1 225 156 ACUTE STRESS-INDUCED EPIGENETIC MODULATIONS AND THEIR POTENTIAL PROTECTIVE ROLE TOWARD DEPRESSION. PSYCHIATRIC DISORDERS ENTAIL MALADAPTIVE PROCESSES IMPAIRING INDIVIDUALS' ABILITY TO APPROPRIATELY INTERFACE WITH ENVIRONMENT. AMONG THEM, DEPRESSION IS CHARACTERIZED BY DIVERSE DEBILITATING SYMPTOMS INCLUDING HOPELESSNESS AND ANHEDONIA, DRAMATICALLY IMPACTING THE PROPENSITY TO LIVE A SOCIAL AND ACTIVE LIFE AND SERIOUSLY AFFECTING WORKING CAPABILITY. RELEVANTLY, BESIDES GENETIC PREDISPOSITION, FOREMOST RISK FACTORS ARE STRESS-RELATED, SUCH AS EXPERIENCING CHRONIC PSYCHOSOCIAL STRESS-INCLUDING BULLYING, MOBBING AND ABUSE-, AND UNDERGOING ECONOMIC CRISIS OR CHRONIC ILLNESSES. IN THE LAST FEW YEARS THE FIELD OF EPIGENETICS PROMISED TO UNDERSTAND CORE MECHANISMS OF GENE-ENVIRONMENT CROSSTALK, CONTRIBUTING TO GET INTO PATHOGENIC PROCESSES OF MANY DISORDERS HIGHLY INFLUENCED BY STRESSFUL LIFE CONDITIONS. HOWEVER, STILL VERY LITTLE IS KNOWN ABOUT MECHANISMS THAT TUNE GENE EXPRESSION TO ADAPT TO THE EXTERNAL MILIEU. IN THIS PERSPECTIVE ARTICLE, WE DISCUSS A SET OF PROTECTIVE, FUNCTIONALLY CONVERGENT EPIGENETIC PROCESSES INDUCED BY ACUTE STRESS IN THE RODENT HIPPOCAMPUS AND DEVOTED TO THE NEGATIVE MODULATION OF STRESS-INDUCED IMMEDIATE EARLY GENES (IEGS) TRANSCRIPTION, HINDERING STRESS-DRIVEN MORPHOSTRUCTURAL MODIFICATIONS OF CORTICOLIMBIC CIRCUITRY. WE ALSO SUGGEST THAT CHRONIC STRESS DAMAGING PROTECTIVE EPIGENETIC MECHANISMS, COULD BIAS THE FUNCTIONAL TRAJECTORY OF STRESS-INDUCED NEURONAL MORPHOSTRUCTURAL MODIFICATION FROM ADAPTIVE TO MALADAPTIVE, CONTRIBUTING TO THE ONSET OF DEPRESSION IN VULNERABLE INDIVIDUALS. A BETTER UNDERSTANDING OF THE EPIGENETIC RESPONSE TO STRESS WILL BE PIVOTAL TO NEW AVENUES OF THERAPEUTIC INTERVENTION TO TREAT DEPRESSION, ESPECIALLY IN LIGHT OF LIMITED EFFICACY OF AVAILABLE ANTIDEPRESSANT DRUGS. 2018 2 5 33 "THE MOTHERS HAVE EATEN UNRIPE GRAPES AND THE CHILDREN'S TEETH ARE SET ON EDGE": THE POTENTIAL INTER-GENERATIONAL EFFECTS OF THE HOLOCAUST ON CHRONIC MORBIDITY IN HOLOCAUST SURVIVORS' OFFSPRING. MODERN EPIDEMIOLOGY HAS EVOLVED IN THE LAST DECADES FROM THE SIMPLIFIED "CAUSE-EFFECT" PARADIGM TO A MULTI-FACTORIAL FRAMEWORK OF CAUSALITY. THE CONCEPT OF "FETAL ORIGIN OF ADULT DISEASES" (FOAD) IS A GOOD EXAMPLE: IT SUGGESTS THAT PRECONCEPTION CIRCUMSTANCES AND FETAL EXPOSURES AS WELL AS INFANCY AND EARLY CHILDHOOD EXPERIENCES MAY EVENTUALLY CHANGE AN INDIVIDUAL'S SUSCEPTIBILITY TO ADULT MORBIDITY THROUGH FETAL PROGRAMMING AND EPIGENETIC CHANGES. THE FOAD CONCEPT WAS SUPPORTED, BETWEEN OTHERS, BY WELL-DESIGNED COHORT STUDIES CARRIED OUT ON NON-JEWISH WORLD WAR II (WWII) SURVIVORS, EXPOSED TO HUNGER DURING THE WAR YEARS. HOWEVER, DATA ON LATE PHYSICAL MORBIDITY OF JEWISH WWII SURVIVORS ARE STILL SCARCE.THE CURRENT PAPER PRESENTS SOME COHORTS ADDRESSING THE FOAD HYPOTHESIS IN RELATION TO THE LONG-TERM IMPACT OF EARLY EXPOSURES TO HUNGER AND THEIR MAIN RESULTS. IT STRESSES THE NEED FOR THE ESTABLISHING OF A SIMILAR COHORT IN ISRAEL, IN ORDER TO STUDY THE LONG-TERM EFFECTS OF THE HOLOCAUST ON THE HEALTH OF HOLOCAUST CHILD SURVIVORS AND ON THAT OF THE "SECOND" AND "THIRD" GENERATIONS. A FRAMEWORK FOR SUCH A COHORT IN ISRAEL IS ALSO PROPOSED.ESTABLISHING A COHORT OF THIS CHARACTER IN ISRAEL SHOULD BE A NATIONAL PRIORITY AND POLICY. FIRST, TAKING SPECIAL CARE OF HOLOCAUST SURVIVORS IS A SOMEWHAT NEGLECTED NATIONAL OBLIGATION. SECOND, IF THE POPULATION OF HOLOCAUST SURVIVORS AND THEIR OFFSPRING IS INDEED A HIGH RISK GROUP FOR LATE CHRONIC MORBIDITY, HIGHER AWARENESS MAY LEAD TO BETTER PRIMARY PREVENTION AND TO TAILORED SECONDARY PREVENTION PROGRAMS. THIRD, THE POPULATION AT STACK IS UNIQUE AND ITS CONTRIBUTION TO THE CONSOLIDATION OF THE FOAD THEORY AND ITS TRANSLATIONAL APPLICATIONS MAY BE OF FOREMOST IMPORTANCE, IN THE GLOBAL AND NATIONAL SENSE. 2014 3 544 38 ATTAINMENT OF THERMOREGULATION AS AFFECTED BY ENVIRONMENTAL FACTORS. THE REVIEW ADDRESSES THE DEVELOPMENT OF THERMOREGULATION IN POULTRY EMBRYOS AS WELL AS THE EFFECT OF ACUTE AND CHRONIC CHANGES OF ENVIRONMENTAL FACTORS ON THIS PROCESS AND THE INCUBATION TEMPERATURE BEING THE FOREMOST. IN POULTRY, THE EARLY DEVELOPMENT OF ADAPTIVE BODY FUNCTIONS, LIKE THE THERMOREGULATORY SYSTEM, IS CHARACTERIZED BY THE FOLLOWING PECULIARITIES. FIRST, THE DEVELOPMENT OF PERIPHERAL AS WELL AS CENTRAL NERVOUS THERMOREGULATORY MECHANISMS START DURING THE PRENATAL ONTOGENY. HOWEVER, THEIR MATURITY IS ATTAINED DURING EARLY POSTNATAL DEVELOPMENT. IN THE PERINATAL PERIOD, ENVIRONMENTAL FACTORS HAVE A HIGH EFFECT ON DEVELOPMENT OF TEMPERATURE REGULATION. SECOND, ACUTE CHANGES IN THE ENVIRONMENTAL CONDITIONS INDUCE AS A RULE FIRST UNCOORDINATED AND IMMEDIATELY NONADAPTIVE REACTIONS. LATER, THE UNCOORDINATED NONADAPTIVE REACTIONS CHANGE INTO COORDINATED (ADAPTIVE) REACTIONS. PRENATAL ENVIRONMENTAL INFLUENCES MAY HAVE A TRAINING EFFECT ON THE POSTNATAL EFFICIENCY OF THE THERMO-REGULATORY SYSTEM. THIRD, FUNCTIONAL SYSTEMS OF THE ORGANISM DEVELOP FROM AN OPEN LOOP SYSTEM WITHOUT FEEDBACK CONTROL INTO A CLOSED SYSTEM CONTROLLED BY A FEEDBACK MECHANISM. DURING THIS CRITICAL PERIOD, THE ACTUAL ENVIRONMENT MODULATES THE DEVELOPMENT OF THE RESPECTIVE PHYSIOLOGICAL CONTROL SYSTEMS FOR THE ENTIRE LIFE PERIOD, ESPECIALLY BY CHANGES IN NEUROORGANIZATION AND EXPRESSION OF RELATED EFFECTOR GENES. KNOWLEDGE ON THESE MECHANISMS MIGHT BE SPECIFICALLY USED TO GENERATE LONG-TERM ADAPTATION OF THE ORGANISM TO THE POSTNATAL CLIMATIC CONDITIONS (PERINATAL EPIGENETIC TEMPERATURE ADAPTATION). IN POULTRY, PERINATAL EPIGENETIC TEMPERATURE ADAPTATION WAS DEVELOPED BY CHANGES IN THE INCUBATION TEMPERATURE. WHEN A COMPARISON IS MADE IN BIRDS, WHICH WERE INCUBATED AT 37.5 DEGREES C, A LOW INCUBATION TEMPERATURE INDUCED POSTNATAL COLD ADAPTATION, AND WARM INCUBATION TEMPERATURE INDUCED POSTNATAL HEAT ADAPTATION. PERINATAL EPIGENETIC TEMPERATURE ADAPTATION EXHIBITED CHANGES IN THE NEURONAL THERMOSENSITIVITY IN THE HYPOTHALAMUS AS WELL AS IN THE PERIPHERAL THERMOREGULATORY MECHANISMS. THESE ALTERATIONS COULD BE ALREADY FOUND AT THE END OF INCUBATION. FURTHER, TEMPERATURE-EXPERIENCED EMBRYOS HAVE A LOWER C-FOS EXPRESSION THAN IN THE CONTROL AFTER ACUTE HEAT STRESS. 2007 4 6123 29 THE EPIGENETIC MACHINERY IN VASCULAR DYSFUNCTION AND HYPERTENSION. HYPERTENSION (HT) IS AMONG THE MAJOR COMPONENTS OF THE METABOLIC SYNDROME, I.E., OBESITY, DYSLIPIDEMIA, AND HYPERGLYCEMIA/INSULIN RESISTANCE. IT REPRESENTS A SIGNIFICANT HEALTH PROBLEM WITH FOREMOST RISKS FOR CHRONIC CARDIOVASCULAR DISEASE AND A SIGNIFICANT CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. THEREFORE, IT IS NOT SURPRISING THAT THIS DISORDER CONSTITUTES A SERIOUS PUBLIC HEALTH CONCERN. ALTHOUGH MULTIPLE STUDIES HAVE STRESSED THE MULTIFACTORIAL NATURE OF HT, THE PATHOGENESIS REMAINS LARGELY UNKNOWN. HOWEVER, IF WE WANT TO REDUCE THE GLOBAL PREVALENCE OF HT, RESTRAIN THE NUMBER OF DEATHS (CURRENTLY 9.4 MILLION/YEAR IN THE WORLD), AND ALLEVIATE THE SOCIO-ECONOMIC BURDEN, A DEEPER INSIGHT INTO THE MECHANISMS IS URGENTLY NEEDED IN ORDER TO DEFINE NEW MEANINGFUL THERAPEUTIC TARGETS. RECENTLY, THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF VARIOUS COMPLEX DISEASES HAS ATTRACTED MUCH ATTENTION. IN THE PRESENT REVIEW, WE PROVIDE A CRITICAL UPDATE ON THE AVAILABLE LITERATURE AND ONGOING RESEARCH REGARDING THE EPIGENETIC MODIFICATIONS OF GENES INVOLVED IN SEVERAL PATHWAYS OF ELEVATED BLOOD PRESSURE, ESPECIALLY THOSE LINKED TO THE VASCULAR EPITHELIUM. THIS REVIEW ALSO FOCUSES ON THE ROLE OF MICRORNA (MIRNA) IN THE REGULATION OF GENE EXPRESSION ASSOCIATED WITH HT AND OF FETAL PROGRAMMING MEDIATING SUSCEPTIBILITY TO HT IN ADULTHOOD. 2017 5 6458 29 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021 6 2208 34 EPIGENETIC MODIFICATIONS AND NON-CODING RNA IN DIABETES-MELLITUS-INDUCED CORONARY ARTERY DISEASE: PATHOPHYSIOLOGICAL LINK AND NEW THERAPEUTIC FRONTIERS. DIABETES MELLITUS (DM) IS A GLUCOSE METABOLISM DISORDER CHARACTERIZED BY CHRONIC HYPERGLYCEMIA RESULTING FROM A DEFICIT OF INSULIN PRODUCTION AND/OR ACTION. DM AFFECTS MORE THAN 1 IN 10 ADULTS, AND IT IS ASSOCIATED WITH AN INCREASED RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. CARDIOVASCULAR DISEASE (CVD) ACCOUNTS FOR TWO THIRDS OF THE OVERALL DEATHS IN DIABETIC PATIENTS, WITH CORONARY ARTERY DISEASE (CAD) AND ISCHEMIC CARDIOMYOPATHY AS THE MAIN CONTRIBUTORS. HYPERGLYCEMIC DAMAGE ON VASCULAR ENDOTHELIAL CELLS LEADING TO ENDOTHELIAL DYSFUNCTION REPRESENTS THE MAIN INITIATING FACTOR IN THE PATHOGENESIS OF DIABETIC VASCULAR COMPLICATIONS; HOWEVER, THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS ARE STILL NOT ENTIRELY UNDERSTOOD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE ON THE PATHOPHYSIOLOGICAL LINKS BETWEEN DM AND CAD WITH A FOCUS ON THE ROLE OF EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND NONCODING RNA CONTROL. INCREASED KNOWLEDGE OF EPIGENETIC MECHANISMS HAS CONTRIBUTED TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL TREATMENTS ("EPIDRUGS") WITH EPIGENETIC TARGETS, ALTHOUGH THESE APPROACHES PRESENT SEVERAL CHALLENGES. SPECIFIC EPIGENETIC BIOMARKERS MAY ALSO BE USED TO PREDICT OR DETECT THE DEVELOPMENT AND PROGRESSION OF DIABETES COMPLICATIONS. FURTHER STUDIES ON DIABETES AND CAD EPIGENETICS ARE NEEDED IN ORDER TO IDENTIFY POSSIBLE NEW THERAPEUTIC TARGETS AND ADVANCE PERSONALIZED MEDICINE WITH THE PREDICTION OF INDIVIDUAL DRUG RESPONSES AND MINIMIZATION OF ADVERSE EFFECTS. 2022 7 4074 27 MATERNAL EXPOSURE TO THE HOLOCAUST AND HEALTH COMPLAINTS IN OFFSPRING. ALTHOUGH THE LINK BETWEEN CHRONIC STRESS AND THE DEVELOPMENT OF CARDIOVASCULAR AND METABOLIC DISEASES OF ADULTHOOD HAS BEEN KNOWN FOR SOME TIME, THERE IS GROWING RECOGNITION THAT EARLY ENVIRONMENTAL INFLUENCES MAY RESULT IN DEVELOPMENTAL PROGRAMMING VIA EPIGENETIC MECHANISMS, THEREBY AFFECTING THE DEVELOPMENTAL TRAJECTORY OF DISEASE PROGRESSION. PREVIOUS STUDIES SUPPORT THE IDEA THAT OFFSPRING OF HOLOCAUST SURVIVORS MAY HAVE BEEN SUBJECTED TO EARLY DEVELOPMENTAL PROGRAMMING. WE EVALUATED THE RELATIONSHIP BETWEEN PARENTAL EXPOSURE TO THE HOLOCAUST AND SELF-REPORTED HEALTH RATINGS AND DISORDERS MADE BY THEIR ADULT OFFSPRING (I.E., SECOND GENERATION HOLOCAUST SURVIVORS). A TOTAL OF 137 SUBJECTS WERE EVALUATED. REGRESSION ANALYSES DEMONSTRATED THAT MATERNAL BUT NOT PATERNAL EXPOSURE TO THE HOLOCAUST WAS RELATED TO POORER SUBJECTIVE IMPRESSIONS OF EMOTIONAL AND PHYSICAL HEALTH. THIS RELATIONSHIP WAS DIMINISHED WHEN THE OFFSPRING'S OWN LEVEL OF TRAIT ANXIETY WAS CONSIDERED. OFFSPRING WITH MATERNAL, BUT NOT PATERNAL, HOLOCAUST EXPOSURE ALSO REPORTED GREATER USE OF PSYCHOTROPIC AND OTHER MEDICATIONS, INCLUDING MEDICATIONS FOR THE TREATMENT OF HYPERTENSION AND LIPID DISORDERS. THE MECHANISM LINKING THESE HEALTH OUTCOMES AND MATERNAL EXPOSURE DESERVES FURTHER INVESTIGATION, INCLUDING THE POSSIBILITY THAT FETAL OR EARLY DEVELOPMENTAL PROGRAMMING IS INVOLVED. 2011 8 4355 38 MIR-30 FAMILY MIRNAS MEDIATE THE EFFECT OF CHRONIC SOCIAL DEFEAT STRESS ON HIPPOCAMPAL NEUROGENESIS IN MOUSE DEPRESSION MODEL. DEPRESSION IS A DEBILITATING PSYCHIATRIC DISORDER WITH A HIGH RATE OF RELAPSE AND A LOW RATE OF RESPONSE TO ANTIDEPRESSANT TREATMENT. THERE IS A DEARTH OF NEW ANTIDEPRESSANTS DUE TO AN INCOMPLETE UNDERSTANDING OF THE MOLECULAR MECHANISMS INVOLVED IN ITS ETIOPATHOLOGY. CHRONIC STRESS APPEARS TO BE ONE OF THE FOREMOST UNDERLYING CAUSES OF DEPRESSION. STUDIES IN ANIMAL MODELS IN THE PAST DECADE HAVE IMPLICATED EPIGENETIC MECHANISMS IN MEDIATING THE NEGATIVE EFFECTS OF CHRONIC STRESSFUL EVENTS ON THE PROGRESSION/MANIFESTATION OF DEPRESSION AND OTHER CO-MORBID NEUROPSYCHIATRIC DISORDERS. HOWEVER, NON-CODING RNAS, ANOTHER LAYER OF EPIGENETIC REGULATION IS RELATIVELY LESS STUDIED IN DEPRESSION. HERE, USING THE CHRONIC SOCIAL DEFEAT STRESS (CSDS)-INDUCED DEPRESSION MODEL, WE HYPOTHESIZED DYSREGULATION IN MIRNA-MRNA NETWORKS IN THE NEUROGENIC DENTATE GYRUS (DG) REGION OF MALE C57BL/6 MICE. AMONG SEVERAL DYSREGULATED MIRNAS IDENTIFIED VIA MIRNA ARRAYS, THE MOST STRIKING FINDING WAS THE DOWNREGULATION OF MIRNAS OF THE MIR-30 FAMILY IN STRESSED/DEFEATED MICE. TO INVESTIGATE MIRNAS IN THE DG-RESIDENT NEURAL STEM/PROGENITOR CELLS (NSCS/NPCS), WE USED THE IN VITRO NEUROSPHERE CULTURE, WHERE PROLIFERATING NSCS/NPCS WERE SUBJECTED TO DIFFERENTIATION. AMONG SEVERAL DIFFERENTIALLY EXPRESSED MIRNAS, WE OBSERVED AN UPREGULATION OF MIR-30 FAMILY MIRNAS UPON DIFFERENTIATION. TO SEARCH FOR THE GENE TARGETS OF THESE MIRNAS, WE PERFORMED GENE ARRAYS FOLLOWED BY BIOINFORMATICS ANALYSIS, MIRNA MANIPULATIONS AND LUCIFERASE ASSAYS. OUR RESULTS SUGGEST THAT MIR-30 FAMILY MIRNAS MEDIATE CHRONIC STRESS-INDUCED DEPRESSION-LIKE PHENOTYPE BY ALTERING HIPPOCAMPAL NEUROGENESIS AND NEUROPLASTICITY VIA CONTROLLING THE EPIGENETIC AND TRANSCRIPTION REGULATORS SUCH AS MLL3 AND RUNX1; AND CELL SIGNALING REGULATORS LIKE SOCS3, PPP3R1, GPR125, AND NRP1. 2019 9 2054 41 EPIGENETIC CONTRIBUTIONS IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE JOINTS WITH SEVERE PAIN AND SWELLING, JOINT DAMAGE AND DISABILITY, WHICH LEADS TO JOINT DESTRUCTION AND LOSS OF FUNCTION. DESPITE EXTENSIVE RESEARCH EFFORTS, THE UNDERLYING CAUSE FOR RA IS STILL UNKNOWN AND CURRENT THERAPIES ARE MORE OR LESS EFFECTIVE IN CONTROLLING SYMPTOMS BUT STILL FAIL TO CURE THE DISEASE. IN RECENT YEARS, EPIGENETIC MODIFICATIONS WERE FOUND TO STRONGLY CONTRIBUTE TO THE DEVELOPMENT OF RA BY AFFECTING DIVERSE ASPECTS OF THE DISEASE AND MODIFYING GENE EXPRESSION LEVELS AND BEHAVIOR OF SEVERAL CELL TYPES, FIRST AND FOREMOST JOINT RESIDENT SYNOVIAL FIBROBLASTS (SF). RASF ARE THE MOST COMMON CELL TYPE AT THE SITE OF INVASION. OWING TO THEIR AGGRESSIVE, INTRINSICALLY ACTIVATED PHENOTYPE, RASF ARE ACTIVE CONTRIBUTORS IN JOINT DAMAGE. RASF ARE CHARACTERIZED BY THEIR ABILITY TO SECRETE CYTOKINES, CHEMOKINES AND JOINT-DAMAGING ENZYMES. FURTHERMORE, THESE CELLS ARE RESISTANT TO APOPTOSIS, LEADING TO HYPERPLASIA OF THE SYNOVIUM. IN ADDITION, RASF HAVE INVASIVE AND MIGRATORY PROPERTIES THAT COULD LEAD TO SPREADING OF THE DISEASE TO UNAFFECTED JOINTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE (DE)ACETYLATION, HISTONE METHYLATION AND HISTONE SUMOYLATION WERE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE CELL ACTIVATION IN VITRO AND IN DISEASE OUTCOME IN ANIMAL MODELS IN VIVO. IN THE LAST 5 YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. IN THIS REVIEW WE CONSIDER THE ROLE OF DIVERSE EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON EPIGENETIC MODIFICATIONS IN RASF. 2012 10 3407 30 HOW WELL DO WE UNDERSTAND THE LONG-TERM HEALTH IMPLICATIONS OF CHILDHOOD BULLYING? ONCE DISMISSED AS AN INNOCUOUS EXPERIENCE OF CHILDHOOD, BULLYING IS NOW RECOGNIZED AS HAVING SIGNIFICANT PSYCHOLOGICAL EFFECTS, PARTICULARLY WITH CHRONIC EXPOSURE. VICTIMS OF BULLYING ARE AT RISK FOR A NUMBER OF PSYCHIATRIC DISTURBANCES, AND GROWING EVIDENCE SUGGESTS THAT THE PATHOPHYSIOLOGICAL EFFECTS OF BULLYING, AS WITH OTHER FORMS OF TRAUMA AND CHRONIC STRESS, CREATE ADDITIONAL HEALTH RISKS. WE REVIEW THE LITERATURE ON THE KNOWN SEQUELAE OF BULLYING, INCLUDING PSYCHIATRIC AND PHYSIOLOGICAL HEALTH EFFECTS, WITH A FOCUS ON IMPLICATIONS FOR THE VICTIM. IN ADDITION, SINCE IT IS NOW WELL ESTABLISHED THAT EARLY AND CHRONIC EXPOSURE TO STRESS HAS A SIGNIFICANT NEGATIVE IMPACT ON HEALTH OUTCOMES, WE EXPLORE THE IMPLICATIONS OF THIS RESEARCH IN RELATION TO BULLYING AND VICTIMIZATION IN CHILDHOOD. IN PARTICULAR, WE EXAMINE HOW ASPECTS OF THE STRESS RESPONSE, VIA EPIGENETIC, INFLAMMATORY, AND METABOLIC MEDIATORS, HAVE THE CAPACITY TO COMPROMISE MENTAL AND PHYSICAL HEALTH, AND TO INCREASE THE RISK OF DISEASE. RESEARCH ON THE RELEVANT MECHANISMS ASSOCIATED WITH BULLYING AND ON POTENTIAL INTERVENTIONS TO DECREASE MORBIDITY IS URGENTLY NEEDED. 2017 11 3814 28 INTRAUTERINE HYPOXIA AND EPIGENETIC PROGRAMMING IN LUNG DEVELOPMENT AND DISEASE. CLINICALLY, INTRAUTERINE HYPOXIA IS THE FOREMOST CAUSE OF PERINATAL MORBIDITY AND DEVELOPMENTAL PLASTICITY IN THE FETUS AND NEWBORN INFANT. UNDER HYPOXIA, DEVIATIONS OCCUR IN THE LUNG CELL EPIGENOME. EPIGENETIC MECHANISMS (E.G., DNA METHYLATION, HISTONE MODIFICATION, AND MIRNA EXPRESSION) CONTROL PHENOTYPIC PROGRAMMING AND ARE ASSOCIATED WITH PHYSIOLOGICAL RESPONSES AND THE RISK OF DEVELOPMENTAL DISORDERS, SUCH AS BRONCHOPULMONARY DYSPLASIA. THIS DEVELOPMENTAL DISORDER IS THE MOST FREQUENT CHRONIC PULMONARY COMPLICATION IN PRETERM LABOR. THE PATHOGENESIS OF THIS DISEASE INVOLVES MANY FACTORS, INCLUDING ABERRANT OXYGEN CONDITIONS AND MECHANICAL VENTILATION-MEDIATED LUNG INJURY, INFECTION/INFLAMMATION, AND EPIGENETIC/GENETIC RISK FACTORS. THIS REVIEW IS FOCUSED ON VARIOUS ASPECTS RELATED TO INTRAUTERINE HYPOXIA AND EPIGENETIC PROGRAMMING IN LUNG DEVELOPMENT AND DISEASE, SUMMARIZES OUR CURRENT KNOWLEDGE OF HYPOXIA-INDUCED EPIGENETIC PROGRAMMING AND DISCUSSES POTENTIAL THERAPEUTIC INTERVENTIONS FOR LUNG DISEASE. 2021 12 380 36 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 13 5025 29 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 14 6627 47 UNDERSTANDING RESILIENCE: NEW APPROACHES FOR PREVENTING AND TREATING PTSD. ALL INDIVIDUALS EXPERIENCE STRESSFUL LIFE EVENTS, AND UP TO 84% OF THE GENERAL POPULATION WILL EXPERIENCE AT LEAST ONE POTENTIALLY TRAUMATIC EVENT. IN SOME CASES, ACUTE OR CHRONIC STRESSORS LEAD TO THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD) OR OTHER PSYCHOPATHOLOGY; HOWEVER, THE MAJORITY OF PEOPLE ARE RESILIENT TO SUCH EFFECTS. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. A WEALTH OF RESEARCH HAS BEGUN TO IDENTIFY THE GENETIC, EPIGENETIC, NEURAL, AND ENVIRONMENTAL UNDERPINNINGS OF RESILIENCE, AND HAS INDICATED THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES ENCOMPASSING SEVERAL ENVIRONMENTAL FACTORS, NEURAL CIRCUITS, NUMEROUS NEUROTRANSMITTERS, AND MOLECULAR PATHWAYS. THE FIRST PART OF THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING THE GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS AS WELL AS NEURAL CIRCUITS AND MOLECULAR PATHWAYS THAT UNDERLIE THE DEVELOPMENT OF RESILIENCE. EMERGING AND EXCITING AREAS OF RESEARCH AND NOVEL METHODOLOGICAL APPROACHES, INCLUDING GENOME-WIDE GENE EXPRESSION STUDIES, IMMUNE, ENDOCANNABINOID, OXYTOCIN, AND GLUTAMATERGIC SYSTEMS, ARE EXPLORED TO HELP DELINEATE INNOVATIVE MECHANISMS THAT MAY CONTRIBUTE TO RESILIENCE. THE SECOND PART REVIEWS SEVERAL INTERVENTIONS AND PREVENTATIVE APPROACHES DESIGNED TO ENHANCE RESILIENCE IN BOTH DEVELOPMENTAL AND ADULT POPULATIONS. SPECIFICALLY, THE REVIEW WILL DELINEATE APPROACHES AIMED TO BOLSTER RESILIENCE IN INDIVIDUALS WITH PTSD. FURTHERMORE, WE DISCUSS NOVEL PHARMACOLOGIC APPROACHES, INCLUDING THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR KETAMINE AND NEUROPEPTIDE Y (NPY), AS EXCITING NEW PROSPECTS FOR NOT ONLY THE TREATMENT OF PTSD BUT AS NEW TARGETS TO ENHANCE RESILIENCE. OUR GROWING UNDERSTANDING OF RESILIENCE AND INTERVENTIONS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW STRATEGIES FOR NOT JUST TREATING PTSD BUT ALSO SCREENING AND EARLY IDENTIFICATION OF AT-RISK YOUTH AND ADULTS. TAKEN TOGETHER, EFFORTS AIMED AT DISSEMINATION AND IMPLEMENTATION OF NOVEL INTERVENTIONS TO ENHANCE RESILIENCE WILL HAVE TO KEEP PACE WITH THE GROWTH OF NEW PREVENTIVE AND TREATMENT STRATEGIES. 2016 15 6626 41 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 16 6026 32 THE BIOLOGY OF STRESS INTOLERANCE IN PATIENTS WITH CHRONIC PAIN-STATE OF THE ART AND FUTURE DIRECTIONS. STRESS HAS BEEN CONSISTENTLY LINKED TO NEGATIVE IMPACTS ON PHYSICAL AND MENTAL HEALTH. MORE SPECIFICALLY, PATIENTS WITH CHRONIC PAIN EXPERIENCE STRESS INTOLERANCE, WHICH IS AN EXACERBATION OR OCCURRENCE OF SYMPTOMS IN RESPONSE TO ANY TYPE OF STRESS. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING THIS PHENOMENON REMAIN UNSOLVED. IN THIS STATE-OF-THE-ART PAPER, WE SUMMARISED THE ROLE OF THE AUTONOMIC NERVOUS SYSTEM (ANS) AND HYPOTHALAMUS-PITUITARY-ADRENAL (HPA) AXIS, THE TWO MAJOR STRESS RESPONSE SYSTEMS IN STRESS INTOLERANCE. WE PROVIDED INSIGHTS INTO SUCH MECHANISMS BASED ON EVIDENCE FROM CLINICAL STUDIES IN BOTH PATIENTS WITH CHRONIC PAIN, SHOWING DYSREGULATED STRESS SYSTEMS, AND HEALTHY CONTROLS SUPPORTED BY PRECLINICAL STUDIES, HIGHLIGHTING THE LINK BETWEEN THESE SYSTEMS AND SYMPTOMS OF STRESS INTOLERANCE. FURTHERMORE, WE EXPLORED THE POSSIBLE REGULATING ROLE FOR (EPI)GENETIC MECHANISMS INFLUENCING THE ANS AND HPA AXIS. THE LINK BETWEEN STRESS AND CHRONIC PAIN HAS BECOME AN IMPORTANT AREA OF RESEARCH AS IT HAS THE POTENTIAL TO INFORM THE DEVELOPMENT OF INTERVENTIONS TO IMPROVE THE QUALITY OF LIFE FOR INDIVIDUALS LIVING WITH CHRONIC PAIN. AS STRESS HAS BECOME A PREVALENT CONCERN IN MODERN SOCIETY, UNDERSTANDING THE CONNECTION BETWEEN STRESS, HPA AXIS, ANS, AND CHRONIC HEALTH CONDITIONS SUCH AS CHRONIC PAIN IS CRUCIAL TO IMPROVE PUBLIC HEALTH AND WELL-BEING. 2023 17 5308 27 PSORIASIS AND PHYSICAL ACTIVITY: A REVIEW. PSORIASIS IS A COMMON, CHRONIC INFLAMMATORY SKIN DISEASE THAT CAN CAUSE SIGNIFICANT DISCOMFORT AND IMPAIRMENT TO QUALITY OF LIFE. RECENT RESEARCH INDICATES THAT INDIVIDUALS WITH MODERATE-TO-SEVERE PSORIASIS ARE LIKELY AT GREATER RISK FOR CHRONIC CARDIOMETABOLIC CO-MORBIDITIES SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES, OBESITY AND METABOLIC SYNDROME. PHYSICAL ACTIVITY CAN BE AN EFFECTIVE PRIMARY AND ADJUNCTIVE TREATMENT FOR THESE MALADIES IN OTHER POPULATIONS. UNFORTUNATELY, ONLY A LIMITED NUMBER OF STUDIES HAVE EXAMINED PHYSICAL ACTIVITY IN PSORIASIS, WHICH ARE LIMITED BY POOR DESIGN AND LACK OF VALIDATED PHYSICAL ACTIVITY ASSESSMENT METHODOLOGIES. A VARIETY OF DATA SUGGEST SHARED PHYSIOLOGIC PATHWAYS BETWEEN PHYSICAL ACTIVITY, PSORIASIS, AND PSORIASIS CARDIOMETABOLIC CO-MORBIDITIES. INCREASED ADIPOSITY, INFLAMMATION, OXIDATIVE STRESS, ADHESION MOLECULES AND LIPIDS ARE PHYSIOLOGICALLY LINKED TO PSORIASIS, THE RISK OF PSORIASIS CARDIOMETABOLIC CO-MORBIDITIES, AND LOW LEVELS OF PHYSICAL ACTIVITY. IN ADDITION, EPIGENETIC PATHWAYS ARE INVOLVED IN PSORIASIS AND COULD BE INFLUENCED BY PHYSICAL ACTIVITY. THE PHYSICAL AND PSYCHOSOCIAL IMPAIRMENTS COMMON IN PSORIASIS MAY MAKE IT DIFFICULT TO PARTICIPATE IN REGULAR PHYSICAL ACTIVITY, AND FUTURE STUDIES SHOULD AIM TO DETERMINE IF PHYSICAL ACTIVITY INTERVENTIONS IMPROVE FUNCTIONING AND REDUCE CO-MORBIDITIES IN PSORIASIS. 2012 18 6375 42 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 19 6742 40 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 20 6329 44 THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. THIS REVIEW WILL DISCUSS THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. RELEVANT STUDIES WERE IDENTIFIED VIA MEDLINE (PUBMED) AND PSYCINFO DATABASES PUBLISHED UP TO AND INCLUDING JULY 2015. THIS REVIEW CONTRIBUTES TO A NEW UNDERSTANDING OF THE NEGATIVE CONSEQUENCES OF EARLY LIFE STRESS, AS WELL AS SETTING CHILDHOOD TRAUMA IN A BIOLOGICAL CONTEXT OF SUSCEPTIBILITY AND DISCUSSING NOVEL LONG-TERM PATHOPHYSIOLOGICAL CONSEQUENCES IN BIPOLAR DISORDERS. CHILDHOOD TRAUMATIC EVENTS ARE RISK FACTORS FOR DEVELOPING BIPOLAR DISORDERS, IN ADDITION TO A MORE SEVERE CLINICAL PRESENTATION OVER TIME (PRIMARILY AN EARLIER AGE AT ONSET AND AN INCREASED RISK OF SUICIDE ATTEMPT AND SUBSTANCE MISUSE). CHILDHOOD TRAUMA LEADS TO ALTERATIONS OF AFFECT REGULATION, IMPULSE CONTROL, AND COGNITIVE FUNCTIONING THAT MIGHT DECREASE THE ABILITY TO COPE WITH LATER STRESSORS. CHILDHOOD TRAUMA INTERACTS WITH SEVERAL GENES BELONGING TO SEVERAL DIFFERENT BIOLOGICAL PATHWAYS [HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, SEROTONERGIC TRANSMISSION, NEUROPLASTICITY, IMMUNITY, CALCIUM SIGNALING, AND CIRCADIAN RHYTHMS] TO DECREASE THE AGE AT THE ONSET OF THE DISORDER OR INCREASE THE RISK OF SUICIDE. EPIGENETIC FACTORS MAY ALSO BE INVOLVED IN THE NEUROBIOLOGICAL CONSEQUENCES OF CHILDHOOD TRAUMA IN BIPOLAR DISORDER. BIOLOGICAL SEQUELAE SUCH AS CHRONIC INFLAMMATION, SLEEP DISTURBANCE, OR TELOMERE SHORTENING ARE POTENTIAL MEDIATORS OF THE NEGATIVE EFFECTS OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS, IN PARTICULAR WITH REGARD TO PHYSICAL HEALTH. THE MAIN CLINICAL IMPLICATION IS TO SYSTEMATICALLY ASSESS CHILDHOOD TRAUMA IN PATIENTS WITH BIPOLAR DISORDERS, OR AT LEAST IN THOSE WITH A SEVERE OR INSTABLE COURSE. THE CHALLENGE FOR THE NEXT YEARS WILL BE TO FILL THE GAP BETWEEN CLINICAL AND FUNDAMENTAL RESEARCH AND ROUTINE PRACTICE, SINCE RECOMMENDATIONS FOR MANAGING THIS SPECIFIC POPULATION ARE LACKING. IN PARTICULAR, LITTLE IS KNOWN ON WHICH PSYCHOTHERAPIES SHOULD BE PROVIDED OR WHICH TARGETS THERAPISTS SHOULD FOCUS ON, AS WELL AS HOW CHILDHOOD TRAUMA COULD EXPLAIN THE RESISTANCE TO MOOD STABILIZERS. 2016