global application of NE with or without ACh to ex vivo hearts showed that ACh partially reversed the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. That suggests that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility.
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Transdiferenciación Celular/fisiología , Receptor gp130 de Citocinas/metabolismo , Ganglios Simpáticos/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Neuronas/fisiología , Acetilcolina/metabolismo , Acetilcolina/farmacología , Animales , Transdiferenciación Celular/genética , Colina O-Acetiltransferasa/deficiencia , Colina O-Acetiltransferasa/genética , Modelos Animales de Enfermedad , Dopamina beta-Hidroxilasa/genética , Dopamina beta-Hidroxilasa/metabolismo , Femenino , Genotipo , Masculino , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Norepinefrina/metabolismo , Norepinefrina/farmacología , Conejos , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Acetilcolina/genética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoAsunto(s)
Arritmias Cardíacas/fisiopatología , Frecuencia Cardíaca , Corazón/inervación , Plasticidad Neuronal , Sistema Nervioso Simpático/fisiopatología , Animales , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Humanos , Miocardio/metabolismo , Miocardio/patología , Degeneración Nerviosa , Norepinefrina/metabolismo , Factores de Riesgo , Sistema Nervioso Simpático/metabolismoRESUMEN
The melanocortin 3 receptor (MC3R) is involved in regulation of energy homeostasis. However, its transcript structure is not well understood. We therefore studied initiation and termination sites for hypothalamic murine Mc3r and human MC3R transcripts. Rapid Amplification of cDNA Ends (RACE) was performed for the 5' and 3' ends of murine and human hypothalamic RNA. 5' RACE experiments using hypothalamic murine RNA indicated mouse hypothalamus expresses two major Mc3r transcription start sites: one with a 5' UTR approximately 368 bases in length and another previously unknown transcript with a 5' UTR approximately 440 bases in length. 5' RACE experiments using human hypothalamic RNA identified a 5' UTR beginning 533 bases upstream of the start codon with a 248 base splice. 3' RACE experiments using hypothalamic murine RNA indicated the 3' UTR terminates approximately 1286 bases after the translational stop codon, with a previously unknown 787 base splice between consensus splice donor and acceptor sites. 3' RACE experiments using human MC3R transcript indicated the 3' UTR terminates approximately 115-160 bases after the translational stop codon. These data provide insight into melanocortin 3 receptor transcript structure.
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Hipotálamo/metabolismo , Receptor de Melanocortina Tipo 3/genética , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Animales , Secuencia de Bases , Cartilla de ADN/genética , Humanos , Ratones , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Sitio de Iniciación de la TranscripciónRESUMEN
Sympathetic nerves can regenerate after injury to reinnervate target tissues. Sympathetic regeneration is well documented after chronic cardiac ischemia, so we were surprised that the cardiac infarct remained denervated following ischemia-reperfusion (I-R). We used mice to ask if the lack of sympathetic regeneration into the scar was due to blockade by inhibitory extracellular matrix within the infarct. We found that chondroitin sulfate proteoglycans (CSPGs) were present in the infarct after I-R, but not after chronic ischemia, and that CSPGs caused inhibition of sympathetic axon outgrowth in vitro. Ventricle explants after I-R and chronic ischemia stimulated sympathetic axon outgrowth that was blocked by nerve growth factor antibodies. However, growth in I-R cocultures was asymmetrical, with axons growing toward the heart tissue consistently shorter than axons growing in other directions. Growth toward I-R explants was rescued by adding chondroitinase ABC to the cocultures, suggesting that I-R infarct-derived CSPGs prevented axon extension. Sympathetic ganglia lacking protein tyrosine phosphatase sigma (PTPRS) were not inhibited by CSPGs or I-R explants in vitro, suggesting PTPRS is the major CSPG receptor in sympathetic neurons. To test directly if infarct-derived CSPGs prevented cardiac reinnervation, we performed I-R in ptprs-/- and ptprs+/- mice. Cardiac infarcts in ptprs-/- mice were hyperinnervated, while infarcts in ptprs+/- littermates were denervated, confirming that CSPGs prevent sympathetic reinnervation of the cardiac scar after I-R. This is the first example of CSPGs preventing sympathetic reinnervation of an autonomic target following injury, and may have important consequences for cardiac function and arrhythmia susceptibility after myocardial infarction.
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Proteoglicanos Tipo Condroitín Sulfato/fisiología , Corazón/inervación , Corazón/fisiopatología , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Fibras Simpáticas Posganglionares/metabolismo , Animales , Técnicas de Cocultivo , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Infarto del Miocardio/fisiopatología , Técnicas de Cultivo de Órganos , Fibras Simpáticas Posganglionares/fisiopatologíaRESUMEN
Nucleosome positioning is important for the structural integrity of chromosomes. During metaphase the mitotic spindle exerts physical force on pericentromeric chromatin. The cell must adjust the pericentromeric chromatin to accommodate the changing tension resulting from microtubule dynamics to maintain a stable metaphase spindle. Here we examine the effects of spindle-based tension on nucleosome dynamics by measuring the histone turnover of the chromosome arm and the pericentromere during metaphase in the budding yeast Saccharomyces cerevisiae. We find that both histones H2B and H4 exhibit greater turnover in the pericentromere during metaphase. Loss of spindle-based tension by treatment with the microtubule-depolymerizing drug nocodazole or compromising kinetochore function results in reduced histone turnover in the pericentromere. Pericentromeric histone dynamics are influenced by the chromatin-remodeling activities of STH1/NPS1 and ISW2. Sth1p is the ATPase component of the Remodels the Structure of Chromatin (RSC) complex, and Isw2p is an ATP-dependent DNA translocase member of the Imitation Switch (ISWI) subfamily of chromatin-remodeling factors. The balance between displacement and insertion of pericentromeric histones provides a mechanism to accommodate spindle-based tension while maintaining proper chromatin packaging during mitosis.