Medida da concentração plasmática do fator de crescimento do endotélio vascular em pacientes com câncer prostático: relação com estado clinico, gleason score, volume prostático e PSA sérico

OBJETIVO: Analisar os níveis circulantes do fator de crescimento do endotélio vascular em pacientes com câncer prostático comparados com uma população de indivíduos eutróficos. MÉTODOS: Vinte e seis indivíduos eutróficos e oitenta pacientes com câncer de próstata foram analisados nesse estudo. A coleta sangüínea foi realizada da mesma maneira em todos os pacientes e o plasma foi extraído para a determinação dos níveis do fator de crescimento do endotélio vascular, utilizando-se o método quantitativo ELISA (enzyme-linked immunosorbent assay). RESULTADOS: Os níveis de fator de crescimento do endotélio vascular plasmático encontraram-se significativamente elevados nos pacientes com doença metastática quando comparados com pacientes com doença localizada e com indivíduos sadios. Pacientes com PSA sérico maior que 20 ng/ml apresentaram níveis maiores de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com PSA menor que 20 ng/ml. Houve uma tendência dos pacientes com escore de Gleason de 8 a 10 apresentarem níveis maiores do fator de crescimento do endotélio vascular plasmático em relação a pacientes com escores de Gleason menores que 8. Não houve relação entre fator de crescimento do endotélio vascular plasmático e estado clínico, ou entre fator de crescimento do endotélio vascular e volume prostático em pacientes com câncer de próstata localizado. CONCLUSÃO: Os dados indicam que pacientes com câncer de próstata metastático apresentam níveis significativamente mais elevados de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com câncer localizado e com indivíduos normais.PURPOSE: This study focused on circulating levels of vascular endothelial growth factor in patients with prostate cancer compared to a normal population. METHODS: We analyzed 26 normal individuals and 80 patients with prostate cancer. Blood was drawn from all subjects, and plasma was extracted to determine the concentration of vascular endothelial growth factor using a quantitative immunoassay technique (ELISA-enzyme-linked immunosorbent assay). RESULTS: The median plasma level of vascular endothelial growth factor was significantly elevated in patients with metastatic disease compared to patients with localized disease and with healthy controls. Patients with serum prostate-specific antigen >; 20 ng/mL had significantly higher levels of plasma vascular endothelial growth factor than patients with serum prostate-specific antigen < 20 ng/mL. There was a trend for patients with a Gleason score of 8 to 10 to have higher levels of plasma vascular endothelial growth factor when compared to patients with lower Gleason scores. No relationship was found between plasma vascular endothelial growth factor and clinical staging, or between plasma vascular endothelial growth factor and prostate volume, in patients with localized prostate cancer. CONCLUSION: This study indicates that patients with metastatic prostate cancer have higher plasma vascular endothelial growth factor levels than patients with localized disease or in healthy controls

Bradykinesia in Neurodegenerative Disorders: A Blinded Video Analysis of Pathology-Proven Cases

Background: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. Objective: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. Methods: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. Results: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P &gt; 0.05). Conclusions: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms

Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology

The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.Fil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Sharma, Jennifer. University of Cincinnati; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Migazzi, Alice. Universita degli Studi di Trento; ItaliaFil: Abdelghany, Elhusseini. University of Cincinnati; Estados UnidosFil: Hill, Emily J.. University of Cincinnati; Estados UnidosFil: Duque, Kevin R.. University of Cincinnati; Estados UnidosFil: Hagen, Matthew C.. University of Cincinnati; Estados UnidosFil: Stephen, Christopher D.. Harvard Medical School; Estados UnidosFil: Kovacs, Gabor G.. University of Toronto; CanadáFil: Lang, Anthony E.. University of Toronto; CanadáFil: Hadjivassiliou, Marios. University Of Sheffield (university Of Sheffield);Fil: Basso, Manuela. Universita degli Studi di Trento; ItaliaFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sturchio, Andrea. University of Cincinnati; Estados Unido

Myocardial B cells have specific gene expression and predicted interactions in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy

IntroductionGrowing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy.MethodsWe integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with arrhythmogenic right ventricular cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis.ResultsWe identified 1,100 B cells, including naive B cells and plasma cells. Cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interactions; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation.DiscussionThe human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM

Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders

Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood–brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations

Guía de Práctica Clínica para el Diagnóstico y Tratamiento de Esclerosis Múltiple en Adultos.

Multiple Sclerosis (MS) is a chronic disease of the central nervous system, for which there is still no definitive cure; but there is a diverse variety of therapies with the objective of modifying the course of the disease, which promotes the constant inclusion of new therapeutic strategies. Objective: The Peruvian Society of Neurology, as requested by the Peruvian Health Ministry, convened a committee of experts with the purpose of elaborating a clinical practice guideline for the diagnosis and treatment of MS. Method: Clinical practice guidelines were searched and evaluated according to the AGREE II methodology, choosing the Catalan Clinical Practice Guide as a model. The clinical questions not related to treatment were solved through a systematic review. The clinical treatment questions were assessed under the PICO format and were solved with a meta-analysis of clinical trials available until August 2017, considering the therapies approved by DIGEMID until January 2017. The final recommendations were elaborated using the modified Delphi method with a consensus of at least 80% of the members of its committee. Finally, an external revision of the manuscript was made by international experts in MS. Results: Eighteen clinical questions and twenty-one recommendations for management were developed, including therapeutic algorithms.La Esclerosis Múltiple (EM) es una enfermedad crónica del sistema nervioso central, para la cual aún no hay una cura definitiva; sin embargo, existe una diversa variedad de terapias con el objetivo de modificar el curso natural de la enfermedad, que promueve la inclusión constante de nuevas estrategias terapéuticas. Objetivo: La Sociedad Peruana de Neurología, por encargo del Ministerio de Salud, convocó a un comité de expertos con el objetivo de elaborar una guía de práctica clínica para el diagnóstico y tratamiento de EM. Método: Se realizó una búsqueda y evaluación de guías de práctica clínica bajo la metodología AGREE II, escogiendo como modelo la Guía de Práctica Clínica Catalana. Las preguntas clínicas no concernientes al tratamiento fueron resueltas a través de revisión sistemática. Las preguntas clínicas de tratamiento se diseñaron bajo el formato PICO y se resolvieron con un meta-análisis de ensayos clínicos disponibles hasta agosto del 2017, tomando en consideración las terapias aprobadas por DIGEMID hasta enero del 2017. Las recomendaciones finales fueron elaboradas mediante el método Delphi modificado con un consenso de al menos 80% de los miembros de su comité. Finalmente se realizó una revisión externa del manuscrito por expertos internacionales en EM. &nbsp; Resultados: Se formularon 18 preguntas clínicas y 21 recomendaciones para el manejo, incluyendo algoritmos terapéuticos

Identification of constrained sequence elements across 239 primate genomes

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals

Waveform Modelling for the Laser Interferometer Space Antenna

LISA, the Laser Interferometer Space Antenna, will usher in a new era in gravitational-wave astronomy. As the first anticipated space-based gravitational-wave detector, it will expand our view to the millihertz gravitational-wave sky, where a spectacular variety of interesting new sources abound: from millions of ultra-compact binaries in our Galaxy, to mergers of massive black holes at cosmological distances; from the beginnings of inspirals that will venture into the ground-based detectors' view to the death spiral of compact objects into massive black holes, and many sources in between. Central to realising LISA's discovery potential are waveform models, the theoretical and phenomenological predictions of the pattern of gravitational waves that these sources emit. This white paper is presented on behalf of the Waveform Working Group for the LISA Consortium. It provides a review of the current state of waveform models for LISA sources, and describes the significant challenges that must yet be overcome.Comment: 239 pages, 11 figures, white paper from the LISA Consortium Waveform Working Group, invited for submission to Living Reviews in Relativity, updated with comments from communit