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1.
Perfusion ; 39(3): 624-626, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36600179

RESUMEN

Ventricular arrhythmias following neurological injury have been attributed to sympathetic surge in subarachnoid hemorrhage and traumatic brain injury. Despite associated risks of bleeding and thrombosis, veno-arterial extracorporeal membrane oxygenation (ECMO) in critically ill, clinically unstable postoperative neurosurgical patients can be lifesaving. In the context of neurological injury and the neurosurgical population, the literature available regarding ECMO utilization is limited, especially in children. We report a case of successful ECMO utilization in a child with malignant ventricular tachycardia after decompressive craniectomy for refractory intracranial hypertension following evacuation of extensive subdural empyema.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Hemorragia Subaracnoidea , Niño , Humanos , Enfermedad Crítica
2.
Pediatr Cardiol ; 2023 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-37684488

RESUMEN

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

3.
Cardiol Young ; 31(3): 462-463, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33541467

RESUMEN

Two cases of paediatric patients with gastric pacemakers causing distinct electrocardiographic artefact. Recognition of extracardiac artefact is essential for proper ECG interpretation in patients.


Asunto(s)
Artefactos , Electrocardiografía , Niño , Humanos
4.
Ann Plast Surg ; 84(6): 644-650, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32040001

RESUMEN

BACKGROUND: Geography is an important yet underexplored factor that may influence the care and outcomes of burn survivors. This study aims to examine the impact of geography on physical and psychosocial function after burn injury. METHODS: Data from the Burn Model Systems National Database (1997-2015) were analyzed. Individuals 18 years and older who were alive at discharge were included. Physical and psychosocial functions were assessed at 6, 12, and 24 months postinjury using the following patient-reported outcome measures: Community Integration Questionnaire, Physical Composite Scale and Mental Composite Scale of the 12-Item Short Form Health Survey, Satisfaction with Appearance Scale, and Satisfaction with Life Scale. Descriptive statistics were generated for demographic and medical data, and mixed regression models were used to assess the impact of geography on long-term outcomes. RESULTS: The study included 469 burn survivors from the Centers for Medicare and Medicaid Services regions 10, 31 from region 8, 477 from region 6, 267 from region 3, and 41 from region 1. Participants differed significantly by region in terms of race/ethnicity, burn size, burn etiology, and acute care length of stay (P < 0.001). In adjusted mixed model regression analyses, scores of all 5 evaluated outcome measures were found to differ significantly by region (P < 0.05). CONCLUSIONS: Several long-term physical and psychosocial outcomes of burn survivors vary significantly by region. This variation is not completely explained by differences in population characteristics. Understanding these geographical differences may improve care for burn survivors and inform future policy and resource allocation.


Asunto(s)
Quemaduras , Calidad de Vida , Anciano , Quemaduras/terapia , Humanos , Medicare , Satisfacción Personal , Sobrevivientes , Estados Unidos/epidemiología
5.
Neurobiol Dis ; 130: 104490, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31175985

RESUMEN

Christianson Syndrome is a rare but increasingly diagnosed X-linked intellectual disability disorder that arises from mutations in SLC9A6/NHE6, a pH-regulating transporter that localizes to early and recycling endosomes. We have recently reported that one of the originally identified disease-causing mutations in NHE6 (p.E287-S288del, or ΔES) resulted in a loss of its pH regulatory function. However, the impact of this mutation upon neuronal synapse formation and plasticity is unknown. Here, we investigate the consequences of the ΔES mutant upon mouse hippocampal pyramidal neurons by expressing a fluorescently-labeled ΔES NHE6 construct into primary hippocampal neurons. Neurons expressing the ΔES mutant showed significant reductions in mature dendritic spine density with a concurrent increase in immature filopodia. Furthermore, compared to wild-type (WT), ΔES-containing endosomes are redirected away from early and recycling endosomes toward lysosomes. In parallel, the ΔES mutant reduced the trafficking of glutamatergic AMPA receptors to excitatory synapses and increased their accumulation within lysosomes for potential degradation. Upon long-term potentiation (LTP), neurons expressing ΔES failed to undergo significant structural and functional changes as observed in controls and WT transfectants. Interestingly, synapse density and LTP-induced synaptic remodeling in ΔES-expressing neurons were partially restored by bafilomycin, a vesicular alkalinisation agent, or by leupeptin, an inhibitor of lysosomal proteolytic degradation. Overall, our results demonstrate that the ∆ES mutation attenuates synapse density and structural and functional plasticity in hippocampal neurons. These deficits may be partially due to the mistargeting of AMPA receptors and other cargos to lysosomes, thereby preventing their trafficking during synaptic remodeling. This mechanism may contribute to the cognitive learning deficits observed in patients with Christianson Syndrome and suggests a potential therapeutic strategy for treatment.


Asunto(s)
Ataxia/genética , Epilepsia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipocampo/metabolismo , Hipocampo/patología , Discapacidad Intelectual/genética , Microcefalia/genética , Plasticidad Neuronal/genética , Trastornos de la Motilidad Ocular/genética , Intercambiadores de Sodio-Hidrógeno/genética , Animales , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Ratones , Mutación , Transporte de Proteínas/genética , Receptores AMPA/metabolismo
6.
Pediatr Cardiol ; 40(6): 1253-1257, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31263917

RESUMEN

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) ≥ 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean ± SD, 12.5 ± 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 ± 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 ± 4.1). The overall mean IVST was 20.5 ± 9.6 mm and the overall mean PWT was 11.0 ± 8.4 mm. The mean IVST in the obese patients was 21.6 ± 10.0 mm and mean PWT was 13.3 ± 14.7 mm. The mean IVST in the non-obese patients was 20.1 ± 9.5 mm and mean PWT was 10.4 ± 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied.


Asunto(s)
Cardiomiopatía Hipertrófica/complicaciones , Ventrículos Cardíacos/patología , Obesidad/complicaciones , Tabique Interventricular/patología , Adolescente , Índice de Masa Corporal , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Preescolar , Ecocardiografía , Femenino , Humanos , Masculino , Adulto Joven
7.
J Physiol ; 596(17): 4253-4267, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29928778

RESUMEN

KEY POINTS: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative human disease characterized in part by ataxia and Purkinje cell loss in anterior cerebellar lobules. A knock-out mouse model has been developed that recapitulates several features of ARSACS. Using this ARSACS mouse model, we report changes in synaptic input and intrinsic firing in cerebellar Purkinje cells, as well as in their synaptic output in the deep cerebellar nuclei. Changes in firing are observed in anterior lobules that later exhibit Purkinje cell death, but not in posterior lobules that do not. Our results show that both synaptic and intrinsic alterations in Purkinje cell properties likely contribute to disease manifestation in ARSACS; these findings resemble pathophysiological changes reported in several other ataxias. ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes a pronounced and progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the Sacs gene that encodes the protein sacsin. To better understand the cerebellar pathophysiology in ARSACS, we studied synaptic and firing properties of Purkinje cells from a mouse model of ARSACS, Sacs-/- mice. We found that excitatory synaptic drive was reduced onto Sacs-/- Purkinje cells, and that Purkinje cell firing rate, but not regularity, was reduced at postnatal day (P)40, an age when ataxia symptoms were first reported. Firing rate deficits were limited to anterior lobules that later display Purkinje cell death, and were not observed in posterior lobules where Purkinje cells are not lost. Mild firing deficits were observed as early as P20, prior to the manifestation of motor deficits, suggesting that a critical level of cerebellar dysfunction is required for motor coordination to emerge. Finally, we observed a reduction in Purkinje cell innervation onto target neurons in the deep cerebellar nuclei (DCN) in Sacs-/- mice. Together, these findings suggest that multiple alterations in the cerebellar circuit including Purkinje cell input and output contribute to cerebellar-related disease onset in ARSACS.


Asunto(s)
Ataxia Cerebelosa/fisiopatología , Modelos Animales de Enfermedad , Proteínas de Choque Térmico/fisiología , Espasticidad Muscular/fisiopatología , Células de Purkinje/fisiología , Ataxias Espinocerebelosas/congénito , Sinapsis/fisiología , Animales , Conducta Animal , Humanos , Ratones , Ratones Noqueados , Mutación , Células de Purkinje/citología , Ataxias Espinocerebelosas/fisiopatología
8.
Stroke ; 49(12): 2866-2871, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30571426

RESUMEN

Background and Purpose- A quarter of acute strokes occur in patients hospitalized for another reason. A stroke recognition instrument may be useful for non-neurologists to discern strokes from mimics such as seizures or delirium. We aimed to derive and validate a clinical score to distinguish stroke from mimics among inhospital suspected strokes. Methods- We reviewed consecutive inpatient stroke alerts in a single academic center from January 9, 2014, to December 7, 2016. Data points, including demographics, stroke risk factors, stroke alert reason, postoperative status, neurological examination, vital signs and laboratory values, and final diagnosis, were collected. Using multivariate logistic regression, we derived a weighted scoring system in the first half of patients (derivation cohort) and validated it in the remaining half of patients (validation cohort) using receiver operating characteristics testing. Results- Among 330 subjects, 116 (35.2%) had confirmed stroke, 43 (13.0%) had a neurological mimic (eg, seizure), and 171 (51.8%) had a non-neurological mimic (eg, encephalopathy). Four risk factors independently predicted stroke: clinical deficit score (clinical deficit score 1: 1 point; clinical deficit score ≥2: 3 points), recent cardiac procedure (1 point), history of atrial fibrillation (1 point), and being a new patient (<24 hours from admission: 1 point). The score showed excellent discrimination in the first 165 patients (derivation cohort, area under the curve=0.93) and remaining 165 patients (validation cohort, area under the curve=0.88). A score of ≥2 had 92.2% sensitivity, 69.6% specificity, 62.2% positive predictive value, and 94.3% negative predictive value for identifying stroke. Conclusions- The 2CAN score for recognizing inpatient stroke performs well in a single-center study. A future prospective multicenter study would help validate this score.


Asunto(s)
Hospitalización , Accidente Cerebrovascular/diagnóstico , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Fibrilación Atrial/epidemiología , Encefalopatías/diagnóstico , Procedimientos Quirúrgicos Cardíacos/estadística & datos numéricos , Estudios de Cohortes , Delirio/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias/diagnóstico , Curva ROC , Factores de Riesgo , Convulsiones/diagnóstico , Sensibilidad y Especificidad , Accidente Cerebrovascular/epidemiología , Factores de Tiempo
9.
Nano Lett ; 16(2): 842-8, 2016 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-26727632

RESUMEN

Safe and effective delivery is required for siRNA and mRNA-based therapeutics to reach their potential. Here, we report on the development of poly(glycoamidoamine) brush nanoparticles as delivery vehicles for siRNA and mRNA. These polymers were capable of significant delivery of siRNA against FVII and mRNA-encoding erythropoietin (EPO) in mice. Importantly, these nanoparticles were well-tolerated at their effective dose based on analysis of tissue histology, systemic cytokine levels, and liver enzyme chemistry. The polymer brush nanoparticles reported here are promising for therapeutic applications.


Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética , Nanopartículas/administración & dosificación , ARN Mensajero/administración & dosificación , Animales , Eritropoyetina/antagonistas & inhibidores , Eritropoyetina/genética , Factor VII/genética , Humanos , Ratones , Nanopartículas/efectos adversos , ARN Interferente Pequeño/administración & dosificación
10.
J Cardiovasc Electrophysiol ; 27(10): 1183-1190, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27334356

RESUMEN

INTRODUCTION: Indications for implantable cardioverter defibrillators (ICDs) in young patients have expanded and differ from those in older adults. We sought to provide descriptive characteristics and data regarding ICD therapy and outcomes among younger and older ICD recipients. METHODS AND RESULTS: Demographics, device type and programming, remotely transmitted data, shock events, and survival were compared among younger (≤30 years) and older (>30 years) cohorts with ICDs from a single manufacturer followed on a remote network. The younger cohort included 904 patients (1.6% of all implants). This group had more females (46% vs. 25%; P < 0.01), single-coil leads (21% vs. 4%; P < 0.01), and single-chamber devices (46% vs. 34%; P < 0.01). Shock incidence was higher (40% younger vs. 32% older at 4 years; P < 0.01) and survival was better over comparable follow-up (88% vs. 72%; P < 0.01). Remote monitoring was associated with improved survival in both groups (93% vs. 86% ≤ 30 years, P < 0.01; 73% vs. 66% > 30 years, P < 0.01). Shock for polymorphic ventricular tachycardia/fibrillation (VT/VF) was more frequent in younger patients (12% vs. 5%; P < 0.01); 39% of all shocks were inappropriate. A 10-fold increased risk of mortality was seen among young patients with shocks for atrial fibrillation/flutter (AF/AFL). CONCLUSIONS: Differences in survival, shock incidence, and prognostic significance of VT/VF and AF/AFL exist between younger and older ICD recipients. These suggest distinct differences in myocardial substrates and diseases that ultimately impact ICD management.


Asunto(s)
Fibrilación Atrial/terapia , Aleteo Atrial/terapia , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Taquicardia Ventricular/terapia , Fibrilación Ventricular/terapia , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/mortalidad , Fibrilación Atrial/fisiopatología , Aleteo Atrial/diagnóstico , Aleteo Atrial/mortalidad , Aleteo Atrial/fisiopatología , Niño , Preescolar , Bases de Datos Factuales , Cardioversión Eléctrica/efectos adversos , Cardioversión Eléctrica/mortalidad , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Diseño de Prótesis , Falla de Prótesis , Factores de Riesgo , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/mortalidad , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Fibrilación Ventricular/diagnóstico , Fibrilación Ventricular/mortalidad , Fibrilación Ventricular/fisiopatología , Adulto Joven
11.
PLoS Biol ; 11(10): e1001680, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24143133

RESUMEN

Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors.


Asunto(s)
Eucariontes/enzimología , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Secuencias de Aminoácidos , Aminoácidos/metabolismo , Biocatálisis , Bases de Datos de Proteínas , Activación Enzimática , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Fosforilación , Alineación de Secuencia , Relación Estructura-Actividad
12.
Proc Natl Acad Sci U S A ; 110(5): E387-96, 2013 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-23319652

RESUMEN

cAMP-dependent protein kinase (PKA) regulates a myriad of functions in the heart, including cardiac contractility, myocardial metabolism,and gene expression. However, a molecular integrator of the PKA response in the heart is unknown. Here, we show that the PKA adaptor A-kinase interacting protein 1 (AKIP1) is up-regulated in cardiac myocytes in response to oxidant stress. Mice with cardiac gene transfer of AKIP1 have enhanced protection to ischemic stress. We hypothesized that this adaptation to stress was mitochondrial dependent. AKIP1 interacted with the mitochondrial localized apoptosis inducing factor (AIF) under both normal and oxidant stress. When cardiac myocytes or whole hearts are exposed to oxidant and ischemic stress, levels of both AKIP1 and AIF were enhanced. AKIP1 is preferentially localized to interfibrillary mitochondria and up-regulated in this cardiac mitochondrial subpopulation on ischemic injury. Mitochondria isolated from AKIP1 gene transferred hearts showed increased mitochondrial localization of AKIP1, decreased reactive oxygen species generation, enhanced calcium tolerance, decreased mitochondrial cytochrome C release,and enhance phosphorylation of mitochondrial PKA substrates on ischemic stress. These observations highlight AKIP1 as a critical molecular regulator and a therapeutic control point for stress adaptation in the heart.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Corazón/fisiología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Factor Inductor de la Apoptosis/metabolismo , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Células HEK293 , Células HeLa , Corazón/fisiopatología , Humanos , Peróxido de Hidrógeno/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Mitocondrias Cardíacas/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/citología , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Proteínas Nucleares/genética , Oxidantes/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley
13.
J Neuroinflammation ; 12: 34, 2015 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-25889069

RESUMEN

BACKGROUND: Recent studies have revealed that excessive activation of microglia and inflammation-mediated neurotoxicity are implicated in the progression of several neurological disorders. In particular, chronic inflammation in vivo and exposure of cultured brain cells to lipopolysaccharide (LPS) in vitro can adversely change microglial morphology and function. This can have both direct and indirect effects on synaptic structures and functions. The integrity of dendritic spines, the postsynaptic component of excitatory synapses, dictates synaptic efficacy. Interestingly, dysgenesis of dendritic spines has been found in many neurological diseases associated with ω-3 polyunsaturated fatty acid (PUFA) deficiency and cognitive decline. In contrast, supplemented ω-3 PUFAs, such as docosahexaenoic acid (DHA), can partly correct spine defects. Hence, we hypothesize that DHA directly affects synaptic integrity and indirectly through neuron-glia interaction. Strong activation of microglia by LPS is accompanied by marked release of nitric oxide and formation of lipid bodies (LBs), both dynamic biomarkers of inflammation. Here we investigated direct effects of DHA on synaptic integrity and its indirect effects via microglia in the hippocampal CA1 region. METHODS: Microglia (N9) and organotypic hippocampal slice cultures were exposed to the proinflammagen LPS (100 ng/ml) for 24 h. Biochemical and morphological markers of inflammation were investigated in microglia and CA1 regions of hippocampal slices. As biomarkers of hyperactive microglia, mitochondrial function, nitric oxide release and LBs (number, size, LB surface-associated proteins) were assessed. Changes in synaptic transmission of CA1 pyramidal cells were determined following LPS and DHA (25-50 µM) treatments by recording spontaneous AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs). RESULTS: Microglia responded to LPS stimulation with a significant decrease of mitochondrial function, increased nitric oxide production and an increase in the formation of large LBs. LPS treatment led to a significant reduction of dendritic spine densities and an increase in the AMPA-mediated mEPSC inter-event interval (IEI). DHA normalized the LPS-induced abnormalities in both neurons and microglia, as revealed by the restoration of synaptic structures and functions in hippocampal CA1 pyramidal neurons. CONCLUSION: Our findings indicate that DHA can prevent LPS-induced abnormalities (neuroinflammation) by reducing inflammatory biomarkers, thereby normalizing microglia activity and their effect on synaptic function.


Asunto(s)
Espinas Dendríticas/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Hipocampo/citología , Microglía/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Bencimidazoles/metabolismo , Carbocianinas/metabolismo , Células Cultivadas , Citocromos c/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Gotas Lipídicas/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Neuronas/fisiología , Óxido Nítrico/metabolismo , Técnicas de Cultivo de Órganos , Perilipina-2 , Polisacáridos/farmacología
14.
Crit Care Med ; 43(9): 1859-69, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26102252

RESUMEN

OBJECTIVES: There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury. DESIGN: We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts. SETTING: Multicenter randomized clinical trial of large, academic trauma centers. MEASUREMENTS AND MAIN RESULTS: Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77). CONCLUSIONS: The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.


Asunto(s)
Mediadores de Inflamación/metabolismo , Piridonas/administración & dosificación , Piridonas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Síndrome de Dificultad Respiratoria/prevención & control , Heridas y Lesiones/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Adulto , Proteína C-Reactiva/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Mortalidad Hospitalaria , Humanos , Interleucina-6/biosíntesis , Interleucina-8/efectos de los fármacos , Masculino , Persona de Mediana Edad , Piridonas/efectos adversos , Pirimidinas/efectos adversos , Receptores Tipo I de Factores de Necrosis Tumoral/efectos de los fármacos , Índices de Gravedad del Trauma
15.
J Cardiovasc Electrophysiol ; 26(5): 520-6, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25651872

RESUMEN

BACKGROUND: The ubiquitous presence of internet-connected phones and tablets presents a new opportunity for cost-effective and efficient electrocardiogram (ECG) screening and on-demand diagnosis. Wireless, single-lead real-time ECG monitoring supported by iOS and android devices can be obtained quickly and on-demand. ECGs can be immediately downloaded and reviewed using any internet browser. OBJECTIVE: We compared the standard 12-lead ECG to the smartphone ECG in healthy young adults, elite athletes, and cardiology clinic patients. Accuracy for determining baseline ECG intervals and rate and rhythm was assessed. METHODS: In 381 participants, 30-second lead I ECG waveforms were obtained using an iPhone case or iPad. Standard 12-lead ECGs were acquired immediately after the smartphone tracing was obtained. De-identified ECGs were interpreted by automated algorithms and adjudicated by two board-certified electrophysiologists. RESULTS: Both smartphone and standard ECGs detected atrial rate and rhythm, AV block, and QRS delay with equal accuracy. Sensitivities ranged from 72% (QRS delay) to 94% (atrial fibrillation). Specificities were all above 94% for both modalities. CONCLUSION: Smartphone ECG accurately detects baseline intervals, atrial rate, and rhythm and enables screening in diverse populations. Efficient ECG analysis using automated discrimination and an enhanced smartphone application with notification capabilities are features that can be easily incorporated into the acquisition process.


Asunto(s)
Arritmias Cardíacas/diagnóstico , Electrocardiografía/métodos , Frecuencia Cardíaca , Tamizaje Masivo/instrumentación , Aplicaciones Móviles , Teléfono Inteligente , Telemedicina/instrumentación , Telemetría/instrumentación , Tecnología Inalámbrica/instrumentación , Adolescente , Adulto , Anciano , Algoritmos , Arritmias Cardíacas/fisiopatología , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/fisiopatología , Actitud hacia los Computadores , Automatización , Estudios de Casos y Controles , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Procesamiento de Señales Asistido por Computador , Encuestas y Cuestionarios , Adulto Joven
16.
Biomacromolecules ; 16(9): 3073-82, 2015 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-26218295

RESUMEN

Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology.


Asunto(s)
Región CA1 Hipocampal/metabolismo , Espinas Dendríticas/metabolismo , Glicerol/farmacología , Microglía/metabolismo , Polímeros/farmacología , Células Piramidales/metabolismo , Animales , Línea Celular , Espinas Dendríticas/patología , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Transgénicos , Microglía/patología , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Células Piramidales/patología , Factor de Necrosis Tumoral alfa/metabolismo
17.
Proc Natl Acad Sci U S A ; 109(2): 553-8, 2012 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-22203954

RESUMEN

Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.


Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/genética , Melanoma/tratamiento farmacológico , Melanosomas/efectos de los fármacos , Proteínas de Transporte Vesicular/deficiencia , Secuencia de Aminoácidos , Carboplatino/farmacología , Línea Celular Tumoral , Reparación del ADN , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Humanos , Immunoblotting , Microscopía Electrónica , Microscopía Fluorescente , Datos de Secuencia Molecular , Mutación/genética , Transporte de Proteínas/genética , Interferencia de ARN , Receptor de Melanocortina Tipo 1/metabolismo , Temozolomida , Regulación hacia Arriba/efectos de los fármacos , Proteínas de Transporte Vesicular/genética
18.
Eur J Neurosci ; 40(5): 2766-76, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24925283

RESUMEN

CX 546, an allosteric positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPARs), belongs to a drug class called ampakines. These compounds have been shown to enhance long-term potentiation (LTP), a cellular model of learning and memory, and improve animal learning task performance, and have augmented cognition in neurodegenerative patients. However, the chronic effect of CX546 on synaptic structures has not been examined. The structure and integrity of dendritic spines are thought to play a role in learning and memory, and their abnormalities have been implicated in cognitive disorders. In addition, their structural plasticity has been shown to be important for cognitive function, such that dendritic spine remodeling has been proposed as the morphological correlate for LTP. Here, we tested the effect of CX546 on dendritic spine remodeling following long-term treatment. We found that, with prolonged CX546 treatment, organotypic hippocampal slice cultures showed a significant reduction in CA3-CA1 excitatory synapse and spine density. Electrophysiological approaches revealed that the CA3-CA1 circuitry compensates for this synapse loss by increasing synaptic efficacy through enhancement of presynaptic release probability. CX546-treated slices showed prolonged and enhanced potentiation upon LTP induction. Furthermore, structural plasticity, namely spine head enlargement, was also more pronounced after CX546 treatment. Our results suggest a concordance of functional and structural changes that is enhanced with prolonged CX546 exposure. Thus, the improved cognitive ability of patients receiving ampakine treatment may result from the priming of synapses through increases in the structural plasticity and functional reliability of hippocampal synapses.


Asunto(s)
Espinas Dendríticas/efectos de los fármacos , Dioxanos/farmacología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Piperidinas/farmacología , Terminales Presinápticos/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Espinas Dendríticas/fisiología , Dioxoles , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/citología , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Terminales Presinápticos/fisiología , Receptores AMPA/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Factores de Tiempo , Técnicas de Cultivo de Tejidos
19.
Paediatr Anaesth ; 24(9): 1009-11, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25039494

RESUMEN

Currently, information about airway assessment and tracheal intubation is communicated verbally or in writing. Google Glass can record this information in real time with minimal disruption to work flow, using standard operating room lighting.


Asunto(s)
Computadoras de Mano , Intubación Intratraqueal , Grabación en Video/instrumentación , Adulto , Humanos , Laringoscopía , Masculino , Adulto Joven
20.
PM R ; 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38864328

RESUMEN

OBJECTIVE: To examine the impact of telemedicine on demographic and practice patterns between outpatients receiving virtual versus in-person cancer rehabilitation physiatry care. DESIGN: Multicenter retrospective study. SETTING: Outpatient cancer rehabilitation physiatry clinics at four academic medical centers in the United States. PATIENTS: Patients with cancer diagnoses or history of cancer diagnosis. INTERVENTIONS: Cancer rehabilitation physiatry encounters. MAIN OUTCOME MEASURES: Visit mode (in-person, telemedicine); disparities variables (age, race, and gender) by visit mode, and practice interventions (imaging, medications, procedures, other orders, and orders of any type) by visit mode. RESULTS: Among a total of 7004 encounters, 2687 unique patients were found. In-person participants were significantly older than the average telemedicine participant (mean 62.9 vs. 60.7 years; p < .001). A race effect was seen (p = .037) with individuals reporting as Asian or other being more likely to have telemedicine encounters. No gender disparities were seen. Using a random visit analysis model to compare populations receiving in-person versus telemedicine care, a slight majority (53%) of follow-up visits were via telemedicine, versus 40% of new patient visits (p < .001). No significant differences were seen in medication prescribing frequency (38.9% telemedicine vs. 36.7% in-person, adjusted relative risk [RR]: 0.988, confidence interval [CI]: 0.73-1.34; p = .988) or imaging frequency (2.4% telemedicine vs. 7.6%; adjusted RR: 0.784, CI: 0.44-1.39; p = .408) between telemedicine versus in-person visit types. Other orders were significantly less likely to be placed during telemedicine than in-person visits (19.9% telemedicine vs. 28.6% in-person; adjusted RR: 0.623, CI: 0.45-0.86, p = .004). Order(s) of any type were placed in 54% of visits (52% telemedicine vs. 56% in-person; adjusted RR: 0.92 for telemedicine, CI: 0.83-1.01, p = .082). CONCLUSIONS: Telemedicine has been integrated into cancer rehabilitation physiatry practices and appears to be conducive for placing many types of orders, especially medications. Age was found to be the only major demographic difference between in-person and telehealth patients.

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