Genomic comparison of two strains of Mycobacterium avium subsp. paratuberculosis with contrasting pathogenic phenotype.

In a previous study, we evaluated the degree of virulence of Mycobacterium avium subsp. paratuberculosis (Map) strains isolated from cattle in Argentina in a murine model. This assay allowed us to differentiate between high-virulent MapARG1347 and low-virulent MapARG1543 strains. To corroborate whether the differences in virulence could be attributed to genetic differences between the strains, we performed Whole Genome Sequencing and compared the genomes and gene content between them and determined the differences related to the reference strain MapK10. We found 233 SNPs/INDELS in one or both strains relative to Map K10. The two strains share most of the variations, but we found 15 mutations present in only one of the strains. Considering NS-SNP/INDELS that produced a severe effect in the coding sequence, we focus the analysis on four predicted proteins, putatively related to virulence. Survival of MapARG1347 strain in bMDM was higher than MapARG1543 and was more resistant to acidic pH and H2O2 stresses than MapK10. The genomic differences between the two strains found in genes MAP1203 (a putative peptidoglycan hydrolase), MAP0403 (a putative serine protease) MAP1003c (a member of the PE-PPE family) and MAP4152 (a putative mycofactocin binding protein) could contribute to explain the contrasting phenotype previously observed in mice models.

Stereoelectroencephalography in the preoperative assessment of patients with refractory focal epilepsy: experience at an epilepsy centre.

OBJECTIVE: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE. MATERIAL AND METHODS: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure. RESULTS: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages. CONCLUSION: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications.

[Treatment of epilepsy with perampanel: conversion from add-on therapy to monotherapy]. / Tratamiento de la epilepsia con perampanel: desde la terapia añadida a la conversión a monoterapia.

INTRODUCTION: Perampanel (PER) is an antiepileptic drug approved in Europe as add-on therapy for patients with focal onset seizures (with or without secondary generalisation) from the age of 4 years, and for primary generalised tonic-clonic seizures from 7 years of age. OBJECTIVE: Review current evidence on treatment with PER monotherapy after conversion from adjunctive therapy. DEVELOPMENT: Two retrospective multicentre studies in which PER was used as monotherapy show that low doses (6-8 mg/day) of PER were effective and well tolerated in a subgroup of patients with less severe epilepsies than patients who participated in clinical trials (where PER was used as add-on therapy). In these studies, the retention rate exceeded 90% at 3 months, and 70% at 6, and 12 months. The responder rate was > 75% at 3 months, and the rate of seizure-free patients exceeded 50% at 3 and 6 months, and 37% at 12 months. Compared to other observational studies and clinical trials where PER was used as add-on therapy, no adverse effects other than those already known were observed. Four other studies examining the effects of conversion to PER monotherapy in a small number of patients support these results. CONCLUSIONS: In routine clinical practice, conversion to PER monotherapy, at relatively low doses, is an effective and well-tolerated treatment for patients with focal and generalised tonic-clonic seizures.

TITLE: Tratamiento de la epilepsia con perampanel: desde la terapia añadida a la conversión a monoterapia.Introducción.El perampanel (PER) es un fármaco anticrisis epilépticas aprobado en Europa como terapia añadida para pacientes con crisis de inicio focal (con o sin crisis focal a bilateral tonicoclónica) desde los 4 años, y para las crisis tonicoclónicas generalizadas desde los 7 años. Objetivo. Revisar la evidencia existente sobre el tratamiento con PER en conversión a monoterapia. Desarrollo. Dos estudios multicéntricos retrospectivos en los que el PER se convirtió a monoterapia muestran que este fármaco en dosis bajas (6-8 mg/día) fue especialmente eficaz y bien tolerado en un subgrupo de pacientes con epilepsias menos graves que los pacientes que participaron en los ensayos clínicos en donde el PER se empleó como terapia añadida. En estos estudios, la tasa de retención superó el 90% a los tres meses y el 70% a los seis y a los 12 meses. La tasa de respondedores fue > 75% a los tres meses, y la tasa de pacientes libres de crisis llegó a superar el 50% a los tres y a los seis meses, y el 37% a los 12 meses. En comparación con otros estudios donde el PER se empleó como terapia añadida, no se observaron efectos adversos diferentes a los ya conocidos. Otros cuatro estudios que examinaron los efectos del PER en conversión a monoterapia en un número pequeño de pacientes apoyan estos resultados. Conclusiones. En la práctica clínica habitual, el PER es un tratamiento eficaz y bien tolerado cuando se usa en conversión a monoterapia, en dosis relativamente bajas, en pacientes con crisis focales y tonicoclónicas generalizadas.

Long-term stabilized amorphous calcium carbonate-an ink for bio-inspired 3D printing.

Biominerals formed by organisms in the course of biomineralization often demonstrate complex morphologies despite their single-crystalline nature. This is achieved owing to the crystallization via a predeposited amorphous calcium carbonate (ACC) phase, a precursor that is particularly widespread in biominerals. Inspired by this natural strategy, we used robocasting, an additive manufacturing three-dimensional (3D) printing technique, for printing 3D objects from novel long-term, Mg-stabilized ACC pastes with high solids loading. We demonstrated, for the first time, that the ACC remains stable for at least a couple of months, even after printing. Crystallization, if desired, occurs only after the 3D object is already formed and at temperatures significantly lower than those of common postprinting sintering. We also examined the effects different organic binders have on the crystallization, the morphology, and the final amount of incorporated Mg. This novel bio-inspired method may pave the way for a new bio-inspired route to low-temperature 3D printing of ceramic materials for a multitude of applications.

A systematic review of magnetic resonance imaging in patients with an implanted vagus nerve stimulation system.

PURPOSE: Vagus nerve stimulation (VNS) is an effective adjunctive treatment for drug-resistant epilepsy (DRE) and difficult-to-treat depression (DTD). More than 125.000 patients have been implanted with VNS Therapy® System (LivaNova PLC) since initial approval. Patients with DRE often require magnetic resonance imaging (MRI) of the brain during the course of their disease. VNS Therapy System devices are labeled to allow MRI under certain conditions; however, there are no published comprehensive articles about the real-world experience using MRI in patients with implanted VNS devices. METHODS: A systematic review in accordance with PRISMA statement was performed using PubMed database. Full-length articles reporting MRI (1.5 T or 3 T scanner) of patients with implanted VNS for DRE or DTD and published since 2000 were included. The primary endpoint was a positive outcome that was defined as a technically uneventful MRI scan performed in accordance with the VNS Therapy System manufacturer guidelines and completed according to the researchers' planned scanning protocol without harm to the patient. RESULTS: Twenty-six articles were eligible with 25 articles referring to the VNS Therapy System, and 216 patients were included in the analysis. No serious adverse events or serious device-related adverse events were reported. MRI scan was prematurely terminated in one patient due to a panic attack. CONCLUSION: This systematic review indicates that cranial MRI of patients with an implanted VNS Therapy System can be completed satisfactorily and is tolerable and safe using 1.5 T and 3 T MRI scanners when performed in adherence to the VNS manufacturer's guidelines.

Rare intronic mutation between Exon 62 and 63 (c.9225-285A>G) of the dystrophin gene associated with atypical BMD phenotype.

Dystrophinopathies are predominantly caused by deletions, duplications and point mutations in the coding regions of the dystrophin gene with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a 17-year-old male with a Becker muscular dystrophy diagnosis and mental disability due to an intron mutation that led to aberrant splicing and formation of an additional exon. Histopathological analysis of muscle tissue revealed signs of muscular dystrophy and reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan. Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene did not identify a mutation in the coding regions. However, next generation sequencing revealed an intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame. We report a functional consequence of this mutation as an increased intracellular-weighted sodium signal (assessed by 23Na-magnetic resonance imaging) in leg muscles.

Monoclonal Antibody HlyIIC­15 to C-End Domain HlyII B. cereus Interacts with the Trombin Recognition Site.

Among the panel of monoclonal antibodies to the recombinant protein HlyIICTD Bacillus cereus an antibody was found capable of forming an immune complex with a thrombin recognition region, the amino acid sequence of which is located inside the recombinant HlyIICTD. Localization of the epitope was carried out using peptide phage display methods, as well as enzyme immunoassay and immunoblotting for interaction with recombinant proteins, either containing or not containing individual components HlyIICTD. The identified epitope is located in the region of the thrombin site and retains the ability to interact with the antibody after the proteolyotic attack of the protein by thrombin.

Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract.

BACKGROUND: Endoscopic full-thickness resection (EFTR) significantly expands the spectrum of endoscopic colorectal resection methods for lesions that show no lifting sign, submucosal lesions and mucosal carcinomas. The aim of our study was to evaluate the efficacy and safety of EFTR using a commercially available full thickness resection device (FTRD) by assessing the completeness of the full-thickness resection, the technical success, as well as complications in a cohort of patients from three referral centers in Germany. Another aim was to determine which patient subpopulations benefit most in clinical practice. METHODS: This retrospective multicenter study was conducted on consecutive patients who were admitted to three referral centers in Germany between November 2014 and December 2017. The EFTR was conducted according to the standard indications using the FTRD System (OVESCO, Tübingen, Germany). Data were obtained from prospectively maintained institutional databases. RESULTS: There were 70 patients, 42 males and 25 females with a mean age of 79.5 years (range 25-89 years) who had colonoscopy for EFTR. In three patients EFTR was not feasible because the lesions were too large. Of the remaining 67 patients, 52 had recurrent adenomas, 10 had high-grade intraepithelial neoplasia or mucosal carcinoma and five had a subepithelial lesion. Resection was technically successful in 65 patients (97.0%). Histologically complete resection (R0) was achieved in 59/65 patients (90.8%). The R0 resection rate was lower for lesions > 20 mm (86.5%) versus lesions ≤ 20 mm (92.9%). The total complication rate was 14.9%: there was one major complication (perforation of sigmoid colon), while all other complications were minor. CONCLUSIONS: EFTR yields excellent resection rates for benign recurrent adenomas with non-lifting sign, advanced histopathological findings or submucosal lesions when the procedure is performed in experienced hands and for the correct indication. Thus, surgery can be avoided in many cases. For all lesions the risk of R1 resection goes up with the size of the lesion and careful patient selection is mandatory.

Stereoelectroencephalography in the preoperative assessment of patients with refractory focal epilepsy: Experience at an epilepsy centre. / Estereoelectroencefalografía en la evaluación prequirúrgica de epilepsias focales refractarias: experiencia de un centro de epilepsia.

OBJECTIVE: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE. MATERIAL AND METHODS: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure. RESULTS: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages. CONCLUSION: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications.

Laboratory diagnosis of congenital CMV infection in newborns: Impact of pre-analytic factors.

BACKGROUND: To identify infants with congenital cytomegalovirus (cCMV) saliva polymerase chain reaction (PCR) is an ideal screening method. However, there are only few data on the influence of pre-analytic factors on the analytical sensitivity of the CMV PCR. OBJECTIVES: This study aimed to evaluate the performance of different swabbing materials, transport time and initial virus concentration regarding to the efficacy of recovery of CMV-DNA. STUDY DESIGN: Two CMV suspensions containing a high or low concentration of the laboratory strain AD 169 were prepared as test samples. Sampling was simulated by immersion of different swabs in these CMV suspensions and storing the swabs dry or in specified transport media. Transport conditions were modeled by storing the samples for defined time periods prior to DNA extraction and quantitative PCR analyses. Parallel analyses in two different laboratories allowed determination of lab to lab consistency. RESULTS: The duration of storage under the conditions analysed did not have a major effect on the recovery efficiency for the swabbing materials tested. With exception of flocked dry swabs, all tested swabbing materials demonstrated good recovery of CMV DNA. The flocked swab/eNAT system showed the best overall performance. CONCLUSIONS: All tested swabbing materials (with exception of the flocked dry swabs) seem to be well suited for recovery of CMV DNA and appropriate for use for the diagnosis of cCMV infection in symptomatic cases and in general cCMV screening programs of newborns.

[Update cartilage imaging of the small joints : Focus on high-field MRI]. / Update Knorpelbildgebung der kleinen Gelenke : Fokus Hochfeld-MRT.

BACKGROUND: Cartilage imaging of small joints is increasingly of interest, as early detection of cartilage damage may be relevant regarding individualized surgical therapies and long-term outcomes. PURPOSE: The aim of this review is to explain modern cartilage imaging of small joints with emphasis on MRI and to discuss the role of methods such as CT arthrography as well as compositional and high-field MRI. MATERIALS AND METHODS: A PubMed literature search was performed for the years 2008-2018. RESULTS: Clinically relevant cartilage imaging to detect chondral damage in small joints remains challenging. Conventional MRI at 3 T can still be considered as a reference for cartilage imaging in clinical routine. In terms of sensitivity, MR arthrography (MR-A) and computed tomography arthrography (CT-A) are superior to non-arthrographic MRI at 1.5 T in the detection of chondral damage. Advanced degenerative changes of the fingers and toes are usually sufficiently characterized by conventional radiography. MRI at field strengths of 3 T and ultrahigh-field imaging at 7 T can provide additional quantifiable, functional and metabolic information. CONCLUSION: Standardized cartilage imaging plays an important role in clinical diagnostics in the ankle joint due to the availability of different and individualized therapeutic concepts. In contrast, cartilage imaging of other small joints as commonly performed in clinical studies has not yet become standard of care in daily clinical routine. Although individual study results are promising, additional studies with large patient collectives are needed to validate these techniques. With rapid development of new treatment concepts radiological diagnostics will play a more significant role in the diagnosis of cartilage lesions of small joints.

Discrimination between chewing of coca leaves or drinking of coca tea and smoking of "paco" (coca paste) by hair analysis. A preliminary study of possibilities and limitations.

BACKGROUND: Hair analysis is a suitable way to discriminate between coca chewers and consumers of manufactured cocaine using the coca alkaloids hygrine (HYG) and cuscohygrine (CUS) as markers. In the present preliminary study it was examined whether CUS and HYG can be detected in hair of occasional and moderate coca chewers or coca tea drinkers, whether CUS and HYG appear in hair of PACO consumers (smoking coca paste waste), and whether anhydroecgonine methyl ester (AEME) is a useful cocaine smoking marker in this context. METHOD: Three groups were included: 10 volunteers from Buenos Aires with occasional or moderate chewing of coca leaves or drinking coca tea, 20 Argentinean PACO smokers and 8 German cocaine users. The hair samples (1-4 segments) were analyzed by a validated LC-MS/MS method for cocaine (COC), norcocaine (NC), benzoylecgonine (BE), ecgonine methyl ester (EME), cocaethylene (CE), cinnamoylcocaine (CIN), tropacocaine (TRO), AEME, CUS and HYG. For comparison, eight samples of coca leaves or coca tea were analyzed. RESULTS: Only low concentrations of COC were found in hair of seven occasional users of coca leaves or coca tea (0.010-0.051 ng/mg). For three moderate chewers of coca leaves all compounds were detected including AEME but except TRO. The hair samples of PACO smokers contained much higher concentrations of COC (0.027-341 ng/mg, mean 37.4 ng/mg) and its metabolites. CUS was not found in these samples but traces of HYG were seen in 8 of 37 hair segments. AEME as a marker for coca smoking was detected in hair of 15 smokers. In comparison to COC, the concentrations of EME and CIN were higher for PACO smokers than for German cocaine consumers. AEME (56 ± 20 µg/g) was detected in all coca leave and coca tea samples which explains the detection of this substance in hair of coca chewers. Therefore, its use for differentiation between coca chewers and PACO smokers is limited. CONCLUSION: CUS remains to be the most suitable marker in hair for chewing coca leaves or drinking coca tea more frequently than two times per month since it does not appear in hair of Argentinean PACO smokers and German cocaine users. Contrary to a previous proposal, the ratios CIN/COC and EME/COC appeared not to be applicable as criteria for this purpose because of the higher concentration of these alkaloids in hair of PACO smokers. More research is needed to assess the value of AEME in hair of South American coca leave or cocaine users.

Ascertaining the epidemiology, patient flow and disease management for Dravet syndrome in Spain. / Determinacion de la epidemiologia, el flujo de pacientes y el tratamiento del sindrome de Dravet en España.

INTRODUCTION: Dravet syndrome (DS) is a rare, drug resistant epilepsy that starts very early in life with febrile seizures followed by cognitive impairment and diverse seizure types. AIM: To generate evidence on the epidemiology of DS, its diagnosis, patient-flow, treatment and unmet needs from the perspective of Spanish experts. DEVELOPMENT: A two-round Delphi study involving 19 physicians was conducted. Questionnaires were based on literature review and validated by clinical experts. Consensus was reached when topics were subject to routine clinical practice and individual experience, or the coefficient of variation among answers was <= 0.3. The estimated number of new DS patients is 73 per year. Prevalence is estimated to be between 348-540 patients. DS is mostly diagnosed in children. Survival varies from 5 to 60 years. There is no standardised follow-up of patients beyond the age of 18 and mortality rates are uncertain. No standard guidelines exist for diagnosing or treating DS. It takes 9 to 15 months to confirm the diagnosis and genetic testing is unevenly available. Valproic acid, clobazam, stiripentol and topiramate are commonly used. Poor efficacy and safety are the main reasons for treatment switch. CONCLUSIONS: The epidemiology of DS in Spain is not well known and several areas of unmet needs still exist. Experts' views offer a starting point for further research into the reality of DS in Spain. Epidemiological studies, consensus criteria, easy access to genetic testing, treatment options, training and research into quality of life aspects are highly needed.

TITLE: Determinacion de la epidemiologia, el flujo de pacientes y el tratamiento del sindrome de Dravet en España.Introduccion. El sindrome de Dravet (SD) es una epilepsia rara y resistente a los farmacos que comienza en etapas muy precoces de la vida con convulsiones febriles, seguidas de deterioro cognitivo y diversos tipos de crisis epilepticas. Objetivo. Generar datos objetivos sobre la epidemiologia del SD, su diagnostico, el flujo de pacientes, el tratamiento y las necesidades no cubiertas desde el punto de vista de expertos españoles. Desarrollo. Se efectuo un estudio Delphi de dos rondas en el que participaron 19 medicos. Los cuestionarios se basaron en una revision de la bibliografia y fueron validados por expertos clinicos. Se alcanzo consenso si los temas se referian a la practica clinica habitual y la experiencia individual, o si el coeficiente de variacion entre las respuestas era <= 0,3. El numero estimado de pacientes nuevos con SD es de 73 al año. La prevalencia se calcula entre 348 y 540 pacientes. El SD se diagnostica principalmente en niños. La supervivencia varia entre los 5 y los 60 años. No existe ningun seguimiento normalizado para los pacientes de mas de 18 años de edad, y las tasas de mortalidad son inciertas. No existen guias normalizadas para diagnosticar o tratar el SD. Se tarda de 9 a 15 meses en confirmar el diagnostico, y la disponibilidad de los analisis geneticos es irregular. Normalmente se utilizan el acido valproico, el clobazam, el estiripentol y el topiramato. La escasa eficacia y la seguridad son los motivos principales de los cambios de tratamiento. Conclusiones. La epidemiologia del SD en España es poco conocida, y sigue habiendo necesidades no cubiertas en algunas areas. Las opiniones de expertos suponen un punto de partida para poder investigar la realidad del SD en España. Los estudios epidemiologicos, los criterios de consenso, el acceso facil a las pruebas geneticas, las opciones de tratamiento, la formacion y la investigacion de la calidad de vida relacionada con la salud constituyen todos ellos aspectos muy necesarios.

[«Apuntes en Neurologia¼ (Notes in Neurology): a synthesis of the evidence on common paroxysmal neurological disorders and on neurodegenerative disorders]. / «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.

«Apuntes en Neurologia¼ is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases.

TITLE: «Apuntes en Neurologia¼: una sintesis de la evidencia en trastornos neurologicos comunes paroxisticos y en trastornos neurodegenerativos.«Apuntes en Neurologia¼ es una iniciativa en la cual lideres de primera linea nacional e internacional, con amplio reconocimiento academico, se reunieron para sintetizar los aspectos clinicos mas destacables dentro de su area de interes y acercar las novedades en una lengua mas proxima. Entender los factores que afectan al inicio y progresion de cualquier enfermedad neurologica a traves de una revision es importante para el desarrollo de estrategias en pro de reducir la carga de estas enfermedades, y conocer los aspectos clinicos es esencial para poder resolver los problemas de la practica clinica diaria. Los datos aqui recogidos reflejan el peso de la evidencia y algunos de ellos anticipan un futuro prometedor en el tratamiento de estas enfermedades. Esta primera edicion se centra en trastornos neurologicos comunes paroxisticos como la migraña, la epilepsia y las alteraciones del sueño, y en trastornos neurodegenerativos como la enfermedad de Parkinson y el deterioro cognitivo. Se trata de patologias claramente diferentes, si bien algunas de ellas, como la migraña y la epilepsia, pueden compartir sintomatologia clinica. Los trastornos del sueño, por su parte, son manifestaciones importantes de enfermedades neurodegenerativas que, en ocasiones, son clinicamente evidentes mucho antes del inicio de otros sintomas neurologicos. Tras recordar la fisiopatologia y el diagnostico, la revision actual se centra en acercar los principales avances en cinco de las principales enfermedades neurologicas.

Retrospective study of perampanel efficacy and tolerability in myoclonic seizures.

OBJECTIVES: Perampanel is an antiepileptic drug (AED) approved for add-on treatment of focal seizures (with or without generalization) and primary generalized tonic-clonic (GTC) seizures. Our objective was to explore the effectiveness and tolerability of adjunctive perampanel in patients with drug-resistant myoclonic seizures, after failure of other AEDs. MATERIALS AND METHODS: Retrospective, multicenter, observational study. Data were collected from individual patient clinical files and analysed using appropriate descriptive statistics and inferential analyses. RESULTS: Data are reported for 31 patients with mean age 36.4 years, who had an average epilepsy duration of 18 years, previously taken an average of 5.03 AEDs, and were taking an average of 2.4 AEDs on perampanel initiation. Patients exhibited myoclonic, GTC, absence, tonic and focal seizures, and most had associated cognitive decline and/or ataxia. Median time on perampanel was 6 months, most common dose was 6 mg, and overall retention rate was 84%. The responder rate for myoclonic seizures was defined via reduction of days with myoclonic seizures per month. At 6 months, 15 (48.4%) of the 31 patients were classed as myoclonic seizure responders, 10 (32.3%) were myoclonic seizure free, and 39% saw improvements in functional ability. Of 17 patients with GTC seizures at baseline, 9 (53%) were responders at 6 months, and 8 (47.1%) were seizure free. The most frequent side effects were psychiatric disorders, instability, dizziness and irritability, and mostly resolved with dose reduction. Five patients discontinued perampanel due to side effects. CONCLUSIONS: Perampanel caused clinically meaningful improvements in patients with drug-resistant myoclonic seizures. It was generally well tolerated, but psychiatric and neurological side effects sometimes required follow-up and dose reduction.

Specificity of electroclinical features in the diagnosis of ring chromosome 20.

BACKGROUND: Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. METHODS: In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. RESULTS: We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. CONCLUSIONS: In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.

SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial.

BACKGROUND AND AIMS: Sodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes characterized by sodium retention leads to decreased tissue sodium content due to its pharmacological action. MATERIALS AND METHODS: In a prospective double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to either dapagliflozin 10 mg or placebo once daily for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analysed the sodium content in the skin and muscles of the lower leg by Na-MRI. RESULTS: Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11 mmHg, p = 0.010), and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024), 24-h ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline [24.1 ± 6.6 vs. 22.7 ± 6.4 A.U.(arbitrary unit) p = 0.013]. No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 A.U. p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline. CONCLUSION: SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in tissue sodium content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT02383238) retrospectively registered.

The Impact of Multimorbidity on Resting Metabolic Rate in Community-Dwelling Women over a Ten-Year Period: A Cross-Sectional and Longitudinal Study.

OBJECTIVES: Ageing has been associated with increasing multimorbidity. This study investigated whether the number of diseases is a predictor of resting metabolic rate (RMR) and its long-term changes in community-dwelling elderly women. SUBJECTS AND DESIGN: Cross-sectional and longitudinal data, obtained over ten years with repeated follow-ups, from 180 women aged 60 - 86 years and with a BMI of 18 - 43 kg/m2 at baseline were analyzed. MEASUREMENTS: RMR was measured using indirect calorimetry and body composition by bioelectrical impedance analysis. Diagnosed diseases were assessed by a questionnaire comprising 23 disease categories. Subjects with 0 - 2 diseases were classified as relatively healthy and with > 2 diseases as multimorbid. RESULTS: At baseline, relatively healthy (N = 75) and multimorbid (N = 105) women did not differ in RMR. During the ten-year follow-up, the median (range) number of diseases increased from 2 (0 - 2) to 4 (0 - 8) in relatively healthy and from 5 (3 - 11) to 7 (3 - 15) in multimorbid women. In the longitudinal analyses, only women who were multimorbid at baseline showed a significant increase in RMR of 31 kJ/d per additional disease (P = 0.015), adjusted for fat-free mass, fat mass, waist circumference and age. CONCLUSION: Increasing multimorbidity in community-dwelling women is associated with an increase in RMR independently of body composition and age.

In vivo observation of quadrupolar splitting in (39)K magnetic resonance spectroscopy of human muscle tissue.

The purpose of this work was to explore the origin of oscillations of the T(*)2 decay curve of (39)K observed in studies of (39)K magnetic resonance imaging of the human thigh. In addition to their magnetic dipole moment, spin-3/2 nuclei possess an electric quadrupole moment. Its interaction with non-vanishing electrical field gradients leads to oscillations in the free induction decay and to splitting of the resonance. All measurements were performed on a 7T whole-body MRI scanner (MAGNETOM 7T, Siemens AG, Erlangen, Germany) with customer-built coils. According to the theory of quadrupolar splitting, a model with three Lorentzian-shaped peaks is appropriate for (39)K NMR spectra of the thigh and calf. The frequency shifts of the satellites depend on the angle between the calf and the static magnetic field. When the leg is oriented parallel to the static magnetic field, the satellites are shifted by about 200 Hz. In the thigh, rank-2 double quantum coherences arising from anisotropic quadrupolar interaction are observed by double-quantum filtration with magic-angle excitation. In addition to the spectra, an image of the thigh with a nominal resolution of (16 × 16 × 32) mm(3) was acquired with this filtering technique in 1:17 h. From the line width of the resonances, (39)K transverse relaxation time constants T(*)2, fast = (0.51 ± 0.01) ms and T(*)2, slow = (6.21 ± 0.05) ms for the head were determined. In the thigh, the left and right satellite, both corresponding to the short component of the transverse relaxation time constant, take the following values: T(*)2, fast = (1.56 ± 0.03) ms and T(*)2, fast = (1.42 ± 0.03) ms. The centre line, which corresponds to the slow component, is T(*)2, slow = (9.67 ± 0.04) ms. The acquisition time of the spectra was approximately 10 min. Our results agree well with a non-vanishing electrical field gradient interacting with (39)K nuclei in the intracellular space of muscle tissue.