Redox Status in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy characterized by the progressive loss of vision. It is a rare disease. Despite being a genetic disease, its progression is influenced by oxidative damage and chemokines and cytokines released by the activated immune cells (e.g., macrophages or microglia). The role of oxidative stress is very important in the retina. Rods are the main consumers of oxygen (O2), so they are constantly exposed to oxidative stress and lipid peroxidation. According to the oxidative hypothesis, after rod death in the early stages of the disease, O2 would accumulate in large quantities in the retina, producing hyperoxia and favoring the accumulation of reactive oxygen species and reactive nitrogen species that would cause oxidative damage to lipids, proteins, and DNA, exacerbating the process of retinal degeneration. Evidence shows alterations in the antioxidant-oxidant state in patients and in animal models of RP. In recent years, therapeutic approaches aimed at reducing oxidative stress have emerged as useful therapies to slow down the progression of RP. We focus this review on oxidative stress and its relationship with the progression of RP.

Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder.

Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD.

Genetics, pathogenesis and therapeutic developments for Usher syndrome type 2.

Usher syndrome (USH) is a rare, autosomal recessively inherited disorder resulting in a combination of sensorineural hearing loss and a progressive loss of vision resulting from retinitis pigmentosa (RP), occasionally accompanied by an altered vestibular function. More and more evidence is building up indicating that also sleep deprivation, olfactory dysfunction, deficits in tactile perception and reduced sperm motility are part of the disease etiology. USH can be clinically classified into three different types, of which Usher syndrome type 2 (USH2) is the most prevalent. In this review, we, therefore, assess the genetic and clinical aspects, available models and therapeutic developments for USH2. Mutations in USH2A, ADGRV1 and WHRN have been described to be responsible for USH2, with USH2A being the most frequently mutated USH-associated gene, explaining 50% of all cases. The proteins encoded by the USH2 genes together function in a dynamic protein complex that, among others, is found at the photoreceptor periciliary membrane and at the base of the hair bundles of inner ear hair cells. To unravel the pathogenic mechanisms underlying USH2, patient-derived cellular models and animal models including mouse, zebrafish and drosophila, have been generated that all in part mimic the USH phenotype. Multiple cellular and genetic therapeutic approaches are currently under development for USH2, mainly focused on preserving or partially restoring the visual function of which one is already in the clinical phase. These developments are opening a new gate towards a possible treatment for USH2 patients.

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.

Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

GEDOS-SECOT consensus on the care process of patients with knee osteoarthritis and arthoplasty. / Consenso GEDOS-SECOT sobre el proceso de atención a pacientes con artrosis de rodilla e indicación de artroplastia.

OBJECTIVE: To develop recommendations on the evaluation and management procedure in patients undergoing total knee replacement based on best evidence and the experience of a panel of experts. METHODS: A multidisciplinary group of 12 experts was selected that defined the scope, users and the document parts. Three systematic reviews were performed in patients undergoing knee replacement: (i)efficacy and safety of fast-tracks; (ii)efficacy and safety of cognitive interventions in patients with catastrophic pain, and (iii) efficacy and safety of acute post-surgical pain management on post-surgical outcomes. A narrative review was conducted on the evaluation and management of pain sensitization, and about the efficacy and safety of pre-surgical physiotherapy. The experts generated the recommendations and explicative text. The level of agreement was evaluated in a multidisciplinary group of 85 experts with the Delphi technique. The level of evidence was established as well for each recommendation. RESULTS: A total of 20 recommendations were produced. An agreement higher than 80% was reached in all of them. We found the highest agreement on the need for a full discharge report, on providing proper information about the process and on following available guidelines. CONCLUSIONS: There is consensus among professionals involved in the management of patients undergoing total knee replacement, in that it is important to protocolize the replacement process, performing a proper, integrated and coordinated patient evaluation and follow-up, paying special attention to the surgical procedure and postoperative period.

Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. / Espectro mutacional de la distrofia muscular de Duchenne en España: estudio de 284 casos.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. METHODS: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. RESULTS: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. CONCLUSIONS: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials.

SECOT-GEDOS consensus on pre-surgical pain management in knee and hip arthrosis.

OBJECTIVE: To develop recommendations, based on best evidence and experience, on pain management in patients undertaking total knee or hip replacement. METHODS: Nominal group methodology was followed. A group of experts was selected (5 orthopedics, 1 anesthesiologist), who defined the scope, users, topics, preliminary recommendations, and 3 systematic reviews: efficacy and safety of pre-surgical analgesia regarding to post-surgical pain, efficacy and safety of pre-emptive analgesia and pre-operative factors of post-operative pain. The level of evidence and grade of recommendation was established using the Oxford Centre for Evidence Based Medicine, and the level of agreement with the Delphi technique (2 rounds). The Delphi was extended to 39 orthopedics and anesthesiologists. The whole document was reviewed by all the experts. RESULTS: A total of 21 recommendations were produced. They include specific pharmacological treatment, as well as the evaluation and monitoring of patients on this treatment, and post-operative pre-emptive treatment. Agreement above 70% was reached in 19 recommendations. CONCLUSIONS: In patients undergoing total knee or hip replacement, a proper evaluation, follow-up, pharmacological and non-pharmacological treatment of predictors of poor surgical outcomes should be performed, especially those related to pre-operative pain. This can improve post-operative pain and surgery outcomes.

Management and return of incidental genomic findings in clinical trials.

Whole-genome/exome sequencing used in clinical trials (CTs) to identify 'druggable' mutations and targets uncovers incidental findings unrelated to the trial objectives but of value for participants, although ethically challenging. To be disclosed to trial participants, the analytical validity, clinical validity, clinical utility, clinical relevance and actionability of incidental genomic findings (IGFs) must be established. Special considerations should be taken with minors to disclose only those findings related to early-onset conditions or diseases and in cases where early implementation of measures is necessary to prevent the occurrence of diseases. A plan for disclosing incidental findings that classifies the types that can be found, and who, when and how these findings will be disclosed to participants, should be included in the trial protocol to be approved by the relevant institutional review board. IGFs in CTs raise new ethical challenges that must be discussed by CT stakeholders, professional associations and patient advocates.

A prognostic model based on preoperative MRI predicts overall survival in patients with diffuse gliomas.

BACKGROUND AND PURPOSE: Diffuse gliomas are classified as grades II-IV on the basis of histologic features, with prognosis determined mainly by clinical factors and histologic grade supported by molecular markers. Our aim was to evaluate, in patients with diffuse gliomas, the relationship of relative CBV and ADC values to overall survival. In addition, we also propose a prognostic model based on preoperative MR imaging findings that predicts survival independent of histopathology. MATERIALS AND METHODS: We conducted a retrospective analysis of the preoperative diffusion and perfusion MR imaging in 126 histologically confirmed diffuse gliomas. Median relative CBV and ADC values were selected for quantitative analysis. Survival univariate analysis was made by constructing survival curves by using the Kaplan-Meier method and comparing subgroups by log-rank probability tests. A Cox regression model was made for multivariate analysis. RESULTS: The study included 126 diffuse gliomas (median follow-up of 14.5 months). ADC and relative CBV values had a significant influence on overall survival. Median overall survival for patients with ADC < 0.799 × 10(-3) mm(2)/s was <1 year. Multivariate analysis revealed that patient age, relative CBV, and ADC values were associated with survival independent of pathology. The preoperative model provides greater ability to predict survival than that obtained by histologic grade alone. CONCLUSIONS: ADC values had a better correlation with overall survival than relative CBV values. A preoperative prognostic model based on patient age, relative CBV, and ADC values predicted overall survival of patients with diffuse gliomas independent of pathology. This preoperative model provides a more accurate predictor of survival than histologic grade alone.

Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling.

Tratamiento anestésico del neonato con atresia de esófago asociada a fístula traqueoesofágica y ano imperforado / Anesthetic management of a neonate with esophageal atresia, tracheoesophageal fistula and imperforate anus

La atresia de esófago es una malformación infrecuente (1:2.500-4.500 recién nacidos vivos), incompatible con la vida y una urgencia quirúrgica neonatal. El 30% de los pacientes son prematuros o presentan bajo peso al nacer y el 50% presentan anomalías asociadas, principalmente cardíacas. Las cardiopatías congénitas de orden mayor o el bajo peso al nacer son predictores independientes de mortalidad y eventos críticos perioperatorios. Presentamos el caso de un paciente intervenido de urgencia de atresia de esófago, fístula traqueoesofágica tipo iii b/C e imperforación anal. El objetivo de este artículo es la exposición de las consideraciones anestésicas en pacientes con esta afección, cuyo complejo manejo perioperatorio supone un importante reto y debe realizarse por equipos multidisciplinares con experiencia en neonatología. Establecer una vía aérea segura y obtener una ventilación pulmonar efectiva que minimice la fuga de aire al tracto digestivo debe ser uno de los objetivos prioritarios del manejo anestésico (AU)

Esophageal atresia is a rare condition (1:2,500-4,500), incompatible with life, and a surgical emergency in the neonatal period. It is associated with prematurity in 30% of cases, and to congenital abnormalities in 50% of cases, especially cardiac anomalies. Major congenital heart diseases and low weight are independent predictors of mortality and critical perioperative events. The aim of this article is to describe the most significant anaesthetic challenges presented in a case of a term neonate undergoing emergency surgery after being diagnosed with esophageal atresia, tracheoesophageal fistula type iiib/C, and imperforate anus. The major priorities during the anaesthetic management consist of establishing a safe airway and effective pulmonary ventilation that minimises air leakage to the upper digestive tract (AU)

Guidelines for genetic study of aniridia.

INTRODUCTION: Aniridia is a panocular disorder which occurs in 1/50,000 to 1/100,000 live births and can appear either in isolated form or in the context of a syndrome. Isolated aniridia is inherited as an autosomal dominant condition and is caused by mutations of the PAX6 gene. A variety of techniques and methodologies within molecular genetics and cytogenetics are used to study these mutations. OBJECTIVE: To identify the different aspects of this disease and to provide a guide for proper genetic diagnosis leading to improved clinical management of the disease. DEVELOPMENT: Aniridia is an autosomal dominant disease that primarily affects the iris, though it can impact most of the ocular structures. The disease is mainly caused by mutations in the PAX6 gene located on chromosome 11p13 which encodes a transcription factor that is involved in the development of the eye. Genetic analysis of aniridia is complex and requires the use of both molecular genetics and cytogenetics techniques. These procedures are indicated in all cases of aniridia. It is important bear certain clinical and technical aspects in mind prior to starting analysis or providing genetic counseling for patients and their families. CONCLUSIONS: The use of molecular genetic techniques in the genetic diagnosis of aniridia enables patients and their families to receive better clinical management.

Guía para el estudio genético de la aniridia / Guidelines for genetic study of aniridia

Introducción: La aniridia es una enfermedad panocular con una incidencia de entre 1/50.000 a 1/100.000 nacidos vivos, que puede presentarse de forma aislada o en el contexto de un síndrome. Presenta una herencia autosómica dominante y en la mayoría de los casos está causada por mutaciones en el gen PAX6, para cuyo estudio de mutaciones se emplea una gran variedad de técnicas y metodologías de genética molecular y citogenéticas. Objetivo: Recoger los distintos aspectos de esta enfermedad y ofrecer una guía para el adecuado diagnóstico genético que ayude a un mejor manejo clínico de la misma. Desarrollo: La aniridia es una enfermedad autosómica dominante que afecta fundamentalmente al iris, pero también puede afectar a la mayoría de las estructuras oculares. Está causada principalmente por mutaciones en el gen PAX6, ubicado en la región cromosómica 11p13, que codifica para una proteína reguladora de la transcripción imprescindible en el desarrollo del ojo. El análisis genético de la aniridia es complejo y requiere tanto de técnicas de genética molecular (secuenciación, CGH-array o MLPA) como citogenéticas (cariotipo y FISH). Este estudio está indicado en todos los casos de aniridia y es importante tener en cuenta ciertas consideraciones tanto clínicas como técnicas antes de abordar su análisis y el asesoramiento genético de los pacientes y familias afectados por esta enfermedad. Conclusiones: La aplicación de técnicas de genética molecular al diagnóstico genético de la aniridia permite un mejor manejo clínico tanto de los afectados como de sus familiares(AU)

Introduction: Aniridia is a panocular disorder which occurs in 1/50,000 to 1/100,000 live births and can appear either in isolated form or in the context of a syndrome. Isolated aniridia is inherited as an autosomal dominant condition and is caused by mutations of the PAX6 gene. A variety of techniques and methodologies within molecular genetics and cytogenetics are used to study these mutations. Objective: To identify the different aspects of this disease and to provide a guide for proper genetic diagnosis leading to improved clinical management of the disease. Development: Aniridia is an autosomal dominant disease that primarily affects the iris, though it can impact most of the ocular structures. The disease is mainly caused by mutations in the PAX6 gene located on chromosome 11p13 which encodes a transcription factor that is involved in the development of the eye. Genetic analysis of aniridia is complex and requires the use of both molecular genetics and cytogenetics techniques. These procedures are indicated in all cases of aniridia. It is important bear certain clinical and technical aspects in mind prior to starting analysis or providing genetic counseling for patients and their families. Conclusions: The use of molecular genetic techniques in the genetic diagnosis of aniridia enables patients and their families to receive better clinical management(AU)

Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.

[Anesthetic management of a neonate with esophageal atresia, tracheoesophageal fistula and imperforate anus]. / Tratamiento anestésico del neonato con atresia de esófago asociada a fístula traqueoesofágica y ano imperforado.

Esophageal atresia is a rare condition (1:2,500-4,500), incompatible with life, and a surgical emergency in the neonatal period. It is associated with prematurity in 30% of cases, and to congenital abnormalities in 50% of cases, especially cardiac anomalies. Major congenital heart diseases and low weight are independent predictors of mortality and critical perioperative events. The aim of this article is to describe the most significant anaesthetic challenges presented in a case of a term neonate undergoing emergency surgery after being diagnosed with esophageal atresia, tracheoesophageal fistula type iiib/C, and imperforate anus. The major priorities during the anaesthetic management consist of establishing a safe airway and effective pulmonary ventilation that minimises air leakage to the upper digestive tract.

Severe traumatic head injury: prognostic value of brain stem injuries detected at MRI.

BACKGROUND AND PURPOSE: Traumatic brain injuries represent an important cause of death for young people. The main objectives of this work are to correlate brain stem injuries detected at MR imaging with outcome at 6 months in patients with severe TBI, and to determine which MR imaging findings could be related to a worse prognosis. MATERIALS AND METHODS: One hundred and eight patients with severe TBI were studied by MR imaging in the first 30 days after trauma. Brain stem injury was categorized as anterior or posterior, hemorrhagic or nonhemorrhagic, and unilateral or bilateral. Outcome measures were GOSE and Barthel Index 6 months postinjury. The relationship between MR imaging findings of brain stem injuries, outcome, and disability was explored by univariate analysis. Prognostic capability of MR imaging findings was also explored by calculation of sensitivity, specificity, and area under the ROC curve for poor and good outcome. RESULTS: Brain stem lesions were detected in 51 patients, of whom 66% showed a poor outcome, as expressed by the GOSE scale. Bilateral involvement was strongly associated with poor outcome (P < .05). Posterior location showed the best discriminatory capability in terms of outcome (OR 6.8, P < .05) and disability (OR 4.8, P < .01). The addition of nonhemorrhagic and anterior lesions or unilateral injuries showed the highest odds and best discriminatory capacity for good outcome. CONCLUSIONS: The prognosis worsens in direct relationship to the extent of traumatic injury. Posterior and bilateral brain stem injuries detected at MR imaging are poor prognostic signs. Nonhemorrhagic injuries showed the highest positive predictive value for good outcome.

Acute perfusion changes after spontaneous SAH: a perfusion CT study.

BACKGROUND: Perfusion computed tomography (CT) is a rapid technique that allows the measurement of acute disturbances in local and global cerebral blood flow in patients suffering stroke and spontaneous subarachnoid haemorrhage (SAH). The purpose of this study was to establish the relationship between different measures of brain perfusion made on dynamic-contrast CT reconstructions performed as soon as SAH has been diagnosed and the severity of the bleeding determined by the clinical grade, the extent of the bleeding and the outcome of the patients. METHODS: After the diagnosis of SAH by conventional CT, a perfusion CT was performed before CT angiography. All imaging studies were performed on a six-slice spiral CT scanner. All images were analysed using perfusion software developed by Philips, which produces perfusion CT quantitative data based on temporal changes in signal intensity during the first pass of a bolus of an iodinated contrast agent. Measurements of mean transient time (MTT), time to peak (TTP), cerebral blood volume (CBV) and cerebral blood flow (CBF) in volumes of interest corresponding to territories perfused by the major cerebral arteries were performed. Different data regarding severity of the bleeding-such as level of consciousness, amount of bleeding in conventional CT-were collected. All poor-grade patients received a ventriculostomy catheter so that ICP recordings were obtained. Also, the occurrence of delayed cerebral ischaemia (DCI) was recorded. Outcome was assessed by the Glasgow Outcome Scale 6 months after the bleeding. For statistical analysis, non-parametric correlations between variables were performed. FINDINGS: Thirty-nine patients have been included in the study since January 2007. In SAH patients there are increasing perfusion abnormalities as the severity of the bleeding increases. The most affected perfusion parameters are TTP and MTT, as they significantly increase with the clinical severity of the bleeding and the total volume of bleeding (P < 0.01, Spearman's Rho). When average MTT time is increased over 5.9 s there is a 20-fold (95% CI = 2.1-182) risk of poor outcome. All patients presenting this MTT time suffered from DCI. This value has a positive predictive value of 100% for DCI and 90% for a poor outcome. CONCLUSIONS: SAH causes cerebral blood flow abnormalities even in the acute phase of the illness, consisting mainly of an increase in circulation times (TTP and MTT), which are correlated with the severity of the bleeding.