1 6577 100 TREATMENT STRATEGIES FOR COMPLEX BEHAVIORAL INSOMNIA IN CHILDREN WITH NEURODEVELOPMENTAL DISORDERS. PURPOSE OF REVIEW: THIS REVIEW DESCRIBES RECENT RESEARCH IN PEDIATRIC BEHAVIORAL INSOMNIAS IN NEURODEVELOPMENTAL DISORDERS AND THEIR TREATMENT. RECENT FINDINGS: INSOMNIA IN CHILDREN WITH AUTISM SPECTRUM DISORDER (ASD) AND OTHER NEURODEVELOPMENTAL DISORDERS (NDDS) IS TYPICALLY COMPLEX, CHRONIC, AND DIFFICULT TO ADEQUATELY CONTROL. ABNORMALITIES IN GENETIC AND/OR EPIGENETIC REGULATION OF SLEEP/WAKEFULNESS AND ITS TIMING PREDISPOSE PATIENTS WITH NDD TO INSOMNIA, ALTHOUGH POOR SLEEP HYGIENE, MALADAPTIVE ASSOCIATIONS, AND LIMIT-SETTING ARE LIKELY TO CONTRIBUTE. PARENTS ARE AGENTS FOR CHANGE IN PROBLEMATIC SLEEP BEHAVIORS IN PATIENTS WITH NDD. WE REVIEW THE BENEFITS OF BEHAVIORAL THERAPIES AND MELATONIN TO TREAT SLEEP PROBLEMS IN CHILDREN WITH NDD. PROBLEMATIC SLEEP IS SO PREVALENT IN SOME NEURODEVELOPMENTAL SYNDROMES (RETT, ANGELMAN, WILLIAMS, AND SMITH-MAGENIS) THAT IT IS PART OF THEIR DIAGNOSTIC CRITERIA. SUMMARY: CHILDREN AND ADOLESCENTS WITH NEUROLOGICAL DISORDERS FREQUENTLY HAVE COMPLEX SLEEP DISORDERS THAT REQUIRE TREATMENT. UNDERSTANDING THE BASIC PATHOLOGY AND TREATMENT STRATEGIES PROVIDES AN OPPORTUNITY TO IMPROVE WELL BEING AND QUALITY OF LIFE IN THOSE AFFECTED BY NDD AND THEIR FAMILIES. 2013 2 6188 26 THE IMPACT OF INSOMNIA ON FRAILTY AND THE HALLMARKS OF AGING. THROUGHOUT THE COURSE OF LIFE, THERE ARE AGE-RELATED CHANGES IN SLEEP. DESPITE THESE NORMAL CHANGES, THERE IS A HIGH PERCENTAGE OF OLDER ADULTS THAT REPORT SLEEP DISSATISFACTION WITH A HIGH PERVASIVENESS OF CHRONIC INSOMNIA, THE MOST COMMON SLEEP DISORDER WORLDWIDE, WITH ITS PREVALENCE BEING EXPECTED TO CONTINUOUSLY INCREASE DUE TO THE GROWING RATES OF AGING AND OBESITY. THIS CAN HAVE DIFFERENT ADVERSE HEALTH OUTCOMES, ESPECIALLY BY PROMOTING BOTH PHYSICAL AND COGNITIVE DECLINE, WHICH ULTIMATELY MAY AGGRAVATE FRAILTY IN OLDER ADULTS. MOREOVER, AGE-RELATED FRAILTY AND SLEEP DYSFUNCTION MAY HAVE A COMMON MECHANISM RELATED TO THE HALLMARKS OF CELLULAR AGING. CELLULAR AGING WAS CATEGORIZED INTO NINE HALLMARKS, SUCH AS DNA DAMAGE, TELOMERE ATTRITION AND EPIGENETIC CHANGES. IN THE CONTEXT OF GERIATRIC AND CHRONIC INSOMNIA RESEARCH, THIS REVIEW AIMS AT DISCUSSING THE CURRENT EVIDENCE FROM BOTH ANIMAL MODELS AND HUMAN COHORTS ADDRESSING THE LINK BETWEEN CHRONIC INSOMNIA, THE HALLMARKS OF AGING AND THEIR IMPACT ON FRAILTY. MOREOVER, THE MOST RECENT RESEARCH ABOUT THE PUTATIVE EFFECT OF INSOMNIA THERAPEUTIC APPROACHES ON HALLMARKS OF AGING WILL BE ALSO HIGHLIGHTED. 2023 3 1770 28 EARLY-LIFE ORIGIN OF ADULT INSOMNIA: DOES PRENATAL-EARLY-LIFE STRESS PLAY A ROLE? INSOMNIA IS VERY COMMON IN THE ADULT POPULATION AND IT INCLUDES A WIDE SPECTRUM OF SEQUELAE, THAT IS, NEUROENDOCRINE AND CARDIOVASCULAR ALTERATIONS AS WELL AS PSYCHIATRIC AND NEURODEGENERATIVE DISORDERS. ACCORDING TO THE CONCEPTUALIZATION OF INSOMNIA IN THE CONTEXT OF THE 3-P MODEL, THE IMPORTANCE OF PREDISPOSING, PRECIPITATING, AND PERPETUATING FACTORS HAS BEEN STRESSED. PREDISPOSING FACTORS ARE PRESENT BEFORE INSOMNIA IS MANIFESTED AND THEY ARE HYPOTHESIZED TO INTERACT WITH PRECIPITATING FACTORS, SUCH AS ENVIRONMENTAL STRESSFUL EVENTS, CONTRIBUTING TO THE ONSET OF INSOMNIA. UNDERSTANDING THE EARLY-LIFE ORIGINS OF INSOMNIA MAY BE PARTICULARLY USEFUL IN ORDER TO PREVENT AND TREAT THIS COSTLY PHENOMENON. BASED ON RECENT EVIDENCE, PRENATAL-EARLY-LIFE STRESS EXPOSURE RESULTS IN A SERIES OF RESPONSES THAT INVOLVE THE STRESS SYSTEM IN THE CHILD AND COULD PERSIST INTO ADULTHOOD. THIS MAY ENCOMPASS AN ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACCOMPANIED BY LONG-LASTING MODIFICATIONS IN STRESS REACTIVITY. FURTHERMORE, EARLY-LIFE STRESS EXPOSURE MIGHT PLAY AN IMPORTANT ROLE IN PREDISPOSING TO A VULNERABILITY TO HYPERAROUSAL REACTIONS TO NEGATIVE LIFE EVENTS IN THE ADULT CONTRIBUTING TO THE DEVELOPMENT OF CHRONIC INSOMNIA. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MALADAPTIVE STRESS RESPONSES IN THE NEWBORN, ULTIMATELY PREDISPOSING TO DEVELOP A VARIETY OF (PSYCHO-) PATHOLOGICAL STATES IN ADULT LIFE. 2015 4 6893 23 [SLEEP AND DEMENTIA]. AGING IS ASSOCIATED WITH CHANGES IN SLEEP STRUCTURE AND CEREBRAL DEPOSITION OF AMYLOID BETA AND TAU PROTEINS. SLEEP DISTURBANCES PRECEDE THE ONSET OF DEMENTIA BY YEARS. COMORBID SLEEP DISORDERS, SUCH AS INSOMNIA AND SLEEP-DISORDERED BREATHING, A FAMILY HISTORY OF DEMENTIA AND EPIGENETIC FACTORS CAN CONTRIBUTE TO THE DEVELOPMENT OF DEMENTIA. THIS ARTICLE EXPLORES THE QUESTION OF THE INTERACTION BETWEEN SLEEP AND DEMENTIA BASED ON THE EXISTING LITERATURE. ALTERATIONS CAUSED BY SLOW WAVE SLEEP LEAD TO CHANGES IN THE GLYMPHATIC CLEARANCE OF AMYLOID BETA, TAU PROTEINS AND OTHER PROTEINS. TRANSIENT AND CHRONIC SLEEP DISORDERS CAUSE DISTURBANCES IN THE BRAIN AREAS RESPONSIBLE FOR COGNITION AND BEHAVIOR. SLEEP-REGULATING BRAIN AREAS ARE THE FIRST TO BE AFFECTED IN THE NEURODEGENERATIVE PROCESS AND ACCELERATE THE RISK OF DEMENTIA. CIRCADIAN AGE-RELATED CHANGES IN AMYLOID BETA AND TAU PROTEINS AFFECT THE AMOUNT AND DEPTH OF SLEEP AND VICE VERSA. AMYLOID BETA IN CEREBROSPINAL FLUID SHOWS AN INVERSE CORRELATION WITH SLEEP. OREXINS MODULATE AMYLOID BETA AND SLEEP. 2023 5 3606 25 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 6 5729 32 SLEEP, SLEEP HOMEOSTASIS AND AROUSAL DISTURBANCES IN ALCOHOLISM. THE EFFECTS OF ALCOHOL ON HUMAN SLEEP WERE FIRST DESCRIBED ALMOST 70 YEARS AGO. SINCE THEN, ACCUMULATING EVIDENCES SUGGEST THAT ALCOHOL INTAKE AT BED TIME IMMEDIATELY INDUCES SLEEP [REDUCES THE TIME TO FALL ASLEEP (SLEEP ONSET LATENCY), AND CONSOLIDATES AND ENHANCES THE QUALITY (DELTA POWER) AND THE QUANTITY OF SLEEP]. SUCH POTENT SLEEP PROMOTING ACTIVITY MAKES ALCOHOL AS ONE OF THE MOST COMMONLY USED "OVER THE COUNTER" SLEEP AID. HOWEVER, THE SOMNOGENIC EFFECTS, AFTER ALCOHOL INTAKE, SLOWLY WANE OFF AND OFTEN FOLLOWED BY SLEEP DISRUPTIONS DURING THE REST OF THE NIGHT. REPEATED USE OF ALCOHOL LEADS TO THE DEVELOPMENT OF RAPID TOLERANCE RESULTING INTO AN ALCOHOL ABUSE. MOREOVER, CHRONIC AND EXCESSIVE ALCOHOL INTAKE LEADS TO THE DEVELOPMENT OF ALCOHOL USE DISORDER (AUD). ALCOHOLICS, BOTH DURING DRINKING PERIODS AND DURING ABSTINENCES, SUFFER FROM A MULTITUDE OF SLEEP DISRUPTIONS MANIFESTED BY PROFOUND INSOMNIA, EXCESSIVE DAYTIME SLEEPINESS, AND ALTERED SLEEP ARCHITECTURE. FURTHERMORE, SUBJECTIVE AND OBJECTIVE INDICATORS OF SLEEP DISTURBANCES ARE PREDICTORS OF RELAPSE. FINALLY, WITHIN THE USA, IT IS ESTIMATED THAT SOCIETAL COSTS OF ALCOHOL-RELATED SLEEP DISORDERS EXCEED $18 BILLION. THUS, ALTHOUGH ALCOHOL ASSOCIATED SLEEP PROBLEMS HAVE SIGNIFICANT ECONOMIC AND CLINICAL CONSEQUENCES, VERY LITTLE IS KNOWN ABOUT HOW AND WHERE ALCOHOL ACTS TO AFFECT SLEEP. IN THIS REVIEW, A CONCEPTUAL FRAMEWORK AND CLINICAL RESEARCH FOCUSED ON UNDERSTANDING THE RELATIONSHIP BETWEEN ALCOHOL AND SLEEP IS FIRST DESCRIBED. IN THE NEXT SECTION, OUR NEW AND EXCITING PRECLINICAL STUDIES, TO UNDERSTAND THE CELLULAR AND MOLECULAR MECHANISM OF HOW ACUTE AND CHRONIC ALCOHOL AFFECTS SLEEP, ARE DESCRIBED. IN THE END, BASED ON OBSERVATIONS FROM OUR RECENT FINDINGS AND RELATED LITERATURE, OPPORTUNITIES FOR THE DEVELOPMENT OF INNOVATIVE STRATEGIES TO PREVENT AND TREAT AUD ARE PROPOSED. 2022 7 4525 26 MULTIFACTORIAL CAUSES OF PARANOID SCHIZOPHRENIA WITH AUDITORY-VISUAL HALLUCINATIONS IN A 31-YEAR-OLD MALE WITH HISTORY OF TRAUMATIC BRAIN INJURY AND SUBSTANCE ABUSE. SCHIZOPHRENIA IS A CHRONIC PSYCHIATRIC DISORDER THAT CLASSICALLY PRESENTS WITH DISTORTIONS OF THOUGHT, BEHAVIOR, AND PERCEPTIONS THAT ARE OFTEN MISDIAGNOSED. ONE DIFFICULTY IN DIAGNOSING SCHIZOPHRENIA IS DUE TO ITS PHENOTYPICALLY HETEROGENEOUS CONDITION THAT CAN BE PRECIPITATED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE PREVALENCE OF SCHIZOPHRENIA IS ROUGHLY 1%, BUT IT IS OFTEN MISDIAGNOSED. POSSIBLE DIFFERENTIAL DIAGNOSES INCLUDE DEPRESSION OR BIPOLAR DISORDER WITH PSYCHOSIS, PSYCHOSIS DUE TO A MEDICAL CONDITION, SCHIZOTYPAL AND SCHIZOID PERSONALITY DISORDERS, AND NEUROCOGNITIVE DISORDERS. IN THIS CASE REPORT, A 31-YEAR-OLD MALE PRESENTS WITH THOUGHTS OF SUICIDE FOLLOWING A RECENT EXACERBATION OF HIS HALLUCINATIONS. ON PRESENTATION, THE PATIENT PRESENTED WITH A HISTORICAL DIAGNOSIS OF "PARANOID SCHIZOPHRENIA" AS WELL AS A HISTORY OF TRAUMATIC BRAIN INJURY (TBI), POLY-SUBSTANCE USE DISORDER, AND A FAMILY HISTORY OF SCHIZOPHRENIA. THIS CASE SERVES TO HIGHLIGHT THE DIFFICULTIES OF MAKING AN ACCURATE DIAGNOSIS AND PROVIDING EVIDENCED-BASED TREATMENT. 2022 8 1222 20 CRITICAL MOMENTS IN PRESCHOOL OBESITY: THE CALL FOR NURSES AND COMMUNITIES TO ASSESS AND INTERVENE. THIRTY YEARS AGO OBESITY WAS RARELY SEEN IN CHILDREN BUT IS NOW DESCRIBED AS A WORLD WIDE PANDEMIC. PREVIOUS RESEARCH HAS FOCUSED ON SCHOOL AGE CHILDREN; HOWEVER, RESEARCHERS HAVE NOW IDENTIFIED CRITICAL MOMENTS OF DEVELOPMENT DURING UTERINE LIFE AND EARLY INFANCY WHERE NEGATIVE FACTORS OR INSULTS COULD CAUSE PERMANENT CHANGES IN THE STRUCTURE AND FUNCTION OF TISSUES AND LEAD TO EPIGENETIC CHANGES. OBESITY IN PRESCHOOL CHILDREN CAN CAUSE PREMATURE AND LONG TERM CHRONIC HEALTH PROBLEMS; HAS BEEN ASSOCIATED WITH ACADEMIC AND SOCIAL DIFFICULTIES IN KINDERGARTEN CHILDREN; DIFFICULTY WITH SOCIAL RELATIONSHIPS; INCREASED FEELINGS OF SADNESS, LONELINESS AND ANXIETY; AND NEGATIVE SELF IMAGE IN CHILDREN AS YOUNG AS 5 YEARS OF AGE. THE IMPORTANCE OF IDENTIFYING CHILDREN UNDER THE AGE OF FIVE WITH OBESITY AND ASSOCIATED RISKS IS IMPORTANT YET LESS THAN HALF OF HEALTH PROFESSIONALS INTERVENE IN CASES OF PRESCHOOL OBESITY. THIS PAPER EXPLORES THE CONCERNS AROUND ANTENATAL AND PRESCHOOL OBESITY AND THE CHALLENGES FOR NURSES AND MIDWIVES IN ASSESSING AND PROVIDING APPROPRIATE INTERVENTIONS FOR CHILDREN AND FAMILIES IN COMMUNITY SETTINGS. 2011 9 2096 25 EPIGENETIC EFFECTS OF CHILDHOOD ADVERSITY IN THE BRAIN AND SUICIDE RISK. WITH PREVALENCE ESTIMATES RANGING BETWEEN 6.4% AND 10.1% [-5], MAJOR DEPRESSION RANKS FIRST AMONG THE MOST SIGNIFICANT CAUSES OF DISABILITY AND PREMATURE DEATH, THUS IMPOSING A CONTINUAL ECONOMIC BURDEN ON SOCIETY. FOR INSTANCE, IN THE UNITED STATES, THE DIRECT AND INDIRECT COSTS ARE ESTIMATED AT U.S.$44 BILLION/YEAR [6]. THE GREATEST LOSS TO OUR SOCIETY, HOWEVER, IS THE ASSOCIATED MORTALITY BY SUICIDE RELATED TO MAJOR DEPRESSION. INDEED, IT HAS BEEN ESTIMATED THAT BETWEEN 50% AND 70% OF SUICIDE COMPLETERS WILL DIE DURING AN EPISODE OF MAJOR DEPRESSION [7,8] AND PROSPECTIVE FOLLOW-UP STUDIES OF MAJOR DEPRESSION SUGGEST THAT BETWEEN 7% AND 15% OF THESE PATIENTS WILL DIE BY SUICIDE [-12]. SUICIDE IS A COMPLEX PROBLEM, WHICH IS BELIEVED TO RESULT FROM THE INTERACTION OF SEVERAL DIFFERENT FACTORS [13,14]. INDEED, PSYCHOLOGICAL FACTORS AND PERSONALITY TRAITS SUCH AS IMPULSIVITY AND NEGATIVE AFFECT [14,15], SOCIAL FACTORS [16,17], ENVIRONMENTAL FACTORS SUCH AS EARLY-LIFE ADVERSITY [-20], GENETIC FACTORS [21], AND NEUROBIOLOGICAL FACTORS [22] HAVE BEEN PROPOSED TO INDUCE BEHAVIORAL ALTERATIONS, WHICH IN TURN MAY PREDISPOSE CERTAIN INDIVIDUALS TO DEVELOP DEPRESSIVE AND SUICIDAL BEHAVIORS. HOWEVER, SINCE THESE FACTORS ALONE ARE UNLIKELY TO EXPLAIN SUICIDE AND SUICIDE RISK, IT MAY BE MORE READILY EXPLAINED WHEN CONSIDERING THE INTERACTION BETWEEN THESE DIFFERENT SOURCES OF VARIATION [23,24]. AMONG THESE RISK FACTORS, EARLY-LIFE ADVERSITY, PARTICULARLY CHILDHOOD SEXUAL ABUSE (CSA) AND CHILDHOOD PHYSICAL ABUSE (CPA), IS ONE OF THE STRONGEST PREDICTORS OF MENTAL DISORDERS [25,26] AND SUICIDE [18,19]. FOR EXAMPLE, STUDIES HAVE SHOWN THAT CSA IS ASSOCIATED WITH EARLY ONSET OF DEPRESSION, CHRONIC COURSE, AND MORE SEVERE DEPRESSIVE OUTCOME [-29] BUT, MORE IMPORTANTLY, WITH 12 TIMES HIGHER ODDS OF SUICIDAL BEHAVIORS [26,30]. ALTHOUGH LESS CONSISTENTLY, CPA AND NEGLECT HAVE ALSO BEEN ASSOCIATED WITH SUICIDAL BEHAVIORS [19,31]. CSA AND CPA HAVE BEEN ASSOCIATED WITH HIGHER ODDS OF SELF-HARM [,,-34], SUICIDAL IDEATION [35,36], AND SUICIDE ATTEMPTS [,-39]. MOREOVER, THE PREVALENCE OF SUICIDAL IDEATION AND SUICIDE ATTEMPTS HAS BEEN SHOWN TO INCREASE WITH THE SEVERITY AND INTENSITY OF THE ABUSE [35,36,38]. 2012 10 6917 19 [WHOSE BORDERLINE IS IT? HYPOTHESIZED ETIOLOGIES OF BORDERLINE PERSONALITY]. BORDERLINE PERSONALITY IS A WELL KNOWN CONCEPT IN PSYCHIATRIC LITERATURE, HOWEVER, NOT FULLY UNDERSTOOD AS TO ITS VERY NATURE. THIS ARTICLE PRESENTS A SHORT REVIEW OF HYPOTHESIZED ETIOLOGIES OF THE BORDERLINE PERSONALITY, STARTING WITH SO CALLED TRADITIONAL THEORIES, NAMELY, BORDERLINE PERSONALITY AS A CONSOLIDATED PERSONALITY ORGANIZATION, IN WHICH THE PATIENT PATHOLOGICALLY DEALS WITH HIS OR HER INNER AGGRESSION, OR WITH AN ENDURING DEVELOPMENTAL FAILURE. MORE MODERN HYPOTHESES FOCUS ON POSSIBLE CHILDHOOD SEXUAL ABUSE AS THE ORIGIN OF THE BORDERLINE, VIEWING THE ADULT PERSONALITY AS A CHRONIC, UNRESOLVED, POST-TRAUMATIC DISORDER. ADDITIONALLY, A NEURO-EPIGENETIC VIEW HYPOTHESIZED THAT A UNIQUE CONGENITAL NEUROLOGICAL STRUCTURE INTERACTS WITH CONSEQUENTIAL EVENTS IN EARLY CHILDHOOD TO CREATE THE BORDERLINE PERSONALITY. 2008 11 4067 19 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 12 5648 19 SEX DIFFERENCES IN OPIOID RESPONSE LINKED TO OPRM1 AND COMT GENES DNA METHYLATION/GENOTYPES CHANGES IN PATIENTS WITH CHRONIC PAIN. ANALGESIC-RESPONSE VARIABILITY IN CHRONIC NONCANCER PAIN (CNCP) HAS BEEN REPORTED DUE TO SEVERAL BIOLOGICAL AND ENVIRONMENTAL FACTORS. THIS STUDY WAS UNDERTAKEN TO EXPLORE SEX DIFFERENCES LINKED TO OPRM1 AND COMT DNA METHYLATION CHANGES AND GENETIC VARIANTS IN ANALGESIC RESPONSE. A RETROSPECTIVE STUDY WITH 250 REAL-WORLD CNCP OUTPATIENTS WAS PERFORMED IN WHICH DATA FROM DEMOGRAPHIC, CLINICAL, AND PHARMACOLOGICAL VARIABLES WERE COLLECTED. DNA METHYLATION LEVELS (CPG ISLAND) WERE EVALUATED BY PYROSEQUENCING, AND THEIR INTERACTION WITH THE OPRM1 (A118G) AND COMT (G472A) GENE POLYMORPHISMS WAS STUDIED. A PRIORI-PLANNED STATISTICAL ANALYSES WERE CONDUCTED TO COMPARE RESPONSES BETWEEN FEMALES AND MALES. SEX-DIFFERENTIAL OPRM1 DNA METHYLATION WAS OBSERVED TO BE LINKED TO LOWER OPIOID USE DISORDER (OUD) CASES FOR FEMALES (P = 0.006). PATIENTS WITH LOWER OPRM1 DNA METHYLATION AND THE PRESENCE OF THE MUTANT G-ALLELE REDUCED OPIOID DOSE REQUIREMENTS (P = 0.001), EQUAL FOR BOTH SEXES. MOREOVER, COMT DNA METHYLATION LEVELS WERE NEGATIVELY RELATED TO PAIN RELIEF (P = 0.020), QUALITY OF LIFE (P = 0.046), AND SOME ADVERSE EVENTS (PROBABILITY > 90%) SUCH AS CONSTIPATION, INSOMNIA, OR NERVOUSNESS. FEMALES WERE, SIGNIFICANTLY, 5 YEARS OLDER WITH HIGH ANXIETY LEVELS AND A DIFFERENT SIDE-EFFECTS DISTRIBUTION THAN MALES. THE ANALYSES DEMONSTRATED SIGNIFICANT DIFFERENCES BETWEEN FEMALES AND MALES RELATED TO OPRM1 SIGNALLING EFFICIENCY AND OUD, WITH A GENETIC-EPIGENETIC INTERACTION IN OPIOID REQUIREMENTS. THESE FINDINGS SUPPORT THE IMPORTANCE OF SEX AS A BIOLOGICAL VARIABLE TO BE FACTORED INTO CHRONIC PAIN-MANAGEMENT STUDIES. 2023 13 1774 19 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 14 5961 27 TELOMERE LENGTH IN PRETERM INFANTS: A PROMISING BIOMARKER OF EARLY ADVERSITY AND CARE IN THE NEONATAL INTENSIVE CARE UNIT? PRETERM INFANTS PRESENT AN IMMATURE NEUROBEHAVIORAL PROFILE AT BIRTH, EVEN IN ABSENCE OF SEVERE BRAIN INJURIES AND PERINATAL COMPLICATIONS. AS SUCH, THEY REQUIRE A LONG-LASTING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU), WHICH IS THOUGHT TO GRANT AT-RISK NEWBORNS' SURVIVAL, BUT STILL ENTAILS A NUMBER OF PHYSICAL, PAINFUL, AND SOCIO-EMOTIONAL STRESSORS. HENCE, PRETERM BIRTH AND NICU STAY REPRESENT AN EARLY ADVERSE EXPERIENCE, WHICH HAS BEEN LINKED TO DETRIMENTAL CONSEQUENCES FOR NEUROLOGICAL, NEURO-ENDOCRINAL, BEHAVIORAL, AND SOCIO-EMOTIONAL DEVELOPMENT, AS WELL AS TO DISEASE LATER IN LIFE. RECENT ADVANCES IN THE BEHAVIORAL EPIGENETIC FIELD ARE HELPING US TO UNVEIL THE POTENTIAL MECHANISMS THROUGH WHICH EARLY NICU-RELATED STRESS MAY LEAD TO NEGATIVE DEVELOPMENTAL OUTCOMES. FROM THIS PERSPECTIVE, TELOMERE REGULATION MIGHT BE A KEY PROGRAMMING MECHANISM. TELOMERES ARE THE TERMINAL PORTION OF CHROMOSOMES AND ARE KNOWN TO GET SHORTER WITH AGE. MOREOVER, TELOMERE LENGTH (TL) IS AFFECTED BY THE EXPOSURE TO STRESS DURING EARLY DEVELOPMENT. AS SUCH, TL MIGHT BE AN INNOVATIVE BIOMARKER OF EARLY ADVERSE EXPOSURES IN YOUNG INFANTS AND CHILDREN. UNFORTUNATELY, THERE IS PAUCITY OF STUDIES INVESTIGATING TL IN POPULATIONS OF PRETERM INFANTS AND ITS ASSOCIATION WITH KNOWN NICU-RELATED STRESSORS REMAINS UNEXPLORED. IN THE PRESENT PAPER, THE POTENTIAL RELEVANCE OF TL FOR RESEARCH AND CLINICAL WORK WITH PRETERM INFANTS WILL BE UNDERLINED IN THE LIGHT OF RECENT CONTRIBUTIONS LINKING PROGRESSIVE TELOMERE SHORTENING AND EARLY EXPOSURE TO ADVERSE EXPERIENCES AND STRESSFUL ENVIRONMENTS IN HUMANS. FINALLY, INSIGHTS WILL BE PROVIDED TO GUIDE CLINICALLY RELEVANT TRANSLATIONAL RESEARCH ON TL IN THE FIELD OF VPT BIRTH AND NICU STAY. 2017 15 6897 16 [TELOMERE-TELOMERASE SYSTEM IN AGING, NORM AND PATHOLOGY (LITERATURE REVIEW)]. THIS LITERATURE REVIEW PRESENTS RESULTS OF RESEARCH SHOWING ASSOCIATION BETWEEN FUNCTIONAL ACTIVITY OF THE TELOMERE-TELOMERASE SYSTEM AND MENTAL COGNITIVE AND EMOTIONAL PROCESSES IN NORMAL AND VARIOUS PATHOLOGICAL STATES: CHRONIC STRESS, DEPRESSION, BIPOLAR DISORDER, SCHIZOPHRENIA, MILD COGNITIVE IMPAIRMENT AND DEMENTIA IN AGING. IT ALSO REFERS TO AGE-SPECIFIC, PSYCHO-SOCIAL, ECONOMIC, IMMUNOLOGICAL, GENETIC AND EPIGENETIC FACTORS THAT INFLUENCE THESE RELATIONSHIPS. 2017 16 4847 23 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 17 6483 27 TOXIC STRESS, EPIGENETICS AND CHILD DEVELOPMENT. OBJECTIVES: TO DESCRIBE THE CONCEPT OF TOXIC STRESS, PRESENT THE BASICS OF EPIGENETICS AND DISCUSS THEIR RELATIONSHIP WITH CHILD DEVELOPMENT. DATA SOURCE: NARRATIVE LITERATURE REVIEW THROUGH A SEARCH IN THE SCIELO, LILACS, MEDLINE DATABASES USING THE TERMS ADVERSE CHILDHOOD EXPERIENCE OR EARLY LIFE STRESS, EPIGENOMIC OR EPIGENETIC, CHILD DEVELOPMENT OR INFANT DEVELOPMENT. DATA SYNTHESIS: CONTINUING STRESS RESPONSE, KNOWN AS TOXIC STRESS, CAN OCCUR WHEN A CHILD EXPERIENCES INTENSE, FREQUENT, AND/OR PROLONGED ADVERSITY-SUCH AS PHYSICAL OR EMOTIONAL ABUSE, CHRONIC NEGLECT, FOR EXAMPLE-WITHOUT ADEQUATE ADULT SUPPORT. THIS TOXIC STRESS CAN HAVE HARMFUL EFFECTS ON LEARNING, BEHAVIOR, AND HEALTH THROUGHOUT LIFE. EPIGENETICS, AN EMERGING SCIENTIFIC RESEARCH AREA?, SHOWS HOW ENVIRONMENTAL INFLUENCES AFFECT GENE EXPRESSIONS AND EXPLAINS HOW EARLY EXPERIENCES CAN IMPACT THROUGHOUT LIFE. CONCLUSIONS: TOXIC STRESS CAUSES CHANGES IN THE HUMAN BODY RESPONSE SYSTEMS THAT CAN BE EXPLAINED IN PART BY EPIGENETIC CHANGES, WHICH CAN BE TEMPORARY OR LONG-LASTING. PEDIATRICIANS MUST BE AWARE OF THESE MECHANISMS AND THEIR CONSEQUENCES, SEEKING TO PREVENT THEM AND THUS PROMOTE THE HEALTH, WELL-BEING, AND QUALITY OF LIFE OF CHILDREN, CONTRIBUTING TO THEIR FULL DEVELOPMENT. 2022 18 2949 25 GENETIC AND EPIGENETIC CONSEQUENCE OF EARLY-LIFE SOCIAL STRESS ON DEPRESSION: ROLE OF SEROTONIN-ASSOCIATED GENES. EARLY-LIFE ADVERSITY CAUSED BY POOR SOCIAL BONDING AND DEPRIVED MATERNAL CARE IS KNOWN TO AFFECT MENTAL WELLBEING AND PHYSICAL HEALTH. IT IS A FORM OF CHRONIC SOCIAL STRESS THAT PERSISTS BECAUSE OF A NEGATIVE ENVIRONMENT, AND THE CONSEQUENCES ARE LONG-LASTING ON MENTAL HEALTH. THE PRESENCE OF SOCIAL STRESS DURING EARLY LIFE CAN HAVE AN EPIGENETIC EFFECT ON THE BODY, POSSIBLY RESULTING IN MANY COMPLEX MENTAL DISORDERS, INCLUDING DEPRESSION IN LATER LIFE. HERE, WE REVIEW THE EVIDENCE FOR EARLY-LIFE SOCIAL STRESS-INDUCED EPIGENETIC CHANGES THAT MODULATE JUVENILE AND ADULT SOCIAL BEHAVIOR (DEPRESSION AND ANXIETY). THIS REVIEW HAS A PARTICULAR EMPHASIS ON THE INTERACTION BETWEEN EARLY-LIFE SOCIAL STRESS AND GENETIC VARIATION OF SEROTONIN ASSOCIATE GENES INCLUDING THE SEROTONIN TRANSPORTER GENE (5-HTT; ALSO KNOWN AS SLC6A4), WHICH ARE KEY MOLECULES INVOLVED IN DEPRESSION. 2020 19 5107 24 POLYCYSTIC OVARY SYNDROME: A BRAIN DISORDER CHARACTERIZED BY EATING PROBLEMS ORIGINATING DURING PUBERTY AND ADOLESCENCE. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE CONDITION ASSOCIATED WITH REPRODUCTIVE AND PSYCHIATRIC DISORDERS, AND WITH OBESITY. EATING DISORDERS, SUCH AS BULIMIA AND RECURRENT DIETING, ARE ALSO LINKED TO PCOS. THEY CAN LEAD TO THE EPIGENETIC DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS, THEREBY IMPACTING ON OVARIAN FOLLICULOGENESIS. WE POSTULATE THAT PCOS IS INDUCED BY PSYCHOLOGICAL DISTRESS AND EPISODES OF OVEREATING AND/OR DIETING DURING PUBERTY AND ADOLESCENCE, WHEN BODY DISSATISFACTION AND EMOTIONAL DISTRESS ARE OFTEN PRESENT. WE PROPOSE THAT UPREGULATED ACTIVATION OF THE CENTRAL HPG AXIS DURING THIS PERIOD CAN BE EPIGENETICALLY ALTERED BY PSYCHOLOGICAL STRESSORS AND BY BULIMIA/RECURRENT DIETING, WHICH ARE COMMON DURING ADOLESCENCE AND WHICH CAN LEAD TO PCOS. THIS HYPOTHESIS IS BASED ON EVENTS THAT OCCUR DURING A LARGELY NEGLECTED STAGE OF FEMALE REPRODUCTIVE DEVELOPMENT. TO DATE, MOST RESEARCH INTO THE ORIGINS OF PCOS HAS FOCUSED ON THE PRENATAL INDUCTION OF THIS DISORDER, PARTICULARLY IN UTERO ANDROGENIZATION AND THE ROLE OF ANTI-MULLERIAN HORMONE. ESTABLISHING CAUSALITY IN OUR PERIPUBERTAL MODEL REQUIRES PROSPECTIVE COHORT STUDIES FROM INFANCY. MECHANISTIC STUDIES SHOULD CONSIDER THE ROLE OF THE GUT MICROBIOTA IN ADDITION TO THE EPIGENETIC REGULATION OF (NEURO) HORMONES. FINALLY, CLINICIANS SHOULD CONSIDER THE IMPORTANCE OF UNDERLYING CHRONIC PSYCHOLOGICAL DISTRESS AND EATING DISORDERS IN PCOS. 2020 20 6478 22 TOPICAL REVIEW: THE EMERGING FIELD OF EPIGENETICS: INFORMING MODELS OF PEDIATRIC TRAUMA AND PHYSICAL HEALTH. OBJECTIVE: TRAUMA EXPERIENCED DURING CHILDHOOD AND ADOLESCENCE HAS BEEN LINKED TO A NUMBER OF CHRONIC MEDICAL CONCERNS. WE HIGHLIGHT MAJOR FINDINGS FROM THE PEDIATRIC TRAUMA LITERATURE TO PROVIDE A MODEL FOR UNDERSTANDING THIS ASSOCIATION. METHODS: STUDIES EXAMINING THE EFFECTS OF TRAUMA WERE SYSTEMATICALLY REVIEWED AND SYNTHESIZED INTO A MODEL PROPOSING A CENTRAL ROLE FOR EPIGENETICS IN THE WAYS THAT CHILDHOOD EXPERIENCES CAN AFFECT HEALTH. RESULTS: EARLY HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS RESPONSE MAY IMPACT INITIAL TRAUMA EXPERIENCE, WITH DOWNSTREAM EFFECTS ON POSTTRAUMA ADJUSTMENT REFLECTED IN POSTTRAUMA NEUROBIOLOGY, PSYCHOLOGICAL HEALTH, AND PHYSICAL HEALTH. CONCLUSIONS: PROSPECTIVE RESEARCH WITH CHILDREN AND ADOLESCENTS EXPOSED TO TRAUMA IS NEEDED TO BETTER CHARACTERIZE THE GENETIC AND EPIGENETIC INFLUENCES ON THE COURSE OF HPA AND IMMUNE PROCESSES AS RELATED TO POSTTRAUMA PSYCHOLOGICAL AND PHYSICAL HEALTH OUTCOMES. 2016