Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy.

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.

Intervención mediante imaginería motora tras una encefalopatía post-hipóxica. A propósito de un caso / Motor imagery intervention after hipoxic brain injury. A case study

Objetivos: valorar las diferencias pre y post intervención en la motricidad fina, funcionalidad de miembros superiores y control de espasmos a través de la imaginería motora en una persona que ha sufrido una encefalopatía post-hipoxia. Métodos: el paciente es un varón de 52 años que sufrió una encefalopatía post-hipoxia que cursó con una alteración de la respuesta motora en forma de espasmos incontrolados ante estímulos inesperados que provocaba una imposibilidad de manipulación o uso funcional de objetos. Se realizó una intervención a través de imaginería motora con el fin de reducir el número de espasmos y aumentar la funcionalidad de miembros superiores. Se estructuró en sesiones de 45 minutos, dos sesiones semanales durante tres meses. Se realizó una valoración a través de las escalas Motor Assessment Scale, Purdue Pegboard Test y Nine Hole Peg Test, además de una serie de tareas funcionales para medir el número de espasmos durante la ejecución de cada actividad. Conclusión: al finalizar la intervención se evidenció una mejoría tanto en motricidad fina como en funcionalidad de miembros superiores. Por lo tanto, la imaginería motora podría suponer una herramienta eficaz a la hora de abordar este tipo de clínica tan específica.(AU)

Objective: An intervention was designed and carried out to increase To assess pre- and post-intervention differences in fine motor skills, upper limb functionality and spasm control through motor imagery in a person who has suffered post-hypoxic encephalopathy. Methods: The patient is a 52-year-old male who has suffered post-hypoxic encephalopathy with an altered motor response in the form of uncontrolled spasms to unexpected stimuli that made it impossible to manipulate or functionally use objects. An intervention was carried out through motor imagery to reduce the number of spasms and increase the functionality of the upper limbs. It was structured in 45-minute sessions, twice a week for three months. An assessment was performed using the Motor Assessment Scale, Purdue Pegboard Test and Nine Hole Peg Test, as well as a series of functional tasks to measure the number of spasms during the execution of each activity. Conclusion: At the end of the intervention there was an improvement in both fine motor skills and upper limb function. Therefore, motor imagery could be an effective tool when dealing with this type of very specific clinical condition.(AU)

Neumomediastino y enfisema subcutáneo como complicación de la colonoscopia / Pneumomediastinum and subcutaneous emphysema as complication of colonoscopy

Las perforaciones intestinales en el curso de una colonoscopia diagnóstica es una complicación poco frecuente pero descrita. Por lo general, no trae mayores consecuencias salvo la afectación local. Se presenta un caso de neumomediastino y enfisema subcutáneo, luego de una perforación accidental del colon en el curso de una colonoscopia. Se trata de una paciente femenina, de 64 años de edad, la cual en una pesquisa activa resultó positiva a un examen de sangre oculta en heces fecales, por lo que se indica una colonoscopia. Durante la realización el estudio fue interrumpido por el médico, al advertir una pequeña hemorragia que le impresiona perforación de colon, y traslada a la paciente al cuerpo de guardia de cirugía, donde luego de evaluar su estado clínico y realizar los exámenes complementarios, tanto humorales como imagenológicos, se constata neumoperitoneo, neumomediastino y enfisema subcutáneo que abarca fascie, cuello y tercio superior del tórax. Se lleva de urgencia a la sala de operaciones. Se realiza laparotomía constatando una perforación puntiforme en colon sigmoide, que se trata mediante sutura primaria en un solo plano. Luego de la recuperación anestésica, la paciente fue trasladada a la unidad de cuidados intensivos. En el transcurso del postoperatorio inmediato desaparece totalmente el neumomediastino y, progresivamente, el enfisema subcutáneo. La paciente evoluciona de forma satisfactoria y se traslada a sala abierta, egresándose a los diez días sin complicaciones. En la actualidad, se encuentra en perfecto estado de salud y totalmente asintomática(AU)

An intestinal perforation in the course of a diagnostic colonoscopy is an infrequent complication, but it has been described. In general, it does not develop greater consequences, except local damage. This study presents a case of pneumomediastinum and subcutaneous emphysema after an accidental perforation of the colon in the course of a colonoscopy. A 64-year-old female patient was ordered a colonoscopy since the result of an occult blood exam during an active investigation was positive. While performing the intervention the doctor interrupted it when noticing a small amount of bleeding that suggested a perforation of the colon and moved the patient to the emergency department of general surgery. The assessment of the patients clinical state and the running the corresponding investigations, both humoral and radiological, indicated the presence of a pneumoperitoneum, pneumomediastinum, as well as a subcutaneous emphysema embracing fascia, neck and the upper third of the thorax. The patient is emergently taken to the operating room. A laparotomy is performed confirming a pinhole perforation in the sigmoid colon which was treated with a single layer suturing. After the anesthetic recovery the patient was transferred to the intensive care unit. During the immediate postoperative period the pneumomediastinum disappeared totally, and the subcutaneous emphysema progressively. The patient progressed satisfactorily and was transferred to an inpatient ward, being discharged from the hospital after ten days without complications. Nowadays the patient is in a perfect health state and totally asymptomatic(AU)

VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis.

OBJECTIVE: To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. METHODS: Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. RESULTS: ALLELE FREQUENCY DIFFERENCES WERE FOUND IN FOUR NOVEL LOCI: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-α loci were observed. INTERPRETATION: The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG.

Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia.

Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.

The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.

Tabaco de liar: una prioridad de salud pública y consumo / Fine-cut tobacco: a priority for public health and consumer advocacy

Objetivos Valorar si el tabaco de liar supone un problema en materia de salud pública y consumo. Métodos Se estudia el 70% del mercado español. En materia de salud pública, se analizan los contenidos de nicotina, alquitrán y monóxido de carbono del humo, y se comparan con los de los cigarrillos convencionales. En materia de consumo, se examina el etiquetado. Resultados Los contenidos de nicotina, alquitrán y monóxido de carbono alcanzan valores de hasta el 70%, el 85% y el 84%, respectivamente, más de lo permitido para los cigarrillos convencionales. El 67% de las muestras no indican los contenidos de nicotina y alquitrán, y el 100% el monóxido de carbono. A pesar de la existencia de etiquetado, éste no garantiza una información suficiente al consumidor. Conclusiones El tabaco de liar supone un problema tanto en materia de salud pública como en consumo. Por ello, sería necesaria alguna medida que permita resolver esta cuestión (AU)

Objectives To study whether fine-cut tobacco poses a problem for public health and consumer affairs. Methods We analyzed up to 70% of the fine-cut tobacco market in Spain. Regarding public health, the contents of nicotine, tar and carbon monoxide were analyzed and compared with levels in conventional cigarettes. Concerning consumer affairs, the labeling of samples was checked. Results The contents of nicotine, tar and carbon monoxide reached values of 70%, 85% and 84%, respectively. These values are higher than those allowed in conventional cigarettes. A total of 67% of the samples analyzed did not show nicotine and tar contents on the labeling. None of the labels showed carbon monoxide contents. The presence of labeling per se did not guarantee sufficient information for consumers. Conclusions Fine-cut tobacco is a problem in both public health and consumer affairs. Solutions are required to resolve both problems (AU)

[Fine-cut tobacco: a priority for public health and consumer advocacy]. / Tabaco de liar: una prioridad de salud pública y consumo.

OBJECTIVES: To study whether fine-cut tobacco poses a problem for public health and consumer affairs. METHODS: We analyzed up to 70% of the fine-cut tobacco market in Spain. Regarding public health, the contents of nicotine, tar and carbon monoxide were analyzed and compared with levels in conventional cigarettes. Concerning consumer affairs, the labeling of samples was checked. RESULTS: The contents of nicotine, tar and carbon monoxide reached values of 70%, 85% and 84%, respectively. These values are higher than those allowed in conventional cigarettes. A total of 67% of the samples analyzed did not show nicotine and tar contents on the labeling. None of the labels showed carbon monoxide contents. The presence of labeling per se did not guarantee sufficient information for consumers. CONCLUSIONS: Fine-cut tobacco is a problem in both public health and consumer affairs. Solutions are required to resolve both problems.

Processivity and subcellular localization of glycogen synthase depend on a non-catalytic high affinity glycogen-binding site.

Glycogen synthase, a central enzyme in glucose metabolism, catalyzes the successive addition of α-1,4-linked glucose residues to the non-reducing end of a growing glycogen molecule. A non-catalytic glycogen-binding site, identified by x-ray crystallography on the surface of the glycogen synthase from the archaeon Pyrococcus abyssi, has been found to be functionally conserved in the eukaryotic enzymes. The disruption of this binding site in both the archaeal and the human muscle glycogen synthases has a large impact when glycogen is the acceptor substrate. Instead, the catalytic efficiency remains essentially unchanged when small oligosaccharides are used as substrates. Mutants of the human muscle enzyme with reduced affinity for glycogen also show an altered intracellular distribution and a marked decrease in their capacity to drive glycogen accumulation in vivo. The presence of a high affinity glycogen-binding site away from the active center explains not only the long-recognized strong binding of glycogen synthase to glycogen but also the processivity and the intracellular localization of the enzyme. These observations demonstrate that the glycogen-binding site is a critical regulatory element responsible for the in vivo catalytic efficiency of GS.

Diagnóstico definitivo de los tumores neuroendocrinos (TNE) mediante PAAF ecodirigida por ultrasonografía endoscópica (USE) / No disponible

Introducción: la localización y diagnóstico de los tumores neuroendocrinos (TNE) es difícil. La ultrasonografía endoscópica (USE) tiene un papel significativo en la detección de TNE sospechados por la clínica u otras técnicas de imagen, así como en la localización exacta y confirmación citológica mediante USEPAAF. Objetivo: valorar la utilidad y precisión de la PAAF-USE en el diagnóstico diferencial y de confirmación de los TNE, en una revisión retrospectiva de la experiencia de nuestro grupo. Pacientes y métodos: de un total de 55 enfermos con sospecha de TNE a los que se le practicó USE radial o sectorial, se detectaron 42 tumores en 40 casos. En 16 casos con sospecha de TNE funcionantes (trastornos hormonales: 6 casos) y no funcionantes (10 casos), se les practicó USE-PAAF con 22 G. En todos se efectuó Ki 67 o inmunocitoquímica (ICQ). Hubo confirmación quirúrgica en 9 casos (5 M y 4 V), con una media de edad de 51 años (rango: 41-81 años). Los tumores se localizaban todos en el páncreas, excepto uno en el mediastino y uno en el recto, con un tamaño medio de 19 mm (rango: 10-40 mm). Resultados: no hubo complicaciones atribuibles a la PAAF. La sensibilidad fue del 100% (8/8), y la precisión y el VPP fue del 89% (8/9), ya que hubo un falso positivo que en el estudio cito - lógico sugirió el diagnóstico de TNE pero que su resección quirúrgica confirmó el diagnóstico de tumor sólido seudopapilar del páncreas. Conclusiones: la USE-PAAF con 22 G de los TNE posee una alta sensibilidad y VPP en la confirmación citológica de estos pacientes, con muy escasas complicaciones(AU)

Background: the detection and diagnosis of neuroendocrine tumors (NETs) is challenging. Endoscopic ultrasonography (EUS) has a significant role in the detection of NETs suspected from clinical manifestations or imaging techniques, as well as in their precise localization and cytological confirmation using EUS-Fine-needle aspiration-puncture (FNA). Objective: to assess the usefulness and precision of EUSFNAP in the differential diagnosis and confirmation of NETs, in a retrospective review of our experience. Patients and methods: in a total of 55 patients with suspected NETs who underwent radial or sectorial EUS, 42 tumors were detected in 40 cases. EUS-FNA using a 22G needle was performed for 16 cases with suspected functional (hormonal disorders: 6 cases) and non-functional NETs (10 cases). Ki 67 or immunocytochemistry (ICC) testing was performed for all. There was confirmation in 9 cases (5 female and 4 male) with a mean age of 51 years (range: 41-81 years). All tumors were located in the pancreas except for one in the mediastinum and one in the rectum, with a mean size of 19 mm (range: 10-40 mm). Results: there were no complications attributable to FNA. Sensitivity was 100% and both precision and PPV were 89%, as a false positive result suggested a diagnosis with NET during cytology that surgery finally revealed to be a pancreatic pseudopapillary solid tumor. Conclusions: EUS-FNA with a 22G needle for NETs has high sensitivity and PPV at cytological confirmation with few complications(AU)