Maximum dose, safety, tolerability and ketonemia after triheptanoin in glucose transporter type 1 deficiency (G1D).

Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4-6, 6.8-10 and 11-16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, ß-ketopentanoate and ß-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.

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.

Prevalencia de los trastornos del espectro autista en niños en Estados Unidos, Europa y España: coincidencias y discrepancias / Prevalence of autism spectrum disorders in USA, Europe and Spain: coincidences and discrepancies

Los trastornos del espectro autista (TEA) engloban a un grupo heterogéneo de trastornos del neurodesarrollo que tienen en común la presencia de problemas para la interacción/comunicación social y la tendencia a mostrar intereses restringidos o conductas repetitivas. Diversos estudios epidemiológicos realizados en diferentes países en los últimos años han mostrado de forma consistente dos características: el incremento progresivo en la prevalencia de los TEA a nivel mundial y la existencia de una gran variabilidad geográfica entre territorios y dentro de un mismo territorio. En el presente artículo analizamos los datos de prevalencia más recientemente publicados en EE.UU. y en diversos países de Europa (incluyendo España), que muestran tasas de prevalencia muy variables, con un rango que abarca desde 1/59 niños con trastornos del espectro autista en EE. UU., hasta 1/806 en Portugal. En un segundo tiempo describimos brevemente algunas de las principales hipótesis que intentan explicar esta variabilidad.

Autism spectrum disorders are a heterogeneous group of disorders that share the presence of two core symptoms: problems in social interaction / communication and the tendency to present restricted interests and repetitive behavior. Over the last years, several epidemiologic studies have been published by different authors in diverse countries, having all of them shown two common characteristics: a global increase in the prevalence rates of autism spectrum disorders, and the existence of a great geographical variability no only between geographical areas, but also within the same geographical areas. At the present manuscript, we analyze some of the most recent prevalence data published in USA and some European countries (including Spain). All of them show different prevalence rates, ranging from 1/59 children with autism spectrum disorders in the USA to 1/806 in Portugal. In a second part, we briefly describe some of the current scientific hypotheses that try to explain this variability.

Cirugía Pancreática: Rol de la evaluación nutricional como parte del manejo interdisciplinario / Pancreatic Surgery: Role of nutritional assessment as part of interdisciplinary management

El soporte nutricional óptimo en el campo de la cirugía pancreática aún es objeto de debate. Se buscó evaluar la importancia de la evaluación nutricional en pacientes con resecciones pancreáticas. Análisis retrospectivo de una base de datos prospectiva. Se realizó evaluación nutricional sistemática. Las variables analizadas fueron, tiempo de estadía hospitalaria y en UTI, complicaciones y mortalidad. No se observaron diferencias estadísticamente significativas usando test de forma aislada. Sin embargo la asociación de desnutrición severa por más de un test se asoció a un aumento significativo en la mortalidad post-operatoria. La evaluación interdisciplinaria de los pacientes con tumores bilio-pancreáticos, debe incluir una adecuada valoración del estado nutricional para identificar aquellos con mayor riesgo

The optimal nutritional support in pancreatic surgery is still under debate. We performed a retrospective analysis of a prospective data base. Systematic nutritional assessment was performed. Length of hospital stay and in ICU, morbidityand mortality, were analyzed. We didn't find significative differences between any of the nutritional test. However, patients with severe malnutrition in different tests were associated with higher mortality. Interdisciplinary management of patients with biliopancreatic tumors should include an adequate nutritional evaluation to identify high risk patients.

Reutilización de materiales de colangiografía endoscópica. Estudio prospectivo de minimización de costos / Reusing materials in endoscopic cholangiography. A prospective study on cost minimization

ANTECEDENTES: la colangiografía endoscópica enfrenta el desafío del control de costos en un área de constantes avances tecnológicos. La reutilización es el uso de un dispositivo médico más veces de las especificadas por el fabricante. Esta práctica se halla precedida por las maniobras de reprocesamiento y amparada por la legislación vigente. OBJETIVOS: cuantificar la reducción en el costo de los insumos y evaluar las complicaciones. Método: estudio prospectivo, descriptivo y análisis sobre minimización de costos comparando la reutilización de dispositivos médicos con el uso único de los mismos. RESULTADOS: durante un período de tres meses se realizaron 144 estudios. Con la estrategia de reutilización, se utilizaron: 9 papilótomos, 12 guías hidrofílica, 3 canastillas de Dormia, 4 balones extractor, 5 balones dilatadores y 2 cuchillos de precorte. Representó un costo total de U$ 10 943 (promedio de costo de materiales por cada estudio: U$ 76). Con la estrategia de uso único se hubieran utilizado: 144 papilótomos, 144 alambres guías, 24 canastillas de Dormia, 20 balones dilatadores, 72 balones extractores y 24 agujas de precorte. Esta estrategia hubiera generado un costo total de U$ 126 280 (promedio por estudio U$ 877). Al comparar los valores entre ambas estrategias observamos una minimización significativa en el costo (p< 0.001). No se registraron complicaciones. Conclusión: Con la estrategia de reutilización de los DM los costos se minimizaron significativamente sin generarse complicaciones

BACKGROUND: cost control is challenging endoscopic cholangiography in an area of constant technological advances. Reusing is using a medical device more times than what was specified by the manufacturer. This practice is preceded by reprocessing maneuvers and protected by the applicable laws. OBJECTIVES: to quantify the cost reduction of supplies and assess the complications. Method: a prospective descriptive study and an analysis of cost minimization by comparing the reuse and the single use of medical devices. Results: 144 studies were conducted during a period of three months. The reuse strategy included: 9 papillotomes, 12 hydrophilic guide wires, 3 Dormia baskets, 4 balloon extraction catheters, 5 balloon dilatation catheters and 2 pre-cut knives. It accounted for a total cost of USD 10,943 (average cost of materials per study: USD 76). The single-use strategy would have included: 144 papillotomes, 144 hydrophilic guide wires, 24 Dormia baskets, 20 balloon extraction catheters, 72 balloon dilatation catheters and 24 pre-cut needle knives. This strategy would have amounted to a total cost of USD 126,280 (average per study: USD 877). By comparing the values of both strategies, a significant minimization is seen in the cost (p< 0.001). No complications were seen. CONCLUSION: the strategy for reusing MD involveda significant minimization of costs without causing any complications.

Recommendations for the radiological diagnosis and follow-up of neuropathological abnormalities associated with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic condition with multisystem involvement, characterized by the development of tumors and other abnormalities in organs such as the brain, retina, skin, heart, kidneys, and lungs. Most patients have neuropathological abnormalities such as cortical tubers, white matter radial migration lines, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). These lesions are associated with different neurological manifestations that are frequently associated with TSC. These manifestations consist of epilepsy, intellectual disability, and neurobehavioral and psychiatric problems, including autism spectrum disorder. Hydrocephalus may also develop in patients with SEGAs due to ventricular obstruction, when this usually slow-growing tumor reaches sufficient size. Surgery has been the classical approach to treat SEGAs, although this treatment is associated with substantial morbidity and does not completely prevent tumor recurrence. Recently, the mammalian target of rapamycin (mTOR) inhibitor, everolimus, has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of patients with SEGAs associated with TSC. However, the treatment of SEGAs with these agents requires the development of guidelines that establish a differential diagnosis between SENs and SEGAs, in which neuroradiological examinations play an essential role. With the aim of improving the neuroradiological diagnosis and follow-up of the neuropathological abnormalities associated with TSC, a group of experts in this field has reviewed different aspects related to these issues and put together, a series of statements and recommendations intended to provide guidance to specialists involved in the management of TSC.

Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.

OBJECTIVE: To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. STUDY DESIGN: Review of clinical data, long-term follow-up, and immunologic studies performed in a single center in Spain in the last 4 years. RESULTS: The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%), the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in 2 patients, 1 at onset of encephalitis and the other 1 year later. Two novel observations (1 patient each) include, the identification of an electroencephalographic pattern ("extreme delta brush") considered characteristic of this disorder, and the development of anti-NMDAR encephalitis as post herpes simplex encephalitis choreoathetosis. CONCLUSIONS: The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post herpes simplex encephalitis choreoathetosis and anti-NMDAR encephalitis.

Two cases of painful gynecomastia and lower extremity pain in association with pregabalin therapy.

We report two patients with refractory epilepsy who developed unilateral painful gynecomastia and lower extremity pain (one of them localized and the other one diffuse), shortly after receiving Pregabalin (PGB). Neither of them had previous endocrinologic problems or complaints about pain on their medical history. PGB was stopped in one patient and reduced in the other one, with complete disparition of the symptoms in the following weeks in both patients. This supports the hypothesis that gynecomastia could be a drug-induced and easy to manage secondary effect of PGB, with a higher incidence than observed on previous clinical trials.