Study protocol for investigating the clinical performance of an automated blood test for glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 blood concentrations in elderly patients with mild traumatic BRAIN Injury and reference values (BRAINI-2 Elderly European study): a prospective multicentre observational study.

INTRODUCTION: Two blood brain-derived biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), can rule out intracranial lesions in patients with mild traumatic brain injury (mTBI) when assessed within the first 12 hours. Most elderly patients were excluded from previous studies due to comorbidities. Biomarker use in elderly population could be affected by increased basal levels. This study will assess the performance of an automated test for measuring serum GFAP and UCH-L1 in elderly patients to predict the absence of intracranial lesions on head CT scans after mTBI, and determine both biomarkers reference values in a non-TBI elderly population. METHODS AND ANALYSIS: This is a prospective multicentre observational study on elderly patients (≥65 years) that will be performed in Spain, France and Germany. Two patient groups will be included in two independent substudies. (1) A cohort of 2370 elderly patients (1185<80 years and 1185≥80 years; BRAINI2-ELDERLY DIAGNOSTIC AND PROGNOSTIC STUDY) with mTBI and a brain CT scan that will undergo blood sampling within 12 hours after mTBI. The primary outcome measure is the diagnostic performance of GFAP and UCH-L1 measured using an automated assay for discriminating between patients with positive and negative findings on brain CT scans. Secondary outcome measures include the performance of both biomarkers in predicting early (1 week) and midterm (3 months) neurological status and quality of life after trauma. (2) A cohort of 480 elderly reference participants (BRAINI2-ELDERLY REFERENCE STUDY) in whom reference values for GFAP and UCHL1 will be determined. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Review Boards of Hospital 12 de Octubre in Spain (Re#22/027) and Southeast VI (Clermont Ferrand Hospital) (Re# 22.01782.000095) in France. The study's results will be presented at scientific meetings and published in peer-review publications. TRIAL REGISTRATION NUMBER: NCT05425251.

KidsBrainIT: A New Multi-centre, Multi-disciplinary, Multi-national Paediatric Brain Monitoring Collaboration.

OBJECTIVES: Validated optimal cerebral perfusion pressure (CPP) treatment thresholds in children do not exist. To improve the intensive care unit (ICU) management of the paediatric traumatic brain injury (TBI) population, we are forming a new paediatric multi-centre collaboration to recruit standardised ICU data for running and reporting upon models for assessing autoregulation and optimal CCP (CPPopt). MATERIALS AND METHODS: We are adapting the adult BrainIT group's approach to develop a new Paediatric Brain Monitoring and Information Technology Group (KidsBrainIT), which will include a repository to store prospectively collected high-resolution physiological, clinical, and outcome data. In the first phase of this project there are 7 UK Paediatric Intensive Care Units, 1 Spanish, 1 Belgium, and 1 Romanian Centre interested in participating. In subsequent phases, we plan to open recruitment to other centres both within Europe, US and abroad. We are collaborating with the Leuven Group and plan to use their LAx (low-frequency autoregulation index), DATACAR (dynamic adaptive target of active cerebral autoregulation), CPPopt and visualisation methodologies. We also plan to use the continuous diffuse optical monitoring and tomography technology developed in Barcelona as an acute surrogate end-point for optimising brain perfusion. This technology allows non-invasive continuous monitoring of deep tissue perfusion and oxygenation in adults but its clinical application in infants and children with TBI has not been studied previously. RESULTS: We report on the current status of setting up this new collaboration and also on pilot analyses in two centres which are the basis of our rationale for the need for a prospective validation study of CPPopt in children. Specifically, we demonstrated that CPPopt varied with time for each patient during their paediatric intensive care unit (PICU) stay, and the median overall CPPopt levels for children aged 2-6 years, 7-11 years and 12-16 years were 68.83, 68.09, and 72.17 mmHg respectively. Among survivors and patients with favourable outcome (GOS 4 and 5), there were significantly higher proportions with CPP monitoring time within CPPopt (p = 0.04 and p = 0.01 respectively). CONCLUSIONS: There is a need and an interest in forming a multi-centre PICU collaboration for acquiring data and performing analyses for determining validated CPPopt thresholds in the paediatric TBI population. KidsBrainIT is being formed to meet that need.

Neuropsychological alterations and neuroradiological findings in patients with post-traumatic concussion: Results of a pilot study. / Alteraciones neuropsicológicas y hallazgos neurorradiológicos en pacientes con conmoción cerebral postraumática. Resultados de un estudio piloto.

INTRODUCTION: Mild traumatic brain injury (mTBI) has traditionally been considered to cause no significant brain damage since symptoms spontaneously remit after a few days. However, this idea is facing increasing scrutiny. The purpose of this study is to demonstrate the presence of early cognitive alterations in a series of patients with mTBI and to link these findings to different markers of brain damage. METHODS: We conducted a prospective study of a consecutive series of patients with mTBI who were evaluated over a 12-month period. Forty-one (3.7%) of the 1144 included patients had experienced a concussion. Patients underwent a routine clinical evaluation and a brain computed tomography (CT) scan, and were also administered a standardised test for post-concussion symptoms within the first 24hours of mTBI and also 1 to 2 weeks later. The second assessment also included a neuropsychological test battery. The results of these studies were compared to those of a control group of 28 healthy volunteers with similar characteristics. Twenty patients underwent an MRI scan. RESULTS: Verbal memory and learning were the cognitive functions most affected by mTBI. Seven out of the 20 patients with normal CT findings displayed structural alterations on MR images, which were compatible with diffuse axonal injury in 2 cases. CONCLUSIONS: Results from this pilot study suggest that early cognitive alterations and structural brain lesions affect a considerable percentage of patients with post-concussion syndrome following mTBI.

Predictive model of mortality in patients with spontaneous bacterial peritonitis.

BACKGROUND: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function. AIM: To determine the independent predictive factors of in-hospital mortality and to create and validate a predictive model of mortality in patients with SBP. METHODS: We analysed all cirrhotic patients with high-risk SBP (serum urea ≥11 mmol/L and/or serum bilirubin ≥68 µmol/L) between 2001 and 2011. We developed a predictive model of in-hospital mortality and validated this in a different cohort. RESULTS: We included 118 high-risk SBP episodes treated with antibiotics and albumin. In-hospital mortality was 33/118 (28%). The independent predictive factors of in-hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777-0.922. A cut-off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in-hospital mortality was 28/49 (57.1%) in patients with a model value ≥0.245, and 5/69 (7.2%) in patients with a model value <0.245 (P < 0.001). The validation series included 161 patients with an in-hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value ≥0.245, and 10/84 (11.9%) in those with a model value <0.245 (P < 0.001). CONCLUSIONS: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure in high-risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies.

Brainstem auditory and somatosensory evoked potentials: a methodological study to evaluate the reproducibility of two devices.

We aimed to determine whether statistical significant differences exist between the sets of results obtained from two devices used in our department for measuring brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials (SEPs). We obtained BAEP and median and posterior tibial nerve SEP values bilaterally in ten healthy subjects. The tests were performed on the same subject using two devices consecutively. The equipment consisted of a Nicolet Viking-IV (Nicolet, Madison, WI, USA) and a Viking Select (Viasys Healthcare, Madison, WI, USA), and the same recording electrodes and stimulator (auditory and electrical) were used without modifying any postural position of the subject. The stimuli and recording parameters were the same for both devices. We obtained 20 sets of data for each type of test. The Bland­Altman plots as well as the one-sample t-test or Wilcoxon signed rank test were used to compare data between the two groups of data sets. We found no significant differences between the sets of values obtained with the two devices. Our analysis indicates that the two devices are equal in recording all different variables of BAEP and SEP, which allows us to combine the BAEP and SEP data obtained from the two devices for follow-up studies involving quantitative statistical methods. This study received institutional approval (protocol number PRAG-154/2013).

[Cortical spreading depolarization phenomena in patients with traumatic and ischemic brain injuries. Results of a pilot study]. / Fenómenos de despolarización cortical propagada en los pacientes con lesiones cerebrales traumáticas e isquémicas. Resultados de un estudio piloto.

OBJECTIVES: To determine the frequency and duration of cortical spreading depolarization (CSD) and CSD-like episodes in patients with traumatic brain injury (TBI) and malignant middle cerebral artery infarction (MMCAI) requiring craniotomy. DESIGN: A descriptive observational study was carried out during 19 months. SETTING: Neurocritical patients. PATIENTS: Sixteen patients were included: 9 with MMCAI and 7 with moderate or severe TBI, requiring surgical treatment. INTERVENTIONS: A 6-electrode subdural electrocorticographic (ECoG) strip was placed onto the perilesional cortex. MAIN VARIABLES OF INTEREST: An analysis was made of the time profile and the number and duration of CSD and CSD-like episodes recorded from the ECoGs. RESULTS: Of the 16 patients enrolled, 9 presented episodes of CSD or CSD-like phenomena, of highly variable frequency and duration. CONCLUSIONS: Episodes of CSD and CSD-like phenomena are frequently detected in the ischemic penumbra and/or traumatic cortical regions of patients with MMCAI who require decompressive craniectomy or of patients with contusional TBI.

Sleep disturbance: a forgotten syndrome in patients with Chiari I malformation.

INTRODUCTION: Chiari type I malformation (CM-I) is characterised by caudal ectopia of the cerebellar tonsils through the foramen magnum. This is associated with brain stem, high spinal cord, and cranial nerve compression phenomena. The most frequent symptoms are occipital headaches and dizziness. Less well-known symptoms are sleep disorders and nocturnal respiratory abnormalities. SOURCES: MEDLINE and information from patients evaluated at the Neurosurgery and Clinical Neurophysiology Departments at Hospital Universitario Vall d'Hebron. DEVELOPMENT: Review article based on data obtained from MEDLINE articles since 1966, using combinations of the following keywords: «Chiari malformation¼ or «Arnold-Chiari malformation¼ and «sleep apnea¼ or «sleep disorders¼. CONCLUSIONS: CM-I patients show a higher prevalence of sleep disorders than that observed in the general population. Some studies report a 50% prevalence of sleep apnea-hypopnea syndrome (SAHS), probably associated with sudden death in some cases. These results support analysing sleep respiratory parameters in theses patients. Identifying SAHS symptoms may help optimise treatment, thereby improving quality of life and prognosis.

Late-onset achalasia after esophageal atresia repair.

The development of achalasia in a patient with a history of esophageal atresia (EA) is rare. Here, we report a patient who had undergone surgery for EA at birth and presented achalasia at 30 years of age. He was successfully treated with laparoscopic surgery.

Infrared pupillometry. Basic principles and their application in the non-invasive monitoring of neurocritical patients.

INTRODUCTION: Pupil assessment is a fundamental part of the neurological examination. Size and reactivity to light of each pupil should be recorded periodically since changes in these parameters may represent the only detectable sign of neurological deterioration in some patients. However, there is great intraobserver and interobserver variability in pupil examination due to the influence of many factors, such as the difference in ambient lighting, the visual acuity and experience of the examiner, the intensity of the luminous stimulus, and the method used to direct this stimulus. In recent years, digital cameras have incorporated infrared devices allowing the development of user-friendly portable devices that permit repeated, non-invasive examinations of pupil size and its reactivity to light with an objective, accessible and inexpensive method. DEVELOPMENT: The purpose of this review is to describe the fundamentals of infrared pupillometry and discuss potential applications in the monitoring of neurocritical patients. We also present some recommendations in the routine assessment of pupils in neurocritical patients. CONCLUSIONS: The possibility of evaluating the changes in pupil reactivity in an early, objective and almost continuous way provides a new non-invasive monitoring method. This method could improve the predictive factor of neurological deterioration and the bedside monitoring of the neurological state of the patient, avoiding unnecessary examinations and enabling early therapeutic intervention.

Proteomic analysis of cerebrospinal fluid from obese women with idiopathic intracranial hypertension: a new approach for identifying new candidates in the pathogenesis of obesity.

Body weight control is tightly regulated in the hypothalamus. The inaccessibility of human brain tissue can be partially solved by using cerebrospinal fluid (CSF) as a tool for assessing the central nervous system's production of orexigen and anorexigen factors. Using proteomic analysis, the present study investigated the differentially displayed proteins in human CSF from obese and non-obese subjects. We designed a case-control study conducted in a reference hospital where eight obese (cases) and eight non-obese (controls) women with idiopathic intracranial hypertension were included. Intracranial hypertension was normalised through the placement of a ventriculo- or lumboperitoneal shunt in the 12 months before their inclusion in the study. Isotope-coded protein label (for proteins > 10 kDa) and label-free liquid chromatography (for proteins < 10 kDa) associated with mass spectrometry analysis were used. Eighteen differentially expressed proteins were identified. Many of them fall into three main groups: inflammation (osteopontin, fibrinogen γ and ß chain, α1 acid glycoprotein 2 and haptoglobin), neuroendocrine mediators (neurosecretory protein VGF, neuroendocrine protein 7B2, chromogranin-A and chromogranin B), and brain plasticity (testican-1, isoform 10 of fibronectin, galectin-3 binding protein and metalloproteinase inhibitor type 2). The differential production of osteopontin, neurosecretory protein VGF, chromogranin-A and fibrinogen γ chain was further confirmed by either enzyme-linked immunosorbent assay or western blotting. In conclusion, we have identified potential candidates that could be involved in the pathogenesis of obesity. Further studies aiming to investigating the precise role of these proteins in the pathogenesis of obesity and their potential therapeutic implications are needed.

TGF-ß Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.

Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-ß inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-ß inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-ß pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

[Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients]. / ¿Es el lactato un buen indicador de hipoxia tisular? Resultados de un estudio piloto en 21 pacientes con un traumatismo craneoencefálico.

UNLABELLED: Lactate and the lactate-pyruvate index (LPI) are two hypoxia markers widely used to detect brain tissue hypoxia in patients with acute traumatic brain injury. These two markers have a more complex behavior than expected as they can be abnormally high in circumstances with no detectable brain hypoxia. This condition must be considered in the differential diagnosis because it also reflects an alteration of brain energy metabolism. OBJECTIVES: 1. To describe cerebral energy metabolism characteristics observed in the acute phase of traumatic brain injury (TBI) based on two traditional indicators of anaerobic metabolism: lactate and LPI, 2. To determine the concordance between these two biomarkers in order to classify the incidence of anaerobic metabolism and 3. To classify the different types of metabolic abnormalities found in patients with moderate and severe TBI using both lactate and LPI. MATERIALS AND METHODS: Twenty-one patients were randomly selected from a cohort of moderate or severe TBI patients admitted to the neurotraumatology intensive care unit. All of them who underwent both cerebral microdialysis and brain tissue oxygen monitoring (PtiO(2)). We analyzed the levels of lactate and the LPI for every microvial within the first 96 hours after head trauma. These data were correlated with PtiO(2) values. RESULTS: Lactate levels and the LPI were respectively increased during 49.5% and 38.4% of the monitoring time. The incidence and behavior of high levels of both markers were extremely heterogeneous. The concordance between these two biomarkers to determine episodes of dysfunctional metabolism was very weak (Kappa Index=0.29; IC 95%: 0.24-0.34). Based on the levels of lactate and the LPI, we defined four metabolic patterns: I: L>2.5 mmol/L and LPR>25; II: L>2.5 mmol/L and LPR< or = 25; III: L< or = 2.5 mmol/L and LPR< or = 25; IV: L< or = 2.5 mmol/L and LPR>25). In more than 80% of cases in which lactate or LPI were increased, PtiO(2) values were within the normal range (PtiO(2)> 15 mmHg). CONCLUSIONS: Increased lactate and LPI were frequent findings after acute TBI and in most cases they were not related to episodes of brain tissue hypoxia. Furthermore, the concordance between both biomarkers to classify metabolic dysfunction was weak. LPI and lactate should not be used indistinctly in everyday clinical practice because of the weak correlation between these two markers, the difficulty in their interpretation and the heterogeneous and complex nature of the pathophysiology. Other differential diagnoses apart from tissue hypoxia should always be considered when high lactate and/or LPI are detected in the acute injured brain.

[Matrix metaloproteinases in neurological brain lesions: a new therapeutic target?]. / Metaloproteinasas de matriz en las lesiones neurológicas: ¿una nueva diana terapéutica?

INTRODUCTION: Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP. AIM: To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target. DEVELOPMENT: A bibliographic search was performed on Medline database. CONCLUSIONS: Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets.

Metaloproteinasas de matriz en las lesiones neurológicas: ¿una nueva diana terapéutica? / Matrix metaloproteinases in neurological brain lesions: a new therapeutic target?

Introducción. Las metaloproteinasas de matriz (MMP) constituyen una familia de enzimas proteolíticas presentes en la mayoría de tejidos humanos y responsables de degradar la matriz extracelular. Sus principales funciones son mantener la integridad de la matriz extracelular, modular la interacción entre células durante el desarrollo, la remodelación tisular, participar directamente en la angiogénesis y facilitar la migración celular. Dada la importancia de su función en el mantenimiento de la matriz extracelular, su expresión está estrechamente regulada a nivel transcripcional, mediante la activación de la proforma y a partir de inhibidores tisulares. Sin embargo, la regulación de estas proteasas puede alterarse, produciendo una sobreexpresión que puede llegar a alterar e incluso destruir la estructura tisular, como se ha observado en patologías neurológicas como la esclerosis múltiple, la formación de aneurismas y la isquemia cerebral. El papel que las MMP desempeñan en la fisiopatología de las lesiones neurotraumáticas es poco conocido y procede fundamentalmente de estudios experimentales in vitro e in vivo, y de sólo tres estudios en humanos. Algunos estudios experimentales relacionan las alteraciones encefálicas producidas tras la lesión traumática con incrementos de las concentraciones de diversas MMP. Objetivo. Revisar el papel de dichas proteasas en las lesiones cerebrales, incidiendo en la relación de estas proteínas con el traumatismo craneoencefálico y su posible aplicación terapéutica. Desarrollo. Se realizó una búsqueda bibliográfica en la base de datos Medline. Conclusiones. Ciertas MMP podrían relacionarse con la alteración de la barrera hematoencefálica y la formación del edema postraumático, siendo su inhibición una prometedora diana terapéutica (AU)

Introduction. Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP. Aim. To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target. Development. A bibliographic search was performed on Medline database. Conclusions. Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets (AU)

[Cognitive event-related brain potentials (P300) in patients with normal pressure hydrocephalus. Results of a prospective study]. / Potenciales evocados cognitivos (P300) en pacientes con hidrocefalia de presión normal.

OBJECTIVE: To determine the response to cognitive event-related potentials (P300) in patients with normal-pressure hydrocephalus (NPH) and their relationship with clinical and cognitive status before and after shunt surgery. METHODS: We performed a prospective study in a series of 26 patients with NPH who underwent clinical and cognitive assessment before surgery and 6 months afterwards. Visual P300 potentials obtained before and after treatment were also compared with those obtained in 18 healthy volunteers. RESULTS: Before shunting, the P300 wave was detected in 11 (42.3%) NPH patients, compared with the 18 (100%) volunteers. Six months after shunting, the P300 wave was found in 20 (76.9%) NPH patients. P300 latency was significantly longer in NPH patients than in the control group before surgery, but not at 6 months after surgery. No significant differences in neuropsychological studies or in the level of dependence for daily life activities were found between the subgroups of NPH patients with and without pre-surgical P300 waves, or between changes in P300 parameters and clinical and cognitive changes. CONCLUSIONS: The P300 wave was delayed or undetectable in a substantial percentage of patients with NPH before surgery. These alterations can be reversed by shunting. P300 analysis and neuropsychological tests could be complementary measures to evaluate functional status in patients with NPH.

Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients.

BACKGROUND: Toll-like receptor (TLR) 4 genetic polymorphisms, mainly D299G, have been associated with increased predisposition to infection in several populations. AIM: To retrospectively analyse the relationship between the presence of the TLR4 D299G polymorphism and the incidence of bacterial infections in cirrhotic patients. METHODS: We included 111 consecutive cirrhotic patients hospitalized with ascites and we determined the presence of the TLR4 D299G polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and its relationship with the incidence of previous bacterial infections. RESULTS: Ten out of 111 (9%) cirrhotic patients presented with the TLR4 D299G polymorphism. The mean follow-up from first decompensation of cirrhosis until current admission was longer in D299G polymorphism patients than in wild-type patients (53.8 +/- 40.7 vs. 35.4 +/- 48.3 months, P = 0.03). D299G polymorphism patients showed a trend towards a higher incidence of history of previous infections (80% vs. 56.4%, P = 0.19), as well as a higher number of infections (2.8 +/- 2.3 vs. 1.0 +/- 1.3, P = 0.01) and bacteriaemias (0.4 +/- 1.0 vs. 0.04 +/- 0.2, P = 0.02) per patient than wild-type patients. CONCLUSIONS: Toll-like receptor 4 D299G polymorphism could influence not only the predisposition to bacterial infections but also the evolution of the disease in cirrhotic patients. Further prospective studies in larger series of patients are warranted.

[High-resolution microdialysis. methodological issues and application to the study of inflammatory brain response]. / Microdiálisis de alta resolución. Aspectos metodológicos y aplicación al estudio de larespuesta inflamatoria cerebral.

Cerebral microdialysis is a tool that provides very relevant information in the metabolic monitoring of brain injured patients. It is a particularly effective technique for the detection and analysis of small molecules, given that the pores of the dialysis membrane act as a barrier to restrict the transport of larger species, such as proteins and other macromolecules. The recent availability of microdialysis catheters with membrane pores of larger size, termed "high resolution" catheters, would widen the spectrum of molecules detectable in the dialisate. However, there are technical complications related to the use of these catheters for such purposes, and therefore, this potential capacity for the recovery of proteins needs to be validated, in order to begin its application as a tool in studies of proteomics associated with brain injuries. The following review depicts the basic principles of microdialysis, and describes some of the issues involved in the recovery of molecules in the dialisate, including the physical properties of the dialysis membrane and of the molecules of interest.

TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.

[Cognitive impairment in normal pressure hydrocephalus (NPH). A proposal for clinical evaluation protocol]. / Alteraciones cognitivas en pacientes con hidrocefalia crónica del adulto ("normotensiva"). Propuesta de un protocolo para su evaluación clínica.

Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, urinary incontinence and dementia, and is associated with variable ventricular enlargement. The most accepted treatment of NPH is the placement of a cerebrospinal fluid shunt. Owing to the characteristics of the patients and the invasive nature of the surgical treatment, it is fundamental to detect those patients who could obtain a greater benefit from the treatment. Neuropsychological assessment of these patients could significantly contribute to a better diagnosis of NPH, determining a cognitive deterioration profile for these patients, allowing the assessment of treatment efficacy and helping to detect other additional causes of dementia. The aim of this study is to describe the cognitive deterioration profile of NPH patients and to present the clinical, functional and neuropsychological assessment protocol used in our hospital.