Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Climate change and air pollution impacts on cultural heritage building materials in Europe and Mexico.

Climate and air pollution have adverse effects on cultural heritage building materials. However, the quantified damage due to modeled changes in climate and air pollution is still poorly studied. Here, we review first the damage affecting these materials and the associated damage equations in the literature. Across all relevant studies (n = 87), we found only nine independent equations to estimate different damage categories, mainly limited to limestones. Then, by using current meteorological data and future bias-corrected CMIP6 climate and air pollution data at high resolution (1 km; historical and business-as-usual scenario) and applying these equations, we quantified the relative contributions of climate and air pollution changes on the building materials of eight cultural heritage sites of the European project Sustainable COnservation and REstoration of built cultural heritage (SCORE) from 2020 to 2100. On average across the sites, a significant decrease in damage is projected in surface recession (-10 % ± 10 %), biomass accumulation (-20 % ± 18 %), and wind-rain erosion (-7 % ± 6 %) in response to future climate and air pollution changes, except in the regions where precipitation substantially increases (Northern Europe). A large uncertainty in the relative magnitude of the damage to built cultural heritage materials was found for the same site, changes in surface recession vary up to a 40 % difference across the equations. Moreover, thermal expansion and lifetime multiplier equations project an increase in the related damage while all the other types of damage are significantly reduced. Finally, in general, but not systematically, climate-induced damage was found to be predominant over the pollution-induced one. Our results allow prioritizing cultural heritage maintenance decisions in regions where damage will further increase. Beyond simulated damages which are still limited use, we urge more campaign studies to determine real in situ damage in different climate locations to validate or build the best equations.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Familial hypocalciuric hypercalcemia: new mutation in the CASR gene converting valine 697 to methionine.

Familial hypocalciuric hypercalcemia is an uncommon cause of hypercalcemia that arises from mutations in the calcium-sensing receptor gene. Inactivation of this receptor leads to a decreased receptor sensitivity to calcium, determining that higher concentrations of calcium are needed to inhibit the release of parathormone in the parathyroid glands. Patients usually are asymptomatic. Diagnosis is usually made casually after a routine blood analysis. The syndrome is characterized by mild or moderate hypercalcemia, hypocalciuria, and normal or slightly increased levels of parathormone. The degree of hypercalcemia depends on the type of mutation. The accurate diagnosis is important since it is a benign disorder that does not require medical or surgical treatment. We report a 9-year-old female with persistent hypercalcemia in several routine blood analyses, who was diagnosed with familial hypocalciuric hypercalcemia after genetic studies were performed. A new mutation determining a nucleotide change c.2089G>A in the calcium-sensing receptor gene (exon 7) was detected. This mutation was also found in the patient's mother and brother.

Reanimación cardiopulmonar y cerebral en la gestante / Cardiopulmonary and cerebral resuscitation in pregnants

Introducción. El paro cardiorrespiratorio, es un evento extremadamente grave en cualquier persona, máxime en el caso particular de una embarazada, pues resultan dos pacientes potenciales a reanimar y sus consecuencias suelen ser fatales tanto para la madre como para el feto. Objetivo. Hacer una puesta al día de la reanimación cardiopulmonar cerebral en la paciente obstétrica. Desarrollo. Se puso a la consideración del lector, los diferentes conceptos de reanimación cardiopulmonar en la gestante y las particularidades del diagnóstico y tratamiento. Conclusiones. Resulta imprescindible la actualización sobre la reanimación cardiopulmonar en la gestante, toda vez que es una situación que se puede presentar con relativa frecuencia e impone un gran reto al equipo que lo enfrenta sobre todo porque no existen guías basadas en la evidencia que permitan enunciar recomendaciones como las que existen para adultos no gestantes o población pediátrica.

The cardiac-respiratory arrest is a very severe event in any person specially in the case of a pregnant patient since arte two the potential patients to resuscitate and its consequences are terrible for mother and for fetus. Objective: To make an update of cerebral cardiac-pulmonary resuscitation in the obstetric patient. Development: The different concepts of cardiac-pulmonary resuscitation in pregnant and the peculiarities of diagnosis and treatment must to be assessed by lector. Conclusions: It is essential the update on the cardiac-pulmonary resuscitation in the pregnant, since that it is a possible situation with a relative frequency and to impose a great challenge to staff facing it mainly because of there are based on the evidence-guidances allowing to formulate recommendations as the existing ones for the non-pregnant adults patients or for the pediatric population.

Reanimación cardiopulmonar y cerebral en la gestante / Cardiopulmonary and cerebral resuscitation in pregnants

Introducción. El paro cardiorrespiratorio, es un evento extremadamente grave en cualquier persona, máxime en el caso particular de una embarazada, pues resultan dos pacientes potenciales a reanimar y sus consecuencias suelen ser fatales tanto para la madre como para el feto. Objetivo. Hacer una puesta al día de la reanimación cardiopulmonar cerebral en la paciente obstétrica. Desarrollo. Se puso a la consideración del lector, los diferentes conceptos de reanimación cardiopulmonar en la gestante y las particularidades del diagnóstico y tratamiento. Conclusiones. Resulta imprescindible la actualización sobre la reanimación cardiopulmonar en la gestante, toda vez que es una situación que se puede presentar con relativa frecuencia e impone un gran reto al equipo que lo enfrenta sobre todo porque no existen guías basadas en la evidencia que permitan enunciar recomendaciones como las que existen para adultos no gestantes o población pediátrica(AU)

The cardiac-respiratory arrest is a very severe event in any person specially in the case of a pregnant patient since arte two the potential patients to resuscitate and its consequences are terrible for mother and for fetus. Objective: To make an update of cerebral cardiac-pulmonary resuscitation in the obstetric patient. Development: The different concepts of cardiac-pulmonary resuscitation in pregnant and the peculiarities of diagnosis and treatment must to be assessed by lector. Conclusions: It is essential the update on the cardiac-pulmonary resuscitation in the pregnant, since that it is a possible situation with a relative frequency and to impose a great challenge to staff facing it mainly because of there are based on the evidence-guidances allowing to formulate recommendations as the existing ones for the non-pregnant adults patients or for the pediatric population(AU)

Capacitación en soporte vital básico en la clínica central Cira García: resultados preliminares / Training in Basic Life Support in the Central Clinical Cira Garcia: preliminary results

En promedio los pacientes que sobreviven al PCR son aquellos en que la reanimación se inicia durante los primeros cuatro minutos. Determinar los conocimientos, habilidades y nivel de capacitación del personal de enfermería en soporte vital básico antes y después de un proceso educativo. Durante un periodo de 4 meses se impartió un curso-taller de 20 horas a 66 enfermeras del área de hospitalización, con una evaluación al inicio y al final del proceso educativo. La variable fue capacitación con 3 criterios: conocimiento con valor de 50 puntos, habilidad 50 puntos y competencia. Durante un periodo de 4 meses se impartió este curso de 20 horas organizado con 30 minutos para la evaluación inicial teórico-práctica, 2 horas de conferencias orientadoras, 17 horas de actividad práctica y 30 minutos para la evaluación teórica-práctica final. Éste fue impartido por profesores del servicio de anestesiología con experiencia en esta temática La fase teórica incluyó además el estudio individual de los contenidos por un manual elaborado para ello siguiendo las normas internacionales establecidas por el comité de enlace internacional. (ILCOR). Muestreo por conveniencia, instrumentos validados y calificados por el propio investigador. Se consideró capacitada, a la persona que logró aprobar los 2 criterios. En la evaluación inicial ninguna enfermera logró calificar como capacitada y en la evaluación final 100 por ciento. El resultado después del proceso educativo se consideró de bueno a excelente pues el nivel de competencia, habilidad y conocimiento fue alto. Recomendamos realizar investigaciones dirigidas a medir el impacto de la intervención educativa sobre la política de salud hospitalaria. Aún más, si se considera que actualmente la capacitación en RCPC están contenidas en la carpetas de evaluación para la acreditación de hospitales(AU)

Polirradiculopatía diabética dolorosa: tratamiento con inmunoglobulinas intravenosas / Painful diabetic polyradiculoneuropathy: treatment with intravenous immunoglobulins

No disponible

Hiperalgesia postoperatoria: de la molécula a la práctica clínica

El dolor postoperatorio representa en nuestros días uno de los retos no resuelto para el anestesiólogo. Estudios recientes, en los que se involucraron alrededor de 20000 pacientes, se evidenció que 41 por ciento de todos los pacientes quirúrgicos sufrían de dolor moderado a severo en la sala de recuperación y 24 por ciento las consecuencias de un alivio inadecuado. Desafortunadamente, el control del dolor postoperatorio agudo no ha mejorado de forma significativa en la última década incrementándose paralelamente la incidencia del dolor crónico posterior a procedimientos quirúrgicos. Se propone definir los conceptos de hiperalgesia en el paciente quirúrgico, así como los principios fisiológicos. Se realizó una revisión de la literatura sobre el tema, en el cual se aborda la problemática de la hiperalgesia del paciente quirúrgico. Se describen sus ventajas y la posibilidad de evitar complicaciones. Se concluye que los estudios en la última década plantean que la HP ocurre en el postoperatorio inmediato como consecuencia de la nocicepción quirúrgica como también por medicamentos (particularmente opioides). La HP basada en síntomas clínicos solos es difícil de diagnosticar pero, la introducción y adaptación de PSC a la práctica clínica representa un método válido. Estudios demuestran la efectividad de la profilaxis y tratamiento de la HP; sin embargo, se necesitan más para esclarecer el rol de esta en el dolor agudo y crónico postoperatorio(AU)

Cefalea post anestesia subaracnoidea: influnecia de la vía media vs vía lateral en hemorroidectomia ambulatoria: ensayo / clínico / Post-anesthesia subarachnoid headache: influence of the medial versus lateral via in ambulatory hemorroidectomy:a clinical trial

Son controvertidas las opiniones en cuanto a cuál vía de abordaje de la columna vertebral es más beneficiosa en la profilaxis de la cefalea postpunción lumbar (CPP). Empíricamente creemos que el empleo de la vía lateral se acompaña de una menor incidencia de CPP. Para apoyar esta hipótesis, se diseña el presente ensayo clínico con el objetivo de contrastar la vía media y lateral para anestesia intratecal en hemorroidectomia ambulatoria e identificar las posibles diferencias en cuanto a los síntomas postoperatorios asociados a esta técnica. 0Aleatoriamente se conformaron dos grupos de 50 pacientes cada uno. La punción se realizó con trocar 25G con punta de Quincke, en el grupo M por vía media y en el grupo L por vía lateral, siempre por la misma persona. La técnica empleada fue “en silla de montar” con 50 mg de lidocaina hiperbárica. Al día siguiente y antes del alta, otro coordinador del ensayo, que desconocía la vía empleada, aplicó el cuestionario de recolección de datos. Para la evaluación cuantitativa de la evolución de los pacientes se estableció un sistema de puntuación según los síntomas. Ningún paciente tuvo cefalea. No hubo diferencias estadísticamente significativas en cuanto a edades, sexo o puntuación entre los grupos. Todos los pacientes que tuvieron síntomas postoperatorios recibieron dos intentos de punción lumbar. La vía lateral no mostró influencia en relación con la CPP aunque tuvo ventajas en relación con otros síntomas relacionados con la anestesia. Otros factores técnicos tuvieron más influencia sobre los resultados(AU)