Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations

Previously considered passive support cells, mural cells—pericytes and vascular smooth muscle cells—have started to garner more attention in disease research, as more subclassifications, based on morphology, gene expression, and function, have been discovered. Central nervous system (CNS) arteriovenous malformations (AVMs) represent a neurovascular disorder in which mural cells have been shown to be affected, both in animal models and in human patients. To study consequences to mural cells in the context of AVMs, various animal models have been developed to mimic and predict human AVM pathologies. A key takeaway from recently published work is that AVMs and mural cells are heterogeneous in their molecular, cellular, and functional characteristics. In this review, we summarize the observed perturbations to mural cells in human CNS AVM samples and CNS AVM animal models, and we discuss various potential mechanisms relating mural cell pathologies to AVMs

Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations.

Previously considered passive support cells, mural cells-pericytes and vascular smooth muscle cells-have started to garner more attention in disease research, as more subclassifications, based on morphology, gene expression, and function, have been discovered. Central nervous system (CNS) arteriovenous malformations (AVMs) represent a neurovascular disorder in which mural cells have been shown to be affected, both in animal models and in human patients. To study consequences to mural cells in the context of AVMs, various animal models have been developed to mimic and predict human AVM pathologies. A key takeaway from recently published work is that AVMs and mural cells are heterogeneous in their molecular, cellular, and functional characteristics. In this review, we summarize the observed perturbations to mural cells in human CNS AVM samples and CNS AVM animal models, and we discuss various potential mechanisms relating mural cell pathologies to AVMs.This work was supported by the Ohio University Neuroscience Program Confocal Graduate Assistantship and College of Arts and Sciences Graduate Student Research Fund grant to SN; ISCIII and FEDER European institutions through Fondo de Investigación en Salud (FIS) project PI21/ 01844 to AL; NIH R15 NS111376 to CN; and 2020-T1/BMD19985 mod.1 grant funded by “Atracción de Talento Investigador” call from Comunidad de Madrid to HC The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX 2020-001041-S funded by MICIN/AEI/10.13039/501100011033).S

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

Computed tomography; Neurosurgery; Trauma managementTomografia computaritzada; Neurocirurgia; Gestió del traumaTomografía computarizada; Neurocirugía; Gestión del traumaIntroduction 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.This study was supported by a grant from the European Institute of Innovation and Technology (EIT) Health (BP 2022–2024). EIT Health is supported by EIT, a body of the European Union. BioMérieux is responsible for the development and manufacturing of the VIDAS GFAP and VIDAS UCH-L1 assays. BioMérieux will provide in-kind support to this study by supplying the assays for measuring UCH–L1 and GFAP necessary for this study

Effectiveness of flossing loops in the control of the gingival health

One of the key factor in the good condition of periodontal tissues is their daily hygiene. Oral hygiene techniques such brushing and a good interdental hygiene by correct flossing are very important. The aim of this study is to compare the use of dental floss in a loop vs traditional floss in the control of Loe-Silness Gingival Index (IG), Turesky´s Plaque Index (IPT), Gingival Bleeding Index (IS) and the values of interleukin 6 (IL-6) and interleukin 8 (IL-8). A comparative study of 40 patients in which each patient was his own control, using during 45 days each one of the devices (new loop floss and conventional floss) of interdental hygiene analysed. Data for Loe-Silness Gingival Index (IG), Turesky´s Plaque Index (IPT), Gingival Bleeding Index (IS) and the values of interleukin 6 (IL-6) and interleukin 8 (IL-8)were collected and measured in every visit for every type of interdental hygiene device. Our data indicates that the rate of Turesky´s Plaque Index presented statistically significant differences between groups (loop: 1.66 ± 0.8; traditional: 1.12 ± 0.8; p<0.0001). The rest of the indices studied showed no statistically significant differences. The creation of new dental floss designs try to make their use easier and more sensitive, and plaque removal more effective. The loop design can facilitate interdental hygiene, reaching similar effectiveness than traditional floss, improving some indicators, such as Turesky´s Plaque Index

Predicting the outcome of patients with subarachnoid hemorrhage using machine learning techniques

Background: Outcome prediction for subarachnoid hemorrhage (SAH) helps guide care and compare global management strategies. Logistic regression models for outcome prediction may be cumbersome to apply in clinical practice. Objective: To use machine learning techniques to build a model of outcome prediction that makes the knowledge discovered from the data explicit and communicable to domain experts. Material and methods: A derivation cohort (n = 441) of nonselected SAH cases was analyzed using different classification algorithms to generate decision trees and decision rules. Algorithms used were C4.5, fast decision tree learner, partial decision trees, repeated incremental pruning to produce error reduction, nearest neighbor with generalization, and ripple down rule learner. Outcome was dichotomized in favorable [Glasgow outcome scale (GOS) = I–II] and poor (GOS = III–V). An independent cohort (n = 193) was used for validation. An exploratory questionnaire was given to potential users (specialist doctors) to gather their opinion on the classifier and its usability in clinical routine. Results: The best classifier was obtained with the C4.5 algorithm. It uses only two attributes [World Federation of Neurological Surgeons (WFNS) and Fisher’s scale] and leads to a simple decision tree. The accuracy of the classifier [area under the ROC curve (AUC) = 0.84; confidence interval (CI) = 0.80–0.88] is similar to that obtained by a logistic regression model (AUC = 0.86; CI = 0.83–0.89) derived from the same data and is considered better fit for clinical use.This work was supported in part by the Spanish Ministries of Science under Grant TRA2007-67374-C02-02 and Health under Grant FIS PI 070152. The work of A. Lagares and J.F. Alen was supported by the Fundación Mutua Madrileña

Valoración de los alumnos de Práctica Clínica del Grado de Medicina, sobre el contenido, la metodología y la utilidad de la retroalimentación individualizada acerca del portafolio docente generado en las rotaciones clínicas

La valoración del contenido y metodología de la retroalimentación sobre la realización del portafolio ha sido muy positiva. En la valoración sobre el contenido cualitativo la puntuación media de cada una de las variables fue siempre superior a 4 en una escala de Likert de 1 a 5. No se encontraron diferencias en el análisis según el sexo del alumno.Todos los alumnos puntuaron esta variable como un tiempo adecuado. No se ha encontrado una correlación entre la puntuación en los métodos de evaluación que se utilizan en la asignatura Práctica Clínica I, y que incluyen tanto los resultados de la corrección del portafolio sobre el que se ofreció la retroalimentación, como la nota en el examen ECOE (evaluación clínica objetiva estructurada), la nota en el examen de razonamiento clínico tipo emparejamiento ampliado (EM), o la nota global de la asignatura Práctica Clínica I, que incluye todos los conceptos previos además de algunos otros y las evaluaciones de las variable incluidas en este estudio

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which highlights the need of innovative therapeutic options. Although targeted therapies can be successfully used in a subset of patients with lung adenocarcinomas (ADC), they are not appropriate for patients with squamous cell carcinomas (SCC). In addition, there is an unmet need for the identification of prognostic biomarkers that can select patients at risk of relapse in early stages. Here, we have used several cohorts of NSCLC patients to analyze the prognostic value of both protein expression and DNA promoter methylation status of the prometastatic serine protease TMPRSS4. Moreover, expression and promoter methylation was evaluated in a panel of 46 lung cancer cell lines. We have demonstrated that a high TMPRSS4 expression is an independent prognostic factor in SCC. Similarly, aberrant hypomethylation in tumors, which correlates with high TMPRSS4 expression, is an independent prognostic predictor in SCC. The inverse correlation between expression and methylation status was also observed in cell lines. In vitro studies showed that treatment of cells lacking TMPRSS4 expression with a demethylating agent significantly increased TMPRSS4 levels. In conclusion, TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in SCC and a potential therapeutic target in this tumor type, where targeted therapy is still underdeveloped

Valoración de los alumnos de la Unidad docente HU 12 de Octubre- HU Infanta Cristina sobre la implantación de la docencia y evaluación online con utilización del campus virtual en asignaturas teóricas y prácticas

La docencia en el Grado de Medicina se ha producido tradicionalmente mediante métodos presenciales, tanto en lo que se refiere a impartir clases magistrales o seminarios, como en lo referente a la experiencia clínica de los alumnos con pacientes reales o simulados. Sin embargo, la situación epidemiológica actual, con la pandemia producida por el covid-19, ha precipitado que durante los cursos académicos 2019-20 y 2020-21 se hayan comenzado a utilizar métodos de enseñanza virtual, con un profesorado y alumnado sin a penas conocimiento ni experiencia previa. Por estos motivos, se ha realizado una evaluación de la opinión de los alumnos sobre la docencia teórica online, la actividad práctica virtual, los exámenes on line o las características de la docencia práctica en un ambiente de pandemia

Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism

ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.This work was supported by grant IND2018/BMD-9751 (Programa de Doctorados Industriales, Comunidad de Madrid, Spain), SAF2016-77575-R (Spanish Ministerio de Economía, Industria y Competitividad-MINECO), and the contract for technological support ApTLR2019-PC-MS-001 (AptaTargets, S.L., Spain) to FdC. BF-G is currently hired by Aptatargets S.L., PG-M is hired under PEJ-2020-AI/BMD-18541 de la Comunidad de Madrid, Spain (associated with the youth guarantee fund to FdC), SN had a predoctoral contract from the UCLM and was hired under SAF2012-40023, SAF2016- 77575-R, RD12-0032/0012 and RD16-0015/0019 (Spanish Ministerio de Economía, Industria y Competitividad-MINECO) and IND2018/BMD-9751, YL has been contracted under ReTics and SAF (to FdC). We thank David Segarra and Mª Eugenia Zarabozo (AptaTargets S.L.) for their constant technological support, Laude Garmendia for her indispensable constant help at the animal facility (Instituto Cajal-CSIC), including the extra effort during Covid-19 pandemics, Profs María Ángeles Moro (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid and Universidad Complutense de Madrid, Spain) and Ignacio Lizasoaín (Universidad Complutense de Madrid, Spain) for lending us the TLR4 knockout mice, and the former GNDe member Dr. Carolina MeleroJerez (currently working at JazzPharma, Spain) for the initial training of BF-G on EAE animal model and different techniques at the laboratory. Human samples were supplied by the UK Multiple Sclerosis Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (registered charity 207495).N