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1.
BMJ Open ; 13(10): e074141, 2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37827745

RESUMEN

OBJECTIVES: To identify and prioritise interventions, from the perspectives of parents and health professionals, which may be alternatives to current unscheduled paediatric urgent care pathways. DESIGN: FLAMINGO (FLow of AdMissions in chIldren and youNG peOple) is a sequential mixed-methods study, with public and patient involvement (PPI) throughout. Data linkage for urgent admissions and three referral sources: emergency department, out of hours service and general practice, was followed by qualitative interviews with parents and professionals. Findings were presented and discussed at a stakeholder intervention prioritisation event. SETTING: National Health Service in Scotland, UK. PARTICIPANTS: Quantitative data: children with urgent medical admission to hospital from 2015 to 2017. Qualitative interviews: parents and health professionals with experiences of urgent short stay hospital admissions of children. PPI engagement was conducted with nine parent-toddler groups and a university-based PPI advisory group. Stakeholder event: parents, health professionals and representatives from Scottish Government, academia, charities and PPI attended. RESULTS: Data for 171 039 admissions which included 92 229 short stay admissions were analysed and 48 health professionals and 21 parents were interviewed. The stakeholder event included 7 parents, 12 health professionals and 28 other stakeholders. Analysis and synthesis of all data identified seven interventions which were prioritised at the stakeholder event: (1) addressing gaps in acute paediatric skills of health professionals working in community settings; (2) assessment and observation of acutely unwell children in community settings; (3) creation of holistic children's 'hubs'; (4) adoption of 'hospital at home' models; and three specialised care pathways for subgroups of children; (5) convulsions; (6) being aged <2 years old; and (7) wheeze/bronchiolitis. Stakeholders prioritised interventions 1, 2 and 3; these could be combined into a whole population intervention. Barriers to progressing these include resources, staffing and rurality. CONCLUSIONS: Health professionals and families want future interventions that are patient-centred, community-based and aligned to outcomes that matter to them.


Asunto(s)
Vías Clínicas , Medicina Estatal , Niño , Humanos , Adolescente , Preescolar , Personal de Salud , Padres , Escocia
2.
J Immunol ; 206(7): 1425-1435, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33597151

RESUMEN

Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to microbial metabolite Ags or cytokine stimulation. Because of this reactivity and surface expression of CD45RO+, CD45RA-, and CD127+, they are described as effector memory cells. Yet, there is heterogeneity in MAIT cell effector response. It is unclear what factors control MAIT cell effector capacity, whether it is fixed or can be modified and if this differs based on whether activation is TCR dependent or independent. To address this, we have taken a systematic approach to examine human MAIT cell effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cell effector capacity and that the ability to produce an effector response is not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cell effector capacity produced in response to TCR stimulation is associated with increased expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor did not alter MAIT cell effector function to Ag or cytokine stimulation. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cell effector capacity to TCR-dependent stimulation in a partially KDM6B-dependent manner. These results demonstrate that the TCR-dependent effector response of MAIT cells is epigenetically regulated and dependent on the availability of metabolic cofactors.


Asunto(s)
Histona Demetilasas con Dominio de Jumonji/metabolismo , Ácidos Cetoglutáricos/metabolismo , Células T Invariantes Asociadas a Mucosa/inmunología , Células Cultivadas , Citocinas/metabolismo , Epigénesis Genética , Humanos , Inmunidad Innata , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T/metabolismo
3.
J Immunother Cancer ; 8(1)2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32350119

RESUMEN

BACKGROUND: Immunogenicity of cancer vaccines is impacted by adjuvants and schedule, but systematic assessments of their effects have not been performed. Montanide ISA-51, an incomplete Freund's adjuvant (IFA), is used in many vaccine trials, but concerns have been raised about negative effects in murine studies. We found in humans that IFA enhances systemic immune responses and that repeat vaccination at one site (same site vaccination (SSV)) creates tertiary lymphoid structures (TLS) in the vaccine site microenvironment (VSME). We hypothesized that vaccination with peptides+IFA+pICLC or SSV×3 with peptides in IFA would create an immunogenic milieu locally at the VSME, with activated dendritic cells (DC), TLS-associated chemokines and a Th1-dominant VSME. METHODS: Biopsies of the VSME were obtained from participants on two clinical trials who were immunized with multiple melanoma peptides (MELITAC 12.1) in adjuvants comprising IFA and/or the TLR3-agonist pICLC. Biopsies were obtained either a week after one vaccine or a week after SSV×3. Controls included normal skin and skin injected with IFA without peptides. Gene expression analysis was performed by RNAseq. RESULTS: VSME samples were evaluated from 27 patients. One vaccine with peptides in pICLC+IFA enhanced expression of CD80, CD83, CD86 (p<0.01), CD40 and CD40L (p<0.0001) over normal skin; these effects were significantly enhanced for SSV with peptides+IFA. Vaccines containing pICLC increased expression of TBX21 (T-bet) but did not decrease GATA3 over normal skin, whereas SSV with peptides in IFA dramatically enhanced TBX21 and decreased GATA3, with high expression of IFNγ and STAT1. SSV with peptides in IFA also reduced arginase-1 (ARG1) expression and enhanced expression of TLR adapter molecules TICAM-1 (TRIF) and MYD88. Furthermore, SSV with IFA and peptides also enhanced expression of chemokines associated with TLS formation. CONCLUSIONS: These findings suggest that SSV with peptides in IFA enhances CD40L expression by CD4 T cells, supports a Th1 microenvironment, with accumulation of activated and mature DC. Increased expression of TLR adaptor proteins after SSV with peptides in IFA might implicate effects of the skin microbiome. Reduced ARG1 may reflect diminished suppressive myeloid activity in the VSME. TRIAL REGISTRATION NUMBER: (NCT00705640, NCT01585350).


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Adyuvante de Freund/administración & dosificación , Lípidos/administración & dosificación , Melanoma/terapia , Neoplasias Cutáneas/terapia , Vacunación/métodos , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/inmunología , Arginasa/metabolismo , Biopsia , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Vacunas contra el Cáncer/inmunología , Ensayos Clínicos Fase I como Asunto , Femenino , Adyuvante de Freund/inmunología , Humanos , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Inyecciones Intralesiones , Lípidos/inmunología , Masculino , Manitol/administración & dosificación , Manitol/análogos & derivados , Manitol/inmunología , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Ácidos Oléicos/administración & dosificación , Ácidos Oléicos/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Piel/inmunología , Piel/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Receptores Toll-Like/metabolismo , Microambiente Tumoral/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Adulto Joven
4.
J Clin Hypertens (Greenwich) ; 19(12): 1301-1308, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28940643

RESUMEN

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.


Asunto(s)
Negro o Afroamericano/estadística & datos numéricos , Presión Sanguínea , Clortalidona/administración & dosificación , Hipertensión , Metoprolol/administración & dosificación , Población Blanca/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Etnofarmacología/métodos , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/etnología , Masculino , Administración del Tratamiento Farmacológico/organización & administración , Persona de Mediana Edad , Estados Unidos/epidemiología
5.
J Clin Invest ; 126(9): 3453-66, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27525438

RESUMEN

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokine-independent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.


Asunto(s)
Quimiocina CCL17/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Inflamación , Factores Reguladores del Interferón/metabolismo , Animales , Artritis/metabolismo , Células de la Médula Ósea/metabolismo , Silenciador del Gen , Heterocigoto , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Macrófagos/metabolismo , Ratones , Monocitos/citología , Monocitos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Dolor , Manejo del Dolor , Peritonitis/metabolismo
6.
Endocrinology ; 157(10): 3856-3872, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27571134

RESUMEN

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-µg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-µg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-µg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERß (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain.


Asunto(s)
Compuestos de Bencidrilo/toxicidad , Estrógenos no Esteroides/toxicidad , Hipocampo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Fenoles/toxicidad , Transcriptoma/efectos de los fármacos , Administración Oral , Animales , Animales Recién Nacidos , Compuestos de Bencidrilo/administración & dosificación , Estrógenos no Esteroides/administración & dosificación , Femenino , Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Fenoles/administración & dosificación , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales
7.
Eur Respir J ; 45(4): 1027-36, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25359350

RESUMEN

Are maternal vitamin D and E intakes during pregnancy associated with asthma in 10-year-old children? In a longitudinal study of 1924 children born to women recruited during pregnancy, maternal vitamin D intake during pregnancy was assessed by the Food Frequency Questionnaire (FFQ) and vitamin E by FFQ and plasma α-tocopherol; respiratory questionnaires were completed for the 10-year-old children. Their treatment for asthma was also ascertained using administrative data. Longitudinal analyses included data collected at 1, 2, 5 and 10 years. Symptom data were available for 934 (49%) children and use of asthma medication for 1748 (91%). In the children maternal vitamin D intake during pregnancy was negatively associated with doctor-diagnosed asthma at 10 years of age (OR per intake quintile 0.86, 95% CI 0.74-0.99) and over the first 10 years (hazard ratio 0.90, 95% CI 0.81-1.00). Maternal plasma α-tocopherol at 11 weeks gestation was negatively associated with children receiving asthma treatment (OR per standard deviation increase 0.52, 95% CI 0.31-0.87). Maternal vitamin E intake was negatively associated with doctor-diagnosed asthma (OR 0.89, 95% CI 0.81-0.99) in the first 10 years. Low maternal vitamin D and E intakes during pregnancy are associated with increased risk of children developing asthma in the first 10 years of life. These associations may have significant public health implications.


Asunto(s)
Asma/etiología , Suplementos Dietéticos/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Vitamina D/efectos adversos , Vitamina E/efectos adversos , Distribución por Edad , Asma/epidemiología , Asma/fisiopatología , Niño , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Recién Nacido , Estudios Longitudinales , Embarazo , Atención Prenatal , Medición de Riesgo , Distribución por Sexo , Encuestas y Cuestionarios , Vitamina D/administración & dosificación , Vitamina E/administración & dosificación
8.
BMJ Clin Evid ; 20122012 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-24807832

RESUMEN

INTRODUCTION: Acute childhood asthma is a common clinical emergency presenting across a range of ages and with a range of severities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (high-dose nebulised, metered-dose inhaler plus spacer device versus nebuliser, intravenous), corticosteroids (systemic, high-dose inhaled), ipratropium bromide (single- or multiple-dose inhaled), magnesium sulphate, oxygen, and theophylline or aminophylline.


Asunto(s)
Asma , Ruidos Respiratorios , Enfermedad Aguda , Administración por Inhalación , Administración Oral , Corticoesteroides/administración & dosificación , Asma/tratamiento farmacológico , Niño , Humanos , Teofilina/administración & dosificación
9.
Pediatr Pulmonol ; 45(3): 236-40, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20131381

RESUMEN

RATIONALE: Exhaled nitric oxide (FE(NO)) may be a useful biomarker for asthma and is derived from enzymatic activity on the amino acid L-arginine. The aim of the present pilot study was to study the effect of L-arginine ingestion on FE(NO) and also NO production in the proximal and distal airways. METHODS: Asthmatic and control children were enrolled and phenotyped by skin prick reactivity and spirometry. FE(NO) was measured before and after ingestion of 0.2 g/kg L-arginine. Proximal and distal NO production (J'awNO and CANO) were derived using the method of Tsoukias. RESULTS: Twenty children were recruited, 11 steroid-treated asthmatics, 1 steroid-naïve asthmatic, and 8 healthy controls. The median baseline FE(NO) before L-arginine administration was 31 ppb (interquartile range, IQR, 15, 61). At baseline, the median J'awNO was 1000 nl/sec (IQR 650, 2880) and the median CANO was 2.3 ppb (IQR 1.8, 4.5). FE(NO) rose by an average of 5.5 ppb [95% CI 3.5, 7.5] (P < 0.001) 60 min after ingestion of L-arginine and 1.5 ppb [95% CI -0.9, 4.0] (P = 0.188) after 120 min. One hour after L-arginine ingestion, J'awNO did not change but CANO rose by an average of 2.6 ppb [95% CI 0.5, 4.7], P = 0.020. CONCLUSION: The rise in FE(NO) after dietary exposure to L-arginine is modest, transient, and of little or no clinical significance.


Asunto(s)
Arginina/metabolismo , Suplementos Dietéticos , Óxido Nítrico/metabolismo , Administración Oral , Adolescente , Arginina/administración & dosificación , Asma , Pruebas Respiratorias , Estudios de Casos y Controles , Niño , Femenino , Humanos , Mediciones Luminiscentes , Masculino , Óxido Nítrico/análisis , Proyectos Piloto
10.
Int J Sport Nutr Exerc Metab ; 17(1): 70-91, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17460334

RESUMEN

The authors examined the effects of combined creatine (Cr) and glycerol (Gly) supplementation on responses to exercise in the heat. Subjects (N=24) were matched for body mass and assigned to either a Cr or placebo (Pl) group. Twice daily during two 7-d supplementation regimens, the Cr group received 11.4 g of Cr x H2O and the Pl group received 11.4 g of glucose. Subjects in both groups also ingested 1 g of Gly/kg body mass (twice daily) in either the first or the second supplementation regimen. This design allowed 4 possible combinations of supplements to be examined (Pl/Pl, Pl/Gly, Cr/Pl, and Cr/Gly). Exercise trials were conducted pre- and postsupplementation at 30 degrees C and 70% relative humidity. In the Pl group, total body water (TBW) increased by 0.50 +/- 0.28 L after Gly and in the Cr group by 0.63 +/- 0.33 L after Pl and by 0.87 +/- 0.21 L after Gly. Both Cr/Pl and Cr/Gly resulted in significantly attenuated heart rate, rectal temperature, and perceived effort during exercise, although no regimen had any effect on performance. The addition of Gly to Cr significantly increased TBW more than Cr alone (P=0.02) but did not further enhance the attenuation in HR, Tre, and RPE during exercise. These data suggest that combined Cr and Gly is an effective method of hyperhydration capable of reducing thermal and cardiovascular responses.


Asunto(s)
Agua Corporal/metabolismo , Creatina/farmacología , Deshidratación/prevención & control , Ejercicio Físico/fisiología , Glicerol/farmacología , Calor , Adulto , Área Bajo la Curva , Estudios Cruzados , Suplementos Dietéticos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Consumo de Oxígeno , Termogénesis/efectos de los fármacos , Termogénesis/fisiología
11.
Circulation ; 110(3): 356-62, 2004 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-15249504

RESUMEN

BACKGROUND: Electron-beam computed tomography (EBCT) is used to measure coronary calcification but not for aortic valve calcification (AVC). Its accuracy, association with aortic stenosis (AS) severity, and diagnostic and prognostic value with respect to AVC are unknown. METHODS AND RESULTS: In 30 explanted aortic valves, the AVC score by EBCT (1125+/-1294 Agatston units [AU]) showed a strong linear correlation (r=0.96, P<0.0001) with valvular calcium weight (653+/-748 mg) by pathology that allowed estimation of calcium weight as AVC score/1.7, with a small standard error of the estimate (53 mg). In 100 consecutive clinical patients, we measured AVC by EBCT and AS severity by echocardiographic aortic valve area (AVA). The AVC score was 1316+/-1749 AU (range 0 to 7226 AU). Intraobserver and interobserver variabilities were excellent (4+/-4% and 4+/-10%, respectively). AVC and AVA were strongly associated (r=0.79, P<0.0001) but had a curvilinear relationship that suggested that AVC and AVA provide complementary information. AVC score > or =1100 AU provided 93% sensitivity and 82% specificity for diagnosis of severe AS (AVA <1 cm2), with a receiver operator characteristic curve area of 0.89. AVC assessment by echocardiography was often more severe than by EBCT (P<0.0001). During follow-up, 22 patients either died, developed heart failure, or required surgery. With adjustment for age, sex, symptoms, ejection fraction, and AVA, the AVC score was independently predictive of event-free survival (risk ratio 1.06 per 100-AU increment [1.02 to 1.10], P<0.001), even after adjustment for echocardiographic calcifications. CONCLUSIONS: AVC is accurately and reproducibly measured by EBCT and shows a strong association and diagnostic value for severe AS. The curvilinear relationship between AVC and AVA suggests these measures are complementary, and indeed, AVC provides independent outcome information. Thus, AVC is an important measurement in the evaluation of patients with AS.


Asunto(s)
Estenosis de la Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/diagnóstico , Supervivencia sin Enfermedad , Ecocardiografía Doppler , Hemodinámica , Humanos , Reproducibilidad de los Resultados
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