Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

Laboratory study of rotationally inelastic collisions of CO2 at low temperatures.

The rotational relaxation of CO2 by inelastic collisions has been studied in three supersonic jets. The jets were probed by means of Raman spectroscopy with high spectral and spatial resolutions, measuring the rotational populations and the total number density. The time evolution of the rotational populations was analyzed by means of a kinetic master equation, with the help of the energy-corrected sudden power law to relate the numerous state-to-state rate (STS rates) coefficients. In the thermal range investigated, 60-260 K, the STS rates decrease with increasing temperature and with increasing change in the rotational quantum number. Other quantities of interest for fluid dynamics, such as the rotational collision number, the relaxation cross section, and the bulk viscosity, have been derived from the STS rates.

[RYR1 myopathies in childhood: phenotype-genotype correlation and incidence]. / Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.

INTRODUCTION: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. PATIENTS AND METHODS: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. RESULTS: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another. CONCLUSIONS: RYR1-RM in our series exhibited phenotypic and involvement variability, with an incidence in our area of around 1 in 10,000 live births. Most cases were male, with dominant missense variants. We contribute five previously undescribed genetic variants.

TITLE: Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.Introducción. Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos. Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados. De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones. Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.

[Debut and evolution MRI images of a child with a new genetic variant of vanishing white matter leukodystrophy]. / Imágenes de resonancia magnética de inicio y evolución de un niño con nueva variante genética de leucodistrofia evanescente.

TITLE: Imágenes de resonancia magnética de inicio y evolución de un niño con nueva variante genética de leucodistrofia evanescente.

Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo / KIF1A gene-associated neurological disease: the correlation between genotype and phenotype

Introducción: La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos: Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones: En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.(AU)

Introduction: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. Case report: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. Conclusions: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.(AU)

[KIF1A gene-associated neurological disease: the correlation between genotype and phenotype]. / Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo.

INTRODUCTION: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. CASE REPORT: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. CONCLUSIONS: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.

TITLE: Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo.Introducción. La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos. Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones. En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.

Valoración del impacto del pH urinario en la elección de los antibióticos. Una revisión sistemática / Urinary pH and antibiotics, choose carefully. a systematic review

La infección urinaria no complicada es la infección bacteriana más frecuente en las mujeres. Desde 1948 se conoce la relación entre el pH urinario y los antibióticos. Nos propusimos buscar el pH urinario más apropiado para cada familia de antibióticos y evaluar si el pH modifica la sensibilidad bacteriana frente a estos. Se incluyeron ensayos in vitro y estudios in vivo que incluían una o más especies bacterianas y se analizó el efecto de uno o más antibióticos a diferentes valores de pH. También se incluyeron ensayos clínicos controlados aleatorizados en infección urinaria no complicada (con la definición de las directrices de la EAU de 2019), eligiendo los antibióticos en función del pH urinario o utilizando un antibiótico con modificadores del pH urinario (L-metionina, vitamina C, etc.) frente a un antibiótico y un placebo. Se utilizó la herramienta Quadas-2 para evaluar la calidad de los estudios y el conjunto de ítems comprendidos en la declaración PRISMA para las revisiones sistemáticas. Dos autores revisaron y evaluaron los trabajos de forma independiente, y otros dos autores repitieron la búsqueda individualmente. Un quinto investigador actuó como árbitro, y otro autor colaboró como consultor farmacéutico hospitalario. Los antibióticos cuya actividad es favorecida en medios alcalinos son la mayoría de las fluoroquinolonas, los aminoglucósidos y la trimetoprima. Los antibióticos cuya actividad es favorecida en medios ácidos son la fosfomicina, la tetraciclina, la nitrofurantoína y algunos β-lactámicos. Se sugiere realizar urocultivos con antibiograma, tanto en medios ácidos como alcalinos, para definir el perfil de susceptibilidad antimicrobiana. No hay pruebas suficientes de estudios in vivo que respalden la elección de un antibiótico en función del pH urinario del paciente o el uso de modificadores del pH urinario para obtener tasas más altas de curación (AU)

Uncomplicated urinary tract infection (UTI) is the most common bacterial infection in women. Since 1948, the relationship between urinary pH and antibiotics has been established. We aimed to search for the best urinary pH for each family of antibiotics and to assess whether pH changes bacterial susceptibility to them. We included in vitro research and in vivo studies including one or more bacterial species and tested the effect of one or more antibiotics at different pH values. We also included randomized controlled clinical trials in uncomplicated UTI (EAU guidelines 2019 definition), choosing the antibiotics based on urinary pH or using an antibiotic plus urinary pH modifiers (L-methionine, vitamin C...) vs an antibiotic and a placebo. Quadas-2 tool was used as a quality assessment of the studies and PRISMA set of items for systematic reviews. Two authors independently screened and evaluated the papers, while two additional authors individually repeated the search. A fifth researcher acted as an arbiter, and another author collaborated as a hospital pharmaceutical consultant. Alkaline-friendly antibiotics are most fluoroquinolones, aminoglycosides, trimethoprim. Acidic-friendly antibiotics are fosfomycin, tetracycline, nitrofurantoin and some β-lactams. We suggest performing urine cultures with antibiogram tests, in both acidic and alkaline media, to define the bacterial susceptibility profile. There is insufficient in vivo evidence to support whether choosing an antibiotic based on a patient's urinary pH or adding urinary pH modifiers will lead to a higher cure rate (AU)

Embryonic cerebrospinal fluid influence in the subependymal neurogenic niche in adult mouse hippocampus.

The adult mouse hippocampal neurogenic niche is a complex structure which is not completely understood. It has mainly been related to the Subgranular layer of the dentate gyrus; however, as a result of differential neural stem cell populations reported in the subventricular zone of the lateral ventricle and associated with the hippocampus, the possibility remains of a multifocal niche reproducing developmental stages. Here, using a set of molecular markers for neural precursors, we describe in the adult mouse brain hippocampus the existence of a disperse population of neural precursors in the Subependymal Zone, the Dentate Migratory Stream and the hilus; these display dynamic behaviour compatible with neurogenesis. This supports the idea that the adult hippocampal niche cannot be restricted to the dentate gyrus subgranular layer. In other neurogenic niches such as the Subventricular Zone, a functional periventricular dependence has been shown due to the ability to respond to embryonic cerebro-spinal fluid. In this study, we demonstrate that neural precursors from the three areas studied (Sub-ependymal Zone, Dentate Migratory Stream and hilus) are able to modify their behaviour by increasing neurogenesis in a locally differential manner. Our results are compatible with the persistence in the adult mouse hippocampus of a neurogenic niche with the same spatial structure as that seen during development and early postnatal stages.

Miastenia gravis ocular y factores asociados al desarrollo de una generalización secundaria: descripción de una serie española / Ocular myasthenia gravis and risk factors for developing a secondary generalisation: Description of a Spanish series

Introducción: La miastenia gravis ocular (MGo) es la forma de presentación de la enfermedad más frecuente. Un porcentaje variable de estos pacientes desarrollan una forma generalizada (MGg), siendo los factores de riesgo de conversión y el efecto protector del tratamiento inmunosupresor objeto de controversia en el momento actual. Pacientes y métodos: Diseñamos un estudio monocéntrico retrospectivo, con el objetivo de describir las características demográficas, clínicas y de laboratorio de una cohorte española de MGo, a partir de una serie de MG registrada en el Hospital Universitario de Albacete desde enero del 2008 hasta febrero de 2020. Resultados: Seleccionamos 62 pacientes con MGo de una cohorte de 91 sujetos con MG (68,1%). La mediana de edad al diagnóstico fue de 68 (RIQ 52-75,3), con predominio de MGo de inicio muy tardío (n = 34, 54,8%) y de varones (n = 38, 61,3%). La diplopía binocular fue el síntoma inicial más frecuente (51,7%). La tasa de conversión a MGg fue del 50% (n = 31), con una mediana de tiempo de seis meses (RIQ 2-12,8). Encontramos asociación significativa entre ser mujer (OR: 5,46, IC 95% 1,16-25-74, p = 0,03) y tener AcAchR (OR: 8,86, IC 95% 1,15-68,41, p = 0,04), con el riesgo de desarrollar una MGg. Conclusiones: La tasa de conversión de MGo en nuestra serie es relativamente elevada. La generalización tiene lugar principalmente durante los primeros dos años de evolución y está asociada al sexo femenino y, sobre todo, a la presencia de AcAchR.(AU)

Introduction: Ocular myasthenia gravis (MG) is the most common phenotype of MG at onset. A variable percentage of these patients develop secondary generalisation; the risk factors for conversion and the protective effect of immunosuppressive treatment are currently controversial. Patients and methods: We designed a retrospective single-centre study with the aim of describing the demographic, clinical, and laboratory characteristics of a Spanish cohort of patients with ocular MG from Hospital Universitario de Albacete from January 2008 to February 2020. Results: We selected 62 patients with ocular MG from a cohort of 91 patients with MG (68.1%). Median age at diagnosis was 68 (IQR, 52-75.3), and men accounted for 61.3% of the sample (n = 38). Most patients presented very late-onset ocular MG (n = 34, 54.8%). Binocular diplopia was the most frequent initial symptom (51.7%). The rate of progression to generalised MG was 50% (n = 31), with a median time of 6 months (IQR, 2-12.8). Female sex (OR: 5.46; 95% CI, 1.16-25-74; p = .03) and anti–acetylcholine receptor antibodies (OR: 8.86; 95% CI, 1.15-68.41; p = .04) were significantly associated with the risk of developing generalised MG. Conclusions: The conversion rate observed in our series is relatively high. Generalisation of MG mainly occurs during the first 2 years of progression, and is strongly associated with female sex and especially with the presence of anti–acetylcholine receptor antibodies.(AU)

Descripción de una serie de pacientes con miastenia gravis refractaria / A series of patients with refractory myasthenia gravis

Introducción: Los avances en el tratamiento de la miastenia gravis (MG) han conseguido mejoría en la calidad de vida y el pronóstico de la mayoría de los pacientes. Sin embargo, un 10-20% presenta la denominada MG refractaria sin alcanzar mejoría, con frecuentes recaídas e importante repercusión funcional. Pacientes y métodos: Se seleccionó a pacientes con MG refractaria a partir de una cohorte de pacientes con MG diagnosticados desde enero del 2008 hasta junio del 2019. Se definió MG refractaria como falta de respuesta al tratamiento con prednisona y al menos 2 inmunosupresores o imposibilidad para la retirada del tratamiento sin recaídas en los últimos 12 meses o intolerancia al mismo con graves efectos secundarios. Resultados: Se registraron 84 pacientes con MG, 11 cumplían los criterios de MG refractaria (13%), con una edad media de 47 ± 18 años; un 64% los pacientes con MG refractaria fueron clasificados como miastenia generalizada de comienzo precoz (p < 0,01) con una mayor proporción de mujeres (p < 0,01). La gravedad de la enfermedad al diagnóstico, así como en el momento del análisis de los datos, fue superior en el grupo de MG refractaria con un mayor número de recaídas en el seguimiento. En el modelo de regresión logística se obtuvo una asociación independiente entre MG-R y el número de reagudizaciones graves. Conclusiones: El porcentaje de pacientes con MG refractaria en nuestra serie (13%) es similar al descrito en estudios previos, con frecuencia mujeres con inicio precoz, formas graves de inicio y reiteradas reagudizaciones con ingreso hospitalario en el seguimiento.(AU)

Introduction: Advances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%-20% of patients present refractory MG, with frequent relapses and significant functional limitations. Patients and methods: Patients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. Results: We identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P<.01), with a higher proportion of women in this group (P<.01). Disease severity at diagnosis and at the time of data analysis was higher among patients with refractory MG, who presented more relapses during follow-up. Logistic regression analysis revealed an independent association between refractory MG and the number of severe relapses. Conclusions: The percentage of patients with refractory MG in our series (13%) is similar to those reported in previous studies; these patients were often women and presented early onset, severe forms of onset, and repeated relapses requiring hospital admission during follow-up.(AU)

A series of patients with refractory myasthenia gravis.

INTRODUCTION: Advances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%-20% of patients present refractory MG, with frequent relapses and significant functional limitations. PATIENTS AND METHODS: Patients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. RESULTS: We identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P < .01), with a higher proportion of women in this group (P < .01). Disease severity at diagnosis and at the time of data analysis was higher among patients with refractory MG, who presented more relapses during follow-up. Logistic regression analysis revealed an independent association between refractory MG and the number of severe relapses. CONCLUSIONS: The percentage of patients with refractory MG in our series (13%) is similar to those reported in previous studies; these patients were often women and presented early onset, severe forms of onset, and repeated relapses requiring hospital admission during follow-up.

Urinary pH and antibiotics, choose carefully. A systematic review.

Uncomplicated urinary tract infection (UTI) is the most common bacterial infection in women. Since 1948, the relationship between urinary pH and antibiotics (ABs) has been established. We aimed to search for the best urinary pH for each family of antibiotics and to assess whether pH changes bacterial susceptibility to them. We included in vitro research and in vivo studies including one or more bacterial species and tested the effect of one or more ABs at different pH values. We also included randomized controlled clinical trials (RCTs) in uncomplicated UTI (EAU guidelines 2019 definition), choosing the ABs based on urinary pH or using an antibiotic plus urinary pH modifiers (L-methionine, vitamin C…) vs. an antibiotic and a placebo. Quadas-2 tool was used as a quality assessment of the studies and PRISMA set of items for systematic reviews. Two authors independently screened and evaluated the papers, while two additional authors individually repeated the search. A fifth researcher acted as an arbiter, and another author collaborated as a hospital pharmaceutical consultant. Alkaline-friendly antibiotics are most fluoroquinolones, aminoglycosides, trimethoprim. Acidic-friendly antibiotics are fosfomycin, tetracycline, nitrofurantoin and some ß-lactams. We suggest performing urine cultures with antibiogram tests, in both acidic and alkaline media, to define the bacterial susceptibility profile. There is insufficient in vivo evidence to support whether choosing an antibiotic based on a patient's urinary pH or adding urinary pH modifiers will lead to a higher cure rate.

[Congenital myotonia. Incidence and presentation of a series of cases]. / Miotonía congénita. Incidencia y presentación de una serie de casos.

INTRODUCTION: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. CASES REPORT: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). CONCLUSIONS: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.

TITLE: Miotonía congénita. Incidencia y presentación de una serie de casos.Introducción. La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones. La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.

Miotonía congénita. Incidencia y presentación de una serie de casos / Congenital myotonia. Incidence and presentation of a series of cases

Introducción: La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones: La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.(AU)

Introduction: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. Cases report: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker’s disease and two with Thomsen’s disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). Conclusions: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.(AU)

Ocular myasthenia gravis and risk factors for developing a secondary generalisation: description of a Spanish series.

INTRODUCTION: Ocular myasthenia gravis (MG) is the most common phenotype of MG at onset. A variable percentage of these patients develop secondary generalisation; the risk factors for conversion and the protective effect of immunosuppressive treatment are currently controversial. PATIENTS AND METHODS: We designed a retrospective single-centre study with the aim of describing the demographic, clinical, and laboratory characteristics of a Spanish cohort of patients with ocular MG from Hospital Universitario de Albacete from January 2008 to February 2020. RESULTS: We selected 62 patients with ocular MG from a cohort of 91 patients with MG (68.1%). Median age at diagnosis was 68 (IQR, 52-75.3), and men accounted for 61.3% of the sample (n = 38). Most patients presented very late-onset ocular MG (n = 34, 54.8%). Binocular diplopia was the most frequent initial symptom (51.7%). The rate of progression to generalised MG was 50% (n = 31), with a median time of 6 months (IQR, 2-12.8). Female sex (OR: 5.46; 95% CI, 1.16-25-74; P= .03) and anti-acetylcholine receptor antibodies (OR: 8.86; 95% CI, 1.15-68.41; P = .04) were significantly associated with the risk of developing generalised MG. CONCLUSIONS: The conversion rate observed in our series is relatively high. Generalisation of MG mainly occurs during the first 2 years of progression, and is strongly associated with female sex and especially with the presence of anti-acetylcholine receptor antibodies.

Regulatory and metabolic adaptations in the nitrogen assimilation of marine picocyanobacteria.

Prochlorococcus and Synechococcus are the two most abundant photosynthetic organisms on Earth, with a strong influence on the biogeochemical carbon and nitrogen cycles. Early reports demonstrated the streamlining of regulatory mechanisms in nitrogen metabolism and the removal of genes not strictly essential. The availability of a large series of genomes, and the utilization of latest generation molecular techniques have allowed elucidating the main mechanisms developed by marine picocyanobacteria to adapt to the environments where they thrive, with a particular interest in the strains inhabiting oligotrophic oceans. Given that nitrogen is often limited in those environments, a series of studies have explored the strategies utilized by Prochlorococcus and Synechococcus to exploit the low concentrations of nitrogen-containing molecules available in large areas of the oceans. These strategies include the reduction in the GC and the cellular protein contents; the utilization of truncated proteins; a reduced average amount of N in the proteome; the development of metabolic mechanisms to perceive and utilize nanomolar nitrate concentrations; and the reduced responsiveness of key molecular regulatory systems such as NtcA to 2-oxoglutarate. These findings are in sharp contrast with the large body of knowledge obtained in freshwater cyanobacteria. We will outline the main discoveries, stressing their relevance to the ecological success of these important microorganisms.

Ensayo clínico aleatorizado, controlado con placebo y doble ciego para evaluar la eficacia y la seguridad del ácido tranexámico tópico en el ahorro de pérdidas sanguíneas en pacientes tratados mediante cirugía protésica de rodilla / Randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of topical tranexamic acid in saving blood loss in patients undergoing prosthetic knee surgery

Antecedentes y objetivo: Durante la artroplastia de rodilla se produce una pérdida sanguínea importante. El objetivo de nuestro estudio es valorar la eficacia y la seguridad de la administración tópica de 3 g de ácido tranexámico (TXA) en cuanto a la reducción de pérdidas sanguíneas en artroplastia de rodilla. Material y método: Se ha realizado un ensayo clínico aleatorizado, fase iii, doble ciego, controlado con placebo. Se incluyó a 150 pacientes en 2grupos paralelos de tratamiento (75 por brazo). La solución se administró de forma tópica intraarticular tras la cementación y previo al cierre capsular. Se realizaron determinaciones analíticas antes y después de la cirugía. Resultados: La pérdida total de sangre media para el grupo placebo fue de 831,5ml y 662,3ml para el grupo TXA con una diferencia entre ambos de 169,2ml, lo que supone un ahorro del 20,4%, siendo estadísticamente significativa (p<0,001). No se obtuvieron diferencias en el inicio de la deambulación, días de ingreso o escala visual analógica al mes de la cirugía. Se retiró a 10pacientes por infección del tracto urinario prequirúrgico, alergia a metales, fallo de selección, debilitamiento rotuliano, inestabilidad protésica, fractura tibial intraquirúrgica, cambio de indicación a prótesis unicompartimental y una pérdida de seguimiento. Hubo una única complicación no relacionada con el fármaco (globos vesicales de repetición). Conclusión: La administración de TXA de forma tópica tras la cementación de los componentes protésicos en artroplastia de rodilla en una única dosis demuestra que es segura y eficaz.(AU)

Background and objective: Knee arthroplasty is a major surgery with potential significant blood loss. Assess the efficacy and safety of topical administration of 3g of tranexamic acid (TXA) in terms of reducing blood loss in knee arthroplasty. Material and method: A randomized, phase III, double-blind, placebo-controlled clinical trial has been conducted. We included 150 patients in 2parallel treatment groups (75 per arm). The solution was administered topically intra-articular after cementation and prior to capsular closure. Analytical determinations were made before and after surgery to quantify blood loss. Results: Total blood loss for the placebo group was 831.5ml and 662.3ml for the TXA group. The difference between the 2groups was 169.2ml; which means a save of 20.4 per cent; this difference being statistically significant (P<.001). There were no differences in terms of the onset of ambulation, days of admission or Visual Analogue Scale at one month of surgery. Ten patients were rejected for presurgical urinary tract infection, metal allergy, selection failure, patellar weakening, prosthetic instability, intrasurgical tibial fracture, change of indication to unicompartimental prosthesis and a loss of follow-up. There was only one complication unrelated to the investigational drug (bladder balloon). Conclusion: The administration of TXA topically after cementation of the prosthetic components in total knee arthroplasty in a single dose has demonstrated being safe and effective.(AU)

[Translated article] Randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of topical tranexamic acid in saving blood loss in patients undergoing prosthetic knee surgery / Ensayo clínico aleatorizado, controlado con placebo y doble ciego para evaluar la eficacia y la seguridad del ácido tranexámico tópico en el ahorro de pérdidas sanguíneas en pacientes tratados mediante cirugía protésica de rodilla

Antecedentes y objetivo: Durante la artroplastia de rodilla se produce una pérdida sanguínea importante. El objetivo de nuestro estudio es valorar la eficacia y la seguridad de la administración tópica de 3 g de ácido tranexámico (TXA) en cuanto a la reducción de pérdidas sanguíneas en artroplastia de rodilla. Material y método: Se ha realizado un ensayo clínico aleatorizado, fase iii, doble ciego, controlado con placebo. Se incluyó a 150 pacientes en 2grupos paralelos de tratamiento (75 por brazo). La solución se administró de forma tópica intraarticular tras la cementación y previo al cierre capsular. Se realizaron determinaciones analíticas antes y después de la cirugía. Resultados: La pérdida total de sangre media para el grupo placebo fue de 831,5ml y 662,3ml para el grupo TXA con una diferencia entre ambos de 169,2ml, lo que supone un ahorro del 20,4%, siendo estadísticamente significativa (p<0,001). No se obtuvieron diferencias en el inicio de la deambulación, días de ingreso o escala visual analógica al mes de la cirugía. Se retiró a 10pacientes por infección del tracto urinario prequirúrgico, alergia a metales, fallo de selección, debilitamiento rotuliano, inestabilidad protésica, fractura tibial intraquirúrgica, cambio de indicación a prótesis unicompartimental y una pérdida de seguimiento. Hubo una única complicación no relacionada con el fármaco (globos vesicales de repetición). Conclusión: La administración de TXA de forma tópica tras la cementación de los componentes protésicos en artroplastia de rodilla en una única dosis demuestra que es segura y eficaz.(AU)

Background and objective: Knee arthroplasty is a major surgery with potential significant blood loss. Assess the efficacy and safety of topical administration of 3g of tranexamic acid (TXA) in terms of reducing blood loss in knee arthroplasty. Material and method: A randomized, phase III, double-blind, placebo-controlled clinical trial has been conducted. We included 150 patients in 2parallel treatment groups (75 per arm). The solution was administered topically intra-articular after cementation and prior to capsular closure. Analytical determinations were made before and after surgery to quantify blood loss. Results: Total blood loss for the placebo group was 831.5ml and 662.3ml for the TXA group. The difference between the 2groups was 169.2ml; which means a save of 20.4 per cent; this difference being statistically significant (P<.001). There were no differences in terms of the onset of ambulation, days of admission or Visual Analogue Scale at one month of surgery. Ten patients were rejected for presurgical urinary tract infection, metal allergy, selection failure, patellar weakening, prosthetic instability, intrasurgical tibial fracture, change of indication to unicompartimental prosthesis and a loss of follow-up. There was only one complication unrelated to the investigational drug (bladder balloon). Conclusion: The administration of TXA topically after cementation of the prosthetic components in total knee arthroplasty in a single dose has demonstrated being safe and effective.(AU)

[Translated article] Randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of topical tranexamic acid in saving blood loss in patients undergoing prosthetic knee surgery.

BACKGROUND AND OBJECTIVE: Knee arthroplasty is a major surgery with potential significant blood loss. Assess the efficacy and safety of topical administration of 3g of tranexamic acid (TXA) in terms of reducing blood loss in knee arthroplasty. MATERIAL AND METHOD: A randomized, phase III, double-blind, placebo-controlled clinical trial has been conducted. We included 150 patients in 2 parallel treatment groups (75 per arm). The solution was administered topically intra-articular after cementation and prior to capsular closure. Analytical determinations were made before and after surgery to quantify blood loss. RESULTS: Total blood loss for the placebo group was 831.5ml and 662.3ml for the TXA group. The difference between the 2 groups was 169.2ml; which means a save of 20.4%; this difference being statistically significant (p<.001). There were no differences in terms of the onset of ambulation, days of admission or visual analogue scale at one month of surgery. Ten patients were rejected for presurgical urinary tract infection, metal allergy, selection failure, patellar weakening, prosthetic instability, intrasurgical tibial fracture, change of indication to unicompartimental prosthesis and a loss of follow-up. There was only one complication unrelated to the investigational drug (bladder balloon). CONCLUSION: The administration of TXA topically after cementation of the prosthetic components in total knee arthroplasty in a single dose has demonstrated being safe and effective.

Usefulness of chest X-rays for detecting COVID 19 pneumonia during the SARS-CoV-2 pandemic.

OBJECTIVE: To review the prognostic usefulness of chest X-rays in selecting patients with suspected SARS-CoV-2 infection. MATERIAL AND METHODS: This cross-sectional descriptive observational study analyzed 978 patients with suspected SARS-CoV-2 infections who underwent chest X-ray examinations in the emergency department of a tertiary hospital in March 2020. We separately analyzed demographic, clinical, and prognostic variables in two groups of patients: those in whom reverse-transcriptase polymerase chain reaction (RT-PCR) was done (n = 535) and those in whom RT-PCR was not done because of low clinical suspicion (n = 443). RESULTS: In the group of patients with RT-PCR, the prevalence of SARS-CoV-2 was 70.4%, and the sensitivity of chest X-rays was 62.8%. In the group of patients without RT-PCR, chest X-rays were negative in 97.5%, corroborating the low clinical suspicion; these patients were discharged, and 5.6% of them reconsulted with mild forms of the disease. In the group of patients with RT-PCR, we observed no statistically significant differences in the percentage of pathologic chest X-rays between patients hospitalized in the ICU (72.9%) and in those hospitalized in other wards (68.3%) (p = 0.22). CONCLUSION: In the context of the pandemic, patients with low clinical suspicion and negative chest X-rays can be discharged with a low probability of reconsultation or of developing severe COVID19. In patients with RT-PCR positive for SARS-CoV-2, chest X-rays have no prognostic usefulness.