1 5451 150 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 2 107 54 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 3 1988 44 EPIGENETIC ANALYSIS IN A MURINE GENETIC MODEL OF GULF WAR ILLNESS. OF THE NEARLY 1 MILLION MILITARY PERSONNEL WHO PARTICIPATED IN THE 1990-1991 GULF WAR, BETWEEN 25% AND 35% BECAME ILL WITH WHAT NOW IS REFERRED TO AS GULF WAR ILLNESS (GWI) BY THE DEPARTMENT OF DEFENSE. SYMPTOMS VARIED FROM GASTROINTESTINAL DISTRESS TO LETHARGY, MEMORY LOSS, INABILITY TO CONCENTRATE, DEPRESSION, RESPIRATORY, AND REPRODUCTIVE PROBLEMS. THE SYMPTOMS HAVE PERSISTED FOR 30 YEARS IN THOSE AFFLICTED BUT THE BASIS OF THE ILLNESS REMAINS LARGELY UNKNOWN. NERVE AGENTS AND OTHER CHEMICAL EXPOSURES IN THE WAR ZONE HAVE BEEN IMPLICATED BUT THE LONG-TERM EFFECTS OF THESE ACUTE EXPOSURES HAVE LEFT FEW IF ANY IDENTIFIABLE SIGNATURES. THE MAJOR AIM OF THIS STUDY IS TO ELUCIDATE THE POSSIBLE GENOMIC BASIS FOR THE PERSISTENCE OF SYMPTOMS, ESPECIALLY OF THE NEUROLOGICAL AND BEHAVIORAL EFFECTS. TO ADDRESS THIS, WE PERFORMED A WHOLE GENOME EPIGENETIC ANALYSIS OF THE PROPOSED CAUSE OF GWI, VIZ., EXPOSURE TO ORGANOPHOSPHATE NEUROTOXICANTS COMBINED WITH HIGH CIRCULATING GLUCOCORTICOIDS IN TWO INBRED MOUSE STRAINS, C57BL/6J AND DBA/2J. THE ANIMALS RECEIVED CORTICOSTERONE IN THEIR DRINKING WATER FOR 7 DAYS FOLLOWED BY INJECTION OF DIISOPROPYLFLUOROPHOSPHATE, A NERVE AGENT SURROGATE. SIX WEEKS AFTER DFP INJECTION, THE ANIMALS WERE EUTHANIZED AND MEDIAL PREFRONTAL CORTEX HARVESTED FOR GENOME-WIDE DNA METHYLATION ANALYSIS USING HIGH-THROUGHPUT SEQUENCING. WE OBSERVED 67 DIFFERENTIALLY METHYLATED GENES, NOTABLY AMONG THEM, TTLL7, AKR1C14, SLC44A4, AND RUSC2, ALL RELATED TO DIFFERENT SYMPTOMS OF GWI. OUR RESULTS SUPPORT PROOF OF PRINCIPLE OF GENETIC DIFFERENCES IN THE CHRONIC EFFECTS OF GWI-RELATED EXPOSURES AND MAY REVEAL WHY THE DISEASE HAS PERSISTED IN MANY OF THE NOW AGING GULF WAR VETERANS. 2023 4 336 37 ALTERATIONS IN DNA METHYLATION STATUS ASSOCIATED WITH GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) AFFECTS ABOUT 25% OF PERSIAN GULF VETERANS WITH A CLUSTER OF CHRONIC SYMPTOMS, INCLUDING IMMUNE DYSFUNCTION AND NEUROLOGICAL ISSUES. RECENT STUDIES IMPLICATE GENE EXPRESSION CHANGES IN IMMUNE FUNCTION TO BE ASSOCIATED WITH GWI. SINCE DNA METHYLATION CAN REGULATE SUCH CHANGES IN GENE EXPRESSION, AND DISRUPTION OF DNA METHYLATION PATTERN IS IMPLICATED IN VARIOUS IMMUNE AND NEUROLOGICAL DISEASES, WE AIMED TO STUDY THE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM GWI PATIENTS. GLOBAL DNA METHYLATION LEVELS WERE SIMILAR IN GWI PATIENTS AND CONTROLS. HOWEVER, THE GENOME-WIDE MICROARRAY TECHNOLOGY DETECTED 10,767 DIFFERENTIALLY METHYLATED CPG SITES ACROSS GENE REGULATORY ELEMENTS AND WITHIN CODING REGIONS. APPROXIMATELY 88% OF THEM WERE HYPERMETHYLATED IN GWI PATIENTS. THE SEPARATE ANALYSIS FOUND 776 DIFFERENTIALLY METHYLATED GENE PROMOTERS (DMP), WHICH WERE PREDOMINANTLY HYPERMETHYLATED. PYROSEQUENCING VALIDATION CONFIRMED MICROARRAY RESULTS. FUNCTIONAL ANALYSIS REVEALED THAT MAJORITY OF THE DMPS BELONGED TO GENES RESPONSIBLE FOR METABOLISM AND IMMUNE SYSTEM. THIS IS THE FIRST PILOT HUMAN STUDY CHARACTERIZING GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH GWI. IT SUGGESTS A SIGNIFICANT CONTRIBUTION OF EPIGENETIC DYSFUNCTION IN GWI. MOREOVER, IT SUPPORTS THE DYSREGULATION OF IMMUNE FUNCTION IN GWI. LASTLY, IT SUGGESTS STUDIES WITH THE LARGER COHORT TO VALIDATE OUR FINDINGS. 2019 5 2123 40 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 6 3980 46 LONG-TERM EPIGENETIC ALTERATIONS IN A RAT MODEL OF GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC, MULTISYMPTOM ILLNESS THAT AFFECTS 25% OF THE 700,000 US VETERANS DEPLOYED TO THE PERSIAN GULF DURING THE 1990-1991 GULF WAR. CENTRAL NERVOUS SYSTEM IMPAIRMENTS ARE AMONG THE MOST COMMON SYMPTOMS REPORTED, INCLUDING MEMORY DYSFUNCTION AND DEPRESSION. AFTER 25 YEARS, THE DIAGNOSIS REMAINS ELUSIVE, USEFUL TREATMENTS ARE LACKING, AND THE CAUSE IS POORLY UNDERSTOOD, ALTHOUGH EXPOSURES TO PYRIDOSTIGMINE BROMIDE (PB) AND PESTICIDES ARE CONSISTENTLY IDENTIFIED TO BE AMONG THE STRONGEST RISK FACTORS. EPIGENETIC CHANGES INCLUDING ALTERED MICRORNA (MIRNA) EXPRESSION AND DNA METHYLATION PLAY AN IMPORTANT ROLE IN LEARNING, MEMORY, AND EMOTION REGULATION AND HAVE BEEN IMPLICATED IN VARIOUS NEUROLOGICAL DISORDERS. IN THIS STUDY, WE USED AN ESTABLISHED RAT MODEL OF GWI TO DETERMINE WHETHER 1) CHRONIC ALTERATIONS IN MIRNA EXPRESSION AND GLOBAL DNA METHYLATION AND DNA HYDROXYMETHYLATION ARE MECHANISMS INVOLVED IN THE PATHOBIOLOGY OF GWI, AND 2) PLASMA EXOSOME SMALL RNAS MAY SERVE AS POTENTIAL NONINVASIVE BIOMARKERS OF THIS DEBILITATING DISEASE. ONE YEAR AFTER A 28-DAY EXPOSURE REGIMEN OF PB, DEET (N,N-DIETHYL-3-METHYLBENZAMIDE), PERMETHRIN, AND MILD STRESS, EXPRESSION OF 84 MATURE MIRNAS AND GLOBAL 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) CONTENT WERE ANALYZED IN THE BRAINS OF GWI RATS AND VEHICLE CONTROLS BY PCR ARRAY AND ENZYME-LINKED IMMUNOSORBENT ASSAY, RESPECTIVELY. PLASMA EXOSOME RNA NEXT-GENERATION SEQUENCING ANALYSIS WAS PERFORMED IN POOLED SAMPLES TO DISCOVER POTENTIAL NONINVASIVE BIOMARKERS. WE FOUND THAT COMBINED EXPOSURE TO LOW DOSES OF GW-RELATED CHEMICALS AND MILD STRESS CAUSED EPIGENETIC MODIFICATIONS IN THE BRAIN THAT PERSISTED ONE YEAR AFTER EXPOSURE, INCLUDING INCREASED EXPRESSION OF MIR-124-3P AND MIR-29B-3P IN THE HIPPOCAMPUS AND REGIONAL ALTERATIONS IN GLOBAL 5MC AND 5HMC CONTENT. GW-RELEVANT EXPOSURES ALSO INDUCED THE DIFFERENTIAL EXPRESSION OF TWO PIWI-INTERACTING RNAS (PIRNAS) IN CIRCULATION (PIR-007899 AND PIR-019162). RESULTS FROM THIS STUDY IMPLICATE A ROLE FOR EPIGENETIC ALTERATIONS IN GWI. EVALUATION OF THE DIAGNOSTIC POTENTIAL OF PLASMA EXOSOME RNAS IN VETERANS WITH GWI IS WARRANTED. 2016 7 6159 41 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 8 1314 31 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 9 6375 35 THE ROLE OF NEURO-IMMUNE INTERACTION IN CHRONIC PAIN CONDITIONS; FUNCTIONAL SOMATIC SYNDROME, NEUROGENIC INFLAMMATION, AND PERIPHERAL NEUROPATHY. FUNCTIONAL SOMATIC SYNDROMES ARE INCREASINGLY DIAGNOSED IN CHRONICALLY ILL PATIENTS PRESENTING WITH AN ARRAY OF SYMPTOMS NOT ATTRIBUTED TO PHYSICAL AILMENTS. CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, OR IRRITABLE BOWEL SYNDROME ARE COMMON DISORDERS THAT BELONG IN THIS BROAD CATEGORY. SUCH SYNDROMES ARE CHARACTERISED BY THE PRESENCE OF ONE OR MULTIPLE CHRONIC SYMPTOMS INCLUDING WIDESPREAD MUSCULOSKELETAL PAIN, FATIGUE, SLEEP DISORDERS, AND ABDOMINAL PAIN, AMONGST OTHER ISSUES. SYMPTOMS ARE BELIEVED TO RELATE TO A COMPLEX INTERACTION OF BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WHERE A DEFINITE AETIOLOGY HAS NOT BEEN ESTABLISHED. THEORIES SUGGEST CAUSATIVE PATHWAYS BETWEEN THE IMMUNE AND NERVOUS SYSTEMS OF AFFECTED INDIVIDUALS WITH SEVERAL RISK FACTORS IDENTIFIED IN PATIENTS PRESENTING WITH ONE OR MORE FUNCTIONAL SYNDROMES. RISK FACTORS INCLUDING STRESS AND CHILDHOOD TRAUMA ARE NOW RECOGNISED AS IMPORTANT CONTRIBUTORS TO CHRONIC PAIN CONDITIONS. EMOTIONAL, PHYSICAL, AND SEXUAL ABUSE DURING CHILDHOOD IS CONSIDERED A SEVERE STRESSOR HAVING A HIGH PREVALENCE IN FUNCTIONAL SOMATIC SYNDROME SUFFERS. SUCH TRAUMA PERMANENTLY ALTERS THE BIOLOGICAL STRESS RESPONSE OF THE SUFFERS LEADING TO NEUROEXCITATORY AND OTHER NERVE ISSUES ASSOCIATED WITH CHRONIC PAIN IN ADULTS. TRAUMATIC AND CHRONIC STRESS RESULTS IN EPIGENETIC CHANGES IN STRESS RESPONSE GENES, WHICH ULTIMATELY LEADS TO DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY AXIS, THE AUTONOMIC NERVOUS SYSTEM, AND THE IMMUNE SYSTEM MANIFESTING IN A BROAD ARRAY OF SYMPTOMS. IMPORTANTLY, THESE SYSTEMS ARE KNOWN TO BE DYSREGULATED IN PATIENTS SUFFERING FROM FUNCTIONAL SOMATIC SYNDROME. FUNCTIONAL SOMATIC SYNDROMES ARE ALSO HIGHLY PREVALENT CO-MORBIDITIES OF PSYCHIATRIC CONDITIONS, MOOD DISORDERS, AND ANXIETY. CONSEQUENTLY, THIS REVIEW AIMS TO PROVIDE INSIGHT INTO THE ROLE OF THE NERVOUS SYSTEM AND IMMUNE SYSTEM IN CHRONIC PAIN DISORDERS ASSOCIATED WITH THE MUSCULOSKELETAL SYSTEM, AND CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. 2022 10 2816 46 FIBROMYALGIA: PATHOGENESIS, MECHANISMS, DIAGNOSIS AND TREATMENT OPTIONS UPDATE. FIBROMYALGIA IS A SYNDROME CHARACTERIZED BY CHRONIC AND WIDESPREAD MUSCULOSKELETAL PAIN, OFTEN ACCOMPANIED BY OTHER SYMPTOMS, SUCH AS FATIGUE, INTESTINAL DISORDERS AND ALTERATIONS IN SLEEP AND MOOD. IT IS ESTIMATED THAT TWO TO EIGHT PERCENT OF THE WORLD POPULATION IS AFFECTED BY FIBROMYALGIA. FROM A MEDICAL POINT OF VIEW, THIS PATHOLOGY STILL PRESENTS INEXPLICABLE ASPECTS. IT IS KNOWN THAT FIBROMYALGIA IS CAUSED BY A CENTRAL SENSITIZATION PHENOMENON CHARACTERIZED BY THE DYSFUNCTION OF NEURO-CIRCUITS, WHICH INVOLVES THE PERCEPTION, TRANSMISSION AND PROCESSING OF AFFERENT NOCICEPTIVE STIMULI, WITH THE PREVALENT MANIFESTATION OF PAIN AT THE LEVEL OF THE LOCOMOTOR SYSTEM. IN RECENT YEARS, THE PATHOGENESIS OF FIBROMYALGIA HAS ALSO BEEN LINKED TO OTHER FACTORS, SUCH AS INFLAMMATORY, IMMUNE, ENDOCRINE, GENETIC AND PSYCHOSOCIAL FACTORS. A RHEUMATOLOGIST TYPICALLY MAKES A DIAGNOSIS OF FIBROMYALGIA WHEN THE PATIENT DESCRIBES A HISTORY OF PAIN SPREADING IN ALL QUADRANTS OF THE BODY FOR AT LEAST THREE MONTHS AND WHEN PAIN IS CAUSED BY DIGITAL PRESSURE IN AT LEAST 11 OUT OF 18 ALLOGENIC POINTS, CALLED TENDER POINTS. FIBROMYALGIA DOES NOT INVOLVE ORGANIC DAMAGE, AND SEVERAL DIAGNOSTIC APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS, INCLUDING THE ANALYSIS OF GENETIC, EPIGENETIC AND SEROLOGICAL BIOMARKERS. SYMPTOMS OFTEN BEGIN AFTER PHYSICAL OR EMOTIONAL TRAUMA, BUT IN MANY CASES, THERE APPEARS TO BE NO OBVIOUS TRIGGER. WOMEN ARE MORE PRONE TO DEVELOPING THE DISEASE THAN MEN. UNFORTUNATELY, THE CONVENTIONAL MEDICAL THERAPIES THAT TARGET THIS PATHOLOGY PRODUCE LIMITED BENEFITS. THEY REMAIN LARGELY PHARMACOLOGICAL IN NATURE AND TEND TO TREAT THE SYMPTOMATIC ASPECTS OF VARIOUS DISORDERS REPORTED BY THE PATIENT. THE STATISTICS, HOWEVER, HIGHLIGHT THE FACT THAT 90% OF PEOPLE WITH FIBROMYALGIA ALSO TURN TO COMPLEMENTARY MEDICINE TO MANAGE THEIR SYMPTOMS. 2021 11 38 29 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 12 1736 29 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 13 675 30 BRAIN AGE AND OTHER BODILY 'AGES': IMPLICATIONS FOR NEUROPSYCHIATRY. AS OUR BRAINS AGE, WE TEND TO EXPERIENCE COGNITIVE DECLINE AND ARE AT GREATER RISK OF NEURODEGENERATIVE DISEASE AND DEMENTIA. SYMPTOMS OF CHRONIC NEUROPSYCHIATRIC DISEASES ARE ALSO EXACERBATED DURING AGEING. HOWEVER, THE AGEING PROCESS DOES NOT AFFECT PEOPLE UNIFORMLY; NOR, IN FACT, DOES THE AGEING PROCESS APPEAR TO BE UNIFORM EVEN WITHIN AN INDIVIDUAL. HERE, WE OUTLINE RECENT NEUROIMAGING RESEARCH INTO BRAIN AGEING AND THE USE OF OTHER BODILY AGEING BIOMARKERS, INCLUDING TELOMERE LENGTH, THE EPIGENETIC CLOCK, AND GRIP STRENGTH. SOME OF THESE TECHNIQUES, USING STATISTICAL APPROACHES, HAVE THE ABILITY TO PREDICT CHRONOLOGICAL AGE IN HEALTHY PEOPLE. MOREOVER, THEY ARE NOW BEING APPLIED TO NEUROLOGICAL AND PSYCHIATRIC DISEASE GROUPS TO PROVIDE INSIGHTS INTO HOW THESE DISEASES INTERACT WITH THE AGEING PROCESS AND TO DELIVER INDIVIDUALISED PREDICTIONS ABOUT FUTURE BRAIN AND BODY HEALTH. WE DISCUSS THE IMPORTANCE OF INTEGRATING DIFFERENT TYPES OF BIOLOGICAL MEASUREMENTS, FROM BOTH THE BRAIN AND THE REST OF THE BODY, TO BUILD MORE COMPREHENSIVE MODELS OF THE BIOLOGICAL AGEING PROCESS. FINALLY, WE PROPOSE SEVEN STEPS FOR THE FIELD OF BRAIN-AGEING RESEARCH TO TAKE IN COMING YEARS. THIS WILL HELP US REACH THE LONG-TERM GOAL OF DEVELOPING CLINICALLY APPLICABLE STATISTICAL MODELS OF BIOLOGICAL PROCESSES TO MEASURE, TRACK AND PREDICT BRAIN AND BODY HEALTH IN AGEING AND DISEASE. 2019 14 5133 37 POTENTIAL EPIGENETIC MECHANISM(S) ASSOCIATED WITH THE PERSISTENCE OF PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN RECEIVING CHEMOTHERAPY FOR BREAST CANCER: A HYPOTHESIS. DUE TO RECENT TREATMENT ADVANCES, THERE HAVE BEEN IMPROVEMENTS IN THE PROPORTION OF WOMEN SURVIVING A DIAGNOSIS OF BREAST CANCER (BC). HOWEVER, MANY OF THESE SURVIVORS REPORT PERSISTENT ADVERSE SIDE EFFECTS FOLLOWING TREATMENT, SUCH AS COGNITIVE DYSFUNCTION, DEPRESSIVE SYMPTOMS, ANXIETY, FATIGUE, SLEEP DISTURBANCES, AND PAIN. INVESTIGATORS HAVE EXAMINED CIRCULATING LEVELS OF INFLAMMATORY MARKERS, PARTICULARLY SERUM CYTOKINES, FOR A POTENTIAL CAUSAL RELATIONSHIP TO THE DEVELOPMENT/PERSISTENCE OF THESE PSYCHONEUROLOGICAL SYMPTOMS (PNS). WHILE INFLAMMATORY ACTIVATION, RESULTING FROM PERCEIVED STRESS OR OTHER FACTORS, MAY DIRECTLY CONTRIBUTE TO THE DEVELOPMENT OF PNS, WE OFFER AN ALTERNATIVE HYPOTHESIS, SUGGESTING THAT THESE SYMPTOMS ARE AN EARLY STEP IN A CASCADE OF BIOLOGICAL CHANGES LEADING TO EPIGENETIC ALTERATIONS AT THE LEVEL OF DEOXYRIBONUCLEIC ACID (DNA) METHYLATION, HISTONE MODIFICATIONS, AND/OR CHROMATIN STRUCTURE/CHROMOSOMAL INSTABILITY. GIVEN THAT EPIGENETIC PATTERNS HAVE PLASTICITY, IF THIS CONJECTURED RELATIONSHIP BETWEEN EPIGENOMIC/ACQUIRED GENOMIC ALTERATIONS AND THE DEVELOPMENT/PERSISTENCE OF PNS IS CONFIRMED, IT COULD PROVIDE FOUNDATIONAL KNOWLEDGE FOR FUTURE RESEARCH LEADING TO THE RECOGNITION OF PREDICTIVE MARKERS AND/OR TREATMENTS TO ALLEVIATE PNS IN WOMEN WITH BC. IN THIS ARTICLE, WE DISCUSS AN EVOLVING THEORY OF THE BIOLOGICAL BASIS OF PNS, INTEGRATING KNOWLEDGE RELATED TO INFLAMMATION AND DNA REPAIR IN THE CONTEXT OF GENETIC AND EPIGENETIC SCIENCE TO EXPAND THE PARADIGM FOR UNDERSTANDING SYMPTOM ACQUISITION/PERSISTENCE FOLLOWING CHEMOTHERAPY. 2014 15 2918 35 GENE-ENVIRONMENT INTERACTIONS IN MAJOR MENTAL DISORDERS IN THE CZECH REPUBLIC. BACKGROUND: MENTAL DISORDERS AFFECT ABOUT ONE?-THIRD OF THE HUMAN POPULATION, ARE TYPICALLY CHRONIC AND SIGNIFICANTLY DECREASE THE QUALITY OF LIFE. PRESENTLY, THE TREATMENT OF MENTAL ILLNESSES IS FAR FROM ADEQUATE WITH A SUBSTANTIAL PROPORTION OF THE PATIENTS BEING PHARMACORESISTANT AND SUFFERING FROM RELAPSES. ONE OF THE REASONS FOR THIS COMPLICATED SITUATION IS THAT WE DO NOT PRECISELY KNOW ABOUT THE CAUSES OF MENTAL DISORDERS, SO THEIR TREATMENT CANNOT BE CAUSAL. THE ETIOLOGY OF A MENTAL DISORDER IS TYPICALLY BASED ON A COMBINATION OF MOLECULAR (GENETIC) AND ENVIRONMENTAL FACTORS. AIM: THE AIM OF THE PROJECT IS TO DISCOVER THE GENE-ENVIRONMENT INTERACTIONS (GXE) IN A WIDE SPECTRUM OF MENTAL DISORDERS. METHODS: THE DESIGN OF OUR STUDY IS INNOVATIVE IN THE SENSE THAT WE INTEND TO STUDY LARGE GROUPS OF ASSOCIATED MENTAL DISORDERS AS A WHOLE INSTEAD OF IN ISOLATION. THIS WOULD ENABLE US TO MAP OUT THE POSSIBLE ENVIRONMENTAL CAUSAL FACTORS IN DETAIL IN RELATION TO THEIR CHARACTER, MAGNITUDE AND TIMING. THE PROJECT ALSO ALLOWS A STUDY OF GENETICS (INCLUDING EPIGENETICS AND MICROBIOMES) AS WELL AS THE ENVIRONMENT SIMULTANEOUSLY. WE PLAN ON INVOLVING THREE STUDY GROUPS: THE FIRST GROUP ARE PATIENTS SUFFERING FROM SCHIZOPHRENIA OR A MOOD DISORDER SUCH AS MAJOR DEPRESSION, RECURRENT DEPRESSIVE DISORDER AND BIPOLAR AFFECTIVE DISORDER; THE SECOND GROUP OF PATIENTS HAVE ANXIETY DISORDERS; AND THE THIRD GROUP ARE HEALTHY VOLUNTEERS FROM THE GENERAL POPULATION WHO ARE GENETICALLY UNRELATED. ALL OF THE STUDY SUBJECTS WILL UNDERGO THE FOLLOWING ASSESSMENTS: A PSYCHIATRIC EXAMINATION, THE IDENTIFICATION OF STRESSFUL LIFE EVENTS WITH THE AID OF A QUESTIONNAIRE, THE EXAMINATION OF THEIR REACTION TO STRESS, GENETIC AND EPIGENETIC (MICRORNA) ASSESSMENTS AND THE ANALYSIS OF ORAL AND GUT MICROBIOME. CONCLUSION: WE EXPECT THAT SOME OF THE GENETIC AS WELL AS ENVIRONMENTAL FACTORS IN THE STUDIED MENTAL DISORDERS ARE SHARED, WHILE SOME OTHERS ARE SPECIFIC. WE ALSO EXPECT THAT THE GXE (GENE-ENVIRONMENT INTERACTION) IN SCHIZOPHRENIC AND AFFECTIVE DISORDERS WILL BE DIFFERENT FROM THE GXE IN ANXIETY DISORDERS AND THAT THE GXE IN THE STUDIED MENTAL DISORDERS WILL DIFFER GENERALLY FROM THE GXE IN HEALTHY VOLUNTEERS. OUR RESULTS CAN HELP IN THE PREVENTION AND INDIVIDUALIZED TREATMENT OF A RANGE OF MENTAL DISORDERS. 2020 16 641 36 BIOMARKERS OF MAJOR DEPRESSIVE DISORDER: KNOWING IS HALF THE BATTLE. MAJOR DEPRESSIVE DISORDER (MDD) IS A HETEROGENEOUS DISEASE WHICH IS WHY THERE ARE CURRENTLY NO SPECIFIC METHODS TO ACCURATELY TEST THE SEVERITY, ENDOPHENOTYPE OR THERAPY RESPONSE. THIS LACK OF PROGRESS IS PARTLY ATTRIBUTED TO THE COM-PLEXITY AND VARIABILITY OF DEPRESSION, IN ASSOCIATION WITH ANALYTICAL VARIABILITY OF CLINICAL LITERATURE AND THE WIDE NUMBER OF THEORETICALLY COMPLEX BIOMARKERS. THE LITERATURE ACCESSIBLE, INDICATES THAT MARKERS INVOLVED IN INFLAMMATORY, NEURO-TROPHIC AND METABOLIC PROCESSES AND COMPONENTS OF NEUROTRANSMITTERS AND NEUROENDOCRINE SYSTEMS ARE RATHER STRONG INDICATORS TO BE CONSIDERED CLINICALLY AND CAN BE MEASURED THROUGH GENETIC AND EPIGENETIC, TRANSCRIPTOMIC AND PROTEOMIC, METABOLOMICS AND NEUROIMAGING ASSESSMENTS. PROMISING BIOLOGIC SYSTEMS/MARKERS FOUND WERE I.E., GROWTH BIOMARKERS, ENDOCRINE MARKERS, OXIDANT STRESS MARKERS, PROTEOMIC AND CHRONIC INFLAMMATORY MARKERS, ARE DISCUSSED IN THIS REVIEW. SEVERAL LINES OF EVIDENCE SUGGEST THAT A PORTION OF MDD IS A DOPAMINE AGONIST-RESPONSIVE SUBTYPE. THIS REVIEW ANALYZES CONCISE REPORTS ON THE PATHOPHYSIOLOGICAL BIOMARKERS OF MDD AND THERAPEUTIC REACTIONS VIA PERIPHERAL DEVELOPMENTAL FACTORS, INFLAMMATIVE CYTOKINES, ENDOCRINE FACTORS AND METABOLIC MARKERS. VARIOUS LITERATURES ALSO SUPPORT THAT ENDOCRINE AND METABOLISM CHANGES ARE ASSOCIATED WITH MDD. ACCUMULATING EVIDENCE SUGGESTS THAT AT LEAST A PORTION OF MDD PATIENTS SHOW CHARACTERISTICS PATHOLOGICAL CHANGES REGARDING DIFFERENT CLINICAL PATHOLOGICAL BIOMARKERS. BY THIS REVIEW WE SUM UP ALL THE DIFFERENT BIOMARKERS PLAYING AN IMPORTANT ROLE IN THE DETECTION OR TREATMENT OF THE DIFFERENT PATIENTS SUFFERING FROM MDD. THE REVIEW ALSO GIVES AN OVERVIEW OF DIFFERENT BIOMARKER'S PLAYING A POTENTIAL ROLE IN MODULATING EFFECT OF MDD. 2021 17 2526 28 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 18 1329 34 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 19 2021 28 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 20 5164 33 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017