1 4847 174 OPIOID DEPENDENCE AND PREGNANCY: MINIMIZING STRESS ON THE FETAL BRAIN. INCREASE IN THE NUMBER OF OPIOID-DEPENDENT PREGNANT WOMEN DELIVERING BABIES AT RISK FOR NEONATAL ABSTINENCE SYNDROME PROMPTED A US GOVERNMENT ACCOUNTABILITY OFFICE REPORT DOCUMENTING DEFICITS IN RESEARCH AND PROVIDER KNOWLEDGE ABOUT CARE OF THE MATERNAL/FETAL UNIT AND THE NEONATE. THERE ARE 3 GENERAL SOURCES OF DEPENDENCE: UNTREATED OPIOID USE DISORDER, PAIN MANAGEMENT, AND MEDICATION-ASSISTED TREATMENT WITH METHADONE OR BUPRENORPHINE. A SURVEY OF METHADONE PATIENTS' EXPERIENCES WHEN TELLING A PHYSICIAN OF THEIR PREGNANCY AND OPIOID DEPENDENCE DEMONSTRATED PHYSICIAN CONFUSION ABOUT PROPER CARE, FREQUENT NEGATIVE INTERACTIONS WITH THE MOTHER, AND FAILURES TO PROVIDE APPROPRIATE REFERRAL. PATIENTS IN PAIN MANAGEMENT WERE DISCHARGED WITHOUT REFERRAL WHEN THE PHYSICIAN WAS TOLD OF THE PREGNANCY. METHADONE AND BUPRENORPHINE WERE FREQUENTLY SEEN NEGATIVELY BECAUSE THEY "CAUSED" NEONATAL ABSTINENCE SYNDROME. MOST MOTHERS SURVEYED HAD TO FIND OPIOID TREATMENT ON THEIR OWN. HOW DEPENDENCE IS MANAGED MEDICALLY IS A CRITICAL DETERMINANT OF THE LEVEL OF STRESS ON BOTH MOTHER AND FETUS, AND THEREFORE ANOTHER DETERMINANT OF NEONATAL HEALTH. THE EFFECTS OF BOTH OPIOID WITHDRAWAL STRESS AND MATERNAL EMOTIONAL STRESS ON NEONATAL AND DEVELOPMENTAL OUTCOMES ARE REVIEWED. CURRENTLY, THERE HAVE BEEN EFFORTS TO CRIMINALIZE MATERNAL OPIOID DEPENDENCE AND TO ENCOURAGE OR COERCE PREGNANT WOMEN TO UNDERGO WITHDRAWAL. THIS PRACTICE POSES BOTH ACUTE RISKS OF FETAL HYPOXIA AND LONG-TERM RISKS OF ADVERSE EPIGENETIC PROGRAMMING RELATED TO CATECHOLAMINE AND CORTICOSTEROID SURGES DURING WITHDRAWAL. CONTEMPORARY STUDIES OF THE EFFECTS OF WITHDRAWAL STRESS ON THE DEVELOPING FETAL BRAIN ARE URGENTLY NEEDED TO ELUCIDATE AND QUANTIFY THE RISKS OF SUCH PRACTICES. AT BIRTH, INCONSISTENCIES IN THE HOSPITAL MANAGEMENT OF NEONATES AT RISK FOR NEONATAL ABSTINENCE SYNDROME HAVE BEEN OBSERVED. NEGLECT OF THE CRITICAL ROLE OF MATERNAL COMFORTING IN NEONATAL ABSTINENCE SYNDROME MANAGEMENT IS AN IATROGENIC AND PREVENTABLE CAUSE OF POOR OUTCOMES AND LONG HOSPITALIZATIONS. ROOMING-IN ALLOWS FOR CONTINUOUS CARE OF THE BABY AND MATERNAL/NEONATAL ATTACHMENT, OFTEN UNWITTINGLY DISRUPTED BY THE NEONATAL INTENSIVE CARE UNIT ENVIRONMENT. RECOMMENDATIONS ARE MADE FOR FURTHER RESEARCH INTO PHYSICIAN/PATIENT INTERACTIONS AND INTO OPTIMAL DOSING OF METHADONE AND BUPRENORPHINE TO MINIMIZE MATERNAL/FETAL WITHDRAWAL. 2017 2 6755 34 WILL WIDESPREAD SYNTHETIC OPIOID CONSUMPTION INDUCE EPIGENETIC CONSEQUENCES IN FUTURE GENERATIONS? A GROWING NUMBER OF EVIDENCE DEMONSTRATES THAT ANCESTRAL EXPOSURE TO XENOBIOTICS (POLLUTANTS, DRUGS OF ABUSE, ETC.) CAN PERTURB THE PHYSIOLOGY AND BEHAVIOR OF DESCENDANTS. BOTH MATERNAL AND PATERNAL TRANSMISSION OF PHENOTYPE ACROSS GENERATIONS HAS BEEN PROVED, DEMONSTRATING THAT PARENTAL DRUG HISTORY MAY HAVE SIGNIFICANT IMPLICATIONS FOR SUBSEQUENT GENERATIONS. IN THE LAST YEARS, THE BURDEN OF NOVEL SYNTHETIC OPIOID (NSO) CONSUMPTION, DUE TO INCREASED MEDICAL PRESCRIPTION OF PAIN MEDICATIONS AND TO EASIER ACCESSIBILITY OF THESE SUBSTANCES ON ILLEGAL MARKET, IS RAISING NEW QUESTIONS FIRST IN TERM OF PUBLIC HEALTH, BUT ALSO ABOUT THE CONSEQUENCES OF THE PARENTAL USE OF THESE DRUGS ON FUTURE GENERATIONS. BESIDES BEING ASSOCIATED TO THE NEONATAL ABSTINENCE SYNDROME, IN UTERO EXPOSURE TO OPIOIDS HAS AN IMPACT ON NEURONAL DEVELOPMENT WITH LONG-TERM REPERCUSSIONS THAT ARE POTENTIALLY TRANSMITTED TO SUBSEQUENT GENERATIONS. IN ADDITION, RECENT REPORTS SUGGEST THAT OPIOID USE EVEN BEFORE CONCEPTION INFLUENCES THE REACTIVITY TO OPIOIDS OF THE PROGENY AND THE FOLLOWING GENERATIONS, LIKELY THROUGH EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES THE CURRENT KNOWLEDGE ABOUT THE TRANSGENERATIONAL EFFECTS OF OPIOID CONSUMPTION. WE SUMMARIZE THE PRECLINICAL AND CLINICAL FINDINGS SHOWING THE IMPLICATIONS FOR THE SUBSEQUENT GENERATIONS OF PARENTAL EXPOSURE TO OPIOIDS EARLIER IN LIFE. LIMITATIONS OF THE EXISTING DATA ON NSOS AND NEW PERSPECTIVES OF THE RESEARCH ARE ALSO DISCUSSED, AS WELL AS CLINICAL AND FORENSIC CONSEQUENCES. 2018 3 6853 42 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 4 5000 38 PERINATAL PROGRAMMING PREVENTION MEASURES. OVER THE PAST 10 YEARS, THERE HAS BEEN OUTSTANDING SCIENTIFIC PROGRESS RELATED TO PERINATAL PROGRAMMING AND ITS EPIGENETIC EFFECTS IN HEALTH, AND WE CAN ANTICIPATE THIS TREND WILL CONTINUE IN THE NEAR FUTURE. WE NEED TO MAKE USE AND APPLY THESE ACHIEVEMENTS TO HUMAN NEURODEVELOPMENT VIA PREVENTION INTERVENTIONS. BASED ON THE CONCEPT OF THE INTERACTION BETWEEN GENOME AND AMBIOME, THIS CHAPTER PROPOSES LOW-COST EASY-IMPLEMENTATION PREVENTIVE STRATEGIES FOR MATERNAL AND INFANT HEALTH INSTITUTIONS.BREASTFEEDING AND HUMAN MILK ADMINISTRATION ARE THE FIRST PREVENTIVE MEASURES, AS HAS BEEN REVIEWED IN THE POLICY STATEMENT OF THE AMERICAN ACADEMY OF PEDIATRICS. ANOTHER STRATEGY IS THE SAFE AND FAMILY-CENTERED MATERNITY HOSPITALS INITIATIVE THAT PROMOTES AND EMPOWERS THE INCLUSION OF THE FAMILIES AND THE RESPECT FOR THEIR RIGHTS, ESPECIALLY DURING PREGNANCY AND BIRTH. (THIS CHANGE OF PARADIGM WAS APPROVED AND IS RECOMMENDED BY BOTH UNITED NATIONS CHILDREN'S FUND, UNICEF, AND PAN AMERICAN HEALTH ORGANIZATION, PAHO.) THEN, THERE IS ALSO AN IMPORTANT EMPHASIS GIVEN TO THE SACRED HOUR-WHICH HIGHLIGHTS THE IMPACT OF BONDING, ATTACHMENT, AND BREASTFEEDING DURING THE FIRST HOUR OF LIFE-THE PAIN PREVENTION AND TREATMENT IN NEWBORNS, THE CONTROL OF THE "NEW MORBIDITY" REPRESENTED BY LATE PRETERM INFANTS, AND FINALLY, THE IMPORTANCE OF AVOIDING INTRAUTERINE AND EXTRAUTERINE GROWTH RESTRICTION. (HOWEVER, THERE ARE NOT YET CLEAR RECOMMENDATIONS ABOUT NUTRITIONAL INTERVENTIONS IN ORDER TO DIMINISH THE POTENTIAL METABOLIC SYNDROME CONSEQUENCE IN THE ADULT.). 2015 5 5650 28 SEX DIFFERENCES IN THE DEVELOPMENT OF PHYSICAL AGGRESSION: AN INTERGENERATIONAL PERSPECTIVE AND IMPLICATIONS FOR PREVENTIVE INTERVENTIONS. THIS ARTICLE REVIEWS THE STATE OF KNOWLEDGE ON THE DEVELOPMENT OF CHRONIC PHYSICAL AGGRESSION (CPA), WITH THE AIM OF IDENTIFYING THE MOST EFFECTIVE PREVENTION STRATEGIES. WE SPECIFICALLY FOCUS ON THE EARLY DEVELOPMENT OF PHYSICAL AGGRESSION, ON SEX DIFFERENCES IN THE USE OF PHYSICAL AGGRESSION, AND ON THE TRANSMISSION OF BEHAVIOR PROBLEMS FROM ONE GENERATION TO THE OTHER. THE BODY OF RESEARCH ON THE DEVELOPMENT OF CPA FROM THE PAST THREE DECADES THAT WE REVIEW SHOWS INCREASING EVIDENCE THAT ITS PREVENTION REQUIRES A LONG-TERM BIOPSYCHOSOCIAL DEVELOPMENTAL APPROACH WHICH ALSO MUST INCLUDE AN INTERGENERATIONAL PERSPECTIVE. RECENT GENETIC AND EPIGENETIC RESEARCH HAS INDICATED THAT THERE ARE BOTH IMPORTANT GENETIC AND ENVIRONMENTAL EFFECTS ON GENE EXPRESSION WHICH START AT CONCEPTION. WE CONCLUDE THAT ONE OF THE MOST EFFECTIVE STRATEGIES TO BREAK THE INTERGENERATIONAL TRANSMISSION OF CPA INVOLVES GIVING LONG-TERM SUPPORT TO PREGNANT WOMEN WITH A HISTORY OF BEHAVIOR PROBLEMS, THEIR SPOUSE, AND THEIR OFFSPRING. 2019 6 4631 35 NEUROGENETICS OF ACUTE AND CHRONIC OPIATE/OPIOID ABSTINENCE: TREATING SYMPTOMS AND THE CAUSE. THIS REVIEW BEGINS WITH A COMPREHENSIVE HISTORY OF OPIOID DEPENDENCE AND TREATMENT IN THE UNITED STATES. THE FOCUS IS AN EVIDENCE-BASED TREATMENT MODEL FOR OPIOID/OPIATE DEPENDENT INDIVIDUALS. THE ROLE OF REWARD GENETIC POLYMORPHISMS AND THE EPIGENETIC MODIFICATIONS THAT LEAD TO VULNERABILITY TO USE AND MISUSE OF OPIATES/OPIOID TO TREAT PAIN ARE REVIEWED. THE NEUROCHEMICAL MECHANISMS OF ACUTE OPIATE WITHDRAWAL AND OPIATE/OPIOID REWARD MECHANISMS ARE EXPLORED WITH A GOAL OF IDENTIFYING SPECIFIC TREATMENT TARGETS. ALTERATIONS IN FUNCTIONAL BRAIN CONNECTIVITY BASED ON NEUROBIOLOGICAL MECHANISMS IN HEROIN DEPENDENCE AND ABSTINENCE ARE ALSO REVIEWED. A NEW CLINICAL MODEL AN ALTERNATIVE TO MERELY BLOCKING ACUTE WITHDRAWAL SYMPTOMS AS IDENTIFIED IN THE DSM -5 IS PROPOSED. GENETIC DIAGNOSIS AT THE ONSET OF DETOXIFICATION, TO DETERMINE RISK STRATIFICATION, AND IDENTIFY POLYMORPHIC GENE TARGETS FOR PHARMACEUTICAL AND NUTRACEUTICAL INTERVENTIONS, FOLLOWED BY THE SIMULTANEOUS INITIATION OF MEDICATION ASSISTED THERAPY (MAT), TO ENABLE PSYCHOLOGICAL EXTINCTION, AND STEADY PRO-DOPAMINERGIC THERAPY WITH THE GOAL OF DEVELOPING "DOPAMINE HOMEOSTASIS" IS RECOMMENDED. THE OBJECTIVE OF THESE INTERVENTIONS IS TO PREVENT FUTURE RELAPSE BY TREATING ALL "REWARD DEFICIENCY SYNDROME" (RDS) BEHAVIORS AND EVENTUALLY MAKE AN ADDICTION-FREE LIFE POSSIBLE. 2017 7 5569 38 ROLE OF MATERNAL VITAMINS IN PROGRAMMING HEALTH AND CHRONIC DISEASE. VITAMIN CONSUMPTION PRIOR TO AND DURING PREGNANCY HAS INCREASED AS A RESULT OF PROACTIVE RECOMMENDATIONS BY HEALTH PROFESSIONALS, WIDE AVAILABILITY OF VITAMIN SUPPLEMENTS, AND LIBERAL FOOD-FORTIFICATION POLICIES. FOLIC ACID, ALONE OR IN COMBINATION WITH OTHER B VITAMINS, IS THE MOST RECOMMENDED VITAMIN CONSUMED DURING PREGNANCY BECAUSE DEFICIENCY OF THIS VITAMIN LEADS TO BIRTH DEFECTS IN THE INFANT. FOLIC ACID AND OTHER B VITAMINS ARE ALSO INTEGRAL COMPONENTS OF BIOCHEMICAL PROCESSES THAT ARE ESSENTIAL TO THE DEVELOPMENT OF REGULATORY SYSTEMS THAT CONTROL THE ABILITY OF THE OFFSPRING TO ADAPT TO THE EXTERNAL ENVIRONMENT. ALTHOUGH FEW HUMAN STUDIES HAVE INVESTIGATED THE LASTING EFFECTS OF HIGH VITAMIN INTAKES DURING PREGNANCY, ANIMAL MODELS HAVE SHOWN THAT EXCESS VITAMIN SUPPLEMENTATION DURING GESTATION IS ASSOCIATED WITH NEGATIVE METABOLIC EFFECTS IN BOTH THE MOTHERS AND THEIR OFFSPRING. THIS RESEARCH FROM ANIMAL MODELS, COMBINED WITH THE RECOGNITION THAT EPIGENETIC REGULATION OF GENE EXPRESSION IS PLASTIC, PROVIDES EVIDENCE FOR FURTHER EXAMINATION OF THESE RELATIONSHIPS IN THE LATER LIFE OF PREGNANT WOMEN AND THEIR CHILDREN. 2016 8 1779 40 EDITORIAL: MATERNAL INFLAMMATION DURING PREGNANCY: A MODIFIABLE PATHWAY TOWARD IMPROVING OFFSPRING SOCIOEMOTIONAL OUTCOMES IN CHILDHOOD AND ADOLESCENCE. CHILDHOOD PSYCHOPATHOLOGY IS A WELL-ESTABLISHED PREDICTOR OF POOR ADULT LIFE-COURSE OUTCOMES INCLUDING LOWER RATES OF EDUCATIONAL ATTAINMENT AND REDUCED FAMILY INCOME, WITH A TOTAL ECONOMIC LOSS OF $2.1 TRILLION IN THE UNITED STATES.(1) GIVEN THIS HIGH LEVEL OF INDIVIDUAL AND SOCIETAL BURDEN, MUCH EFFORT HAS BEEN DEVOTED TO IDENTIFYING THE MODIFIABLE RISK FACTORS THAT CONFER RISK FOR PSYCHIATRIC DISORDERS DURING EARLY CHILDHOOD. INDEED, NUMEROUS ASPECTS OF EARLY LIFE ADVERSITY, SUCH AS SOCIOECONOMIC DISADVANTAGE, STRESSFUL/TRAUMATIC LIFE EVENTS, AND DISRUPTED PARENT-CHILD RELATIONSHIPS, DEMONSTRATE STRONG ASSOCIATIONS WITH SOCIOEMOTIONAL PROBLEMS AND PSYCHIATRIC DISORDERS INTO ADOLESCENCE.(2) HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS THAT ALSO CONTRIBUTE TO THIS RISK TRAJECTORY REMAIN LESS WELL UNDERSTOOD. ONE PROPOSED BIOLOGICAL MECHANISM THAT IS RAPIDLY GAINING MOMENTUM IN THE FIELD OF DEVELOPMENTAL PSYCHOPATHOLOGY CONCERNS EXCESSIVE IMMUNE SYSTEM ACTIVATION AND/OR PROINFLAMMATORY RESPONSES IN THE ORIGINS OF HEALTH AND DISEASE.(3) OF PARTICULAR INTEREST IS THE PRENATAL PERIOD, REPRESENTING A WINDOW OF VULNERABILITY IN WHICH PRENATAL EXPOSURES PREPARE OR PROGRAM THE FETUS FOR THE EXPECTED POSTNATAL ENVIRONMENT.(3-5) MORE SPECIFICALLY, FETAL PROGRAMMING POSITS THAT THE EFFECTS OF MATERNAL ADVERSITY DURING PREGNANCY ARE, AT LEAST IN PART, TRANSMITTED TO THE FETUS VIA MULTIPLE RELATED PATHWAYS INCLUDING CHRONIC MATERNAL INFLAMMATION AND/OR OVERACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, RESULTING IN ABERRANT MATERNAL-FETAL IMMUNE/GLUCOCORTICOID SYSTEMS AND DOWNSTREAM EPIGENETIC ALTERATIONS IN THE DEVELOPING FETUS. TOGETHER, THESE FACTORS WORK TO INCREASE THE SUSCEPTIBILITY OF OFFSPRING TO ADVERSITY IN THE POSTNATAL ENVIRONMENT AND, IN TURN, ENHANCE RISK FOR PSYCHIATRIC DISORDERS.(3-6) HOWEVER, MUCH OF THE EXISTING LITERATURE IS BASED ON PRECLINICAL ANIMAL MODELS WITH COMPARATIVELY FEWER CLINICAL STUDIES.(3) AS SUCH, THERE REMAINS A PAUCITY OF LARGE, PROSPECTIVELY DESIGNED CLINICAL STUDIES EXAMINING MATERNAL PROINFLAMMATORY CONDITIONS DURING PREGNANCY IN RELATION TO PSYCHOPATHOLOGY IN OFFSPRING. AS PART OF THE LANDMARK NATIONAL INSTITUTES OF HEALTH-FUNDED ECHO (ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES) CONSORTIUM, THE STUDY BY FRAZIER ET AL.(7) REPRESENTS ONE OF THE LARGEST INVESTIGATIONS LINKING PERINATAL MATERNAL PROINFLAMMATORY CONDITIONS WITH CO-OCCURRING PSYCHIATRIC SYMPTOMS IN CHILDREN AND ADOLESCENTS. 2023 9 14 29 3RD COLLEGE OF PAEDIATRICS AND CHILD HEALTH LECTURE--THE PAST, THE PRESENT AND THE SHAPE OF THINGS TO COME.. THE GROWTH TRENDS OF SINGAPORE CHILDREN SPANNING 5 DECADES ARE REVIEWED, BASED ON 8 ANTHROPOMETRIC STUDIES FROM 1957 TILL 2002. THE HEIGHTS OF PRE-SCHOOL CHILDREN AND SCHOOL AGE CHILDREN APPEAR TO HAVE OPTIMISED ACCORDING TO THEIR GENETIC POTENTIAL, BUT THE WEIGHTS AND BODY MASS INDICES OF CHILDREN STILL APPEAR TO BE INCREASING FROM 6 TO 18 YEARS FOR BOTH SEXES, PROBABLY AS A CONSEQUENCE OF INCREASING AFFLUENCE. THIS TREND IS REFLECTED IN THE INCREASING OBESITY PREVALENCE IN SCHOOL CHILDREN OVER THE PAST 30 YEARS, AND THE CONCOMITANT INCREASED MORBIDITY ASSOCIATED WITH THE METABOLIC SYNDROME, NECESSITATES FURTHER RESEARCH INTO THE CAUSES OF OBESITY. BARKER'S HYPOTHESIS FIRST SUGGESTED THAT CHANGES IN THE INTRA-UTERINE ENVIRONMENT CAN CAUSE FETAL ADAPTATIONS WHICH PERSIST INTO ADULTHOOD, AND ARE RESPONSIBLE FOR MANY CHRONIC DISEASES OF ADULT LIFE. MORE RECENTLY, INTENSE RESEARCH IN THE FIELD OF EPIGENETICS SUGGESTS THAT THE ENVIRONMENT CAN ALSO INFLUENCE THE PHENOTYPE THROUGH GENE EXPRESSION, THROUGH MODIFICATION OF DNA METHYLATION AND HISTONES WHICH, IN TURN, INFLUENCES GENE EXPRESSION. THE CHALLENGE FOR THE FUTURE IS TO DETERMINE IF THERE ARE CLEAR EPIGENETIC CHANGES, WHICH ARE RESPONSIBLE FOR THE INCREASED PREVALENCE OF CHILDHOOD AND ADOLESCENT OBESITY, AND WHETHER THESE CHANGES ARE TRANSMITTED THROUGH GENERATIONS. UNRAVELLING THESE EPIGENETIC MECHANISMS MAY BE THE KEY TO THE PREVENTION OF OBESITY AND THE METABOLIC SYNDROME. 2008 10 2808 38 FETAL PROGRAMMING OF HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION AND BEHAVIOR BY SYNTHETIC GLUCOCORTICOIDS. REDUCED FETAL GROWTH HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE IN LATER LIFE. ACCUMULATING EVIDENCE INDICATES THAT FETAL EXPOSURE TO EXCESS GLUCOCORTICOIDS REPRESENTS A CRITICAL MECHANISM UNDERLYING THIS ASSOCIATION. APPROXIMATELY 7% OF PREGNANT WOMEN ARE AT RISK OF PRETERM DELIVERY AND THESE WOMEN ARE ROUTINELY TREATED WITH SYNTHETIC GLUCOCORTICOIDS (SGC) BETWEEN 24 AND 34 OF WEEKS GESTATION TO IMPROVE NEONATAL OUTCOME. ANIMAL STUDIES HAVE DEMONSTRATED THAT MATERNALLY ADMINISTERED SGC CROSSES THE PLACENTA, AFFECTING FETAL HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) DEVELOPMENT, RESULTING IN CHANGES IN HPA AXIS FUNCTION THAT PERSIST THROUGHOUT LIFE. THESE CHANGES APPEAR TO BE MODULATED AT THE LEVEL OF GLUCOCORTICOID RECEPTORS (GR) AND MINERALOCORTICOID RECEPTORS (MR) IN THE BRAIN AND PITUITARY. AS THE HPA AXIS INTERACTS WITH MANY OTHER PHYSIOLOGICAL PATHWAYS, THE CHANGES IN ENDOCRINE FUNCTION ARE ALSO SEX-SPECIFIC AND AGE-DEPENDENT. ALTERATIONS IN BEHAVIOR, PARTICULARLY LOCOMOTION, IN ANIMALS EXPOSED TO SGC IN UTERO HAVE ALSO BEEN DEMONSTRATED. CONSISTENT WITH THE FINDING IN ANIMAL MODELS, EMERGING HUMAN DATA ARE INDICATING ATTENTION DEFICIT-HYPERACTIVITY DISORDER (ADHD)-LIKE SYMPTOMS IN CHILDREN EXPOSED TO REPEATED COURSES OF SGC IN UTERO. THIS BEHAVIORAL PHENOTYPE IS LIKELY LINKED TO ALTERATIONS IN DOPAMINE (DA) SIGNALING, SUGGESTING THAT SGC ARE ABLE TO PERMANENTLY MODIFY OR 'PROGRAM' THIS SYSTEM. FINALLY, IT IS EMERGING THAT CHANGES IN HPA AXIS FUNCTION AND BEHAVIOR FOLLOWING ANTENATAL EXPOSURE TO SGC ARE TRANSGENERATIONAL AND LIKELY INVOLVE EPIGENETIC MECHANISMS. A COMPREHENSIVE UNDERSTANDING OF THE ACUTE AND LONG-TERM IMPACT OF SGC EXPOSURE IN UTERO IS NECESSARY TO BEGIN TO DEVELOP RECOMMENDATIONS AND TREATMENT OPTIONS FOR PREGNANT WOMEN AT RISK OF PRETERM DELIVERY. 2008 11 421 30 ANIMAL MODELS IN EPIGENETIC RESEARCH: INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE CONSIDERATIONS ACROSS THE LIFESPAN. THE RAPID EXPANSION AND EVOLUTION OF EPIGENETICS AS A CORE SCIENTIFIC DISCIPLINE HAVE RAISED NEW QUESTIONS ABOUT HOW ENDOGENOUS AND ENVIRONMENTAL FACTORS CAN INFORM THE MECHANISMS THROUGH WHICH BIOLOGICAL FORM AND FUNCTION ARE REGULATED. EXISTING AND PROPOSED ANIMAL MODELS USED FOR EPIGENETIC RESEARCH HAVE TARGETED A MYRIAD OF HEALTH AND DISEASE ENDPOINTS THAT MAY BE ACUTE, CHRONIC, AND TRANSGENERATIONAL IN NATURE. INITIATING EVENTS AND OUTCOMES MAY EXTEND ACROSS THE ENTIRE LIFESPAN TO ELICIT UNANTICIPATED PHENOTYPES THAT ARE OF PARTICULAR CONCERN TO INSTITUTIONAL ANIMAL CARE AND USE COMMITTEES (IACUCS). THE DYNAMICS AND PLASTICITY OF EPIGENETIC MECHANISMS PRODUCE EFFECTS AND CONSEQUENCES THAT ARE MANIFEST DIFFERENTIALLY WITHIN DISCREET SPATIAL AND TEMPORAL CONTEXTS, INCLUDING PRENATAL DEVELOPMENT, STEM CELLS, ASSISTED REPRODUCTIVE TECHNOLOGIES, PRODUCTION OF SEXUAL DIMORPHISMS, SENESCENCE, AND OTHERS. MANY DIETARY AND NUTRITIONAL INTERVENTIONS HAVE ALSO BEEN SHOWN TO HAVE A SIGNIFICANT IMPACT ON BIOLOGICAL FUNCTIONS AND DISEASE SUSCEPTIBILITIES THROUGH ALTERED EPIGENETIC PROGRAMMING. THE ENVIRONMENTAL, CHEMICAL, TOXIC, THERAPEUTIC, AND PSYCHOSOCIAL STRESSORS USED IN ANIMAL STUDIES TO ELICIT EPIGENETIC CHANGES CAN BECOME EXTREME AND SHOULD RAISE IACUC CONCERNS FOR THE WELL-BEING AND PROPER CARE OF ALL RESEARCH ANIMALS INVOLVED. EPIGENETICS RESEARCH IS RAPIDLY BECOMING AN INTEGRAL PART OF THE SEARCH FOR MECHANISMS IN EVERY MAJOR AREA OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND WILL FOSTER THE CONTINUED DEVELOPMENT OF NEW ANIMAL MODELS. FROM THE IACUC PERSPECTIVE, CARE MUST BE TAKEN TO ACKNOWLEDGE THE PARTICULAR NEEDS AND CONCERNS CREATED BY SUPERIMPOSITION OF EPIGENETIC MECHANISMS OVER DIVERSE FIELDS OF INVESTIGATION TO ENSURE THE PROPER CARE AND USE OF ANIMALS WITHOUT IMPEDING SCIENTIFIC PROGRESS. 2012 12 1766 34 EARLY-LIFE EXPERIENCES AND THE DEVELOPMENT OF ADULT DISEASES WITH A FOCUS ON MENTAL ILLNESS: THE HUMAN BIRTH THEORY. IN MAMMALS, EARLY ADVERSE EXPERIENCES, INCLUDING MOTHER-PUP INTERACTIONS, SHAPE THE RESPONSE OF AN INDIVIDUAL TO CHRONIC STRESS OR TO STRESS-RELATED DISEASES DURING ADULT LIFE. THIS HAS LED TO THE ELABORATION OF THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, IN PARTICULAR ADULT DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISORDERS. IN ADDITION, IN HUMANS, AS STATED BY MASSIMO FAGIOLI'S HUMAN BIRTH THEORY, BIRTH IS HEALTHY AND EQUAL FOR ALL INDIVIDUALS, SO THAT MENTAL ILLNESS DEVELOP EXCLUSIVELY IN THE POSTNATAL PERIOD BECAUSE OF THE QUALITY OF THE RELATIONSHIP IN THE FIRST YEAR OF LIFE. THUS, THIS REVIEW FOCUSES ON THE IMPORTANCE OF PROGRAMMING DURING THE EARLY DEVELOPMENTAL PERIOD ON THE MANIFESTATION OF ADULT DISEASES IN BOTH ANIMAL MODELS AND HUMANS. CONSIDERING THE OBVIOUS DIFFERENCES BETWEEN ANIMALS AND HUMANS WE CANNOT SYSTEMATICALLY MOVE FROM ANIMAL MODELS TO HUMANS. CONSEQUENTLY, IN THE FIRST PART OF THIS REVIEW, WE WILL DISCUSS HOW ANIMAL MODELS CAN BE USED TO DISSECT THE INFLUENCE OF ADVERSE EVENTS OCCURRING DURING THE PRENATAL AND POSTNATAL PERIODS ON THE DEVELOPMENTAL TRAJECTORIES OF THE OFFSPRING, AND IN THE SECOND PART, WE WILL DISCUSS THE ROLE OF POSTNATAL CRITICAL PERIODS ON THE DEVELOPMENT OF MENTAL DISEASES IN HUMANS. EPIGENETIC MECHANISMS THAT CAUSE REVERSIBLE MODIFICATIONS IN GENE EXPRESSION, DRIVING THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE IN RESPONSE TO A NEGATIVE EARLY POSTNATAL ENVIRONMENT, MAY LIE AT THE CORE OF THIS PROGRAMMING, THEREBY PROVIDING POTENTIAL NEW THERAPEUTIC TARGETS. THE CONCEPT OF THE HUMAN BIRTH THEORY LEADS TO A COMPREHENSION OF THE MENTAL ILLNESS AS A PATHOLOGY OF THE HUMAN RELATIONSHIP IMMEDIATELY AFTER BIRTH AND DURING THE FIRST YEAR OF LIFE. 2017 13 2419 34 EPIGENETIC SIGNATURE OF CHRONIC MATERNAL STRESS LOAD DURING PREGNANCY MIGHT BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. PRETERM BIRTH IS THE LEADING CAUSE OF MORTALITY IN NEWBORN INFANTS AND CAN LEAD TO SIGNIFICANT NEONATAL MORBIDITIES. SPONTANEOUS PRETERM BIRTH ACCOUNTS FOR AT LEAST 50.0% OF ALL PRETERM BIRTHS. WE ARGUE THAT CHRONIC MATERNAL STRESS LOAD, WHICH IS AN IMPORTANT RISK FACTOR FOR SPONTANEOUS PRETERM BIRTH, COULD BE REPRESENTED BY EPIGENETIC SIGNATURE OF SEVERAL SPECIFIC GENETIC LOCI IN THE MOTHER'S BLOOD. A LITERATURE SEARCH WAS DONE IN PUBMED WITH THE FOLLOWING KEYWORDS: "DNA METHYLATION," "EPIGENETICS," "MATERNAL STRESS" AND "PRETERM BIRTH" FROM YEAR 2000 TO 2017. WE SUGGEST THAT THESE GENETIC LOCI MIGHT BE RELATED TO VULNERABILITY AND HYPERSENSIBILITY OF STRESS RESPONSE DURING PREGNANCY IN WOMEN WITH PRETERM BIRTHS. THE MOTHER'S EPI-GENETIC STRESS BIOPROFILE WAS SUPPOSED TO BE A RESULT OF CHRONIC MATERNAL STRESS LOAD SINCE HER BIRTH. THIS EPIGENETIC BIOPROFILE MIGHT ALSO BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. DNA METHYLATION CHANGES ARE TISSUE-SPECIFIC AND HUMAN STRESS RESPONSE MANIFESTS MOSTLY THROUGH THE CENTRAL NERVOUS SYSTEM (CNS). NEVERTHELESS, WE FOUND EVIDENCE THAT METHYLATION CHANGES OF DNA ISOLATED FROM BLOOD LEUCOCYTES MIGHT BE A RELIABLE MEASURE OF STRESS-RELATED EPIGENETIC CHANGES THAT OCCUR IN THE CNS. EVALUATING BIOLOGICAL MECHANISMS THROUGH THE DEVELOPMENT OF SIMPLE ASSAYS BASED ON EPIGENETIC CHANGES TO MEASURE CHRONIC STRESS LOADS IN EXPECTANT MOTHERS CAN LEAD TO OUR ABILITY TO PREPARE MORE EFFECTIVE MEASURES FOR THE PREVENTION OF PRETERM BIRTHS, AS WELL AS LEADING TO MORE EFFECTIVE TREATMENT STRATEGIES FOR BOTH EXPECTANT MOTHERS AND THEIR NEWBORNS. 2018 14 1747 18 EARLY LIFE ADVERSITY: EPIGENETIC REGULATION UNDERLYING DRUG ADDICTION SUSCEPTIBILITY. DRUG ADDICTION IS A LEADING CAUSE OF DISABILITY WORLDWIDE, WITH MORE THAN 70,000 AMERICANS DYING FROM DRUG OVERDOSE IN 2019 ALONE. WHILE ONLY A SMALL PERCENTAGE OF CHRONIC DRUG USERS ESCALATE TO DRUG ADDICTION, LITTLE IS UNDERSTOOD ON THE PRECISE MECHANISMS OF THIS SUSCEPTIBILITY. EARLY LIFE ADVERSITY IS CAUSALLY RELEVANT TO ADULT PSYCHIATRIC DISEASE AND MAY CONTRIBUTE TO THE RISK OF ADDICTION. HERE WE REVIEW RECENT PRE-CLINICAL EVIDENCE SHOWING THAT EARLY LIFE EXPOSURE TO STRESS AND/OR DRUGS REGULATES CHANGES IN BEHAVIOR, GENE EXPRESSION, AND THE EPIGENOME THAT PERSIST INTO ADULTHOOD. WE SUMMARIZE THE MAJOR FINDINGS AND GAPS IN THE PRECLINICAL LITERATURE, HIGHLIGHTING STUDIES THAT DEMONSTRATE THE OFTEN PROFOUND DIFFERENCES BETWEEN FEMALE AND MALE SUBJECTS. 2023 15 1375 30 DEVELOPMENTAL PROGRAMMING OF ADULT HAEMATOPOIESIS SYSTEM. THE BARKER HYPOTHESIS OF 'FOETAL ORIGIN OF ADULT DISEASES' HAS LED TO EMPHASIZE THE CONCEPT OF 'DEVELOPMENTAL PROGRAMMING', BASED ON THE CRUCIAL ROLE OF EPIGENETIC FACTORS. ACCORDINGLY, IT HAS BEEN DEMONSTRATED THAT PARENTAL ADVERSITY (BEFORE CONCEPTION AND DURING PREGNANCY) AND FOETAL FACTORS (I.E., HYPOXIA, MALNUTRITION AND PLACENTAL INSUFFICIENCY) PERMANENTLY MODIFY THE PHYSIOLOGICAL SYSTEMS OF THE PROGENY, PREDISPOSING THEM TO PREMATURE AGEING AND CHRONIC DISEASE DURING ADULTHOOD. THUS, AN ALTERED FUNCTIONALITY OF THE ENDOCRINE, IMMUNE, NERVOUS AND CARDIOVASCULAR SYSTEMS IS OBSERVED IN THE PROGENY. HOWEVER, IT REMAINS TO BE UNDERSTOOD WHETHER THE HAEMATOPOIETIC SYSTEM ITSELF ALSO REPRESENTS A PORTRAIT OF FOETAL PROGRAMMING. HERE, WE PROVIDE EVIDENCE, REPORTING AND DISCUSSING RELATED THEORIES, AND RESULTS OF STUDIES DESCRIBED IN THE LITERATURE. IN ADDITION, WE HAVE OUTLINED OUR OPINIONS AND SUGGEST HOW IT IS POSSIBLE TO INTERVENE TO CORRECT FOETAL MAL-PROGRAMMING. SOME PRO-HEALTH INTERVENTIONS AND RECOMMENDATIONS ARE PROPOSED, WITH THE HOPE OF GUARANTEE THE HEALTH OF FUTURE GENERATIONS AND TRYING TO COMBAT THE CONTINUOUS INCREASE IN AGE-RELATED DISEASES IN HUMAN POPULATIONS. 2019 16 5091 35 PLACENTAL DISEASES ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGY. THE PLACENTA DEVELOPS FROM THE OUTER TROPHOBLASTIC LAYER FOLLOWING THE DIFFERENTIATION OF THE FERTILIZED OVUM AND IS THEREFORE MORE SUSCEPTIBLE TO EPIGENETIC REGULATORY CHANGES CAUSED BY ENVIRONMENTAL INTERVENTIONS AND INFLUENCES DURING ASSISTED REPRODUCTIVE TECHNOLOGY. FURTHERMORE, THE PLACENTA REGULATES THE DEVELOPMENT OF THE FETAL HEART, BRAIN, KIDNEYS, BONES, AND OTHER TISSUES AND ORGANS [1]. PLACENTAL DYSPLASIA LEADS TO POOR PERINATAL OUTCOMES AS WELL AS LONG-TERM HEALTH RISKS LATER IN LIFE, INCLUDING NEURODEVELOPMENTAL DISORDERS, TUMORS, AND ADULT METABOLIC SYNDROME [2,3]. IN VIEW OF THE DECISIVE ROLE OF THE PLACENTA DURING INTRAUTERINE FETAL DEVELOPMENT, GRAHAM J. BURTON, AN EXPERT IN PLACENTOLOGY FROM THE UNIVERSITY OF CAMBRIDGE, FORMALLY PROPOSED THE THEORY OF "PLACENTA-DERIVED CHRONIC DISEASES" IN 2018 BASED ON EMBRYONIC-DERIVED DISEASES [4]. IN THIS REVIEW, WE SUMMARIZED THE CHANGES IN PLACENTAL MORPHOLOGY AND STRUCTURE, GROWTH DYNAMICS, IMPRINTED AND NON-IMPRINTED GENES, AND OTHER ASPECTS ATTRIBUTABLE TO ASSISTED REPRODUCTION TECHNOLOGY. OUR REVIEW PROVIDES A THEORETICAL BASIS FOR FURTHER RESEARCH ON PLACENTAL CHANGES CAUSED BY ASSISTED REPRODUCTIVE TECHNOLOGY THAT ARE MOST STRONGLY ASSOCIATED WITH AN INCREASED RISK OF NEONATAL LONG-TERM DISEASES. 2021 17 1363 32 DEVELOPMENTAL INFLUENCES ON MEDICALLY UNEXPLAINED SYMPTOMS. BACKGROUND: MEDICALLY UNEXPLAINED (OR 'FUNCTIONAL') SYMPTOMS (MUS) ARE PHYSICAL SYMPTOMS THAT PROMPT THE SUFFERER TO SEEK HEALTHCARE BUT REMAIN UNEXPLAINED AFTER AN APPROPRIATE MEDICAL EVALUATION. EXAMPLES OF MUS ALSO OCCUR IN VETERINARY MEDICINE. FOR EXAMPLE, DOMESTIC CATS SUFFER A SYNDROME COMPARABLE TO INTERSTITIAL CYSTITIS, A CHRONIC PELVIC PAIN SYNDROME OF HUMANS. METHOD: REVIEW OF CURRENT EVIDENCE SUGGESTS THE HYPOTHESIS THAT DEVELOPMENTAL FACTORS MAY PLAY A ROLE IN SOME CASES OF MUS. MATERNAL PERCEPTION OF A THREATENING ENVIRONMENT MAY BE TRANSMITTED TO THE FETUS WHEN HORMONES CROSS THE PLACENTA AND AFFECT FETAL PHYSIOLOGY, EFFECTIVELY 'PROGRAMMING' THE FETAL STRESS RESPONSE SYSTEM AND ASSOCIATED BEHAVIORS TOWARD ENHANCED VIGILANCE. AFTER BIRTH, INTENSE STRESS RESPONSES IN THE INDIVIDUAL MAY RESULT IN SIMILAR VULNERABILITY, WHICH MAY BE UNMASKED BY SUBSEQUENT STRESSORS. RESULTS: EPIGENETIC MODULATION OF GENE EXPRESSION (EMGEX) APPEARS TO PLAY A CENTRAL ROLE IN CREATION OF THIS 'SURVIVAL PHENOTYPE'. THE RECENT DEVELOPMENT OF TECHNIQUES TO IDENTIFY THE PRESENCE OF EMGEX PROVIDES NEW TOOLS TO INVESTIGATE THESE QUESTIONS, AND DRUGS AND OTHER INTERVENTIONS THAT MAY REVERSE EMGEX ARE ALSO UNDER ACTIVE INVESTIGATION. CONCLUSION: VIEWING MUS FROM THE PERSPECTIVE OF UNDERLYING DEVELOPMENTAL INFLUENCES INVOLVING EMGEX THAT AFFECT FUNCTION OF A VARIETY OF ORGANS BASED ON FAMILIAL (GENETIC AND ENVIRONMENTAL) PREDISPOSITIONS RATHER THAN FROM THE TRADITIONAL VIEWPOINT OF ISOLATED ORGAN-ORIGINATING DISEASES HAS AT LEAST TWO IMPORTANT IMPLICATIONS: IT PROVIDES A PARSIMONIOUS EXPLANATION FOR FINDINGS HERETOFORE DIFFICULT TO RECONCILE, AND IT OPENS WHOLE NEW AREAS OF INVESTIGATION INTO CAUSES AND TREATMENTS FOR THIS CLASS OF DISORDERS. 2009 18 5810 24 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 19 1755 36 EARLY NUTRITION AND LATER OUTCOMES IN PRETERM INFANTS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IS AN EMERGING AREA OF INTEREST THAT AMALGAMATES MANY AREAS OF SCIENTIFIC STUDIES AND ENCOMPASSES A WIDE RANGE OF DIVERSE DISCIPLINES FROM EPIDEMIOLOGY TO MOLECULAR BIOLOGY. EVIDENCE HAS ACCUMULATED TO SHOW THAT EARLY LIFE EXPERIENCES, BOTH IN UTERO AND IN INFANCY HAVE LONG-TERM EFFECTS ON MANY BODY SYSTEMS. THERE ARE NOW GOOD DATA TO SHOW THAT SUBOPTIMAL IN UTERO GROWTH, ESPECIALLY WHEN COMBINED WITH RAPID GROWTH ACCELERATION IN EARLY POSTNATAL LIFE MAY INCREASE THE RISK OF LATER LIFE METABOLIC DISEASE. THE MECHANISMS ARE COMPLEX BUT LIKELY TO INVOLVE EPIGENETIC MARKS SUCH AS DNA METHYLATION. PRETERM INFANTS FREQUENTLY EXPERIENCE SUBOPTIMAL NUTRIENT INTAKES IN EARLY POSTNATAL LIFE AND EXHIBIT GROWTH FAILURE WITHIN THE NICU. THEY ALSO RECEIVE PRODUCTS THAT MAY NOT PROVIDE EITHER AN OPTIMAL QUANTITY OR QUALITY OF NUTRIENTS. FOLLOW-UP STUDIES HAVE NOW SHOWN MUCH HIGHER RISKS FOR LONG-TERM CHRONIC DISEASE IN CHILDREN AND ADULTS WHO WERE BORN PRETERM. THERE ARE HIGHER LEVELS OF INSULIN RESISTANCE AND ABNORMAL PARTITIONING OF FAT DEPOSITION. THE ONSET OF PUBERTY SEEMS EARLIER, AVERAGE HEIGHT IS LESS AND BLOOD PRESSURE, MEASURES OF VASCULAR HEALTH AND LIPID PROFILES SUGGEST CARDIOVASCULAR HEALTH IS LIKELY TO DIFFER FROM HEALTHY TERM BORN CONTROLS. DESPITE THIS, THERE ARE NO DATA TO SUGGEST AN OVERALL BENEFIT OF LIMITING NUTRIENT INTAKE, OR RESTRICTING GROWTH IN PRETERM INFANTS. THERE ARE STRONG DATA TO SHOW THAT THE PRETERM BRAIN IS EXQUISITELY VULNERABLE TO UNDERNUTRITION, AND THAT SUBOPTIMAL NUTRIENT INTAKES MAY PERMANENTLY AFFECT LATER COGNITIVE ATTAINMENT. A CLINICAL FOCUS ON EARLY NUTRIENT INTAKES AND BREAST MILK PROVISION IS KEY TO OPTIMISING LONG-TERM HEALTH OUTCOMES. 2013 20 1248 28 CURRENT EVIDENCE FOR BIOLOGICAL BIOMARKERS AND MECHANISMS UNDERLYING ACUTE TO CHRONIC PAIN TRANSITION ACROSS THE PEDIATRIC AGE SPECTRUM. CHRONIC PAIN IS HIGHLY PREVALENT IN THE PEDIATRIC POPULATION. MANY FACTORS ARE INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN. CURRENTLY, THERE ARE CONCEPTUAL MODELS PROPOSED, BUT THEY LACK A MECHANISTICALLY SOUND INTEGRATED THEORY CONSIDERING THE STAGES OF CHILD DEVELOPMENT. OBJECTIVE BIOMARKERS ARE CRITICALLY NEEDED FOR THE DIAGNOSIS, RISK STRATIFICATION, AND PROGNOSIS OF THE PATHOLOGICAL STAGES OF PAIN CHRONIFICATION. IN THIS ARTICLE, WE SUMMARIZE THE CURRENT EVIDENCE ON MECHANISMS AND BIOMARKERS OF ACUTE TO CHRONIC PAIN TRANSITIONS IN INFANTS AND CHILDREN THROUGH THE DEVELOPMENTAL LENS. THE GOAL IS TO IDENTIFY GAPS AND OUTLINE FUTURE DIRECTIONS FOR BASIC AND CLINICAL RESEARCH TOWARD A DEVELOPMENTALLY INFORMED THEORY OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. AT THE OUTSET, THE IMPORTANCE OF OBJECTIVE BIOMARKERS FOR CHRONIFICATION OF PAIN IN CHILDREN IS OUTLINED, FOLLOWED BY A SUMMARY OF THE CURRENT EVIDENCE ON THE MECHANISMS OF ACUTE TO CHRONIC PAIN TRANSITION IN ADULTS, IN ORDER TO CONTRAST WITH THE DEVELOPMENTAL MECHANISMS OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. EVIDENCE IS PRESENTED TO SHOW THAT CHRONIC PAIN MAY HAVE ITS ORIGIN FROM INSULTS EARLY IN LIFE, WHICH PRIME THE CHILD FOR THE DEVELOPMENT OF CHRONIC PAIN IN LATER LIFE. FURTHERMORE, AVAILABLE GENETIC, EPIGENETIC, PSYCHOPHYSICAL, ELECTROPHYSIOLOGICAL, NEUROIMAGING, NEUROIMMUNE, AND SEX MECHANISMS ARE DESCRIBED IN INFANTS AND OLDER CHILDREN. IN CONCLUSION, FUTURE DIRECTIONS ARE DISCUSSED WITH A FOCUS ON RESEARCH GAPS, TRANSLATIONAL AND CLINICAL IMPLICATIONS. UTILIZATION OF DEVELOPMENTAL MECHANISMS FRAMEWORK TO INFORM CLINICAL DECISION-MAKING AND STRATEGIES FOR PREVENTION AND MANAGEMENT OF ACUTE TO CHRONIC PAIN TRANSITIONS IN CHILDREN, IS HIGHLIGHTED. 2023