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CNS disease

Achut Prasad Silwal, H Peter Lu
Dopamine (DA) is the catecholamine neurotransmitter which interacts with dopamine receptors (DARs) to generate dopaminergic signals in nervous system. Dopamine transporter (DAT) interacts with DA to maintain DA's homeostasis in synaptic and perisynaptic space. DAT and DARs have great importance in central nervous system (CNS) since they are associated to the targeted binding of drugs. Interactions of DA, or its analogue with DARs, or DAT have been studied extensively to understand the mechanism of the dopaminergic signaling process and several neurodegenerative diseases including schizophrenia, Parkinson's diseases, addiction, attention deficit hyperactivity disorder (ADHD), and bipolar disorder...
July 19, 2018: ACS Chemical Neuroscience
Hisayuki Yao, Trevor T Price, Gaia Cantelli, Brandon Ngo, Matthew J Warner, Lindsey Olivere, Sarah M Ridge, Elizabeth M Jablonski, Joseph Therrien, Stacey Tannheimer, Chad M McCall, Anjen Chenn, Dorothy A Sipkins
Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space...
July 18, 2018: Nature
Hugo Geerts, Ronald Gieschke, Richard Peck
The success rate of pharmaceutical Research & Development (R&D) is much lower compared to other industries such as micro-electronics or aeronautics with the probability of a successful clinical development to approval In Central Nervous Systems (CNS) disorders hovering in the single digits (7%). Areas Covered. Inspired by adjacent engineering-based industries, we argue that quantitative modeling in CNS R&D might improve success rates. We will focus on quantitative techniques in early clinical development, such as PharmacoKinetic-PharmacoDynamic modeling, Clinical Trial Simulation, Model-based meta-analysis and the mechanism-based Physiology-based Pharmacokinetic Modeling and Quantitative Systems Pharmacology...
July 18, 2018: Expert Review of Clinical Pharmacology
Beata Kowalska-Krochmal, Radosław Chaber, Katarzyna Jermakow, Magdalena Hurkacz, Elżbieta Piątkowska, Grażyna Gościniak, Grażyna Wróbel
BACKGROUND: Infections in pediatric patients with oncohematological diseases pose a huge therapeutic and diagnostic problem. OBJECTIVES: The aim of the study was to investigate the etiology of bacteremia and the antibiotic susceptibility of pathogenic and colonizing bacterial strains in pediatric oncohematological patients. MATERIAL AND METHODS: In the period 2011-2014, 17,209 positive test results, including 1,129 positive blood cultures, were subjected to a detailed analysis...
July 18, 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Vivian B Neis, Priscila B Rosa, Morgana Moretti, Ana Lucia S Rodrigues
Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions...
July 17, 2018: Current Pharmaceutical Design
Katherine Elizabeth Warren
Over the past decade, we have made considerable progress in establishing diffuse intrinsic pontine glioma (DIPG) as a disease entity and developing preclinical tools to interrogate potential therapeutics. However, translation to improved clinical outcomes in children with DIPG has not yet been realized. This is in part due to difficulties encountered in delivering active drugs adequately to the tumor site. However, most preclinical evaluations gloss over the fundamental concepts of central nervous system (CNS) pharmacokinetics and requirements needed to optimize drug delivery and exposure and translate this into efficacious therapy...
2018: Frontiers in Oncology
Sai-Hong Ignatius Ou, Mark A Socinski, Shirish Gadgeel, Leena Gandhi, Howard West, Alberto Alejandro Chiappori, Victor Cohen, Gregory J Riely, Vlatka Smoljanovic, Walter Bordogna, Elaine Wright, Kendra Debusk, Ali Zeaiter, Alice T Shaw
Background: In a phase II North American study (NP28761; NCT01871805), the anaplastic lymphoma kinase (ALK) inhibitor alectinib demonstrated both systemic and central nervous system (CNS) efficacy with good tolerability in patients with ALK -positive non-small cell lung cancer. We describe patient-reported outcomes (PROs) from the NP28761 study. Patients and methods: PROs and health-related quality of life (HRQoL) benefits were assessed using two self-administered questionnaires (the European Organisation for Research and Treatment of Cancer 30-Item Quality of Life Questionnaire-Core (EORTC QLQ-C30), and the 13-item EORTC QLQ-lung cancer-specific module) at enrolment and every 6 weeks until week 66, disease progression or death...
2018: ESMO Open
Andrea Markovinovic, Tereza Ljutic, Louis-Charles Béland, Ivana Munitic
Mutations in a ubiquitin (Ub)-binding adaptor protein optineurin have been found in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a prominent neuroinflammatory component. Unlike more frequent ALS mutations which cause disease by gaining toxic properties such as aggregation, mutated optineurin is thought to cause disease by loss-of-function, highlighting its neuroprotective role. Optineurin regulates inflammatory signalling by acting as a scaffold for Tank-binding kinase 1 (TBK1) activation and interferon (IFN)-β production in peripheral immune cells...
July 11, 2018: Neuroscience
Ronan Gealageas, Alice Devineau, Pauline P L So, Catrina M J Kim, Jayakumar Surendradoss, Christian Buchwalder, Markus Heller, Verena Goebeler, Edith Dullaghan, David S Grierson, Edward E Putnins
Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that don't permeate the BBB the MAO-B selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para -OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal and hepatocyte stability assays...
July 18, 2018: Journal of Medicinal Chemistry
Rocío A Ruiz-Romero, Roberto A Cervantes-Olivares, Andrés E Ducoing-Watty, Daniel Martínez-Gómez, Efrén Díaz-Aparicio, Estela T Méndez-Olvera
Mastitis in goats is mainly caused by coagulase-negative Staphylococcus (CNS). The identification methods for this group are based on evaluating the expression of phenotypic characteristics such as the ability to metabolize various substrates; however, this is disadvantageous as these methods are dependent on gene expression. In recent years, genotyping methods such as the Multiple Locus Variable-Number Tandem Repeat Analysis (MLVA) and gene identification have been useful for epidemiological study of several bacterial species...
June 30, 2018: Polish Journal of Microbiology
Vafa Baradaran Rahimi, Vahid Reza Askari, Reza Shirazinia, Sina Soheili-Far, Nafiseh Askari, Pouria Rahmanian-Devin, Zahra Sanei-Far, Seyed Hadi Mousavi, Razieh Ghodsi
Teminalia chebula (TC) has been traditionally used in the Iranian traditional medicine (ITM) and Ayurvedic medicine primarily for neurologic disorders and inflammation. Mainly, its fruits have been applied for CNS disorders. The effects of Terminalia chebula as herbal medicine with anti-inflammatory and anti-oxidant properties were aimed on lipopolysaccharide (LPS)-induced microglial inflammation. Cytotoxicity of TC extract (0-80) µg/ml on microglial cells was evaluated using the MTT assay. Also, the protective effect of TC extract concentrations with specified amount of LPS-induced mice microglial cells was studied...
July 11, 2018: Multiple Sclerosis and related Disorders
Tamara Maghathe, William K Miller, Luke Mugge, Tarek R Mansour, Jason Schroeder
INTRODUCTION: Pituitary adenomas (PAs) are primary central nervous system (CNS) tumors, accounting for as much as 25% of intracranial neoplasms. Although existing remedies show success in treating most PAs, treatment of invasive and non-functioning PAs, in addition to functioning PAs unresponsive to standard therapy, remains challenging. With the continually increasing understanding of biochemical pathways involved in tumorigenesis, immunotherapy stands as a promising alternative therapy for pituitary tumors that are resistant to standard therapy...
July 17, 2018: Journal of Neurosurgical Sciences
Melania Spadaro, Stephan Winklmeier, Eduardo Beltrán, Caterina Macrini, Romana Höftberger, Elisabeth Schuh, Franziska S Thaler, Lisa-Ann Gerdes, Sarah Laurent, Ramona Gerhards, Simone Brändle, Klaus Dornmair, Constanze Breithaupt, Markus Krumbholz, Markus Moser, Gurumoorthy Kirshnamoorthy, Frits Kamp, Dieter Jenne, Reinhard Hohlfeld, Tania Kümpfel, Hans Lassmann, Naoto Kawakami, Edgar Meinl
OBJECTIVE: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the CNS. We analyzed their pathogenic activity by affinity-purifying these Abs from patients and transferring them to experimental animals. METHODS: Patients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and determined the recognized MOG-epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients...
July 16, 2018: Annals of Neurology
Timothy E Richardson, Megan Wachsmann, Dwight Oliver, Zahidur Abedin, Diana Ye, Dennis K Burns, Jack M Raisanen, Benjamin M Greenberg, Kimmo J Hatanpaa
Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extra-nodal, or extremely rarely in central nervous system-restricted form. RDD is characterized histologically as a non-Langerhans cell histiocytosis composed of atypical CD68+/S-100+/CD1a- macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the MAP kinase pathway...
July 16, 2018: Annals of Neurology
Ann A Coulter, Candida J Rebello, Frank L Greenway
For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term...
July 16, 2018: Drugs
Aiysha Abid, Saba Shahid, Madiha Shakoor, Ali A Lanewala, Seema Hashmi, Shagufta Khaliq
Mutations in the NPHS1, NPHS2, LAMB2 , and the WT1 genes are responsible for causing nephrotic syndrome (NS) in two third of the early onset cases. This study was carried out to assess the frequencies of mutations in these genes in a cohort of pediatric NS patients. A total of 64 pediatric familial or sporadic SRNS cases were recruited. Among these, 74% had a disease onset of up to 3 years of age. We found one homozygous frameshift mutation in the NPHS1 gene in one CNS case and two homozygous mutations in the NPHS2 gene...
2018: Frontiers in Genetics
Justine Renard, Walter J Rushlow, Steven R Laviolette
Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical evidence supports the hypothesis that adolescent neurodevelopmental exposure to high levels of the principal psychoactive component in marijuana, -delta-9-tetrahydrocanabinol (THC), is associated with a high risk of developing psychiatric diseases, such as schizophrenia later in life. This marijuana-associated risk is believed to be related to increasing levels of THC found within commonly used marijuana strains. Adolescence is a highly vulnerable period for the development of the brain, where the inhibitory GABAergic system plays a pivotal role in the maturation of regulatory control mechanisms in the central nervous system (CNS)...
2018: Frontiers in Psychiatry
Aino Vesikansa
The complex structure and highly variable gene expression profile of the brain makes it among the most challenging fields to study in both basic and translational biological research. Most of the brain diseases are multifactorial and despite the rapidly increasing genomic data, molecular pathways and causal links between genes and central nervous system (CNS) diseases are largely unknown. The advent of an easy and flexible CRISPR-Cas genome editing technology has rapidly revolutionized the field of functional genomics and opened unprecedented possibilities to dissect the mechanisms of CNS disease...
2018: Journal of Central Nervous System Disease
Robert D Dayton, Mychal S Grames, Ronald L Klein
Engineered recombinant adeno-associated virus (AAV) vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis since the papers first using AAV9 for this purpose. Wide-scale CNS expression is relevant to gene therapy as well as indispensable for basic studies such as disease modeling. For example, the wide-scale gene transfer approach could expedite hypothesis testing in vivo relative to the generation of germ-line transgenic mice for all of the genes of interest. Wide-scale gene transfer is more efficient in neonates than in adults, so improving gene transfer efficiency in adults is an important goal...
July 16, 2018: Gene Therapy
Alex McCampbell, Tracy Cole, Amy J Wegener, Giulio S Tomassy, Amy Setnicka, Brandon J Farley, Kathleen M Schoch, Mariah L Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Sai Thankamony, David W Salzman, Merit Cudkowicz, Danielle L Graham, C Frank Bennett, Holly B Kordasiewicz, Eric E Swayze, Timothy M Miller
Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application...
July 16, 2018: Journal of Clinical Investigation
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