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OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.
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Ensayos Clínicos como Asunto/métodos , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/tratamiento farmacológico , Marihuana Medicinal/uso terapéutico , Niño , HumanosAsunto(s)
Pustulosis Exantematosa Generalizada Aguda/diagnóstico , Dermatitis Alérgica por Contacto/diagnóstico , Eritema/etiología , Pitiriasis Rubra Pilaris/diagnóstico , Psoriasis/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/complicaciones , Psoriasis/tratamiento farmacológicoRESUMEN
PURPOSE: To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children. METHODS: We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits. RESULTS: Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events. CONCLUSION: Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy. PROSPERO: CRD42018084755.
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Cannabidiol/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Epilepsia/tratamiento farmacológico , Marihuana Medicinal/uso terapéutico , Cannabidiol/efectos adversos , Moduladores de Receptores de Cannabinoides/efectos adversos , Niño , Humanos , Marihuana Medicinal/efectos adversosRESUMEN
Expanding pharmacist-driven antimicrobial stewardship efforts in the emergency department (ED) can improve antibiotic management for both admitted and discharged patients. We piloted a pharmacist-driven culture and rapid diagnostic technology (RDT) follow-up program in patients discharged from the ED. This was a single-center, pre- and post-implementation, cohort study examining the impact of a pharmacist-driven culture/RDT follow-up program in the ED. Adult patients discharged from the ED with subsequent positive cultures and/or RDT during the pre- (21 August 2018-18 November 2018) and post-implementation (19 November 2018-15 February 2019) periods were screened for inclusion. The primary endpoints were time from ED discharge to culture/RDT review and completion of follow-up. Secondary endpoints included antimicrobial agent prescribed during outpatient follow-up, repeat ED encounters within 30 days, and hospital admissions within 30 days. Baseline characteristics were analyzed using descriptive statistics. Time-to-event data were analyzed using the Wilcoxon signed-rank test. One-hundred-and-twenty-seven patients were included, 64 in the pre-implementation group and 63 in the post-implementation group. There was a 36.3% reduction in the meantime to culture/RDT data review in the post-implementation group (75.2 h vs. 47.9 h, p < 0.001). There was a significant reduction in fluoroquinolone prescribing in the post-implementation group (18.1% vs. 5.4%, p = 0.036). The proportion of patients who had a repeat ED encounter or hospital admission within 30 days was not significantly different between the pre- and post-implementation groups (15.6 vs. 19.1%, p = 0.78 and 9.4% vs. 7.9%, p = 1.0, respectively). Introduction of a pharmacist culture and RDT follow-up program in the ED reduced time to data review, time to outpatient intervention and outpatient follow-up of fluoroquinolone prescribing.
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CASE PRESENTATION: A 39-year-old male presented to the ED with a 2-day history of fever (Temperature-Maximum 39°C), nonbloody productive cough, and worsening right-sided pleuritic chest pain. The patient denied shortness of breath, nausea, vomiting, sinus symptoms, and abdominal pain. His medical history included type 2 diabetes mellitus (glycated hemoglobin, 11.1), hyperlipidemia, and depression. He smoked marijuana but denied tobacco or illicit drug use. He reported no recent travels. He reported a 1-week history of left molar pain that began after he siphoned stagnant water with a straw from a refrigerator drip pan. He lived in Ohio all of his life. He denied any sick contacts. His medications include Lantus insulin at night, metformin, glimepiride, pravastatin, and Remeron.
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Infecciones por Bacterias Gramnegativas/diagnóstico por imagen , Infecciones por Bacterias Gramnegativas/microbiología , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/microbiología , Sphingomonas/aislamiento & purificación , Adulto , Antibacterianos/uso terapéutico , Dolor en el Pecho , Angiografía por Tomografía Computarizada , Diabetes Mellitus Tipo 2 , Diagnóstico Diferencial , Ecocardiografía , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Masculino , Nódulos Pulmonares Múltiples/tratamiento farmacológico , PleuresiaRESUMEN
BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers. METHODS: We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings. DISCUSSION: Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755.
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Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Cannabis/química , Epilepsia/tratamiento farmacológico , Niño , Epilepsia/psicología , Humanos , Calidad de Vida/psicología , Convulsiones/prevención & controlRESUMEN
Depigmented patches covering approximately 15% of newborn's body, surrounded by areas of thickened skin. Mild scaling and hyperpigmentation.
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Piebaldismo/diagnóstico , Piebaldismo/terapia , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/terapia , Adulto , Negro o Afroamericano , Femenino , Humanos , Recién Nacido , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
Lifestyle changes and metabolic syndrome management are the best interventions for NAFLD. Less clear is which agents to use for liver-directed pharmacotherapy.
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Hipolipemiantes/uso terapéutico , Síndrome Metabólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/prevención & control , Adulto , Humanos , Estilo de Vida , Masculino , Factores de Riesgo , Resultado del Tratamiento , Estados UnidosRESUMEN
Because the androgen and estrogen nuclear hormone receptors are subject to acetylation, we speculated that the nuclear thyroid hormone receptor-beta1 (TRbeta1), another superfamily member, was also subject to this posttranslational modification. Treatment of 293T cells that contain TRbeta1(wt) with l-thyroxine (T4)(10(-7)M, total concentration) resulted in the accumulation of acetylated TR in nuclear fractions at 30-45 min and a decrease in signal by 60 min. A similar time course characterized recruitment by TR of p300, a coactivator protein with intrinsic transacetylase activity. Recruitment by the receptor of SRC-1, a TR coactivator that also acetylates nucleoproteins, was also demonstrated. Inhibition of the MAPK (ERK1/2) signal transduction cascade by PD 98059 blocked the acetylation of TR caused by T4. Tetraiodothyroacetic acid (tetrac) decreased T4-induced acetylation of TR. At 10(-7)M, 3,5,3'-triiodo-l-thyronine (T3) was comparably effective to T4 in causing acetylation of TR. We studied acetylation in TR that contained mutations in the DNA-binding domain (DBD) (residues 128-142) that are known to be relevant to recruitment of coactivators and to include the MAPK docking site. In response to T4 treatment, the K128A TR mutant transfected into CV-1 cells recruited p300, but not SRC-1, and was subject to acetylation. R132A complexed with SRC-1, but not p300; it was acetylated equally well in both the absence and presence of T4. S142E was acetylated in the absence and presence of T4 and bound SRC-1 under both conditions; this mutant was also capable of binding p300 in the presence of T4. There was no serine phosphorylation of TR in any of these mutants. We conclude that (1) TRbeta1, like AR and ER, is subject to acetylation; (2) the process of acetylation of TR requires thyroid hormone-directed MAPK activity, but not serine phosphorylation of TR by MAPK, suggesting that the contribution of MAPK is upstream in the activation of the acetylase; (3) the amino acid residue 128-142 region of the DBD of TR is important to thyroid hormone-associated recruitment of p300 and SRC-1; (4) acetylation of TR DBD mutants that is directed by T4 appears to be associated with recruitment of p300.
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Sistema de Señalización de MAP Quinasas , Receptores Citoplasmáticos y Nucleares/metabolismo , Hormonas Tiroideas/metabolismo , Acetilación , Animales , Línea Celular , Núcleo Celular/metabolismo , Activación Enzimática , Flavonoides/farmacología , Humanos , Mutación , Fosforilación , Plásmidos/metabolismo , Estructura Terciaria de Proteína , Receptores de Hormona Tiroidea/metabolismo , Serina/química , Transducción de Señal , Fracciones Subcelulares/metabolismo , Receptores beta de Hormona Tiroidea , Tiroxina/metabolismo , Factores de Tiempo , Transfección , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Expansions of a (GCN)10/polyalanine tract in the Poly(A) Binding Protein Nuclear 1 (PABPN1) cause autosomal dominant oculopharyngeal muscular dystrophy (OPMD). In OPMD muscles, as in models, PABPN1 accumulates in intranuclear inclusions (INIs) whereas in other diseases caused by similar polyalanine expansions, the mutated proteins have been shown to abnormally accumulate in the cytoplasm. This study presents the impact on the subcellular localization of PABPN1 produced by large expansions or deletion of its polyalanine tract. Large tracts of more than 24 alanines result in the nuclear accumulation of PABPN1 in SFRS2-positive functional speckles and a significant decline in cell survival. These large expansions do not cause INIs formation nor do they lead to cytoplasmic accumulation. Deletion of the polyalanine tract induces the formation of aggregates that are located on either side and cross the nuclear membrane, highlighting the possible role of the N-terminal polyalanine tract in PABPN1 nucleo-cytoplasmic transport. We also show that even though five other proteins with polyalanine tracts tend to aggregate when over-expressed they do not co-aggregate with PABPN1 INIs. This study presents the first experimental evidence that there may be a relative loss of function in OPMD by decreasing the availability of PABPN1 through an INI-independent mechanism.