TRIUMPHS AND WONDERS OF MODERN CHEMISTRY
CONTENTS CHAPTER TRANSIENT ISCHEMIC ATTACK, TRAUMATIC BRAIN INJURY, AND ISCHEMIC STROKE: RISK FACTORS AND TREATMENTS INTRODUCTION DEFINITION OF TIA, TBI, AND STROKE INCIDENCE OF TIA, TBI, AND STROKE RISK FACTORS FOR TIA AND STROKE AGE GENDER RACE HYPERTENSION DIABETES MELLITUS SMOKING PREVIOUS STROKE TIA ATRIAL FIBRILLATION ATHEROSCLEROSIS OF CAROTID ARTERIES CORONARY ARTERY DISEASE OBESITY DIET PHYSICAL ACTIVITY BLOOD LIPIDS HORMONE REPLACEMENT THERAPY TREATMENT OF TIA AND ISCHEMIC STROKE THROMBOLYSIS ANTIPLATELET THERAPY ANTICOAGULANT THERAPY STATIN THERAPY NEUROPROTECTIVE THERAPY THROMBECTOMY HEMORRHAGIC TRANSFORMATION TREATMENT OF TBI CONCLUSION REFERENCES CHAPTER INFLAMMATORY CHANGES IN CEREBRAL ISCHEMIC INJURY: CELLULAR AND MOLECULAR INVOLVEMENT DAMAGE-ASSOCIATED MOLECULAR PATTERNS IN ISCHEMIC BRAIN TISSUE TOLL-LIKE RECEPTORS AS DAMP RECEPTORS INFLAMMATORY CYTOKINES AND MEDIATORS INFILTRATING IMMUNE CELLS IN THE ISCHEMIC BRAIN T CELLS IN ISCHEMIC BRAIN INJURY RESOLUTION OF POST-ISCHEMIC INFLAMMATION BIOMARKERS OF ACUTE BRAIN INJURY AND SURROGATE ENDPOINTS IN TRAUMATIC BRAIN INJURY AND STROKE TRANSLATIONAL STUDIES EPIDEMIOLOGY OF ACUTE TRAUMATIC BRAIN INJURY AND STROKE BRAIN INJURY BIOMARKERS AND SURROGATE ENDPOINTS IN CLINICAL TRIALS BIOMARKERS OF ASTROGLIAL INJURY S100B GLIAL FIBRILLARY ACIDIC PROTEIN BIOMARKERS OF NEURONAL INJURY NEURON-SPECIFIC ENOLASE UBIQUITIN C-TERMINAL HYDROLASE BIOMARKERS OF AXONAL INJURY AII-SPECTRIN BREAKDOWN PRODUCTS TAU PROTEIN NEUROFILAMENTS DI?CULTIES OF TRANSLATING OUTCOMES FROM ANIMAL STUDIES TO CLINICAL TRIALS DI?ERENCES AMONG ANIMAL MODELS OF STROKE, TIA, AND TBI IN THE TYPE AND EXTENT OF CEREBRAL INJURY DI?ERENCES BETWEEN HUMANS AND ANIMAL STROKE MODELS DI?ERENCES IN THE WAYS THAT STUDIES ARE CONDUCTED IN HUMANS AND ANIMAL MODELS DI?ERENCES IN PRIMARY FUNCTIONAL OUTCOMES MEASURED IN CLINICAL TRIALS AND ANIMAL STUDIES STRATEGIES TO IMPROVE THE QUALITY OF ANIMAL AND CLINICAL STUDIES OF STROKE THERAPIES NEUROPROTECTIVE THERAPIES FOR ISCHEMIC STROKE METABOLIC ALTERATIONS THAT INCREASE THE RISK OF DEVELOPING STROKE PATHOPHYSIOLOGY AND POSSIBLE THERAPEUTIC STRATEGIES ENERGY FAILURE BARRIER DYSFUNCTION EXCITOTOXICITY OXIDATIVE STRESS INFLAMMATION IMMUNOMODULATION THE MOLECULAR NEUROPROTECTIVE STRATEGIES IN CEREBRAL ISCHEMIA: AN INSIGHT INTO EMERGING TREATMENTS FOR OXIDATIVE STRESS FREE RADICAL RELEASE AND OXIDATIVE STRESS IN CEREBRAL ISCHEMIA ENDOGENOUS ANTI-OXIDANT DEFENSE MECHANISMS AND THERAPEUTIC TARGETS SODS IN CEREBRAL ISCHEMIA NOX REGULATES ROS GENERATION IN ISCHEMIC STROKE ACTIVATION OF NRF2/ARE SIGNALING ALLEVIATES OXIDATIVE STRESS OTHER ENDOGENOUS OXIDATIVE STRESS TARGETS IN ISCHEMIC STROKE SEQUESTERING OXIDATIVE STRESS-INDUCED APOPTOSIS AND NECROSIS POST-ISCHEMIA APOPTOSIS REGULATION AND THE MECHANISTIC TARGETS TARGETING NECROSIS IN CEREBRAL ISCHEMIA EXOGENOUS ANTI-OXIDANTS TO DECREASE ROS GENERATION NEURONAL RESTORATION STRATEGIES FOLLOWING CEREBRAL ISCHEMIA CELLULAR THERAPY ENDOGENOUS NEUROGENESIS ISCHEMIC PRECONDITIONING ABBREVIATIONS IDENTIFICATION OF MICRORNAS AS TARGETS FOR TREATMENT OF ISCHEMIC STROKE MECHANISMS OF NEURONAL INJURY IN ISCHEMIC STROKE MIRS AND THE REGULATION OF APOPTOSIS AUTOPHAGY, ANOIKIS, AND MIRS HEAT SHOCK PROTEINS AND MIRS MIRS AND GLIA IN ISCHEMIC STROKE ASTROCYTES MICROGLIA CLINICAL UTILITY OF MIRS IN ISCHEMIC STROKE CONCLUSIONS ACKNOWLEDGEMENTS COMBINED DRUG–DIAGNOSTIC TEST CO-DEVELOPMENT FOR PREDICTING AND PREVENTING BRAIN IMPAIRMENTS COMPANION DIAGNOSTIC PRECEDENT PUBLIC HEALTH PERSPECTIVE PERSONALIZED OR PRECISION MEDICINE DRUG-TEST CO-DEVELOPMENT APPROACH FOR BRAIN IMPAIRMENTS REGULATORY CRITERIA FOR DRUG-TEST CO-DEVELOPMENT FDA RX/CDX CONCEPT INTENDED USE AND INDICATION OF USE TRENDS IN POINT-OF-CARE TESTING AND RX ADVANTAGES OF COMBINED BRAIN IMPAIRMENT DRUG–DIAGNOSTIC TEST USE IN THE CLINICAL SETTING OPTIMIZATION OF NEURO-CRITICAL CARE BY RX/CDX RX/CDX FOR PREVENTING AND PREDICTING CHRONIC CVDS ADVANCES IN DIAGNOSTICS AND TREATMENT OF NEUROTOXICITY AFTER SPORTS-RELATED INJURIES REVERSIBLE AND IRREVERSIBLE CEREBROVASCULAR CHANGES AFTER MTBI THE NVU CONCEPT ALTERATIONS IN SMALL- AND MEDIUM-SIZED VESSELS BBB DYSFUNCTION AND NEUROINFLAMMATION AFTER MTBI COMPROMISED BBB NEUROINFLAMMATION VASOGENIC AND CYTOTOXIC EDEMA FORMATION FOCAL AND TRAUMATIC AXONAL INJURY CORRELATES WITH ALTERED CBF TRAUMATIC AXONAL INJURY AND ALTERED CBF RADIOLOGICAL FINDINGS IN MTBI BIOMARKERS FOR ACUTE AND CHRONIC CONDITIONS AFTER MTBI PROSPECTIVE BIOMARKERS OF NVU GLUR PEPTIDE AND AB TRANSLATIONAL RESEARCH CONVENTIONAL TREATMENT OPTIONS FOR MTBI TRENDS IN EMERGENT PHARMACOLOGICAL AGENTS FOR MTBI NON-PHARMACOLOGICAL TREATMENT OPTIONS FOR CONCUSSIONS CHAPTER 10 FUNCTIONAL PREDICTORS FOR PROGNOSIS AND RECOVERY AFTER MILD TRAUMATIC BRAIN INJURY MILD TRAUMATIC BRAIN INJURY STANDARDIZED EVALUATION TOOLS NEUROPSYCHOLOGICAL EVALUATION VESTIBULAR/BALANCE PRE-INJURY RISK FACTORS/CONDITIONS POST-INJURY RISK FACTORS FOR POOR RECOVERY REHABILITATION FACTORS FOR RECOVERY SUMMARY AND FUTURE DIRECTIONS ASSESSMENT MODALITIES AND MULTIDISCIPLINARY TEAM APPROACH FUTURE DIRECTIONS AND EMERGING MTBI ASSESSMENT TOOLS CHAPTER 11 PREDICTORS FOR PROGNOSIS AND RECOVERY FROM UNCONSCIOUSNESS DUE TO BRAIN TRAUMA COMA AND POST-COMATOSE UNCONSCIOUSNESS CONSCIOUSNESS AND UNCONSCIOUSNESS POST-TRAUMATIC COMA AND SCALES POST-COMATOSE UNCONSCIOUSNESS STRUCTURAL AND FUNCTIONAL BASIS OF UNCONSCIOUSNESS NEUROIMAGING AND NOVEL MAGNETIC RESONANCE IMAGING-BASED CLASSIFICATION OF STBI CEREBRAL BLOOD FLOW MAPPING NEUROTRANSMITTER ASPECTS OF UNCONSCIOUSNESS PROGNOSTIC VALUE OF NEUROIMAGING FOR COMA AND UNCONSCIOUSNESS MRI FEATURES AND PREDICTORS IN UNCONSCIOUSNESS PROGNOSTIC VALUE OF NON-STRUCTURAL NEUROIMAGING DATA (FUNCTIONAL MRI) NEUROMETABOLIC IMAGING AND PROGNOSTIC VALUE OF UNCONSCIOUSNESS NEUROCHEMICAL BASIS OF COMA AND PROGNOSTIC BIOMARKERS OF OUTCOME CHAPTER 12 NEUROTOXICITY IN SPINAL CORD IMPAIRMENTS PATHOLOGICAL FEATURES OF SC IMPAIRMENTS HEMODYNAMIC ASPECTS OF SC INJURY BIOCHEMICAL ALTERATIONS IN ACUTE AND CHRONIC CONDITIONS RADIOLOGICAL PATTERNS OF SC IMPAIRMENTS POTENTIAL BIOMARKERS OF SC IMPAIRMENTS NEURONAL MARKERS IN SCI BIOMARKERS OF INFLAMMATION NEUROTOXICITY MARKERS FOR SC ISCHEMIA AND SCI THERAPY OPTIONS FOR SC IMPAIRMENTS ACUTE STATES CHRONIC CONDITIONS TRENDS IN TREATMENT OPTIMIZATION CHAPTER 13 ADVANCED APPROACHES IN STEM CELL THERAPY FOR STROKE AND TRAUMATIC BRAIN INJURY ORIGINS AND SOURCES OF SCS TRANSPLANTATION OF SCS IN ANIMAL MODELS OF STROKE AND TBI SC THERAPY IN STROKE AND TBI: CLINICAL TRIALS STROKE TRAUMATIC BRAIN INJURY NEUROPROTECTIVE AGENTS MAGNESIUM MINOCYCLINE LOVASTATIN CITALOPRAM DONEPEZIL CITICOLINE TOCOTRIENOLS CYCLOSPORINE CUTAMESINE (SA4503) INTRA-ARTERIAL ADMINISTRATION OF NEUROPROTECTIVE DRUGS AS AN ADJUNCT TO MECHANICAL THROMBECTOMY—VERAPAMIL AND BEYOND CHAPTER 15 DI?CULTIES IN CLINICAL TRIALS TO TREAT TRAUMATIC BRAIN INJURY AND STROKE WHY TRANSLATION HAS FAILED: REASONS FOR FAILURE IN THE TRANSLATION FROM ANIMAL TO HUMAN STUDIES ANIMAL MODELS ASSUMPTIONS MADE IN TRANSLATION: TIME OF ADMINISTRATION, MECHANISM, DOSING AND PUBLICATION BIAS CLINICAL TRIALS AND THEIR PROBLEMS CONCLUSIONS: RECOMMENDATIONS TO IMPROVE TRANSLATION CHAPTER 16 CHALLENGES IN USING BIOMARKERS IN CENTRAL NERVOUS SYSTEM APPLICATIONS BIASES AND PITFALLS IN CHOICE OF BIOMARKERS PECULIARITIES IN PRIMARY BIOMARKER TESTING SELECTION OF INDICATORS FOR SECONDARY INJURIES BIOMARKERS OF AUTOIMMUNE RESPONSE POSSIBLE OMISSIONS IN BRAIN BIOMARKER TESTING SINGLE VS MULTIPLE BIOMARKER TESTING TRANSLATIONAL STUDY DESIGN CONSIDERATIONS DETERMINING STUDY POWER BIOLOGICAL FLUID TESTING DRAWBACKS BIOLOGICAL FLUID SELECTION SAMPLE PREPARATION AND STORAGE CHAPTER 17 RESOLVING DI?CULT CASE SCENARIOS BY INCORPORATING STROKE BIOMARKERS IN CLINICAL DECISION-MAKING BLOOD-BASED STROKE BIOMARKERS IN CLINICAL SCENARIOS MALIGNANT CEREBRAL INFARCTION EARLY NEUROLOGIC DETERIORATION STROKE DIAGNOSIS THROMBUS FORMATION STROKE ETIOLOGY STROKE RISK CHAPTER 18 DEVELOPMENT OF NOVEL TEST PLATFORMS FOR THE ASSESSMENT OF BRAIN INJURY DIAGNOSTIC APPROACHES TO BRAIN INJURY CURRENTLY AVAILABLE BRAIN INJURY ASSAYS ROADMAP FOR ASSAY DEVELOPMENT IMMUNOCHEMICAL ASSAYS DEVELOPMENT UNIQUE REAGENTS FOR BRAIN BIOMARKER DETECTION ASSAY DESIGN ASSAY PLATFORM POCT FOR BRAIN INJURY ASSESSMENTS LABORATORY-BASED TESTING AND POCT EMERGING ASSAY TECHNOLOGIES CHAPTER 19 ADVANCEMENTS AND CHALLENGES IN HYPERACUTE STROKE TRANSLATIONAL RESEARCH METABOLIC IMPAIRMENTS AND DIAGNOSTIC IMAGING SELECTED METABOLIC BIOMARKERS AND EMERGING TECHNOLOGIES DIAGNOSTIC BIOMARKERS OF IMAGING REVASCULARIZATION IN HYPERACUTE STROKE PITFALLS IN NEUROPROTECTIVE TRANSLATIONAL RESEARCH CHALLENGES IN NEUROREGENERATIVE TRANSLATIONAL RESEARCH CHAPTER IN PEOPLE EXPERIENCING A TRANSIENT ISCHEMIC ATTACK (TIA), THE INCIDENCE OF SUBSEQUENT STROKE IS AS HIGH AS 11% OVER THE NEXT 7 DAYS AND 24–29% OVER THE FOLLOWING 5 YEARS 9 UNLIKE A STROKE, THE SYMPTOMS OF A TIA CAN RESOLVE TRIUMPHS AND WONDERS OF MODERN CHEMISTRY TBI IS THE GREATEST CAUSE OF MORTALITY AND DISABILITY IN YOUNG ADULTS IN MODERN WESTERN SOCIETIES IN THE UNITED STATES, 1 6 MILLION PEOPLE SUSTAIN A TBI EACH YEAR, APPROXIMATELY 50 000 PEOPLE DIE FROM A TBI, AND 125 PEOPLE ARE DISABLED 1 YEAR AFTER INJURY HOWEVER, THE EXACT FACTS AND FIGURES ON THE INCIDENCE, PREVALENCE, AND LONG-TERM CONSEQUENCES OF TBI ARE UN- CERTAIN, AND IT IS LIKELY THE INCIDENCE FIGURES HAVE TO BE MULTIPLIED BY 5 OR EVEN 10 IN ORDER TO INCLUDE EVERY UNREGISTERED PATIENT 15 TBI IS STRONGLY TRIUMPHS AND WONDERS OF MODERN CHEMISTRY HYPERTENSION HYPERTENSION IS THE MOST IMPORTANT MODIFIABLE STROKE RISK FACTOR, WITH AN AGE-ADJUSTED RELATIVE RISK OF APPROXIMATELY 3 AND AN ATTRIBUTABLE RISK THAT MAY BE AS HIGH AS ABOUT 50%, DEPENDING ON AGE 32 THE RISK FOR STROKE IN- CREASES PROPORTIONATELY WITH INCREASING BLOOD PRESSURE, WITH SYSTOLIC BLOOD PRESSUREZ160 MM HG OR DIASTOLIC BLOOD PRESSUREZ95 MM HG CONSTITUTING A RELATIVE RISK OF APPROXIMATELY 4 EVEN SMALL IMPROVEMENTS IN THE CONTROL OF TRIUMPHS AND WONDERS OF MODERN CHEMISTRY TIA TIA IS A SIGNIFICANT INDEPENDENT RISK FACTOR FOR ISCHEMIC STROKE AND HAS AN AVERAGE ANNUAL RISK OF APPROXIMATELY 4% 40 THE GREATEST RISK IS IN THE FIRST YEAR FOLLOWING A TIA IN ADDITION TO TIA, THE PRESENCE OF OTHER RISK FACTORS, INCLUDING OLDER AGE (460 YEARS), DIABETES MELLITUS, DURATION OF A TIA EVENT 410 MINUTES, AND SIGNS OR SYMPTOMS OF WEAKNESS AND SPEECH IMPAIRMENT TRIUMPHS AND WONDERS OF MODERN CHEMISTRY PHYSICAL ACTIVITY PHYSICAL ACTIVITY REDUCES THE RISK OF CARDIOVASCULAR DISEASE LIGHT TO MODERATE PHYSICAL ACTIVITIES SUCH AS WALKING, JOGGING, AND SWIMMING PROVIDE A STROKE REDUCTION BENEFIT 38 PHYSICAL EXERCISE MAY ALSO HAVE A BENEFICIAL E?ECT ON OTHER RISK FACTORS, SUCH AS BODY WEIGHT AND BLOOD PRESSURE TRIUMPHS AND WONDERS OF MODERN CHEMISTRY ANTIPLATELET THERAPY THE ROLE OF ASPIRIN IN THE PROPHYLAXIS OF ISCHEMIC CEREBROVASCULAR EVENTS AND STROKE HAS BEEN WELL DOCUMENTED NUMEROUS STUDIES AND REVIEWS HAVE TRIUMPHS AND WONDERS OF MODERN CHEMISTRY STATIN THERAPY DUE TO A LACK OF LARGE RANDOMIZED CLINICAL TRIALS, CURRENT GUIDELINES DO NOT PROVIDE SPECIFIC RECOMMENDATIONS ON STATIN INITIATION IN ACUTE ISCHEMIC STROKE A RECENT META-ANALYSIS INDICATES THAT PRE-STROKE STATIN IS ASSOCIATED WITH MILDER INITIAL STROKE SEVERITY, GOOD FUNCTIONAL OUTCOME, AND LOWER MORTALITY IN ADDITION, IN-HOSPITAL STATIN USE IS ASSOCIATED WITH GOOD FUNC- TIONAL OUTCOME AND LOWER MORTALITY IN PATIENTS TREATED WITH THROMBOLYSIS, STATIN USE IS ASSOCIATED WITH GOOD FUNCTIONAL OUTCOME, DESPITE AN INCREASED RISK OF SYMPTOMATIC HEMORRHAGIC TRANSFORMATION (HT) 53 WHILE THESE TRIUMPHS AND WONDERS OF MODERN CHEMISTRY HEMORRHAGIC TRANSFORMATION INTRAVENOUS TPA IS THE MOST E?ECTIVE TREATMENT OF ACUTE ISCHEMIC STROKE HOWEVER, THE MOST SIGNIFICANT CONCERN ABOUT THE USE OF TPA IS AN INCREASED RISK OF HEMORRHAGE MANY STUDIES HAVE SHOWN THROMBOLYSIS IS INDEPEND- ENTLY ASSOCIATED WITH HT 54 HT IS A SPECTRUM OF ISCHEMIA-RELATED BRAIN HEMORRHAGE AND IS A FREQUENT SPONTANEOUS COMPLICATION OF ISCHEMIC STROKE, ESPECIALLY AFTER THROMBOLYTIC THERAPY 55 HT CAN BE DIVIDED INTO HEMORRHAGIC INFARCTION (HI) AND PARENCHYMAL HEMATOMA (PH) 56 HI IS A HETEROGENEOUS HYPERDENSITY OCCUPYING A PORTION OF AN ISCHEMIC INFARCT ZONE ON COMPUTED TOMOGRAPHY (CT) IMAGES, WHEREAS PH REFERS TO A MORE HOMOGENEOUS, DENSE HEMATOMA WITH MASS E?ECT THE INCIDENCE OF SPONTANEOUS HT RANGES FROM 13% TO 43% IN CT STUDIES, WHEREAS THE INCIDENCE OF SYMPTOMATIC HT IS FROM 0 6% TO 7% IN THE PLACEBO GROUP AND FROM 6 4% TO 20% IN THE THROMBOLYSED GROUP 57,58 THE INCIDENCE DEPENDS UPON MANY FACTORS SUCH AS AGE, BLOOD GLUCOSE LEVEL, THROMBOLYTIC AGENT USED, ROUTE OF ADMINISTRATION, AND TIME WINDOW FOR THE INITIATION OF THERAPY 59,60 SYMPTOMATIC HT IMPLIES A CLEAR CAUSAL RELATIONSHIP BETWEEN CLINICAL DETERIORATION AND HT THE RATE OF OCCURRENCE OF HI IS HIGHER THAN THAT OF PH; IN A LARGE GROUP OF CONSECUTIVE PATIENTS WITH ACUTE ISCHEMIC STROKE, THE INCIDENCE OF HI WAS ABOUT 9%, WHEREAS THAT OF PH WAS ABOUT 3% 54 THE RISK OF HT INCREASES REMARKABLY WHEN MASSIVE CEREBRAL INFARCTION IS PRESENT 61,62 MASSIVE CEREBRAL INFARCTION IS OFTEN ACCOMPANIED BY SUBSTANTIAL BRAIN EDEMA, WHICH RESULTS IN COM- PRESSION OF THE PERIPHERAL VASCULATURE THE INCREASED VASCULAR PERMEABILITY BECAUSE OF PROLONGED ISCHEMIA AND HYPOXIA CAUSED BY VASCULAR COMPRESSION GREATLY INCREASES THE LIKELIHOOD OF HT AFTER RELEASE OF THE EDEMA HT OFTEN OCCURS IN THE GRAY MATTER, ESPECIALLY IN THE CEREBRAL CORTEX, BECAUSE OF ITS ABUNDANT COLLATERAL VESSELS GRAY MATTER INFARCTION IS OFTEN DUE TO A LARGE ARTERY OCCLUSION AND CAN LEAD TO MASSIVE EDEMA, CAUSING ISCHEMIC INJURY BY COMPRESSING THE SURROUNDING BLOOD VESSELS MOST INSTANCES OF WHITE MATTER INFARCTION ARE OF LACUNAR TYPE AND ARE CAUSED BY THE TERMINAL VASCULAR OCCLUSION TRIUMPHS AND WONDERS OF MODERN CHEMISTRY CONCLUSION THE INCIDENCE OF STROKE IS INCREASING IN BOTH HIGH-INCOME AND LOWER-TO- MIDDLE-INCOME COUNTRIES RELEVANT TO THIS IS THE INCREASING NUMBER OF PEOPLE, INCLUDING YOUNG CHILDREN, WHO ARE OVERWEIGHT OR OBESE THERE IS ALSO AN INCREASING PREVALENCE OF HYPERTENSION, WHICH IS A MAJOR RISK FACTOR FOR STROKE A STRONG ASSOCIATION HAS BEEN SHOWN BETWEEN TIA OR TBI AND SUB- SEQUENT STROKE THE RISK FOR STROKE IS RELATED, AMONG OTHER FACTORS, TO AGE, GENDER, AND RACE EXISTING COMORBIDITIES, SUCH AS HYPERTENSION, DIABETES MELLITUS, ATRIAL FIBRILLATION, CORONARY ARTERY DISEASE, AND OBESITY, SIGNIFICANTLY INCREASE STROKE RISK TREATMENT USING INTRAVENOUS TPA OR INTRA-ARTERIAL TPA THROMBOLYSIS HAS PROVEN TO BE E?CACIOUS IN IMPROVING OUTCOME AFTER ISCHEMIC STROKE OTHER TREATMENTS THAT HAVE BEEN SHOWN TO PROVIDE BENEFIT INCLUDE ASPIRIN AND STATINS HT IS A FREQUENT SPONTANEOUS COMPLICATION OF ISCHEMIC STROKE, ESPECIALLY AFTER THROMBOLYTIC THERAPY THE RISK OF HT IN- CREASES CONSIDERABLY WHEN MASSIVE CEREBRAL INFARCTION IS PRESENT ATRIAL FIBRILLATION AND CEREBRAL EMBOLISM ARE ASSOCIATED WITH AN INCREASED RISK OF HT HYPERGLYCEMIA HAS A MAJOR ROLE IN POST-ISCHEMIC HT LOWER LEVELS OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL AND LOWER TOTAL CHOLESTEROL ARE ASSOCIATED WITH ALL THE TYPES OF HT AND SYMPTOMATIC HT, RESPECTIVELY REFERENCES 1 V L FEIGIN, M H FOROUZANFAR, R KRISHNAMURTHI, D A BENNETT AND A E MORAN, ET AL , LANCET, 2014, 383, 245 2 M GIROUD, A JACQUIN AND Y BEJOT, LANCET, 2014, 383, 195 3 R V KRISHNAMURTHI, V L FEIGIN, M H FOROUZANFAR, G A MENSAH, M CONNOR, D A BENNETT AND A E MORAN, ET AL , LANCET GLOBAL HEALTH, 2013, 1, E259 4 OBESITY AND OVERWEIGHT WHO FACT SHEET NO 311 JANUARY 2015 HTTP:// WWW WHO INT/MEDIACENTRE/FACTSHEETS/FS311/EN/ (ACCESSED 4 MAY 2017) 5 A B MITCHELL, J W COLE, P F MCARDLE, Y C CHENG, K A RYAN, M J SPARKS, B D MITCHELL AND S J KITTNER, STROKE, 2015, 46, DOI: 10 1161/STROKEAHA 115 008940 TRIUMPHS AND WONDERS OF MODERN CHEMISTRY 6 WORLD HEALTH STATISTICS, 2012 REPORT: INCREASE OF HYPERTENSION AND DIABETES HTTP://WWW EURO WHO INT/EN/HEALTH-TOPICS/NONCOMMUNICABLE- DISEASES/DIABETES/NEWS/NEWS/2012/5/WORLD-HEALTH-STATISTICS-2012-REPORT- INCREASE-OF-HYPERTENSION-AND-DIABETES (ACCESSED 9 MAY 2017) 7 NEW DATA HIGHLIGHT INCREASES IN HYPERTENSION, DIABETES INCIDENCE HTTP:// WWW WHO INT/MEDIACENTRE/NEWS/RELEASES/2012/WORLD_HEALTH_STAT- ISTICS_20120516/EN/ (ACCESSED 9 MAY 2017) 8 B B JOHANSSON, CLIN EXP PHARMACOL PHYSIOL , 1999, 26, 563 9 A NANDA, TRANSIENT ISCHEMIC ATTACK, 2015 HTTP://EMEDICINE MEDSCAPE COM/ARTICLE/1910519-OVERVIEW (ACCESSED 9 MAY 2017) 10 TRANSIENT ISCHEMIC ATTACK HTTPS://EN WIKIPEDIA ORG/WIKI/TRANSIENT_ ISCHEMIC_ATTACK (ACCESSED 9 MAY 2017) 11 J F BURKE, J L STULE, L E SKOLARUS, E D SEARS, D B ZAHURANEC AND L B MORGENSTERN, NEUROLOGY, 2013, 81, 33 12 J D EASTON, J L SAVER, G W ALBERS, M J ALBERTS, S CHATURVEDI, E FELDMANN AND T S HATSUKAMI, ET AL , STROKE, 2009, 409, 2276 13 R L SACCO, S E KASNER, J P BRODERICK, L R CAPLAN, J J CONNORS, A CULEBRAS AND M S ELKIND, ET AL , STROKE, 2013, 44, 2064 14 S T DAWODU, TRAUMATIC BRAIN INJURY (TBI) - DEFINITION AND PATHOPHY- SIOLOGY HTTP://EMEDICINE MEDSCAPE COM/ARTICLE/326510-OVERVIEW (ACCESSED 9 MAY 2017) 15 G M RIBBERS, IN BRAIN INJURY: LONG TERM OUTCOME AFTER TRAUMATIC BRAIN INJURY, ED J H STONE AND M BLOUIN, INTERNATIONAL ENCYCLOPEDIA OF REHABILITATION, 2010 HTTP://CIRRIE BU?ALO EDU/ENCYCLOPEDIA/EN/ARTICLE/ 338/ (ACCESSED 4 MAY 2017) 16 S C JOHNSTON, P B FAYAD, P B GORELICH, D F HANLEY, P SHWAYDER, D VAN HUSEN AND T WEISKOPF, NEUROLOGY, 2003, 60, 1429 17 T R PRICE, B PSATY, D O’LEARY, G BURKE AND J GARDIN, ANN EPIDEMIOL , 1993, 3, 504 18 J F TOOLE, L E CHAMBLESS, G HEISS, H A TYROLER AND C C PATON, ANN EPIDEMIOL , 1993, 3, 500 19 B OVBIAGELE, C S KIDWELL AND J L SAVER, STROKE, 2003, 34, 919 20 AHS/ASA STATISTICAL FACT SHEET, 2016, UPDATE HTTP://WWW STROKEASSOCIATION ORG/STROKEORG/ABOUTSTROKE/IMPACT-OF-STROKE-STROKE- STATISTICS_UCM_310728_ARTICLE JSP# WQPTSOWLNSM (ACCESSED 4 MAY 2017) 21 G W ALBERS, L R CAPLAN, J D EASTON, P B FAYAD, J P MOHR, J L SAVER AND D G SHERMAN, N ENG J MED , 2002, 347, 1713 22 P B GORELICK, CLIN CARDIOL , 2004, 27(SUPPL II), II–4 23 S CRUZ-FLORES, A RABINSTEIN, J BILLER, M S ELKIND, P GRI?TH, P B GORELICK AND G HOWARD, ET AL , STROKE, 2011, 42, 2091 24 THE NEW JERSEY COMPREHENSIVE STROKE CENTER AT UNIVERSITY HOSPITAL TYPES OF STROKE HTTP://WWW UHNJ ORG/STROKE/TYPES HTM (ACCESSED 4 MAY 2017) 25 A ARBOIX AND J ALIO, CURR CARDIOL REV , 2010, 6, 150 26 R L SACCO, IN CURRENT REVIEW OF CEREBROVASCULAR DISEASE, ED M FISHER AND J BOGOUSSLAVSKY, CURRENT MEDICINE, PHILADELPHIA, PA, 1993, PP 3–14 TRIUMPHS AND WONDERS OF MODERN CHEMISTRY 27 J J BAZARIAN, I CERNAK, L NOBLE-HAEUSSLEIN, D S POTOLICCHIO AND N TEMKIN, J HEAD TRAUMA REHABIL , 2009, 24, 439 28 R D BROWN, G W PETTY, M O’FALLON, D O WIEBERS AND J P WHISNANT, STROKE, 1998, 29, 2109 29 G HOWARD AND V J HOWARD, IN THE PREVENTION OF STROKE, ED P B GORELICH AND M ALTER, PARTHENON PUBLISHING, NEW YORK, NY, 2002, PP 1–10 30 G W PETTY, R D BROWN, J P WHISNANT, J D SICKS, W M O’FALLON AND D O WIEBERS, STROKE, 1999, 30, 2513 31 D WOO, J GEBEL, R MILLER, R KOTHARI, T BROTT, J KHOURY AND S SALISBURY, ET AL , STROKE, 1999, 30, 2517 32 R L SACCO, NEUROLOGY, 1997, 49(5 SUPPL 4), S39 33 CDC NATIONAL CENTER FOR HEALTH STATISTICS HYPERTENSION AMONG ADULTS IN THE UNITED STATES: NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY, 2011–2012 HTTPS://WWW CDC GOV/NCHS/PRODUCTS/DATABRIEFS/DB133 HTM (ACCESSED 9 MAY 2017) 34 D L COHEN AND R R TOWNSEND, J CLIN HYPERTENS , 2013, 15, 143 35 THE SEVENTH REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, EVALUATION, AND TREATMENT OF HIGH BLOOD PRESSURE HTTP:// WWW NCBI NLM NIH GOV/BOOKS/NBK9626/ (ACCESSED 4 MAY 2017) 36 C M HELGASON AND P A WOLF, CIRCULATION, 1997, 96, 701 37 AMERICAN DIABETES ASSOCIATION STATISTICS ABOUT DIABETES HTTP://WWW DIABETES ORG/DIABETES-BASICS/STATISTICS/ (ACCESSED 9 MAY 2017) 38 L B GOLDSTEIN, R ADAMS, K BECKER, C D FURBERG, P B GORELICK, G HADEMENOS AND M HILL, ET AL , CIRCULATION, 2001, 103, 163 39 P B GORELICH, R L SACCO, D SMITH, M ALBERTS, L MUSTONE-ALEXANDER, D RADAR AND J L ROSS, ET AL , JAMA, 1999, 281, 1112 40 R L SACCO, E J BENJAMIN, J P BRODERICK, M DYKEN, J D EASTON, W M FEINBERRG AND L B GOLDSTEIN, ET AL , STROKE, 1997, 28, 1507 41 P A WOLF, R D ABBOTT AND W B KANNEL, STROKE, 1991, 22, 983 42 Z G NADAREISHVILI, P M ROTHWELL, V BELETSKY, A PAGNIELLO AND J W NORRIS, ARCH NEUROL , 2002, 59, 1162 43 D MOZA?ARIAN, S K KUMANYIKA, R N LEMAITRE, J L OLSON, G L BURKE AND D S SISCOVICK, JAMA, 2003, 289, 1659 44 H ISO, D R JACOBS, D WENTWORTH, J D NEATON AND J D COHEN, N ENG J MED , 1989, 320, 904 45 A PRADHAN, J E MANSON, J E ROSSOUW, D S SISCOVICK, C P MOUTON, N RIFAI, R B WALLACE, R D JACKSON, M B PETTINGER AND P M RIDKER, JAMA, 2002, 288, 980 46 K M CHAPMAN, A R WOOLFENDEN, D GRAEB, D C JOHNSTON, J BECKMAN, M SCHULZER AND P A TEAL, STROKE, 2000, 31, 2920 47 A FURLAN, R HIGASHIDA, L WECHSLER, M GENT, H ROWLEY, C KASE AND M PESSIN, ET AL , JAMA, 1999, 282, 2003 48 G J DEL ZOPPO, J L SAVER, E C JAUCH AND H P ADAMS, STROKE, 2009, 40, 2945 49 H MESTRE, Y COHEN-MINIAN, D ZAJARIAS-FAINSOID AND A IBARRA, IN NEURODEGENERATIVE DISEASES, ED UDAY KISHORE, INTECH, 2013, P 581 TRIUMPHS AND WONDERS OF MODERN CHEMISTRY 50 J G TIJSSEN, NEUROLOGY, 1998, 51(3 SUPPL 3), S15 51 M G LANSBERG, M J O’DONNELL, P KHATRI, E S LANG, M N NGUYEN- HUYNH, N E SCHWARTZ AND F A SONNENBERG, ET AL , CHEST, 2012, 141(2 SUPPL ), E601S 52 C S MILLER, S M GRANDI, A SHIMONY, K B FILION AND M J EISENBERG, AM J CARDIOL , 2012, 110, 453 53 K S HONG AND J S LEE, J STROKE, 2015, 17, 282 54 M PACIARONI, G AGNELLI, F COREA, W AGENO, A ALBERTI, A LANARTI AND V CASO, ET AL , STROKE, 2008, 39, 2249 55 E S SUSSMAN AND E S CONNOLLY, FRONT NEUROL , 2013, 4, 69 56 P TROUILLAS AND R VON KUMMER, STROKE, 2006, 37, 556 57 A JAILLARD, C CORNU, A DURIEUX, T MOULIN, F BOUTITIE, K R LEES AND M HOMMEL, STROKE, 1999, 30, 1326 58 O Y BANG, J L SAVER, S J KIM, G M KIM, C S CHUNG, B OVBIAGELE AND K H LEE, ET AL , STROKE, 2011, 42, 2235 59 C S KIDWELL, J L SAVER, J CARNEADO, J SAYRE, S STARKMAN, G DUCKWILER AND Y P GOBIN, ET AL , STROKE, 2002, 33, 717 60 THE NINDS T-PA STROKE STUDY GROUP, INTRACEREBRAL HEMORRHAGE AFTER INTRAVENOUS T-PA THERAPY FOR ISCHEMIC STROKE, STROKE, 1997, 28, 2109 61 B G WANG, N YANG, M LIN AND B LU, CELL BIOCHEM BIOPHYS , 2014, 70, 135 62 L KERENYI, L KARDOS, J SZASZ, S SZATMARI, D BERECZKI, K HEGEDUS AND L CSIBA, EUR J NEUROL , 2006, 13, 1251 63 S TAN, D WANG, M LIU, S ZHANG, B WU AND B LIU, J NEUROL , 2014, 261, 905 64 R G NOGUEIRA, R GUPTA, T G JOVIN, E I LEVY, D S LIEBESKIND, O O ZAIDAT AND A RAI, ET AL , J NEUROINTERVENT SURG , 2015, 7, 16 65 J H LEE, K Y PARK, J H SHIN, J K CHA, H Y KIM, J H KWON AND H G OH, ET AL , EUR NEUROL , 2010, 64, 193 66 Y XING, X JIANG, Y YANG AND G XI, ACTA NEUROCHIR SUPPL , 2011, 111, 49 67 M PACIARONI, G AGNELLI, V CASO, F COREA, W AGENO, A ALBERTI AND A LANARI ET AL , CEREBROVASC DIS , 2009, 28, 119 68 H KUNTE, M A BUSCH, K TROSTDORF, B VOLLNBERG, L HARMS, R I MEHTA AND R J CASTELLANI, ET AL , ANN NEUROL , 2012, 72, 799 69 K NARDI, D LEYS, P EUSEBI, C CORDONNIER, S GAUTIER, H HENON AND R BORDET, CEREBROVAC DIS EXTRA, 2011, 1, 130 70 O Y BANG, J L SAVER, D S LIEBESKIND, S STARKMAN, P VILLABLANCA, N SALAMON AND B BUCK ET AL , NEUROLOGY, 2007, 68, 737 71 M D’AMELIO, V TERRUSO, G FAMOSO, P RAGONESE, P ARIDON AND G SAVETTIERI, CEREBROVASC DIS , 2011, 32, 234 72 GLASGOW COMA SCALE – ADULT HTTP://EMEDICINE MEDSCAPE COM/ARTICLE/ 2172603-OVERVIEW (ACCESSED 9 MAY 2017) 73 TRAUMATIC BRAIN INJURY TREATMENT AND DRUGS HTTP://WWW MAYOCLINIC ORG/DISEASES-CONDITIONS/TRAUMATIC-BRAIN-INJURY/BASICS/TREATMENT/CON- 20029302 (ACCESSED 9 MAY 2017) 74 TREATMENTS FOR TBI HTTP://WWW TRAUMATICBRAININJURY COM/TREATMENTS- FOR-TBI/ (ACCESSED 9 MAY 2017) TRIUMPHS AND WONDERS OF MODERN CHEMISTRY THE PROGRESSION OF THE INFARCT LESION IS DIRECTLY LINKED TO THE PROGNOSIS OF ISCHEMIC STROKE PATIENTS THE CEREBROVASCULAR UNITS, WHICH CONSIST OF GLIAL CELLS, ENDOTHELIAL CELLS, PERICYTES, AND NEURONS,3–5 ARE DAMAGED BY BRAIN IS- CHEMIA, LEADING TO BLOOD–BRAIN BARRIER (BBB) BREAKDOWN IN COMBINATION WITH THE DYSFUNCTION OF THE BBB, VARIOUS BLOOD-BORNE IMMUNE CELLS INFILTRATE INTO THE ISCHEMIC BRAIN FROM DISRUPTED VESSELS THESE INFILTRATING IMMUNE CELLS AND THE INJURED BRAIN CELLS PRODUCE INFLAMMATORY MEDIATORS THAT EXAGGERATE BRAIN EDEMA OR DIRECTLY PROMOTE THE DEATH OF BRAIN CELLS IN THE PENUMBRA, RESULTING IN THE SECONDARY PROGRESSION OF THE INFARCT LESION E?ECTORS OF INNATE IMMUNITY, ESPECIALLY MACROPHAGES AND T CELLS, APPEAR TO PLAY A PIVOTAL ROLE IN POST-ISCHEMIC INFLAMMATION 6,7 IT IS KNOWN THAT MACROPHAGES AND NEUTROPHILS ARE KEY PLAYERS IN THE VARIOUS PROCESSES OF BRAIN ISCHEMIA CAUSES THE RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PAT- TERNS (DAMPS) FROM BRAIN CELLS IN THOSE DAMPS, HMGB1, HEAT SHOCK PROTEIN (HSP), PEROXIREDOXIN (PRX), AND HEPARAN SULFATE BIND TO TOLL-LIKE RECEPTOR 2 (TLR2) AND TLR4, MRNA COMPLEXES TO TLR3, AND DNA COMPLEXES TO TLR9 WHILE TLR3 ACTIVATES TRIF AS THE DOWNSTREAM ADAPTOR, TRL2, TLR4, AND TLR9 ACTIVATE MYD88, FORMING A COMPLEX WITH INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE (IRAK) ADAPTED FROM NEUROSCIENCE, 158, B J MARSH, R L WILLIAMS-KARNESKY AND M P STENZEL-POORE, TOLL-LIKE RECEPTOR SIGNALING IN ENDOGENOUS NEURO- PROTECTION AND STROKE, 14, COPYRIGHT (2009), WITH PERMISSION FROM ELSEVIER TRIUMPHS AND WONDERS OF MODERN CHEMISTRY