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Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model
cells Article Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model Erik Axel Andersson 1 , Eridan Rocha-Ferreira 2 , Henrik Hagberg 2, Carina Mallard 1 and Carl Joakim Ek 1,* 1 Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 11, 413 90 Gothenburg, Sweden; [email protected] (E.A.A.); [email protected] (C.M.) 2 Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden; [email protected] (E.R.-F.); [email protected] (H.H.) * Correspondence: [email protected] Abstract: Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB Citation: Andersson, E.A.; Rocha- Ferreira, E.; Hagberg, H.; Mallard, C.; function occurred. -
Hypoxia in Alzheimer's Disease: Effects of Hypoxia Inducible Factors
Perspective associated virus-HIF-1α inhibits neuronal Hypoxia in Alzheimer’s disease: apoptosis of the hippocampus induced by Aβ peptides. HIF-1 increases glycolysis and the hexose monophosphate shunt, maintains effects of hypoxia inducible factors the mitochondrial membrane potential and cytosolic accumulation of cytochrome C, thereby inactivating caspase-9 and caspase-3, * Halimatu Hassan, Ruoli Chen and thus prevents neuronal death in the AD brain. Oxidative damage, caused by Aβ peptide Alzheimer’s disease (AD), a common (Lall et al., 2019). Neuroinflammation plays induces mitochondrial dysfunction, which is neurodegenerative disease, afflicts 26 million a detrimental role in AD pathogenesis, as a major characteristic of neuronal apoptosis. people worldwide currently with projection of a microglia depletion by colony stimulating factor Additional pathological features of AD are fourfold increase in this figure by the year 2050 receptor 1 inhibitors improves AD symptoms in astrocyte activation and reduced glucose (Brookmeyer et al., 2018). The majority of AD in vivo (Rawlinson et al., 2020). metabolism in some selected brain areas. cases (95%) are sporadic, having the late-onset Cells respond to hypoxia by stabilizing hypoxia Maintenance of HIF-1α levels reverses Aβ affecting those over 65 years old. About 15% inducible factor (HIF), a key transcription factor peptide-induced glial activation and glycolytic among those 65 years and older suffer from regulating oxygen homeostasis. The HIF levels changes, thus mediating a neuroprotective AD, and the incidence of AD is close to 50% for in cells are directly regulated by four oxygen- response to Aβ peptide by maintaining those aged over 85 years (Brookmeyer et al., sensitive hydroxylases: 3 prolyl hydroxylases metabolic integrity. -
The Role of Metabolism in Migraine Pathophysiology and Susceptibility
life Review The Role of Metabolism in Migraine Pathophysiology and Susceptibility Olivia Grech 1,2 , Susan P. Mollan 3 , Benjamin R. Wakerley 1,4, Daniel Fulton 5 , Gareth G. Lavery 1,2 and Alexandra J. Sinclair 1,2,4,* 1 Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (O.G.); [email protected] (B.R.W.); [email protected] (G.G.L.) 2 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, UK 3 Birmingham Neuro-Ophthalmology Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK; [email protected] 4 Department of Neurology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham B15 2TH, UK 5 Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK; [email protected] * Correspondence: [email protected] Abstract: Migraine is a highly prevalent and disabling primary headache disorder, however its patho- physiology remains unclear, hindering successful treatment. A number of key secondary headache disorders have headaches that mimic migraine. Evidence has suggested a role of mitochondrial dysfunction and an imbalance between energetic supply and demand that may contribute towards Citation: Grech, O.; Mollan, S.P.; migraine susceptibility. Targeting these deficits with nutraceutical supplementation may provide an Wakerley, B.R.; Fulton, D.; Lavery, additional adjunctive therapy. Neuroimaging techniques have demonstrated a metabolic phenotype G.G.; Sinclair, A.J. The Role of in migraine similar to mitochondrial cytopathies, featuring reduced free energy availability and Metabolism in Migraine increased metabolic rate. -
Guidelines for the Management of Severe Traumatic Brain Injury 4Th Edition
Guidelines for the Management of Severe Traumatic Brain Injury 4th Edition Nancy Carney, PhD Oregon Health & Science University, Portland, OR Annette M. Totten, PhD Oregon Health & Science University, Portland, OR Cindy O'Reilly, BS Oregon Health & Science University, Portland, OR Jamie S. Ullman, MD Hofstra North Shore-LIJ School of Medicine, Hempstead, NY Gregory W. J. Hawryluk, MD, PhD University of Utah, Salt Lake City, UT Michael J. Bell, MD University of Pittsburgh, Pittsburgh, PA Susan L. Bratton, MD University of Utah, Salt Lake City, UT Randall Chesnut, MD University of Washington, Seattle, WA Odette A. Harris, MD, MPH Stanford University, Stanford, CA Niranjan Kissoon, MD University of British Columbia, Vancouver, BC Andres M. Rubiano, MD El Bosque University, Bogota, Colombia; MEDITECH Foundation, Neiva, Colombia Lori Shutter, MD University of Pittsburgh, Pittsburgh, PA Robert C. Tasker, MBBS, MD Harvard Medical School & Boston Children’s Hospital, Boston, MA Monica S. Vavilala, MD University of Washington, Seattle, WA Jack Wilberger, MD Drexel University, Pittsburgh, PA David W. Wright, MD Emory University, Atlanta, GA Jamshid Ghajar, MD, PhD Stanford University, Stanford, CA Reviewed for evidence-based integrity and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. September 2016 TABLE OF CONTENTS PREFACE ...................................................................................................................................... 5 ACKNOWLEDGEMENTS ............................................................................................................................................. -
Studies on the Intracerebral Toxicity of Ammonia
Studies on the Intracerebral Toxicity of Ammonia Steven Schenker, … , Edward Brophy, Michael S. Lewis J Clin Invest. 1967;46(5):838-848. https://doi.org/10.1172/JCI105583. Research Article Interference with cerebral energy metabolism due to excess ammonia has been postulated as a cause of hepatic encephalopathy. Furthermore, consideration of the neurologic basis of such features of hepatic encephalopathy as asterixis, decerebrate rigidity, hyperpnea, and coma suggests a malfunction of structures in the base of the brain and their cortical connections. The three major sources of intracerebral energy, adenosine triphosphate (ATP), phosphocreatine, and glucose, as well as glycogen, were assayed in brain cortex and base of rats given ammonium acetate with resultant drowsiness at 5 minutes and subsequent coma lasting at least 30 minutes. Cortical ATP and phosphocreatine remained unaltered during induction of coma. By contrast, basilar ATP, initially 1.28 ± 0.15 μmoles per g, was unchanged at 2.5 minutes but fell by 28.1, 27.3, and 26.6% (p < 0.001) at 5, 15, and 30 minutes after NH4Ac. At comparable times, basilar phosphocreatine fell more strikingly by 62.2, 96, 77.1, and 71.6% (p < 0.001) from a control level of 1.02 ± 0.38 μmoles per g. These basilar changes could not be induced by anesthesia, psychomotor stimulation, or moderate hypoxia and were not due to increased accumulation of ammonia in the base. Glucose and glycogen concentrations in both cortex and base fell significantly but comparably during development of stupor, and prevention of the cerebral glucose decline by pretreatment with […] Find the latest version: https://jci.me/105583/pdf Journal of Clinical Investigation Vol. -
Hypoxic-Ischemic Brain Injury After Perinatal Asphyxia As a Possible Factor in the Pathology of Alzheimer's Disease
Hypoxic-Ischemic Brain Injury after Perinatal Asphyxia as a Possible Factor in the Pathology of Alzheimer's Disease Agata Tarkowska, MD, PhD Department of Neonate and Infant Pathology, Medical University of Lublin, Lublin, Poland Author for correspondence: Agata Tarkowska, Department of Neonate and Infant Pathology, Medical University of Lublin, Lublin, Poland. Email: [email protected] Cite this chapter as: Tarkowska A. Hypoxic-Ischemic Brain Injury after Perinatal Asphyxia as a Possible Factor in the Pathology of Alzheimer's Disease. In: Pluta R, editor. Cerebral Ischemia. Brisbane (AU): Exon Publications; 2021. Online first Aug 31. Doi: https://doi.org/10.36255/exonpublications.cerebralischemia.2021.perinatalasphyxia Note to the user: This chapter has been peer reviewed and accepted for publication in the book Cerebral Ischemia, but not yet copyedited or typeset. Abstract Perinatal asphyxia is a common pathological condition occurring worldwide in approximately 4 million newborns annually. The result of this phenomenon is multi-organ damage and the development of chronic hypoxic encephalopathy. It is currently believed that an episode of cerebral hypoxia/ischemia may be one of the major factors responsible for the development of Alzheimer's disease-type dementia and/or Alzheimer's disease. It cannot be ruled out that hypoxia in the perinatal period may be a trigger factor for the development of Alzheimer's disease in adulthood. The data from scientific research indicate a possible relationship between hypoxia in the earliest stages of life and the occurrence of long-lasting genetic and biochemical changes leading to the development of neurodegeneration in Alzheimer’s disease-type. Keywords: Alzheimer’s disease; brain ischemia; genes; hypoxic-ischemic encephalopathy; perinatal asphyxia Running title: Perinatal Asphyxia and Alzheimer's Disease 1 INTRODUCTION Perinatal asphyxia (PA) is a condition resulting from insufficient availability of oxygen to various organs and tissues of the fetus and newborn in the antenatal and intranatal periods. -
In Theliver, Bone, Lung, Pleuralcavity, Do Patients Develop Bone Marrow Invasion
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.2.237 on 1 February 1987. Downloaded from Letters 237 troencephalogram (EEG) showed a diffuse with myelofibrosis and symptomatic ana- frontal enhancing nodule abutting the ring. monorhythmical 9-12Hz activity of 50pV emia.2 3 We report the second such case in He was started on dexamethasone with amplitude, with no reactivity to painful stim- which pancytopenia resulting from marrow significant improvement of his intellectual ulation. Multi-drug screening tests estab- invasion was the primary clinical function and to a lesser degree his right sided lished intoxication with a benzodiazepine presentation. In addition, white matter weakness. Over the next 2 months, the later identified as flunitrazepam. degeneration due to the effects of radio- patient's haematological function worsened, On the second day the patient gradually therapy and possible chemotherapy caused a with slowly declining platelets and hae- regained consciousness. A repeat EEG at major diagnostic dilemma. The importance moglobin levels. Intermittent transfusions that time was normal. After recovery he of glial fibrillary acid protein staining to were required to maintain a haematocrit admitted an attempt at suicide taking 25 tab- confirm the diagnosis of metastatic glioma above 20. Alkaline phosphatase continued lets each of 2 mg of flunitrazepam. while the patient is alive is demonstrated. to be elevated. Chest radiograph was inter- This case presented two features which A 52 year old business executive was well preted as showing diffuse bony metastases. have not previously been reported in until 1972 when he suffered a generalised sei- Seizure activity became more difficult to benzodiazepine-intoxication. -
NXP031 Improves Cognitive Impairment in a Chronic Cerebral Hypoperfusion-Induced Vascular Dementia Rat Model Through Nrf2 Signaling
International Journal of Molecular Sciences Article NXP031 Improves Cognitive Impairment in a Chronic Cerebral Hypoperfusion-Induced Vascular Dementia Rat Model through Nrf2 Signaling Jae-Min Lee 1,† , Joo-Hee Lee 2,†, Min-Kyung Song 3 and Youn-Jung Kim 1,* 1 College of Nursing Science, Kyung Hee University, Seoul 02447, Korea; [email protected] 2 Department of Nursing, Graduate School, Kyung Hee University, Seoul 02447, Korea; [email protected] 3 Robert Wood Johnson Medical School Institute for Neurological Therapeutics, Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA; [email protected] * Correspondence: [email protected]; Tel.: +82-2-961-0311 † These authors contributed equally to this work. Abstract: Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C’s antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by Citation: Lee, J.-M.; Lee, J.-H.; permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve Song, M.-K.; Kim, Y.-J. NXP031 weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate Improves Cognitive Impairment in a (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). -
Special Transport Restraint Needs for Children with Disabilities Aged 0-18 Years
SPECIAL TRANSPORT RESTRAINT NEEDS FOR CHILDREN WITH DISABILITIES AGED 0-18 YEARS GR 95-8 VIC• VicRoads REPORT DOCUMENTATION PAGE Report No.: Report Date: ISBN: Pages: GR 95-8 September 1995 0730649342 17 + Appendices Title and Sub-title: Special Transport Restraint Needs for Children with Disabilities Aged 0-18 Years Author: Lisa Vale, Occupational Therapy Department, The Royal Children's Hospital, Melbourne, Victoria 3052 Perfonning Organisation(s): Sponsoring Organisation: Pat Rogerson Deanne Perry VicRoads Federal Office of Road Safety Road Safety Level 5 Cox Building 60 Denmark Street 15 Mort Street KEW VIC 3101 CANBERRA AUSTRALIA ACT 2601 Abstract: The aims of this research project are: 1) Identify the diagnoses that predispose children to difficulty using standard car restraints. 2) Estimate the number of children with the relevant diagnoses who may require special car restraints. 3) Survey a sample of the parents of children with one of the selected diagnoses to investigate the specific problems they are experiencing with car restraints. Seven main neurological diagnoses were selected: cerebral palsy, spina bifida, muscular dystrophy, spinal muscular atrophy, intellectual disability, acquired brain damage (eg cerebral hypoxia), and others (eg encephalitis, meningitis, brain tumor, arteriovenous malformation). The number in Victoria needing specialized restraints was estimated as 6,200 children, 0.52 % of the population aged 0-18 years with neurological disabilities and an additional number of children with behavioural difficulties and orthopaedic disabilities. The problems and improvements centred around the comfort of the child and ease of use of the car restraint, including prevention of misuse by the child. Key Words: (IRRD except where *) Disclaimer: Safety Belt Vehicle Occupant This report is disseminated in the interests Restraints of information exchange. -
Module G: Oxygen Transport • Oxygen Transport Studies • Tissue Hypoxia • Cyanosis • Polycythemia
Topics to Cover • Oxygen Transport • Oxygen Dissociation Curve Module G: Oxygen Transport • Oxygen Transport Studies • Tissue Hypoxia • Cyanosis • Polycythemia Oxygen Transport Dissolved Oxygen • As oxygen diffuses across the A-C membrane, it • Oxygen is carried from the lungs to the dissolves into the plasma and remains in that tissues in two different fashions: fashion until it reaches the tissue. • Oxygen Dissolved in the blood plasma (PO ) 2 • Expressed as a partial pressure - PO2 • Oxygen Combined with Hemoglobin (SO2) • Normal arterial level = 80-100 mm hg • Normal venous level = 35 – 45 mm hg • The quantity of oxygen dissolves is a function of Henry’s law. •At 37 C 0.003 ml of oxygen will dissolve in 100 ml of blood. (Henry’s Law) • At 100 mm hg PaO2, the amount of dissolved oxygen is 0.3 ml O2/100 ml blood (0.3 vol%). Combined Oxygen • Dissolved oxygen is inadequate for metabolic needs. • Need a substance which will bind to oxygen and carry it, BUT will release it when needed. • Voila! Hemoglobin! • Miracle #2…As we’ll see later, hemoglobin also carries carbon dioxide and is a key buffer of [H+]. 1 Hemoglobin chains • Each RBC contains approximately 280 million molecules of hemoglobin chains • Adult Hemoglobin (Hb A) consists of • 4 Heme Groups – Primarily iron in the Fe+2 (ferrous) state. Heme • 4 Globulin – 4 amino acid chains (2 & 2 ) Units • One heme group binds with one of the amino acid chains and oxygen binds with the iron in the heme group in a reversible way. +2 O2 + Fe FeO2 (Oxyhemoglobin) FERROUS Hemoglobin & the RBC • “Normal” hemoglobin level • 15 g/dl (men) & 13-14 g/dl (women) - Malley •15 +1.5 g/dl (men) & 13.5 + 1.5 g/dl (women) – Egan •15 +2 (men) & 14 + 2 (women) - Easy • Why do women have less? • The hemoglobin molecule resides in the erythrocyte and is responsible for giving the blood its red color. -
The Possible Role of Hypoxia in the Formation of Axonal Bulbs
J Clin Pathol 1999;52:203-209 203 The possible role of hypoxia in the formation of axonal bulbs B Kaur, G N Rutty, W R Timperley Abstract head injury and hypoxic changes, and 12 Aims-To assess the possible role of of 28 cases of hypoxia without history of Department of hypoxia in the formation of axonal bulbs. head injury; 22 of 25 cases who had been Forensic Pathology, Methods-Study material comprised sec- ventilated showed positive staining. The University of Sheffield, tions from 28 brains showing evidence of majority of cases showed evidence of Medico-Legal Centre, cerebral cerebral swelling. Watery Street, hypoxia with no history of head Sheffield S3 7ES, UK injury, four with a history of head trauma Conclusions-Axonal bulbs staining posi- B Kaur but no evidence of hypoxic change, eight tively for PAPP may occur in the presence G N Rutty with a history ofhead trauma and hypoxic of hypoxia and in the absence of head change, and four from control brains injury. The role of hypoxia, raised intrac- Department of originally described as "diffuse axonal ranial pressure, oedema, shift effects, and Neuropathology, Royal ventilatory support in the formation of Hallamshire Hospital, injury." These were subjected to micro- Sheffield S10 2JF, UK wave antigen retrieval and inmmunohisto- axonal bulbs is discussed. The presence of W R Timperley chemistry using monoclonal antibodies to axonal bulbs cannot necessarily be attrib- P amyloid precursor protein (PAPP), glial uted to shearing forces alone. Correspondence to: (J Clin Pathol 1999;52:203-209) Dr Rutty. fibrillary acid protein (GFAP), and CD68- email: PGMl. -
Mitochondrial Dysfunction After Severe Tbi: a New Translational Target?
-Edición provisional- MITOCHONDRIAL DYSFUNCTION AFTER SEVERE TBI: A NEW TRANSLATIONAL TARGET? Juan Sahuquillo, MD, PhD1, Marian Vidal-Jorge2, Angela Sánchez-Guerrero2 Department of Neurosurgery1, Neurotraumatology and Neurosurgery Research Unit2 Vall d’Hebron University Hospital Universitat Autònoma de Barcelona, Barcelona, Spain Significant advances in the treatment of TBI have been limited by a lack of knowledge of the biochemical, cellular and molecular changes involved in its pathophysiology. These obstacles have been overcome to a certain degree by new monitoring tools —cerebral microdialysis (MD) and monitoring of partial pressure of oxygen in the brain (PtiO2)— that have allowed clinicians to explore the metabolic disturbances of the injured brain with unprecedented detail. The data gathered by these monitoring tools in the past two decades has provided an opportunity to take a second look at the pathophysiology of TBI, motivating clinical researchers to redefine some of the unchallenged traditional concepts. The hypothesis that mitochondrial dysfunction is at the core of many acute metabolic disorders observed in acute TBI is one of the old concepts that deserves a second look and is the focus of this chapter. New neuromonitoring techniques, including PtiO2 and MD monitoring, are widely used in neurocritical care units, allowing for the quasi-continuous profiling of brain oxygen supply and brain metabolism [1, 2]. Data provided by these tools have cast doubt on the predominant role of ischemia in the pathophysiology of TBI. Many studies have found that the injured brain may experience severe alterations of energetic metabolism in the presence of CBF and oxygen supply well above the ischemic range[3-5].