1 64 179 A HIGH-THROUGHPUT SCREENING ASSAY FOR SILENCING ESTABLISHED HIV-1 MACROPHAGE INFECTION IDENTIFIES NUCLEOSIDE ANALOGS THAT PERTURB H3K9ME3 ON PROVIRAL GENOMES. HIV-INFECTED MACROPHAGES ARE LONG-LIVED CELLS THAT REPRESENT A BARRIER TO FUNCTIONAL CURE. ADDITIONALLY, LOW-LEVEL VIRAL EXPRESSION BY CENTRAL NERVOUS SYSTEM (CNS) MACROPHAGES CONTRIBUTES TO NEUROCOGNITIVE DEFICITS THAT DEVELOP DESPITE ANTIRETROVIRAL THERAPY (ART). WE RECENTLY IDENTIFIED H3K9ME3 AS AN ATYPICAL EPIGENETIC MARK ASSOCIATED WITH CHRONIC HIV INFECTION IN MACROPHAGES. THUS, STRATEGIES ARE NEEDED TO SUPPRESS HIV-1 EXPRESSION IN MACROPHAGES, BUT THE UNIQUE MYELOID ENVIRONMENT AND THE RESPONSIBLE MACROPHAGE/CNS-TROPIC STRAINS REQUIRE CELL/STRAIN-SPECIFIC APPROACHES. HERE, WE GENERATED AN HIV-1 REPORTER VIRUS FROM A CNS-DERIVED STRAIN WITH INTACT AUXILIARY GENES EXPRESSING DESTABILIZED LUCIFERASE. WE EMPLOYED THIS REPORTER VIRUS IN POLYCLONAL INFECTION OF PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES (MDM) FOR A HIGH-THROUGHPUT SCREEN (HTS) TO IDENTIFY COMPOUNDS THAT SUPPRESS VIRUS EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. SCREENING ~6,000 KNOWN DRUGS AND COMPOUNDS YIELDED 214 HITS. A SECONDARY SCREEN WITH 10-DOSE TITRATION IDENTIFIED 24 MEETING CRITERIA FOR HIV-SELECTIVE ACTIVITY. USING THREE REPLICATION-COMPETENT CNS-DERIVED MACROPHAGE-TROPIC HIV-1 ISOLATES AND VIRAL GENE EXPRESSION READOUT IN MDM, WE CONFIRMED THE EFFECT OF THREE PURINE ANALOGS, NELARABINE, FLUDARABINE, AND ENTECAVIR, SHOWING THE SUPPRESSION OF HIV-1 EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. NELARABINE INHIBITED THE FORMATION OF H3K9ME3 ON HIV GENOMES IN MACROPHAGES. THUS, THIS NOVEL HTS ASSAY CAN IDENTIFY SUPPRESSORS OF HIV-1 TRANSCRIPTION IN ESTABLISHED MACROPHAGE INFECTION, SUCH AS NUCLEOSIDE ANALOGS AND HDAC INHIBITORS, WHICH MAY BE LINKED TO H3K9ME3 MODIFICATION. THIS SCREEN MAY BE USEFUL TO IDENTIFY NEW METABOLIC AND EPIGENETIC AGENTS THAT AMELIORATE HIV-DRIVEN NEUROINFLAMMATION IN PEOPLE ON ART OR PREVENT VIRAL RECRUDESCENCE FROM MACROPHAGE RESERVOIRS IN STRATEGIES TO ACHIEVE ART-FREE REMISSION. IMPORTANCE MACROPHAGES INFECTED BY HIV-1 ARE A LONG-LIVED RESERVOIR AND A BARRIER IN CURRENT EFFORTS TO ACHIEVE HIV CURE AND ALSO CONTRIBUTE TO NEUROCOGNITIVE COMPLICATIONS IN PEOPLE DESPITE ANTIRETROVIRAL THERAPY (ART). SILENCING HIV EXPRESSION IN THESE CELLS WOULD BE OF GREAT VALUE, BUT THE REGULATION OF HIV-1 IN MACROPHAGES DIFFERS FROM T CELLS. WE DEVELOPED A NOVEL HIGH-THROUGHPUT SCREEN FOR COMPOUNDS THAT CAN SILENCE ESTABLISHED INFECTION OF PRIMARY MACROPHAGES, AND IDENTIFIED AGENTS THAT DOWNREGULATE VIRUS EXPRESSION AND ALTER PROVIRUS EPIGENETIC PROFILES. THE SIGNIFICANCE OF THIS ASSAY IS THE POTENTIAL TO IDENTIFY NEW DRUGS THAT ACT IN THE UNIQUE MACROPHAGE ENVIRONMENT ON RELEVANT VIRAL STRAINS, WHICH MAY CONTRIBUTE TO ADJUNCTIVE TREATMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS AND/OR PREVENT VIRAL REBOUND IN EFFORTS TO ACHIEVE ART-FREE REMISSION OR CURE. 2023 2 5302 31 PROTEIN-C REACTIVE AS BIOMARKER PREDICTOR OF SCHIZOPHRENIA PHASES OF ILLNESS? A SYSTEMATIC REVIEW. BACKGROUND: SCHIZOPHRENIA IS A COMPLEX ILLNESS IN WHICH GENETIC, ENVIRONMENTAL, AND EPIGENETIC COMPONENTS HAVE BEEN IMPLICATED. HOWEVER, RECENTLY, PSYCHIATRIC DISORDERS APPEAR TO BE RELATED TO A CHRONIC INFLAMMATORY STATE, AT THE LEVEL OF SPECIFIC CEREBRAL AREAS WHICH HAVE BEEN FOUND AS WELL IMPAIRED AND RESPONSIBLE FOR SCHIZOPHRENIA SYMPTOMATOLOGY. HENCE, A ROLE OF INFLAMMATORY MEDIATORS AND CYTOKINES HAS BEEN AS WELL DEFINED. ACCORDINGLY, THE ROLE OF AN ACUTE INFLAMMATORY PHASE PROTEIN, THE C-REACTIVE PROTEIN (CRP) HAS BEEN RECENTLY INVESTIGATED. OBJECTIVE: THE OBJECTIVE OF THE PRESENT STUDY IS TO EVALUATE HOW PCR MAY REPRESENT A BIOMARKER IN SCHIZOPHRENIA, I.E. CORRELATED WITH ILLNESS PHASES AND/OR CLINICAL MANIFESTATION AND/OR PSYCHOPATHOLOGICAL SEVERITY. METHODS: A SYSTEMATIC REVIEW WAS HERE CARRIED OUT BY SEARCHING THE FOLLOWING KEYWORDS ((C-REACTIVE PROTEIN AND ((SCHIZOPHRENIA) OR (PSYCHOTIC DISORDER))) FOR THE TOPICS 'PCR' AND 'SCHIZOPHRENIA', BY USING MESH TERMS. RESULTS: AN IMMUNE DYSFUNCTION AND INFLAMMATION HAVE BEEN DESCRIBED AMONGST SCHIZOPHRENIC PATIENTS. FINDINGS REPORTED ELEVATED CRP LEVELS IN SCHIZOPHRENIA, MAINLY CORRELATED WITH THE SEVERITY OF ILLNESS AND DURING THE RECRUDESCENT PHASE. CRP LEVELS ARE HIGHER WHEN CATATONIC FEATURES, NEGATIVE SYMPTOMATOLOGY AND AGGRESSIVENESS ARE ASSOCIATED. CRP LEVELS APPEARED NOT TO BE RELATED TO SUICIDAL BEHAVIOUR AND IDEATION. CONCLUSION: CRP AND ITS BLOOD LEVELS HAVE BEEN REPORTED HIGHER AMONGST SCHIZOPHRENIC PATIENTS, BY SUGGESTING A ROLE OF INFLAMMATION IN THE PATHOGENESIS OF SCHIZOPHRENIA. FURTHER STUDIES ARE NEEDED TO BETTER UNDERSTAND IF CRP MAY BE CONSIDERED A BIOMARKER IN SCHIZOPHRENIA. 2018 3 6743 42 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2013 4 6742 36 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 5 1810 26 EFFECTS OF ANTIPSYCHOTICS ON THE BDNF IN SCHIZOPHRENIA. BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IS INVOLVED IN THE DEVELOPMENT OF THE BRAIN, AND LIKELY INFLUENCES THE NEUROPLASTICITY IN SCHIZOPHRENIA. BDNF IS ALSO BELIEVED TO INTERACT WITH OTHER NEUROTRANSMITTER SYSTEMS IMPLICATED IN SCHIZOPHRENIA, SUCH AS DOPAMINE, GLUTAMATE, SEROTONIN AND GABA. THEREFORE, BDNF IS A CANDIDATE GENE FOR SCHIZOPHRENIA. IN PAST DECADES, THE BLOOD (SERUM OR PLASMA) BDNF PROTEIN LEVELS AND BDNF GENE ALLELES AND GENOTYPES TO THE CLINICAL FEATURES OF SCHIZOPHRENIA, SUCH AS AGE OF ONSET, CLINICAL SUBTYPES, SYMPTOM SEVERITY, AND DRUG RESPONSE, HAVE BEEN EVALUATED AMONG DIFFERENT POPULATIONS. HOWEVER, THE RESULTS ARE STILL INCONSISTENT. FURTHER, DIFFERENT DRUGS HAVE BEEN REPORTED TO HAVE DIFFERENT EFFECTS ON BDNF PROTEIN LEVELS. A CROSS-SECTIONAL SURVEY REVEALED THAT SERUM BDNF LEVELS IN CHRONIC SCHIZOPHRENIC PATIENTS TREATED WITH CLOZAPINE EXCEEDED THOSE OF PATIENTS TREATED WITH RISPERIDONE OR WITH TYPICAL ANTIPSYCHOTICS. IN RECENT TIMES, BDNF EPIGENETIC STUDIES HAVE ALSO BEEN CONDUCTED IN CLINICAL STUDIES OF SCHIZOPHRENIA TO ADDRESS THE QUESTION OF WHY PATIENTS WITH THE SAME GENE GENOTYPE AND ALLELES HAVE DIFFERENT CLINICAL PRESENTATIONS. IN ADDITION, THE EFFECTS OF DIFFERENT ANTIPSYCHOTIC DRUGS ON GENE METHYLATION AND PROTEIN ACETYLATION HAVE ALSO BEEN REPORTED. IN CONCLUSION, MORE DATA ARE NEEDED REGARDING BDNF IN THE BRAIN AND IN PERIPHERAL BLOOD, INCLUDING PROTEIN LEVELS, SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC REGULATION, AND CLINICAL DATA IN ORDER TO UNDERSTAND THE ROLE OF BDNF IN SCHIZOPHRENIA. 2013 6 3380 46 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY. 2023 7 119 25 A SYSTEMATIC EXAMINATION OF BRAIN VOLUMETRIC ABNORMALITIES IN RECENT-ONSET SCHIZOPHRENIA USING VOXEL-BASED, SURFACE-BASED AND REGION-OF-INTEREST-BASED MORPHOMETRIC ANALYSES. BACKGROUND: BRAIN MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA HAVE BEEN EXTENSIVELY REPORTED IN THE LITERATURE. WHOLE-BRAIN VOLUMETRIC REDUCTIONS ARE ALMOST UNIVERSALLY REPORTED BY MOST STUDIES IRRESPECTIVE OF THE CHARACTERISTICS OF THE SAMPLES STUDIED (E.G., CHRONIC/RECENT-ONSET; MEDICATED/NEUROLEPTIC-NAIVE ETC.). HOWEVER, THE SAME CANNOT BE SAID OF THE REPORTED REGIONAL MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA. WHILE CERTAIN REGIONAL MORPHOMETRIC ABNORMALITIES ARE MORE FREQUENTLY REPORTED THAN OTHERS, THERE ARE NO SUCH ABNORMALITIES THAT ARE UNIVERSALLY REPORTED ACROSS STUDIES. VARIABILITY OF SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS ACROSS STUDY SAMPLES AS WELL AS TECHNICAL AND METHODOLOGICAL ISSUES RELATED TO ACQUISITION AND ANALYSES OF BRAIN STRUCTURAL IMAGES MAY CONTRIBUTE TO INCONSISTENCY OF BRAIN MORPHOMETRIC FINDINGS IN SCHIZOPHRENIA. THE OBJECTIVE OF THE PRESENT STUDY THEREFORE WAS TO SYSTEMATICALLY EXAMINE BRAIN MORPHOMETRY IN PATIENTS WITH RECENT-ONSET SCHIZOPHRENIA TO FIND OUT IF THERE ARE SIGNIFICANT WHOLE-BRAIN OR REGIONAL VOLUMETRIC DIFFERENCES DETECTABLE AT THE APPROPRIATE SIGNIFICANCE THRESHOLD, AFTER ATTEMPTING TO CONTROL FOR VARIOUS CONFOUNDING FACTORS THAT COULD IMPACT BRAIN VOLUMES. METHODS: STRUCTURAL MAGNETIC RESONANCE IMAGES OF 90 SUBJECTS (SCHIZOPHRENIA = 45; HEALTHY SUBJECTS = 45) WERE ACQUIRED USING A 3 TESLA MAGNET. MORPHOMETRIC ANALYSES WERE CARRIED OUT FOLLOWING STANDARD ANALYSES PIPELINES OF THREE MOST COMMONLY USED STRATEGIES, VIZ., WHOLE-BRAIN VOXEL-BASED MORPHOMETRY, WHOLE-BRAIN SURFACE-BASED MORPHOMETRY, AND BETWEEN-GROUP COMPARISONS OF REGIONAL VOLUMES GENERATED BY AUTOMATED SEGMENTATION AND PARCELLATION. RESULTS: IN OUR SAMPLE OF PATIENTS HAVING RECENT-ONSET SCHIZOPHRENIA WITH LIMITED NEUROLEPTIC EXPOSURE, THERE WERE NO SIGNIFICANT WHOLE BRAIN OR REGIONAL BRAIN MORPHOMETRIC ABNORMALITIES NOTED AT THE APPROPRIATE STATISTICAL SIGNIFICANCE THRESHOLDS WITH OR WITHOUT INCLUDING AGE, GENDER AND INTRACRANIAL VOLUME OR TOTAL BRAIN VOLUME IN THE STATISTICAL ANALYSES. CONCLUSIONS: IN THE BACKGROUND OF THE CONFLICTING FINDINGS IN THE LITERATURE, OUR FINDINGS INDICATE THAT BRAIN MORPHOMETRIC ABNORMALITIES MAY NOT BE DIRECTLY RELATED TO THE SCHIZOPHRENIA PHENOTYPE. ANALYSIS OF THE REASONS FOR THE INCONSISTENT RESULTS ACROSS STUDIES AS WELL AS CONSIDERATION OF ALTERNATE SOURCES OF VARIABILITY OF BRAIN MORPHOLOGY IN SCHIZOPHRENIA SUCH AS EPISTATIC AND EPIGENETIC MECHANISMS COULD PERHAPS ADVANCE OUR UNDERSTANDING OF STRUCTURAL BRAIN ALTERATIONS IN SCHIZOPHRENIA. 2015 8 2123 39 EPIGENETIC IMPACTS OF STRESS PRIMING OF THE NEUROINFLAMMATORY RESPONSE TO SARIN SURROGATE IN MICE: A MODEL OF GULF WAR ILLNESS. BACKGROUND: GULF WAR ILLNESS (GWI) IS AN ARCHETYPAL, MEDICALLY UNEXPLAINED, CHRONIC CONDITION CHARACTERISED BY PERSISTENT SICKNESS BEHAVIOUR AND NEUROIMMUNE AND NEUROINFLAMMATORY COMPONENTS. AN ESTIMATED 25-32% OF THE OVER 900,000 VETERANS OF THE 1991 GULF WAR FULFIL THE REQUIREMENTS OF A GWI DIAGNOSIS. IT HAS BEEN HYPOTHESISED THAT THE HIGH PHYSICAL AND PSYCHOLOGICAL STRESS OF COMBAT MAY HAVE INCREASED VULNERABILITY TO IRREVERSIBLE ACETYLCHOLINESTERASE (ACHE) INHIBITORS LEADING TO A PRIMING OF THE NEUROIMMUNE SYSTEM. A NUMBER OF STUDIES HAVE LINKED HIGH LEVELS OF PSYCHOPHYSIOLOGICAL STRESS AND TOXICANT EXPOSURES TO EPIGENETIC MODIFICATIONS THAT REGULATE GENE EXPRESSION. RECENT RESEARCH IN A MOUSE MODEL OF GWI HAS SHOWN THAT PRE-EXPOSURE WITH THE STRESS HORMONE CORTICOSTERONE (CORT) CAUSES AN INCREASE IN EXPRESSION OF SPECIFIC CHEMOKINES AND CYTOKINES IN RESPONSE TO DIISOPROPYL FLUOROPHOSPHATE (DFP), A SARIN SURROGATE AND IRREVERSIBLE ACHE INHIBITOR. METHODS: C57BL/6J MICE WERE EXPOSED TO CORT FOR 4 DAYS, AND EXPOSED TO DFP ON DAY 5, BEFORE SACRIFICE 6 H LATER. THE TRANSCRIPTOME WAS EXAMINED USING RNA-SEQ, AND THE EPIGENOME WAS EXAMINED USING REDUCED REPRESENTATION BISULFITE SEQUENCING AND H3K27AC CHIP-SEQ. RESULTS: WE SHOW TRANSCRIPTIONAL, HISTONE MODIFICATION (H3K27AC) AND DNA METHYLATION CHANGES IN GENES RELATED TO THE IMMUNE AND NEURONAL SYSTEM, POTENTIALLY RELEVANT TO NEUROINFLAMMATORY AND COGNITIVE SYMPTOMS OF GWI. FURTHER EVIDENCE SUGGESTS ALTERED PROPORTIONS OF MYELINATING OLIGODENDROCYTES IN THE FRONTAL CORTEX, PERHAPS CONNECTED TO WHITE MATTER DEFICITS SEEN IN GWI SUFFERERS. CONCLUSIONS: OUR FINDINGS MAY REFLECT THE EARLY CHANGES WHICH OCCURRED IN GWI VETERANS, AND WE OBSERVE ALTERATIONS IN SEVERAL PATHWAYS ALTERED IN GWI SUFFERERS. THESE CLOSE LINKS TO CHANGES SEEN IN VETERANS WITH GWI INDICATES THAT THIS MODEL REFLECTS THE ENVIRONMENTAL EXPOSURES RELATED TO GWI AND MAY PROVIDE A MODEL FOR BIOMARKER DEVELOPMENT AND TESTING FUTURE TREATMENTS. 2018 9 4758 41 NOVEL TREATMENT STRATEGIES TARGETING MYELIN AND OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA. OLIGODENDROCYTES ARE THE GLIAL CELLS RESPONSIBLE FOR THE FORMATION OF THE MYELIN SHEATH AROUND AXONS. DURING NEURODEVELOPMENT, OLIGODENDROCYTES UNDERGO MATURATION AND DIFFERENTIATION, AND LATER REMYELINATION IN ADULTHOOD. ABNORMALITIES IN THESE PROCESSES HAVE BEEN ASSOCIATED WITH BEHAVIORAL AND COGNITIVE DYSFUNCTIONS AND THE DEVELOPMENT OF VARIOUS MENTAL ILLNESSES LIKE SCHIZOPHRENIA. SEVERAL STUDIES HAVE IMPLICATED OLIGODENDROCYTE DYSFUNCTION AND MYELIN ABNORMALITIES IN THE DISORDER, TOGETHER WITH ALTERED EXPRESSION OF MYELIN-RELATED GENES SUCH AS OLIG2, CNP, AND NRG1. HOWEVER, THE MOLECULAR MECHANISMS SUBJACENT OF THESE ALTERATIONS REMAIN ELUSIVE. SCHIZOPHRENIA IS A SEVERE, CHRONIC PSYCHIATRIC DISORDER AFFECTING MORE THAN 23 MILLION INDIVIDUALS WORLDWIDE AND ITS SYMPTOMS USUALLY APPEAR AT THE BEGINNING OF ADULTHOOD. CURRENTLY, THE MAJOR THERAPEUTIC STRATEGY FOR SCHIZOPHRENIA RELIES ON THE USE OF ANTIPSYCHOTICS. DESPITE THEIR WIDESPREAD USE, THE EFFECTS OF ANTIPSYCHOTICS ON GLIAL CELLS, ESPECIALLY OLIGODENDROCYTES, REMAIN UNCLEAR. THUS, IN THIS REVIEW WE HIGHLIGHT THE CURRENT KNOWLEDGE REGARDING OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA, COMPILING DATA FROM (EPI)GENETIC STUDIES AND UP-TO-DATE MODELS TO INVESTIGATE THE ROLE OF OLIGODENDROCYTES IN THE DISORDER. IN ADDITION, WE EXAMINED POTENTIAL TARGETS CURRENTLY INVESTIGATED FOR THE IMPROVEMENT OF SCHIZOPHRENIA SYMPTOMS. RESEARCH IN THIS AREA HAS BEEN INVESTIGATING POTENTIAL BENEFICIAL COMPOUNDS, INCLUDING THE D-AMINO ACIDS D-ASPARTATE AND D-SERINE, THAT ACT AS NMDA RECEPTOR AGONISTS, MODULATING THE GLUTAMATERGIC SIGNALING; THE ANTIOXIDANT N-ACETYLCYSTEINE, A PRECURSOR IN THE SYNTHESIS OF GLUTATHIONE, PROTECTING AGAINST THE REDOX IMBALANCE; AS WELL AS LITHIUM, AN INHIBITOR OF GLYCOGEN SYNTHASE KINASE 3BETA (GSK3BETA) SIGNALING, CONTRIBUTING TO OLIGODENDROCYTE SURVIVAL AND FUNCTIONING. IN CONCLUSION, THERE IS STRONG EVIDENCE LINKING OLIGODENDROCYTE DYSFUNCTION TO THE DEVELOPMENT OF SCHIZOPHRENIA. HENCE, A BETTER UNDERSTANDING OF OLIGODENDROCYTE DIFFERENTIATION, AS WELL AS THE EFFECTS OF ANTIPSYCHOTIC MEDICATION IN THESE CELLS, COULD HAVE POTENTIAL IMPLICATIONS FOR UNDERSTANDING THE DEVELOPMENT OF SCHIZOPHRENIA AND FINDING NEW TARGETS FOR DRUG DEVELOPMENT. 2020 10 6523 39 TRANSCRIPTIONAL AND EPIGENETIC REGULATORY MECHANISMS AFFECTING HTLV-1 PROVIRUS. HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1) IS A RETROVIRUS ASSOCIATED WITH HUMAN DISEASES, SUCH AS ADULT T-CELL LEUKEMIA (ATL) AND HTLV-1-ASSOCIATED MYELOPATHY/TROPIC SPASTIC PARAPARESIS (HAM/TSP). AS A RETROVIRUS, ITS LIFE CYCLE INCLUDES A STEP WHERE HTLV-1 IS INTEGRATED INTO THE HOST GENOMIC DNA AND FORMS PROVIRAL DNA. IN THE CHRONIC PHASE OF THE INFECTION, HTLV?1 IS KNOWN TO PROLIFERATE AS A PROVIRUS VIA THE MITOTIC DIVISION OF THE INFECTED HOST CELLS. THERE ARE GENERALLY TENS OF THOUSANDS OF INFECTED CLONES WITHIN AN INFECTED INDIVIDUAL. THEY EXIST NOT ONLY IN PERIPHERAL BLOOD, BUT ALSO IN VARIOUS LYMPHOID ORGANS. VIRAL PROTEINS ENCODED IN HTLV-1 GENOME PLAY A ROLE IN THE PROLIFERATION AND SURVIVAL OF THE INFECTED CELLS. AS IS THE CASE WITH OTHER CHRONIC VIRAL INFECTIONS, HTLV-1 GENE EXPRESSION INDUCES THE ACTIVATION OF THE HOST IMMUNITY AGAINST THE VIRUS. THUS, THE TRANSCRIPTION FROM HTLV-1 PROVIRUS NEEDS TO BE CONTROLLED IN ORDER TO EVADE THE HOST IMMUNE SURVEILLANCE. THERE SHOULD BE A DYNAMIC AND COMPLEX REGULATION IN VIVO, WHERE AN EQUILIBRIUM BETWEEN VIRAL ANTIGEN EXPRESSION AND HOST IMMUNE SURVEILLANCE IS ACHIEVED. THE MECHANISMS REGULATING VIRAL GENE EXPRESSION FROM THE PROVIRUS ARE A KEY TO UNDERSTANDING THE PERSISTENT/LATENT INFECTION WITH HTLV-1 AND ITS PATHOGENESIS. IN THIS ARTICLE, WE WOULD LIKE TO REVIEW OUR CURRENT UNDERSTANDING ON THIS TOPIC. 2016 11 6266 24 THE NEUROBIOLOGY OF SUICIDE. THE STRESS-DIATHESIS MODEL POSITS THAT SUICIDE IS THE RESULT OF AN INTERACTION BETWEEN STATE-DEPENDENT (ENVIRONMENTAL) STRESSORS AND A TRAIT-LIKE DIATHESIS OR SUSCEPTIBILITY TO SUICIDAL BEHAVIOUR, INDEPENDENT OF PSYCHIATRIC DISORDERS. FINDINGS FROM POST-MORTEM STUDIES OF THE BRAIN AND FROM GENOMIC AND IN-VIVO NEUROIMAGING STUDIES INDICATE A BIOLOGICAL BASIS FOR THIS DIATHESIS, INDICATING THE IMPORTANCE OF NEUROBIOLOGICAL SCREENING AND INTERVENTIONS, IN ADDITION TO COGNITIVE AND MOOD INTERVENTIONS, IN THE PREVENTION OF SUICIDE. EARLY-LIFE ADVERSITY AND EPIGENETIC MECHANISMS MIGHT EXPLAIN SOME OF THE LINK BETWEEN SUICIDE RISK AND BRAIN CIRCUITRY AND NEUROCHEMISTRY ABNORMALITIES. RESULTS FROM A RANGE OF STUDIES USING DIVERSE DESIGNS AND POST-MORTEM AND IN-VIVO TECHNIQUES SHOW IMPAIRMENTS OF THE SEROTONIN NEUROTRANSMITTER SYSTEM AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS STRESS-RESPONSE SYSTEM IN THE DIATHESIS FOR SUICIDAL BEHAVIOUR. THESE IMPAIRMENTS MANIFEST AS IMPAIRED COGNITIVE CONTROL OF MOOD, PESSIMISM, REACTIVE AGGRESSIVE TRAITS, IMPAIRED PROBLEM SOLVING, OVER-REACTIVITY TO NEGATIVE SOCIAL SIGNS, EXCESSIVE EMOTIONAL PAIN, AND SUICIDAL IDEATION, LEADING TO SUICIDAL BEHAVIOUR. BIOMARKERS RELATED TO THE DIATHESIS MIGHT HELP TO INFORM RISK-ASSESSMENT PROCEDURES AND TREATMENT CHOICE IN THE PREVENTION OF SUICIDE. 2014 12 4525 25 MULTIFACTORIAL CAUSES OF PARANOID SCHIZOPHRENIA WITH AUDITORY-VISUAL HALLUCINATIONS IN A 31-YEAR-OLD MALE WITH HISTORY OF TRAUMATIC BRAIN INJURY AND SUBSTANCE ABUSE. SCHIZOPHRENIA IS A CHRONIC PSYCHIATRIC DISORDER THAT CLASSICALLY PRESENTS WITH DISTORTIONS OF THOUGHT, BEHAVIOR, AND PERCEPTIONS THAT ARE OFTEN MISDIAGNOSED. ONE DIFFICULTY IN DIAGNOSING SCHIZOPHRENIA IS DUE TO ITS PHENOTYPICALLY HETEROGENEOUS CONDITION THAT CAN BE PRECIPITATED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE PREVALENCE OF SCHIZOPHRENIA IS ROUGHLY 1%, BUT IT IS OFTEN MISDIAGNOSED. POSSIBLE DIFFERENTIAL DIAGNOSES INCLUDE DEPRESSION OR BIPOLAR DISORDER WITH PSYCHOSIS, PSYCHOSIS DUE TO A MEDICAL CONDITION, SCHIZOTYPAL AND SCHIZOID PERSONALITY DISORDERS, AND NEUROCOGNITIVE DISORDERS. IN THIS CASE REPORT, A 31-YEAR-OLD MALE PRESENTS WITH THOUGHTS OF SUICIDE FOLLOWING A RECENT EXACERBATION OF HIS HALLUCINATIONS. ON PRESENTATION, THE PATIENT PRESENTED WITH A HISTORICAL DIAGNOSIS OF "PARANOID SCHIZOPHRENIA" AS WELL AS A HISTORY OF TRAUMATIC BRAIN INJURY (TBI), POLY-SUBSTANCE USE DISORDER, AND A FAMILY HISTORY OF SCHIZOPHRENIA. THIS CASE SERVES TO HIGHLIGHT THE DIFFICULTIES OF MAKING AN ACCURATE DIAGNOSIS AND PROVIDING EVIDENCED-BASED TREATMENT. 2022 13 5520 35 RISK FACTORS OF POSTPARTUM DEPRESSION. POSTPARTUM DEPRESSION (PPD) IS A WIDESPREAD MENTAL HEALTH PROBLEM AND ONE OF THE PRIME CAUSES OF MATERNAL SUFFERING AND ILL HEALTH. ON A GLOBAL LEVEL, THE PREVALENCE OF THE DISORDER IS ABOUT 10 TO 15%. SYMPTOMS GENERALLY APPEAR WITHIN THE FIRST FOUR TO SIX WEEKS, WHICH IS THE HIGH-RISK PERIOD. HOWEVER, IT MAY DEVELOP UP TO ONE YEAR POST-DELIVERY. PPD PRESENTS WITH SYMPTOMS OF CLASSICAL DEPRESSION, INCLUDING MOOD FLUCTUATIONS, BOUTS OF CRYING, LACK OF INTEREST IN THE CHILD, AND EVEN THOUGHTS OF SUICIDE. PPD NOT ONLY HAS ADVERSE EFFECTS ON THE MOTHER'S HEALTH BUT ALSO HAMPERS THE GROWTH AND DEVELOPMENT OF THE CHILD. IT HAMPERS THE FORMATION OF A HEALTHY MOTHER-CHILD BOND, WHICH IN TURN MAY IMPACT FEEDING PRACTICES. THE SOCIAL ENVIRONMENT OF THE INFANT DURING THE FIRST FEW MONTHS IS PRIMARILY PROVIDED BY THE MOTHER, AND PPD MAY THUS IMPACT THE CHILD'S DEVELOPMENT. IT ALSO INCREASES THE CHILD'S SUSCEPTIBILITY TO MALNUTRITION. RESEARCH ON POSTPARTUM DEPRESSION HAS GARNERED MOMENTUM WITHIN THE LAST FEW YEARS. HOWEVER, THE MASSES ARE STILL LARGELY UNAWARE OF THE DISORDER AND ITS IMPLICATIONS. THERE IS ALSO AN INADEQUACY OF AWARENESS OF THE RISK FACTORS OF PPD. THE CROSS-CULTURAL DIFFERENCES IN MANIFESTATIONS AND APPROPRIATE PREVENTIVE MEASURES HAVE NOT BEEN EXTENSIVELY STUDIED. SOME RISK FACTORS FOR PPD ARE SIMILAR TO THOSE FOR CLASSIC DEPRESSION; HOWEVER, OBSTETRICAL AND PEDIATRIC FACTORS ARE ALSO INVOLVED. THIS LITERATURE REVIEW AIMS TO ASSESS THE CURRENTLY KNOWN RISK FACTORS FOR PPD, THEIR STRENGTH OF ASSOCIATION, AND PROBABLE MECHANISMS TO HELP IDENTIFY THE HIGH-RISK GROUP AND ENABLE THE IMPLEMENTATION OF PREVENTIVE MEASURES OR FACILITATE EARLY DIAGNOSIS. THE FACTORS IDENTIFIED SPANNED SOCIODEMOGRAPHIC, BIOLOGICAL, PSYCHOLOGICAL, AND OBSTETRIC DOMAINS. THESE INCLUDED SOCIOECONOMIC STANDING, MARITAL RELATIONSHIP, HISTORY OF PSYCHIATRIC ILLNESS, SOCIAL SUPPORT, GESTATIONAL DIABETES, VITAMIN D DEFICIENCY, IMMIGRATION STATUS, DELIVERY METHOD, VIOLENCE AND ABUSE, BIRTH EXPERIENCE, AND BIOLOGICAL AND EPIGENETIC MARKERS. THE RISK FACTORS FOR POSTPARTUM DEPRESSION ARE NUMEROUS AND MAY HAVE STRONG TO WEAK ASSOCIATIONS WITH THE DEVELOPMENT OF PPD. A PREVIOUS HISTORY OF DEPRESSION OR PSYCHIATRIC ILLNESS, DEPRESSIVE SYMPTOMS DURING PREGNANCY, GESTATIONAL DIABETES, AND A LACK OF SPOUSAL AND SOCIAL SUPPORT WERE THE MOST POWERFUL RISK FACTORS. OTHER SIGNIFICANT FACTORS INCLUDE COMPLICATIONS DURING PREGNANCY, LOW SOCIOECONOMIC STATUS, AND STRESSFUL LIFE EVENTS. STUDIES ON MATERNAL AGE AND CHRONIC ILLNESS AS RISK FACTORS WERE INCONCLUSIVE. THE ROLES OF GENETIC AND EPIGENETIC MARKERS, CULTURAL FACTORS, AND VITAMIN D INSUFFICIENCY REQUIRE FURTHER INVESTIGATION. 2022 14 3395 42 HOST GENETIC FACTORS PREDISPOSING TO HIV-ASSOCIATED NEUROCOGNITIVE DISORDER. THE SUCCESS OF COMBINATION ANTIRETROVIRAL THERAPY (CART) IN TRANSFORMING THE LIVES OF HIV-INFECTED INDIVIDUALS WITH ACCESS TO THESE DRUGS IS TEMPERED BY THE INCREASING THREAT OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) TO THEIR OVERALL HEALTH AND QUALITY OF LIFE. INTENSIVE INVESTIGATIONS OVER THE PAST TWO DECADES HAVE UNDERSCORED THE ROLE OF HOST IMMUNE RESPONSES, INFLAMMATION, AND MONOCYTE-DERIVED MACROPHAGES IN HAND, BUT THE PRECISE PATHOGENIC MECHANISMS UNDERLYING HAND REMAIN ONLY PARTIALLY DELINEATED. COMPLICATING RESEARCH EFFORTS AND THERAPEUTIC DRUG DEVELOPMENT ARE THE SHEER COMPLEXITY OF HAND PHENOTYPES, DIAGNOSTIC IMPRECISION, AND THE GROWING INTERSECTION OF CHRONIC IMMUNE ACTIVATION WITH AGING-RELATED COMORBIDITIES. YET, GENETIC STUDIES STILL OFFER A POWERFUL MEANS OF ADVANCING INDIVIDUALIZED CARE FOR HIV-INFECTED INDIVIDUALS AT RISK. THERE IS AN URGENT NEED FOR 1) LONGITUDINAL STUDIES USING CONSISTENT PHENOTYPIC DEFINITIONS OF HAND IN HIV-INFECTED SUBPOPULATIONS AT VERY HIGH RISK OF BEING ADVERSELY IMPACTED, SUCH AS CHILDREN, 2) TISSUE STUDIES THAT CORRELATE NEUROPATHOLOGICAL CHANGES IN MULTIPLE BRAIN REGIONS WITH GENOMIC MARKERS IN AFFECTED INDIVIDUALS AND WITH CHANGES AT THE RNA, EPIGENOMIC, AND/OR PROTEIN LEVELS, AND 3) GENETIC ASSOCIATION STUDIES USING MORE SENSITIVE SUBPHENOTYPES OF HAND. THE NIH BRAIN INITIATIVE AND HUMAN CONNECTOME PROJECT, COUPLED WITH RAPIDLY EVOLVING SYSTEMS BIOLOGY AND MACHINE LEARNING APPROACHES FOR ANALYZING HIGH-THROUGHPUT GENETIC, TRANSCRIPTOMIC AND EPIGENETIC DATA, HOLD PROMISE FOR IDENTIFYING ACTIONABLE BIOLOGICAL PROCESSES AND GENE NETWORKS THAT UNDERLIE HAND. THIS REVIEW SUMMARIZES THE CURRENT STATE OF UNDERSTANDING OF HOST GENETIC FACTORS PREDISPOSING TO HAND IN LIGHT OF PAST CHALLENGES AND SUGGESTS SOME PRIORITIES FOR FUTURE RESEARCH TO ADVANCE THE UNDERSTANDING AND CLINICAL MANAGEMENT OF HAND IN THE CART ERA. 2014 15 3136 25 GLOBAL DNA METHYLATION LEVELS IN WHITE BLOOD CELLS OF PATIENTS WITH CHRONIC HEROIN USE DISORDER. A PROSPECTIVE STUDY. BACKGROUND: INCREASING SCIENTIFIC EVIDENCE SHOWS THE SIGNIFICANT ROLE OF EPIGENETIC MECHANISMS IN DRUG USE DISORDER, ABSTINENCE AND RELAPSE. STUDIES ON HUMAN SUBJECTS ARE LIMITED COMPARED TO THOSE ON ANIMALS, FOR VARIOUS REASONS SUCH AS POLY-SUBSTANCE ABUSE, HIGH DROP-OUT RATE AND TECHNICAL DIFFICULTIES. OBJECTIVES: OUR GOAL WAS TO EVALUATE WHETHER A MONITORED ABSTINENCE PERIOD OF 21 DAYS COULD INDUCE CHANGES IN GLOBAL DNA METHYLATION IN CHRONIC HEROIN USERS. METHOD: IN THE CURRENT STUDY, WE PRESENT DATA ON GLOBAL DNA METHYLATION ON A SET OF 18 MALE PATIENTS WITH CHRONIC HEROIN USE DISORDER, CAREFULLY SELECTED BASED ON INCLUSION AND EXCLUSION CRITERIA, WHO WERE HOSPITALIZED AND CLOSELY MONITORED DURING A 21-DAY DETOXIFICATION PROGRAM, ONE OF THE FEW WHERE NO OPIOID AGONIST IS ADMINISTERED. THE PARTICIPANTS WERE SAMPLED TWICE, ONCE UPON ENROLMENT TO THE PROGRAM AND ONCE UPON COMPLETION. RESULTS: ACCORDING TO OUR RESULTS, NO DIFFERENCE IN GLOBAL DNA METHYLATION WAS DETECTED BETWEEN SAMPLES COLLECTED UPON ENROLMENT AND SAMPLES COLLECTED UPON COMPLETION OF THE PROGRAM. CONCLUSION: THE FINDINGS OF THIS STUDY DO NOT RULE OUT THE POSSIBILITY THAT THE 21-DAY ABSTINENCE PERIOD WAS NOT LONG ENOUGH TO OBSERVE CHANGES IN GLOBAL DNA METHYLATION, OR THAT ABSTINENCE INDUCED SITE-SPECIFIC METHYLATION CHANGES (BUT NOT GLOBAL CHANGES), THAT CERTAINLY MERIT FURTHER EVALUATION. 2021 16 108 26 A REVIEW OF THE PROTECTIVE EFFECT OF MELATONIN IN PESTICIDE-INDUCED TOXICITY. PESTICIDES ARE AMONG THE MOST IMPORTANT CHEMICALS USED IN AGRICULTURE SECTOR. HOWEVER, THEIR EXTENSIVE USE HAS POLLUTED THE ENVIRONMENT AND INCREASED HUMAN VULNERABILITY TO VARIOUS CHRONIC DISEASES. PESTICIDE EXPOSURE CAUSES GENETIC AND EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS. AREAS COVERED: THIS REVIEW IS BASED ON THE LITERATURE STUDIES CURRENTLY REPORTED ON PESTICIDE-INDUCED TOXICITY AND THE PROTECTIVE ROLE OF MELATONIN. SCIENTIFIC DATABASES SUCH AS PUBMED, SCOPUS AND WEB OF SCIENCE WERE SEARCHED USING KEYWORDS 'PESTICIDE' AND 'MELATONIN' UP TO JANUARY 2016. FULL LENGTH ARTICLES RELATED TO ANIMAL AND HUMAN EXPOSURE WERE RETRIEVED. A TOTAL NUMBER OF 181 RECORDS WERE OBTAINED, AND AFTER EXCLUDING THE DUPLICATES, 97 PAPERS WERE FURTHER SCREENED ON THE BASIS OF RELEVANCE TO THE TOPIC. EXPERT OPINION: MELATONIN AS A BROAD-SPECTRUM ANTIOXIDANT IS ABLE TO PENETRATE CELLULAR COMPARTMENTS SPECIFICALLY THE MITOCHONDRIA. IT IS A POTENT FREE RADICAL SCAVENGER WITH LOW TOXICITY AND DESIRABLE SOLUBILITY IN ORGANIC AND AQUEOUS PHASES. WE ARE OF THE OPINION THAT MELATONIN IS A PROMISING AGENT IN MINIMIZING ORGAN INJURIES INDUCED BY PESTICIDES. 2017 17 5451 38 REPROGRAMMING CELLS FROM GULF WAR VETERANS INTO NEURONS TO STUDY GULF WAR ILLNESS. GULF WAR ILLNESS (GWI), WHICH AFFLICTS AT LEAST 25% OF VETERANS WHO SERVED IN THE 1990-1991 WAR IN THE PERSIAN GULF, IS THOUGHT TO BE CAUSED BY DEPLOYMENT EXPOSURES TO VARIOUS NEUROTOXICANTS, INCLUDING PESTICIDES, ANTI-NERVE GAS PILLS, AND LOW-LEVEL NERVE AGENTS INCLUDING SARIN/CYCLOSARIN. GWI IS A MULTISYMPTOM DISORDER CHARACTERIZED BY FATIGUE, JOINT PAIN, COGNITIVE PROBLEMS, AND GASTROINTESTINAL COMPLAINTS. THE MOST PROMINENT SYMPTOMS OF GWI (MEMORY PROBLEMS, POOR ATTENTION/CONCENTRATION, CHRONIC HEADACHES, MOOD ALTERATIONS, AND IMPAIRED SLEEP) SUGGEST THAT THE DISEASE PRIMARILY AFFECTS THE CNS. DEVELOPMENT OF URGENTLY NEEDED TREATMENTS DEPENDS ON EXPERIMENTAL MODELS APPROPRIATE FOR TESTING MECHANISTIC HYPOTHESES AND FOR SCREENING THERAPEUTIC COMPOUNDS. RODENT MODELS HAVE BEEN USEFUL THUS FAR, BUT ARE LIMITED BY THEIR INABILITY TO ASSESS THE CONTRIBUTION OF GENETIC OR EPIGENETIC BACKGROUND TO THE DISEASE, AND BECAUSE DISEASE-VULNERABLE PROTEINS AND PATHWAYS MAY BE DIFFERENT IN HUMANS RELATIVE TO RODENTS. AS OF YET, NO POSTMORTEM TISSUE FROM THE VETERANS HAS BECOME AVAILABLE FOR RESEARCH. WE ARE MOVING FORWARD WITH A PARADIGM SHIFT IN THE STUDY OF GWI, WHICH UTILIZES CONTEMPORARY STEM CELL TECHNOLOGY TO CONVERT SOMATIC CELLS FROM GULF WAR VETERANS INTO PLURIPOTENT CELL LINES THAT CAN BE DIFFERENTIATED INTO VARIOUS CELL TYPES, INCLUDING NEURONS, GLIA, MUSCLE, OR OTHER RELEVANT CELL TYPES. SUCH CELL LINES ARE IMMORTAL AND WILL BE A RESOURCE FOR GWI RESEARCHERS TO PURSUE MECHANISTIC HYPOTHESES AND THERAPEUTICS. 2017 18 4849 36 OPIOID-MEDIATED HIV-1 IMMUNOPATHOGENESIS. DESPITE THE ABILITY OF COMBINATION ANTIRETROVIRAL THERAPY TO DRAMATICALLY SUPPRESS VIREMIA, THE BRAIN CONTINUES TO BE A RESERVOIR OF HIV-1 LOW-LEVEL REPLICATION. ADDING FURTHER COMPLEXITY TO THIS IS THE COMORBIDITY OF DRUG ABUSE WITH HIV-1 ASSOCIATED NEUROCOGNITIVE DISORDERS AND NEUROHIV. AMONG SEVERAL ABUSED DRUGS, THE USE OF OPIATES IS HIGHLY PREVALENT IN HIV-1 INFECTED INDIVIDUALS, BOTH AS AN ABUSED DRUG AS WELL AS FOR PAIN MANAGEMENT. OPIOIDS AND THEIR RECEPTORS HAVE ATTAINED NOTABLE ATTENTION OWING TO THEIR ABILITY TO MODULATE IMMUNE FUNCTIONS, IN TURN, IMPACTING DISEASE PROGRESSION. VARIOUS CELL CULTURE, ANIMAL AND HUMAN STUDIES HAVE IMPLICATED THE ROLE OF OPIOIDS AND THEIR RECEPTORS IN MODULATING VIRAL REPLICATION AND VIRUS-MEDIATED PATHOLOGY BOTH POSITIVELY AND NEGATIVELY. FURTHER, THE COMBINATORIAL EFFECTS OF HIV-1/HIV-1 PROTEINS AND MORPHINE HAVE DEMONSTRATED ACTIVATION OF INFLAMMATORY SIGNALING IN THE HOST SYSTEM. HEREIN, WE SUMMARIZED THE CURRENT KNOWLEDGE ON THE ROLE OF OPIOIDS ON PERIPHERAL IMMUNOPATHOGENESIS, VIRAL IMMUNOPATHOGENESIS, EPIGENETIC PROFILES OF THE HOST AND VIRAL GENOME, NEUROPATHOGENESIS OF SIV/SHIV-INFECTED NON-HUMAN PRIMATES, BLOOD-BRAIN-BARRIER, HIV-1 VIRAL LATENCY, AND VIRAL REBOUND. OVERALL, THIS REVIEW PROVIDES RECENT INSIGHTS INTO THE ROLE OF OPIOIDS IN HIV-1 IMMUNOPATHOGENESIS. GRAPHICAL ABSTRACT. 2020 19 5280 30 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 20 639 26 BIOMARKERS FOR MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS): A SYSTEMATIC REVIEW. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A MULTIFACETED CONDITION THAT AFFECTS MOST BODY SYSTEMS. THERE IS CURRENTLY NO KNOWN DIAGNOSTIC BIOMARKER; INSTEAD, DIAGNOSIS IS DEPENDENT ON APPLICATION OF SYMPTOM-BASED CASE CRITERIA FOLLOWING EXCLUSION OF ANY OTHER POTENTIAL MEDICAL CONDITIONS. WHILE THERE ARE SOME STUDIES THAT REPORT POTENTIAL BIOMARKERS FOR ME/CFS, THEIR EFFICACY HAS NOT BEEN VALIDATED. THE AIM OF THIS SYSTEMATIC REVIEW IS TO COLLATE AND APPRAISE LITERATURE PERTAINING TO A POTENTIAL BIOMARKER(S) WHICH MAY EFFECTIVELY DIFFERENTIATE ME/CFS PATIENTS FROM HEALTHY CONTROLS. METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED ACCORDING TO THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES AND COCHRANE REVIEW GUIDELINES. PUBMED, EMBASE AND SCOPUS WERE SYSTEMATICALLY SEARCHED FOR ARTICLES CONTAINING "BIOMARKER" AND "ME/CFS" KEYWORDS IN THE ABSTRACT OR TITLE AND IF THEY INCLUDED THE FOLLOWING CRITERIA: (1) WERE OBSERVATIONAL STUDIES PUBLISHED BETWEEN DECEMBER 1994 AND APRIL 2022; (2) INVOLVED ADULT HUMAN PARTICIPANTS; (3) FULL TEXT IS AVAILABLE IN ENGLISH (4) ORIGINAL RESEARCH; (5) DIAGNOSIS OF ME/CFS PATIENTS MADE ACCORDING TO THE FUKUDA CRITERIA (1994), CANADIAN CONSENSUS CRITERIA (2003), INTERNATIONAL CONSENSUS CRITERIA (2011) OR INSTITUTE OF MEDICINE CRITERIA (2015); (6) STUDY INVESTIGATED POTENTIAL BIOMARKERS OF ME/CFS COMPARED TO HEALTHY CONTROLS. QUALITY AND BIAS WERE ASSESSED USING THE JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLIST FOR CASE CONTROL STUDIES. RESULTS: A TOTAL OF 101 PUBLICATIONS WERE INCLUDED IN THIS SYSTEMATIC REVIEW. POTENTIAL BIOMARKERS RANGED FROM GENETIC/EPIGENETIC (19.8%), IMMUNOLOGICAL (29.7%), METABOLOMICS/MITOCHONDRIAL/MICROBIOME (14.85%), ENDOVASCULAR/CIRCULATORY (17.82%), NEUROLOGICAL (7.92%), ION CHANNEL (8.91%) AND PHYSICAL DYSFUNCTION BIOMARKERS (8.91%). MOST OF THE POTENTIAL BIOMARKERS REPORTED WERE BLOOD-BASED (79.2%). USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE ME/CFS PATHOLOGY WAS PROMINENT AMONG IMMUNE-BASED BIOMARKERS. MOST BIOMARKERS HAD SECONDARY (43.56%) OR TERTIARY (54.47%) SELECTIVITY, WHICH IS THE ABILITY FOR THE BIOMARKER TO IDENTIFY A DISEASE-CAUSING AGENT, AND A MODERATE (59.40%) TO COMPLEX (39.60%) EASE-OF-DETECTION, INCLUDING THE REQUIREMENT OF SPECIALISED EQUIPMENT. CONCLUSIONS: ALL POTENTIAL ME/CFS BIOMARKERS DIFFERED IN EFFICIENCY, QUALITY, AND TRANSLATABILITY AS A DIAGNOSTIC MARKER. REPRODUCIBILITY OF FINDINGS BETWEEN THE INCLUDED PUBLICATIONS WERE LIMITED, HOWEVER, SEVERAL STUDIES VALIDATED THE INVOLVEMENT OF IMMUNE DYSFUNCTION IN THE PATHOLOGY OF ME/CFS AND THE USE OF LYMPHOCYTES AS A MODEL TO INVESTIGATE THE PATHOMECHANISM OF ILLNESS. THE HETEROGENEITY SHOWN ACROSS MANY OF THE INCLUDED STUDIES HIGHLIGHTS THE NEED FOR MULTIDISCIPLINARY RESEARCH AND UNIFORM PROTOCOLS IN ME/CFS BIOMARKER RESEARCH. 2023