ABSTRACT
Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.
Subject(s)
Demyelinating Diseases/pathology , Microglia/physiology , Neuropilin-1/metabolism , Oligodendrocyte Precursor Cells/physiology , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Remyelination , Animals , Cell Differentiation , Cell Lineage , Cell Proliferation , Cells, Cultured , Cerebellum/cytology , Cerebellum/growth & development , Corpus Callosum/cytology , Corpus Callosum/drug effects , Corpus Callosum/growth & development , Corpus Callosum/pathology , Demyelinating Diseases/chemically induced , Disease Models, Animal , Female , Humans , Lysophosphatidylcholines/administration & dosage , Lysophosphatidylcholines/toxicity , Male , Mice , Mice, Transgenic , Microglia/drug effects , Microglia/ultrastructure , Microscopy, Electron, Transmission , Models, Animal , Myelin Sheath/metabolism , Neuropilin-1/genetics , Oligodendroglia/physiology , Platelet-Derived Growth Factor/metabolism , Primary Cell CultureABSTRACT
INTRODUCTION: The Centers for Disease Control and Prevention states that tobacco use is the largest and most preventable cause of disease and mortality in the United States. The Joint Commission implemented inpatient tobacco treatment measures (TTMs) in 2012 to encourage healthcare systems to create processes that help patients quit tobacco use through evidence-based care. METHODS: A tobacco cessation care delivery system was implemented at James A. Haley Veterans' Hospital and Clinics, which included: standardized pathways within the Veterans Health Administration (VHA) electronic health record system to improve nicotine replacement therapy ordering; evidence-based tobacco cessation counseling; and improved care coordination for tobacco cessation treatment through the use of technological innovation. RESULTS: Outcomes were obtained from the VHA quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). TOB-2 and TOB-3 (two Joint Commission inpatient TTMs) equivalent to tob20 and tob40 within SAIL improved by greater than 300% after implementation at James A. Haley Veterans' Hospital and Clinics. CONCLUSION: Implementation of a tobacco cessation care system at James A. Haley Veterans' Hospital and Clinics enhanced interdisciplinary coordination of tobacco cessation care and resulted in improvements of The Joint Commission inpatient TTMs by greater than threefold.
Subject(s)
Delivery of Health Care/standards , Electronic Health Records/standards , Evidence-Based Practice/standards , Organization and Administration/standards , Practice Guidelines as Topic , Quality Improvement/standards , Smoking Cessation/methods , Adult , Aged , Aged, 80 and over , Curriculum , Education, Medical, Continuing , Female , Hospitalization , Humans , Male , Middle Aged , United States , United States Department of Veterans AffairsABSTRACT
Order set design using evidence-based medicine, quality improvement techniques, and standardization increases the likelihood of provider order set adherence and potentially better patient outcomes.
ABSTRACT
While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvß3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.
Subject(s)
Brain Neoplasms/metabolism , Glioblastoma/metabolism , Glucose Transporter Type 3/metabolism , Integrin alphaVbeta3/metabolism , Transcriptome , Animals , Antineoplastic Agents/pharmacology , Brain Neoplasms/mortality , Cell Line, Tumor , Gene Expression Profiling , Glioblastoma/mortality , Humans , Kaplan-Meier Estimate , Mice , Mice, Nude , Signal Transduction , Snake Venoms/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The European medicinal leech, Hirudo verbana, harbors simple microbial communities in the digestive tract and bladder. The colonization history, infection frequency, and growth dynamics of symbionts through host embryogenesis are described using diagnostic PCR and quantitative PCR. Symbiont species displayed diversity in temporal establishment and proliferation through leech development.
Subject(s)
Bacteria/classification , Bacteria/isolation & purification , Biodiversity , Gastrointestinal Tract/microbiology , Leeches/growth & development , Leeches/microbiology , Animals , DNA, Bacterial/genetics , DNA, Ribosomal/genetics , Polymerase Chain Reaction/methods , RNA, Ribosomal, 16S/geneticsABSTRACT
Immunodeficiency states have been implicated in autoimmune diseases. Early recognition of these states is important because prophylaxis can prevent morbidity and mortality. The following is a case report of a 57-year-old male who presented with recurrent infections. He was found to have IgM deficiency. All of his infections were treated appropriately with successful responses. He developed glomerulonephritis, which was read by the pathologist as post-infectious glomerulonephritis. Despite antibiotic therapy, his renal function never recovered, leading to permanent hemodialysis. The patient's renal biopsy exhibited histological features compatible with a membrano-proliferative glomerulonephritis. Retrospectively, it is likely that this patient had autoimmune glomerulonephritis, explaining his failure to respond to antimicrobials.
