PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.

We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3' splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.

Exploring miRNA-target gene pair detection in disease with coRmiT.

A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.

Significance of utilizing in silico structural analysis and phenotypic data to characterize phenylalanine hydroxylase variants: A PAH landscape.

Phenylketonuria (PKU) is a genetic disorder caused by variations in the phenylalanine hydroxylase (PAH) gene. Among the 3369 reported PAH variants, 33.7% are missense alterations. Unfortunately, 30% of these missense variants are classified as variants of unknown significance (VUS), posing challenges for genetic risk assessment. In our study, we focused on analyzing 836 missense PAH variants following the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines specified by ClinGen PAH Variant Curation Expert Panel (VCEP) criteria. We utilized and compared variant annotator tools like Franklin and Varsome, conducted 3D structural analysis of PAH, and examined active and regulatory site hotspots. In addition, we assessed potential splicing effect of apparent missense variants. By evaluating phenotype data from 22962 PKU patients, our aim was to reassess the pathogenicity of missense variants. Our comprehensive approach successfully reclassified 309 VUSs out of 836 missense variants as likely pathogenic or pathogenic (37%), upgraded 370 likely pathogenic variants to pathogenic, and reclassified one previously considered likely benign variant as likely pathogenic. Phenotypic information was available for 636 missense variants, with 441 undergoing 3D structural analysis and active site hotspot identification for 180 variants. After our analysis, only 6% of missense variants were classified as VUSs, and three of them (c.23A>C/p.Asn8Thr, c.59_60delinsCC/p.Gln20Pro, and c.278A >T/p.Asn93Ile) may be influenced by abnormal splicing. Moreover, a pathogenic variant (c.168G>T/p.Glu56Asp) was identified to have a risk exceeding 98% for modifications of the consensus splice site, with high scores indicating a donor loss of 0.94. The integration of ACMG/AMP guidelines with in silico structural analysis and phenotypic data significantly reduced the number of missense VUSs, providing a strong basis for genetic counseling and emphasizing the importance of metabolic phenotype information in variant curation. This study also sheds light on the current landscape of PAH variants.

HepG2 PMM2-CDG knockout model: A versatile platform for variant and therapeutic evaluation.

Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent congenital disorder of glycosylation, is an autosomal recessive disease caused by biallelic pathogenic variants in the PMM2 gene. There is no cure for this multisystemic syndrome. Some of the therapeutic approaches that are currently in development include mannose-1-phosphate replacement therapy, drug repurposing, and the use of small chemical molecules to correct folding defects. Preclinical models are needed to evaluate the efficacy of treatments to overcome the high lethality of the available animal model. In addition, the number of variants with unknown significance is increasing in clinical settings. This study presents the generation of a cellular disease model by knocking out the PMM2 gene in the hepatoma HepG2 cell line using CRISPR-Cas9 gene editing. The HepG2 knockout model accurately replicates the PMM2-CDG phenotype, exhibiting a complete absence of PMM2 protein and mRNA, a 90% decrease in PMM enzymatic activity, and altered ICAM-1, LAMP1 and A1AT glycoprotein patterns. The evaluation of PMM2 disease-causing variants validates the model's utility for studying new PMM2 clinical variants, providing insights for diagnosis and potentially for evaluating therapies. A CRISPR-Cas9-generated HepG2 knockout model accurately recapitulates the PMM2-CDG phenotype, providing a valuable tool for assessing disease-causing variants and advancing therapeutic strategies.

The relations among prosocial behavior, hedonic, and eudaimonic well-being in everyday life.

INTRODUCTION: Existing research highlights the significance of prosocial behavior (voluntary, intentional behavior that results in benefits for another) to people's well-being. Yet, the extent to which this expected positive relation operates at the within-person level (e.g., is more prosocial behavior than usual related to a higher than usual level of well-being?) while taking into account stable interindividual differences, remains a research question that deserves further investigation. In this study, we aimed to explore the relations between prosocial behavior and hedonic (HWB; subjective assessment of life satisfaction and happiness) and eudaimonic (EWB; actualization of human potential in alignment with personal goals, including concepts like meaning in life and closeness to others) well-being in daily life. METHOD: Using ecological momentary assessment for 4 weeks, data were collected from two British samples, comprising 82 adolescents and 166 adults. RESULTS: Dynamic Structural Equation Modeling revealed a positive relations between prosocial behavior and HWB/EWB at both between and within-person levels across the samples. CONCLUSION: In summary, these findings further support the positive link between prosocial behavior and well-being in everyday life. Notably, this association was consistent across different age groups (adolescent and adults) at both between and within-person levels.

Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient.

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.

Histone deacetylase inhibition by suberoylanilide hydroxamic acid during reperfusion promotes multifaceted brain and vascular protection in spontaneously hypertensive rats with transient ischaemic stroke.

Hypertension is the most prevalent modifiable risk factor for stroke and is associated with worse functional outcomes. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid (SAHA) modulates gene expression and has emerged as a promising therapeutic approach to reduce ischaemic brain injury. Here, we have tested the therapeutic potential of SAHA administered during reperfusion in adult male spontaneously hypertensive (SHR) rats subjected to transient middle cerebral artery occlusion (tMCAO; 90 min occlusion/24 h reperfusion). Animals received a single dose of SAHA (50 mg/kg) or vehicle i.p. at 1, 4, or 6 h after reperfusion onset. The time-course of brain histone H3 acetylation was studied. After tMCAO, drug brain penetrance and beneficial effects on behavioural outcomes, infarct volume, oedema, angiogenesis, blood-brain barrier integrity, cerebral artery oxidative stress and remodelling, and brain and vascular inflammation were evaluated. SAHA increased brain histone H3 acetylation from 1 to 6 h after injection, reaching the ischaemic brain administered during reperfusion. Treatment given at 4 h after reperfusion onset improved neurological score, reduced infarct volume and oedema, attenuated microglial activation, prevented exacerbated MCA angiogenic sprouting and blood-brain barrier breakdown, normalised MCA oxidative stress and remodelling, and modulated brain and cerebrovascular cytokine expression. Overall, we demonstrate that SAHA administered during early reperfusion exerts robust brain and vascular protection after tMCAO in hypertensive rats. These findings are aligned with previous research in ischaemic normotensive mice and help pave the way to optimise the design of clinical trials assessing the effectiveness and safety of SAHA in ischaemic stroke.

Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.

An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH2); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH2 to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII activity in skeletal muscle. We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. This metabolon maintains total Q levels, minimizes QH2-reductive stress and improves OXPHOS efficiency. Muscle-specific Etfdh-/- mice develop myopathy due to CIII dysfunction, indicating that ETFDH is a required OXPHOS component and a potential therapeutic target for mitochondrial redox medicine.

Long-Term Outcomes of Intravenous Ustekinumab Maintenance Treatment in Patients With Loss of Response to Subcutaneous Dosing.

BACKGROUND: Ustekinumab (UST) is commonly used to treat Crohn's disease and ulcerative colitis. However, some patients may experience diminishing response or require increased dosage. Intravenous (IV) UST maintenance is explored as a solution. OBJECTIVES: We sought to evaluate IV UST maintenance effectiveness and safety in inflammatory bowel disease patients with partial or lost subcutaneous UST response. METHODS: This was a multicenter retrospective study of inflammatory bowel disease patients on IV UST maintenance. Clinical response and remission at weeks 12 and 52, defined as Harvey-Bradshaw Index ≤4 for Crohn's disease or partial Mayo score ≤2 for ulcerative colitis. Objective markers reduction (fecal calprotectin, C-reactive protein), UST trough levels pre- and post-IV maintenance, and adverse events were assessed. RESULTS: A total of 59 patients were included. Clinical remission at weeks 12 and 52 achieved by 47.5% and 64.3% respectively. 96.6% continued IV UST at follow-up. UST serum levels quadrupled. No adverse events reported. CONCLUSIONS: IV UST maintenance effectively sustained remission in most patients at 52 weeks.

When patients lose response to subcutaneous ustekinumab, strategies include reinduction, interval shortening, and less explored intravenous maintenance. Its high rescue rate and safety profile make it a valuable option for managing active inflammatory bowel disease.

Comparison of the ABC and ACMG systems for variant classification.

The ABC and ACMG variant classification systems were compared by asking mainly European clinical laboratories to classify variants in 10 challenging cases using both systems, and to state if the variant in question would be reported as a relevant result or not as a measure of clinical utility. In contrast to the ABC system, the ACMG system was not made to guide variant reporting but to determine the likelihood of pathogenicity. Nevertheless, this comparison is justified since the ACMG class determines variant reporting in many laboratories. Forty-three laboratories participated in the survey. In seven cases, the classification system used did not influence the reporting likelihood when variants labeled as "maybe report" after ACMG-based classification were included. In three cases of population frequent but disease-associated variants, there was a difference in favor of reporting after ABC classification. A possible reason is that ABC step C (standard variant comments) allows a variant to be reported in one clinical setting but not another, e.g., based on Bayesian-based likelihood calculation of clinical relevance. Finally, the selection of ACMG criteria was compared between 36 laboratories. When excluding criteria used by less than four laboratories (<10%), the average concordance rate was 46%. Taken together, ABC-based classification is more clear-cut than ACMG-based classification since molecular and clinical information is handled separately, and variant reporting can be adapted to the clinical question and phenotype. Furthermore, variants do not get a clinically inappropriate label, like pathogenic when not pathogenic in a clinical context, or variant of unknown significance when the significance is known.

Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Recomendaciones para el diagnóstico y tratamiento de la baja masa ósea para la edad cronológica y la osteoporosis infantil en Atención Primaria / Recommendations for the diagnosis and treatment of low bone mass for chronological age and childhood osteoporosis in primary care

Introducción: la ausencia en nuestro medio de protocolos de manejo y de derivación de los pacientes de riesgo hace que exista una gran variabilidad en la actividad preventiva y en el manejo clínico respecto a la osteoporosis infantil en los pediatras de nuestro país. Método: recientemente, el Grupo de Trabajo de Osteogénesis Imperfecta y Osteoporosis Infantil, de la Sociedad Española de Reumatología Pediátrica (SERPE) ha publicado un documento de consenso con recomendaciones sobre el diagnóstico y tratamiento de la osteoporosis secundaria infantil. En este artículo, resumimos aquellas más relevantes en el ámbito de Atención Primaria. Un panel de expertos, compuesto por pediatras y reumatólogos, elaboró una serie de recomendaciones basadas en la evidencia tras realizar una revisión cualitativa de la literatura. El nivel de evidencia se determinó para cada sección utilizando el sistema del Centro de Medicina basada en la Evidencia de Oxford (CEBM). Se realizó una encuesta Delphi para aquellas recomendaciones con un nivel de evidencia de IV o V. Se incluyeron todas las recomendaciones que tuvieron un nivel de concordancia superior o igual al 70%. Esta encuesta se envió a todos los miembros de la Sociedad Española de Reumatología Pediátrica. Resultados: se obtuvieron 51 recomendaciones, categorizadas en ocho secciones. Las recomendaciones resultantes son: cuándo sospechar y cómo prevenir la osteoporosis infantil y la baja masa ósea según la edad cronológica; qué métodos de detección y diagnóstico utilizar; cuáles son los tratamientos actuales y cómo prevenir la osteoporosis inducida por los corticoesteroides. Conclusión: la detección precoz y un enfoque terapéutico adecuado de la baja masa mineral ósea desde Atención Primaria (AP) son fundamentales para mejorar la salud ósea de nuestra población infantil. Las recomendaciones expuestas pueden ayudar a tomar las medidas de prevención y tratamiento correctas en la población infantil de riesgo (AU)

Introduction: due to the lack of standardised protocols for the management and referral of at-risk patients, there is substantial variability in the prevention and clinical management of childhood osteoporosis among paediatricians in Spain.Methods: the Working Group on Osteogenesis Imperfecta and Childhood Osteoporosis of the Sociedad Española de Reumatología Pediátrica (SERPE) recently published a consensus document with recommendations on the diagnosis and management of secondary childhood osteoporosis. An expert panel comprised of paediatricians and rheumatologists carried out a qualitative literature review and developed evidence-based recommendations.For each section, the level of evidence was determined using the Oxford Centre for Evidence-based Medicine (CEBM) system. A Delphi survey was conducted for those recommendations with a level of evidence of IV or V. All recommendations for which the level of agreement was 70% or greater were included. This survey was sent to all members of the SERPE.Results: the process yielded 51 recommendations categorized into 8 sections. The resulting recommendations concern when to suspect and how to prevent childhood osteoporosis and low bone mass according to chronological age; which screening and diagnosis methods to use; the current treatments and how to prevent corticosteroid-induced osteoporosis.Conclusions: early detection and an adequate approach to the treatment of low bone mass at the primary care (PC) level are essential to improve bone health in our paediatric population. These recommendations could contribute to improving prevention and treatment measures in at-risk children. (AU)

Lactant amb torticoli aguda. És sempre una entitat benigna? / Lactante con tortícolis aguda. ¿És siempre una entidad benigna? / Infant with acute torticollis. Is it always a benign entity?

Introducció. L’encefalomielitis aguda disseminada (EMAD) és una malaltia inflamatòria immunomediada desmielinitzant del sistema nerviós central. Associa simptomatologia neurològica multifocal i encefalopatia. Afecta fonamentalment la població infantil, amb una incidència anual estimada en menors de catorze anys del 0,64/100.000. El diagnòstic de l’EMAD és d’exclusió. Cas clínic. Lactant de quatre mesos, sana i amb neurodesenvolupament adequat, és portada a urgències per desviació lateral dreta de cap i coll. Associa quadre catarral sense febre. A les 48 hores de l’ingrés desenvolupa oftalmoplegia, sialorrea i nivell d’alerta alternant. Atesa l’aparició de simptomatologia neurològica, es deriva a centre de referència on s’amplia l’estudi etiològic. La ressonància magnètica (RM) cerebroespinal mostra alteració d’intensitat de senyal de tàlems, nuclis lenticulars i tronc de l’encèfal esquerre. Davant la sospita d’EMAD, rep tractament amb glucocorticoides i gammaglobulina. També rep biotina i tiamina a l’espera de l’estudi metabòlic. La RM cerebroespinal al cap de deu dies mostra reducció de les lesions. La recuperació dels dèficits neurològics dos mesos després és completa. Comentaris. La clínica, l’evolució i els estudis complementaris són suggestius d’EMAD. Les lesions típiques d’aquesta entitat a la RM afecten la substància blanca subcortical profunda de forma bilateral i asimètrica. També hi pot haver afectació de ganglis de base, tàlem i tronc de l’encèfal. El diagnòstic diferencial inclou encefalitis infecciosa, esclerosi múltiple i metabolopaties. La primera línia de tractament són els bols de glucocorticoides. La majoria de casos presenta recuperació completa. L’interès del cas exposat rau en l’edat de presentació. (AU)

Introducción. La encefalomielitis aguda diseminada (EMAD) es una enfermedad inflamatoria inmunomediada desmielinizante del sistema nervioso central. Asocia sintomatología neurológica multifocal y encefalopatía. Afecta fundamentalmente la población infantil con una incidencia anual estimada en menores de 14 años del 0,64/100.000. El diagnóstico de EMAD es de exclusión. Caso clínico. Lactante de 4 meses, sana y con adecuado neurodesarrollo, es traída a urgencias por desviación lateral derecha de cabeza y cuello; asocia cuadro catarral sin fiebre. A las 48 horas del ingreso desarrolla oftalmoplejía, sialorrea y nivel de alerta alternante. Dada la aparición de sintomatología neurológica, se deriva a centro de referencia donde se amplía el estudio etiológico. La resonancia magnética (RM) cerebroespinal muestra alteración de intensidad de señal de tálamos, núcleos lenticulares y tronco del encéfalo izquierdo. Ante la sospecha de EMAD, recibe tratamiento con glucocorticoides y gammaglobulina. También recibe biotina y tiamina a la espera del estudio metabólico. La RM cerebroespinal a los 10 días muestra reducción de las lesiones. La recuperación de los déficits neurológicos dos meses después es completa. Comentarios. La clínica, evolución y estudios complementarios son sugestivos de EMAD. Las lesiones típicas de esta entidad en la RM afectan la sustancia blanca subcortical profunda de forma bilateral y asimétrica. También puede haber afectación de ganglios de base, tálamo y tronco del encéfalo. El diagnóstico diferencial incluye encefalitis infecciosa, esclerosis múltiple y metabolopatías. La primera línea de tratamiento son bolus de glucocorticoides. La mayoría de casos presenta recuperación completa. El interés del caso expuesto radica en la edad de presentación. (AU)

Introduction. Acute disseminated encephalomyelitis (ADEM) is a demyelinating immune mediated inflammatory disease affecting the central nervous system. It associates multifocal neurological symptoms and encephalopathy. It predominantly affects children, and its annual cumulative incidence in children under 14 years is 0.64/100,000. The diagnosis of ADEM is one of exclusion. Case report. A previously healthy 4-month-old infant with adequate neurodevelopment was seen in the emergency department due to acute onset of right lateral deviation of head and neck, associated with cold symptoms without fever. 48 hours after admission, the infant developed ophthalmoplegia, sialorrhea and alternating alert level. Given the development of neurological symptoms, she was referred to a tertiary hospital for evaluation. Cerebrospinal magnetic resonance imaging (MRI) showed altered signal intensity of the thalamus, lenticular nuclei, and left brainstem. ADEM was suspected and glucocorticoids and gamma globulin were administered. She also received biotin and thiamine while awaiting results of a metabolic panel. Cerebrospinal MRI at 10 days showed improvement of the lesions, and a full recovery was reached after two months. Comments. The clinical presentation, diagnostic studies, and clinical evolution are suggestive of ADEM. Typical MRI lesions involve deep subcortical white matter bilaterally and asymmetrically. There may also be involvement of the basal ganglia, thalamus, and brainstem. Differential diagnosis includes infectious encephalitis, multiple sclerosis, and metabolic diseases. First line treatment are glucocorticoids. Most cases have complete recovery. The interest of the case lies in the age of presentation. (AU)

Demanda de medicamentos sin receta: evaluación de la intervención farmacéutica / Demand for drugs without prescription: Evaluation of pharmaceutical intervention

Introducción: La modificación de los usos y actitudes de los demandantes de dispensación de medicamentos que precisan receta médica sin presentarla, es un campo donde el farmacéutico comunitario, desde su responsabilidad profesional, puede contribuir a obtener importantes resultados en la consecución de su uso correcto.Objetivo: Evaluar el resultado de la intervención del farmacéutico en la demanda de medicamentos (ibuprofeno y paracetamol) sin presentar receta médica en presentaciones que la requieren. Método: Diseño: estudio experimental transversal aleatorizado con intervención farmacéutica mediante educación sanitaria.Emplazamiento: nueve farmacias de Pontevedra y Ourense. Octubre-noviembre de 2019.Participantes: usuarios de la farmacia que solicitaban sin receta presentaciones de paracetamol o ibuprofeno que la requerían.Mediciones principales: número de solicitudes, problemas de salud y motivos, aceptación o no de una alternativa de medicamento sinreceta (MSR).Resultados:Se registraron 424 peticiones, 303 (71,5%) aceptaron la dispensación del MSR. Ibuprofeno 600 mg fue el principio activo más solicitado (73,3%) y la automedicación el principal motivo de petición sin receta (89,9%). Entre los problemas de salud referidos destacó el dolor de cabeza (22,9%). No se encontraron diferencias significativas entre el resultado de la intervención y el medicamento solicitado, el sexo, el motivo, ni el problema de salud que originó la solicitud. Sí entre edad de los pacientes, medicamento solicitado y resultado de la intervención. 30 (14,2%) pacientes fueron derivados al médico.Conclusiones:La actuación del farmacéutico en el cambio a un medicamento sin receta logró una alta aceptación por los pacientes, lo que contribuye a su uso adecuado.(AU)

Introduction: The change in the usage and the attitudes of the petitioners who ask for the dispensing of medications that require a medical prescription without deliver it, is a field in which the community pharmacist, from his or her professional responsibility, can contribute to obtain important outcomes in the achievement of their correct usage.Objective:This study pursues to evaluate the result of the pharmacist intervention on the demand for drugs (ibuprofen and paracetamol) without delivering a medical prescription in cases in which it is needed. Method: Design: It was carried out an experimental, cross-sectional and randomized study with pharmaceutical intervention through health education.Location: nine pharmacies from Pontevedra and Ourense. October –November 2019.Participants: pharmacy users that ask for paracetamol or ibuprofeno without having a medical prescription although it was needed. Main measurements: number of requests, health problems and causes, acceptance or not of an alternative, an over the counter (OTC) drug. Results: 424 requests were registered, 303 (71.5%) accepted the OTC dispensation. Ibuprofeno 600 mg was the most requested active ingredient (73.3%) and self-medication the main cause of request without a prescription (89.9%). Among the health problems referred, headache stood out (22.9%). There were not found significant differences between the outcome of the intervention and the requested medication, the sex, the reason, or the health problem that was the origin of the request. On the other hand, important differences were found in the age of the patients, the requested medication and the result of the intervention. 30 (14.2%) patients were referred to the doctor. Conclusions: The intervention of the pharmacist in the change to an over the counter drug achieved a high acceptance from the patients, which contributes to their correct usage.(AU)

La sexualidad en entredicho: nuevas negociaciones del significado de ser mujer en el deporte de alto rendimiento / Sexualidade sob suspeita: novas negociações do significado de ser mulher no esporte de alto desempenho / Sexuality in question: new negotiations of the meaning of being a woman in high performance sports

Resumen: Esta investigación tiene como objetivos, por un lado, explorar las percepciones de las deportistas acerca de cómo son evaluadas por su entorno social con relación a la feminidad y a su orientación sexual por su vinculación con una práctica deportiva de alto rendimiento. Por otro, analizar la visibilidad y aceptación de la homosexualidad en el contexto deportivo tanto por las deportistas como por los agentes sociales que las rodean. La metodología fue de tipo cualitativo. Se llevaron a cabo cinco grupos focales en los que participaron 46 mujeres practicantes de futbol sala, balonmano, voleibol, atletismo y natación. Los resultados muestran que las deportistas presentan un discurso de resistencia frente al estereotipo de marimacho-lesbiana que, comprobamos, continúa vigente en el imaginario colectivo. A pesar de que se perciben avances sociales en este sentido, la homosexualidad sigue estigmatizada y aún persisten formas de rechazo cognitivo-afectivo en parte de la sociedad española.

Resumo: Esta pesquisa tem como objetivo, por um lado, explorar as percepções das atletas sobre como são avaliadas pelo seu ambiente social em relação à feminilidade e sua orientação sexual, para vincular-se a uma prática esportiva de alto desempenho e, por outro, analisar a visibilidade e aceitação da homossexualidade no contexto esportivo, tanto pelos atletas como pelos agentes sociais ao seu redor. A metodologia foi qualitativa. Foram feitos cinco grupos focais nos quais participaram 46 mulheres praticando futsal, handebol, vôlei, atletismo e natação. Os resultados mostram que as atletas apresentam um discurso de resistência contra o estereótipo da "Maria-João" o "sapatão" que, verificamos, ainda está em vigor na imaginação coletiva. Embora os avanços sociais sejam percebidos nesse sentido, a homossexualidade permanece estigmatizada e ainda persistem as formas de rejeição cognitivo-afetiva em parte da sociedade espanhola.

Abstract: On the one hand, this research aims to explore the perceptions of women practicing high-performance sports about how they are viewed by their social environment in terms of their femininity and sexual orientation. On the other hand, it analyzes the visibility and acceptance of homosexuality in the sports context by both athletes and the social agents surrounding them. The research methodology was qualitative, with five focus groups including 46 women who practiced futsal, handball, volleyball, athletics and swimming. Results show that they present a resistance-oriented discourse against butch-lesbian stereotypes that, as we prove, are still present in collective imagination. Despite social advances perceived in this regard, homosexuality remains stigmatized and forms of cognitive-affective rejection persist in part of Spanish society.

Novedades para el diagnóstico de la toxoplasmosis ocular: uso de la tomografía de coherencia óptica / Advances in the diagnosis of ocular toxoplasmosis: Use of optical coherence tomography

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¿Es posible ofrecer un algoritmo de decisión clínica en la enfermedad COVID-19 en Atención Primaria? / Is it possible to offer a clinical decision algorithm in COVID-19 disease in Primary Care?

Hasta ahora, los datos recogidos en los casos de procesos clínicos provocados por el coronavirus SARS-CoV-2 (COVID-19) en niños sugieren que son cuadros leves en comparación con las infecciones en pacientes adultos; no obstante, se ha informado de casos graves, como el síndrome inflamatorio multisistémico (SIM), que precisa de valoración y actuación de emergencia. En el contexto de la consulta del pediatra de Atención Primaria y coincidiendo con el inicio del curso escolar, en una época en la que habitualmente aumenta la incidencia de procesos como la gripe, infección por el virus respiratorio sincitial (VRS) y otros cuadros respiratorios, es habitual la demanda por síntomas que pueden hacer sospechar cualquiera de estas infecciones. En este sentido, es importante llegar a un diagnóstico que permita el manejo más adecuado del paciente. Epidemiológicamente, de manera que se pueda disminuir la transmisión comunitaria tomando las medidas adecuadas y clínicamente para así poder ponderar el nivel de gravedad y poner en marcha las actuaciones más adecuadas. Dado que no existen escalas válidas que ofrezcan un puntaje para valorar cuál es la actuación más adecuada ante la sospecha de una infección COVID-19, planteamos los beneficios de un algoritmo de decisión clínica que tiene en cuenta las connotaciones epidemiológicas, basado en la gravedad clínica, para ofrecer la atención clínica más adecuada a los pacientes

So far, the data collected in the cases of clinical processes caused by the SARS-CoV-2 (COVID-19) coronavirus in children suggest that they are mild compared to infections in adult patients; However, serious cases such as multisystemic inflammatory syndrome (SIM) have been reported, which requires assessment and emergency action. In the context of the of the Primary Care pediatrician consultation and coinciding with the beginning of the school year, at a time when the incidence of influenza, RSV infection and other respiratory conditions usually increases, consultations for symptoms that can lead to suspect these infections. Therefore, it is important to reach a diagnosis that allows the most appropriate management of the patient and decreasing the community transmission by taking pertinent measures. Given that there are no valid scales that offer a score to assess which is the most appropriate action in the event of a suspected COVID-19 infection, we propose the benefits of a clinical decision algorithm that takes into account epidemiological connotations, based on clinical severity to offer the most appropriate clinical care to patients

Síndrome SAPHO en la infancia. Presentación de un caso clínico / SAPHO syndrome in childhood. A case report

El acrónimo síndrome SAPHO (sinovitis, acné, pustulosis, hiperostosis y osteítis) engloba tanto manifestaciones cutáneas como muculoesqueléticas, entre ellas hiperostosis de los huesos y de las articulaciones de la pared torácica anterior, asociado a manifestaciones cutáneas; acné fulminans e hidradenitis supurativa. Los criterios diagnósticos no han sido validados en niños. El tratamiento inicial con antiinflamatorios no esteroideos en ocasiones es insuficiente y puede ser preciso asociar corticoides, fármacos modificadores de la enfermedad, antagonistas del factor de necrosis tumoral o bifosfonatos. Presentamos el caso clínico de un escolar con afectación poliarticular, osteoartritis de articulación esternoclavicular con importante componente inflamatorio y acné conglobata, con buena respuesta al tratamiento con pamidronato por vía intravenosa (AU)

The acronym of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) combines a cluster of cutaneous and musculoskeletal manifestations, such as hyperostosis of bones of the anterior chest wall associated with acne fulminans and hidradenitis suppurativa. There are no validated diagnostic criteria in children. Nonsteroidal anti-inflammatory drugs are not always sufficient, and the use of corticosteroids, disease-modifying agents, tumor necrosis factor-α inhibitors or bisphosphonates may be necessary. We present the case of a child with polyarticular involvement, osteoarthritis of the sternoclavicular joint with severe inflammatory disorders and acne conglobata, with an excellent response to intravenous pamidronate (AU)

Migración tardía de prótesis tras drenaje ecoendoscópico de pseudoquiste pancreático abscesificado / Late migration of a metal stent after EUS-drainage of a pancreatic pseudocyst abscess

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