1 2415 109 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS: STRESS AND DEPRESSION. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL DISORDERS INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS PLAY A ROLE IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION, ADDICTION, AND SCHIZOPHRENIA, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY POINT TO THE IMPORTANCE OF ADDITIONAL FACTORS. ENVIRONMENTAL FACTORS, SUCH AS STRESS, PLAY A MAJOR ROLE IN THE PSYCHIATRIC DISORDERS BY INDUCING STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR. INSULTS AT THE DEVELOPMENTAL STAGE AND IN ADULTHOOD APPEAR TO INDUCE DISTINCT MALADAPTATIONS. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS, AND THESE STUDIES CAN PROVIDE A MORE GENERAL UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSYCHIATRIC DISORDERS. UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS IS PROVIDING NEW INSIGHTS INTO DISEASE MECHANISMS IN HUMANS. 2014 2 2414 96 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION AND ADDICTION, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS OR PRIOR DRUG EXPOSURE ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. SUCH EXPOSURE TO ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL AND ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION AND ADDICTION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS (E.G., CHRONIC STRESS, DRUG ADMINISTRATION). UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS REVEALS NEW INSIGHT INTO DISEASE MECHANISMS IN HUMANS. 2014 3 6626 30 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 4 2011 87 EPIGENETIC BASIS OF MENTAL ILLNESS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION AS WELL AS LIKELY ABNORMALITIES IN GLIAL CELLS. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF MOST MENTAL DISORDERS, THE RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS, PARTICULARLY FOR DEPRESSION AND OTHER STRESS-RELATED SYNDROMES, CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. EXPOSURE TO SUCH ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL VERSUS ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND THE ABERRANT EPIGENETIC REGULATION THAT UNDERLIES THIS DYSREGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. HERE, WE PROVIDE A PROGRESS REPORT OF EPIGENETIC STUDIES OF THE THREE MAJOR PSYCHIATRIC SYNDROMES, DEPRESSION, SCHIZOPHRENIA, AND BIPOLAR DISORDER. WE REVIEW THE LITERATURE DERIVED FROM ANIMAL MODELS OF THESE DISORDERS AS WELL AS FROM STUDIES OF POSTMORTEM BRAIN TISSUE FROM HUMAN PATIENTS. WHILE EPIGENETIC STUDIES OF MENTAL ILLNESS REMAIN AT EARLY STAGES, UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY WITHIN SPECIFIC BRAIN REGIONS TO CAUSE LASTING CHANGES IN DISEASE SUSCEPTIBILITY AND PATHOPHYSIOLOGY IS REVEALING NEW INSIGHT INTO THE ETIOLOGY AND TREATMENT OF THESE CONDITIONS. 2016 5 3606 30 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 5310 27 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 7 367 29 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM. 2014 8 4067 24 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 9 128 21 A UNIFYING MECHANISM OF KETOGENIC DIET ACTION: THE MULTIPLE ROLES OF NICOTINAMIDE ADENINE DINUCLEOTIDE. THE ABILITY OF A KETOGENIC DIET TO TREAT SEIZURES AND RENDER A NEURONAL NETWORK MORE RESISTANT TO STRONG ELECTRICAL ACTIVITY HAS BEEN OBSERVED FOR A CENTURY IN CLINICS AND FOR DECADES IN RESEARCH LABORATORIES. ALONGSIDE ONGOING EFFORTS TO UNDERSTAND HOW THIS THERAPY WORKS TO STOP SEIZURES, METABOLIC HEALTH IS INCREASINGLY APPRECIATED AS CRITICAL BUFFER TO RESISTING AND RECOVERING FROM ACUTE AND CHRONIC DISEASE. ACCORDINGLY, LINKS BETWEEN METABOLISM AND HEALTH, AND THE BROADER EMERGING IMPACT OF THE KETOGENIC DIET IN IMPROVING DIVERSE METABOLIC, IMMUNOLOGICAL AND NEUROLOGICAL CONDITIONS, HAVE SERVED TO INTENSIFY THE SEARCH FOR ITS KEY AND/OR COMMON MECHANISMS. HERE WE REVIEW DIVERSE EVIDENCE FOR INCREASED LEVELS OF NAD(+), AND THUS AN ALTERED RATIO OF NAD(+)/NADH, DURING METABOLIC THERAPY WITH A KETOGENIC DIET. WE PROPOSE THIS AS A POTENTIAL UNIFYING MECHANISM, AND HIGHLIGHT SOME OF THE EVIDENCE LINKING ALTERED NAD(+)/NADH WITH REDUCED SEIZURES AND WITH A RANGE OF SHORT AND LONG-TERM CHANGES ASSOCIATED WITH THE BENEFICIAL EFFECTS OF A KETOGENIC DIET. AN INCREASE IN NAD(+)/NADH IS CONSISTENT WITH MULTIPLE LINES OF EVIDENCE AND HYPOTHESES, AND THEREFORE WE SUGGEST THAT INCREASED NAD(+) MAY BE A COMMON MECHANISM UNDERLYING BENEFICIAL EFFECTS OF KETOGENIC DIET THERAPY. 2020 10 5829 24 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 11 6577 20 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 12 6090 31 THE EFFECTS OF EARLY LIFE ADVERSITY ON THE IMMUNE SYSTEM. EARLY LIFE ADVERSITY (ELA) IS ASSOCIATED WITH A HIGHER RISK FOR DISEASES IN ADULTHOOD. ALTHOUGH THE PATHOPHYSIOLOGICAL EFFECTS OF ELA ARE VARIED, THERE MAY BE A UNIFYING ROLE FOR THE IMMUNE SYSTEM IN ALL OF THE LONG-TERM PATHOLOGIES SUCH AS CHRONIC INFLAMMATORY DISORDERS (AUTOIMMUNE DISEASES, ALLERGY, AND ASTHMA). RECENTLY, SIGNIFICANT EFFORTS HAVE BEEN MADE TO ELUCIDATE THE LONG-TERM EFFECTS ELA HAS ON IMMUNE FUNCTION, AS WELL AS THE MECHANISMS UNDERLYING THESE IMMUNE CHANGES. IN THIS REVIEW, WE FOCUS ON DATA FROM HUMAN STUDIES INVESTIGATING IMMUNE PARAMETERS IN RELATION TO POST-NATAL ADVERSE EXPERIENCES. WE DESCRIBE THE CURRENT UNDERSTANDING OF THE 'ELA IMMUNE PHENOTYPE', CHARACTERIZED BY INFLAMMATION, IMPAIRMENT OF THE CELLULAR IMMUNE SYSTEM, AND IMMUNOSENESCENCE. HOWEVER, AT PRESENT, DATA ADDRESSING SPECIFIC IMMUNE FUNCTIONS ARE LIMITED AND THERE IS A NEED FOR HIGH-QUALITY, WELL POWERED, LONGITUDINAL STUDIES TO UNRAVEL CAUSE FROM EFFECT. BESIDES THE IMMUNE SYSTEM, ALSO THE STRESS SYSTEM AND HEALTH BEHAVIORS ARE ALTERED IN ELA. WE DISCUSS PROBABLE UNDERLYING MECHANISMS BASED ON EPIGENETIC PROGRAMMING THAT COULD EXPLAIN THE ELA IMMUNE PHENOTYPE AND WHETHER THIS IS A DIRECT EFFECT OF IMMUNE PROGRAMMING OR AN INDIRECT CONSEQUENCE OF CHANGES IN BEHAVIOR OR STRESS REACTIVITY. UNDERSTANDING THE UNDERLYING MECHANISMS WILL HELP DEFINE EFFECTIVE STRATEGIES TO PREVENT OR COUNTERACT NEGATIVE ELA-ASSOCIATED OUTCOMES. 2017 13 5466 27 RESILIENCE: SAFETY IN THE AFTERMATH OF TRAUMATIC STRESSOR EXPERIENCES. THE RELATIONSHIP BETWEEN ADVERSE EXPERIENCES AND THE EMERGENCE OF PATHOLOGY HAS OFTEN FOCUSED ON CHARACTERISTICS OF THE STRESSOR OR OF THE INDIVIDUAL (STRESSOR APPRAISALS, COPING STRATEGIES). THESE FEATURES ARE THOUGHT TO INFLUENCE MULTIPLE BIOLOGICAL PROCESSES THAT FAVOR THE DEVELOPMENT OF MENTAL AND PHYSICAL ILLNESSES. LESS OFTEN HAS ATTENTION FOCUSED ON THE AFTERMATH OF TRAUMATIC EXPERIENCES, AND THE IMPORTANCE OF SAFETY AND REASSURANCE THAT IS NECESSARY FOR LONGER-TERM WELL-BEING. IN SOME CASES (E.G., POST-TRAUMATIC STRESS DISORDER) THIS MAY BE REFLECTED BY A FAILURE OF FEAR EXTINCTION, WHEREAS IN OTHER INSTANCES (E.G., HISTORICAL TRAUMA), THE UNCERTAINTY ABOUT THE FUTURE MIGHT FOSTER CONTINUED ANXIETY. IN ESSENCE, THE QUESTION BECOMES ONE OF HOW INDIVIDUALS ATTAIN FEELINGS OF SAFETY WHEN IT IS FULLY UNDERSTOOD THAT THE WORLD IS NOT NECESSARILY A SAFE PLACE, UNCERTAINTIES ABOUND, AND FEELINGS OF AGENCY ARE OFTEN ILLUSORY. WE CONSIDER HOW INDIVIDUALS ACQUIRE RESILIENCE IN THE AFTERMATH OF TRAUMATIC AND CHRONIC STRESSORS. IN THIS RESPECT, WE REVIEW CHARACTERISTICS OF STRESSORS THAT MAY TRIGGER PARTICULAR BIOLOGICAL AND BEHAVIORAL COPING RESPONSES, AS WELL AS FACTORS THAT UNDERMINE THEIR EFFICACY. TO THIS END, WE EXPLORE STRESSOR DYNAMICS AND SOCIAL PROCESSES THAT FOSTER RESILIENCE IN RESPONSE TO SPECIFIC TRAUMATIC, CHRONIC, AND UNCONTROLLABLE STRESSOR CONTEXTS (INTIMATE PARTNER ABUSE; REFUGEE MIGRATION; COLLECTIVE HISTORICAL TRAUMA). WE POINT TO RESILIENCE FACTORS THAT MAY COMPRISE NEUROBIOLOGICAL CHANGES, SUCH AS THOSE RELATED TO VARIOUS STRESSOR-PROVOKED HORMONES, NEUROTROPHINS, INFLAMMATORY IMMUNE, MICROBIAL, AND EPIGENETIC PROCESSES. THESE BEHAVIORAL AND BIOLOGICAL STRESS RESPONSES MAY INFLUENCE, AND BE INFLUENCED BY, FEELINGS OF SAFETY THAT COME ABOUT THROUGH RELATIONSHIPS WITH OTHERS, SPIRITUAL AND PLACE-BASED CONNECTIONS. 2020 14 29 28 A BIOPSYCHOSOCIAL OVERVIEW OF THE OPIOID CRISIS: CONSIDERING NUTRITION AND GASTROINTESTINAL HEALTH. THE OPIOID CRISIS HAS REACHED EPIDEMIC PROPORTIONS IN THE UNITED STATES WITH RISING OVERDOSE DEATH RATES. IDENTIFYING THE UNDERLYING FACTORS THAT CONTRIBUTE TO ADDICTION VULNERABILITY MAY LEAD TO MORE EFFECTIVE PREVENTION STRATEGIES. SUPPLY SIDE ENVIRONMENTAL FACTORS ARE A MAJOR CONTRIBUTING COMPONENT. PSYCHOSOCIAL FACTORS SUCH AS STRESS, TRAUMA, AND ADVERSE CHILDHOOD EXPERIENCES HAVE BEEN LINKED TO EMOTIONAL PAIN LEADING TO SELF-MEDICATION. GENETIC AND EPIGENETIC FACTORS ASSOCIATED WITH BRAIN REWARD PATHWAYS AND IMPULSIVITY ARE KNOWN PREDICTORS OF ADDICTION VULNERABILITY. THIS REVIEW ATTEMPTS TO PRESENT A BIOPSYCHOSOCIAL APPROACH THAT CONNECTS VARIOUS SOCIAL AND BIOLOGICAL THEORIES RELATED TO THE ADDICTION CRISIS. THE EMERGING ROLE OF NUTRITION THERAPY WITH AN EMPHASIS ON GASTROINTESTINAL HEALTH IN THE TREATMENT OF OPIOID USE DISORDER IS PRESENTED. THE BIOPSYCHOSOCIAL MODEL INTEGRATES CONCEPTS FROM SEVERAL DISCIPLINES, EMPHASIZING MULTICAUSALITY RATHER THAN A REDUCTIONIST APPROACH. POTENTIAL SOLUTIONS AT MULTIPLE LEVELS ARE PRESENTED, CONSIDERING INDIVIDUAL AS WELL AS POPULATION HEALTH. THIS SINGLE COHESIVE FRAMEWORK IS BASED ON THE INTERDEPENDENCY OF THE ENTIRE SYSTEM, IDENTIFYING RISK AND PROTECTIVE FACTORS THAT MAY INFLUENCE SUBSTANCE-SEEKING BEHAVIOR. NUTRITION SHOULD BE INCLUDED AS ONE FACET OF A MULTIDISCIPLINARY APPROACH TOWARD IMPROVED RECOVERY OUTCOMES. CROSS-DISCIPLINARY COLLABORATIVE EFFORTS, NEW IDEAS, AND FISCAL RESOURCES WILL BE CRITICAL TO ADDRESS THE EPIDEMIC. 2019 15 4006 27 LOST AMONG THE TREES? THE AUTONOMIC NERVOUS SYSTEM AND PAEDIATRICS. THE AUTONOMIC NERVOUS SYSTEM (ANS) HAS BEEN STRIKINGLY NEGLECTED IN WESTERN MEDICINE. DESPITE ITS PROFOUND IMPORTANCE FOR REGULATION, ADJUSTMENT AND COORDINATION OF BODY SYSTEMS, IT LACKS PRIORITY IN TRAINING AND PRACTICE AND RECEIVES SCANT ATTENTION IN NUMEROUS MAJOR TEXTBOOKS. THE ANS IS INTEGRAL TO MANIFESTATIONS OF ILLNESS, UNDERLYING FAMILIAR PHYSICAL AND PSYCHOLOGICAL SYMPTOMS. WHEN ANS ACTIVITY IS ITSELF DYSFUNCTIONAL, USUAL INDICATORS OF ACUTE ILLNESS MAY PROVE DECEPTIVE. RECOGNISING THE RELEVANCE OF THE ANS CAN INVOLVE SEEING THE FAMILIAR THROUGH FRESH EYES, CHALLENGING ASSUMPTIONS IN CLINICAL ASSESSMENT AND IN APPROACHES TO PRACTICE. ITS IMPORTANCE EXTENDS FROM PHYSICAL AND PSYCHOLOGICAL WELL-BEING TO PARENTING AND SAFEGUARDING, PUBLIC SERVICES AND THE FUNCTIONING OF SOCIETY. EXPLORATION OF ITS ROLE IN CONDITIONS RANGING FROM NEUROLOGICAL, GASTROINTESTINAL AND CONNECTIVE TISSUE DISORDERS, DIABETES AND CHRONIC FATIGUE SYNDROME, TO AUTISM, BEHAVIOURAL AND MENTAL HEALTH DIFFICULTIES MAY OPEN THERAPEUTIC AVENUES. THE ANS OFFERS A MECHANISM FOR SO-CALLED FUNCTIONAL ILLNESSES AND ILLUSTRATES THE IMPORTANCE OF RECOGNISING THAT 'STRESS' TAKES MANY FORMS, PHYSICAL, PSYCHOLOGICAL AND ENVIRONMENTAL, DESIRABLE AND OTHERWISE. EVIDENCE OF INTRAUTERINE AND POST-NATAL PROGRAMMING OF ANS REACTIVITY SUGGESTS THAT NEONATAL CARE AND SAFEGUARDING PRACTICE MAY OFFER PREVENTIVE OPPORTUNITY, AS MAY GREATER UNDERSTANDING OF EPIGENETIC CHANGE OF ANS ACTIVITY THROUGH, FOR EXAMPLE, ACCIDENTAL OR PSYCHOLOGICAL TRAUMA OR INFECTION. THE AIM OF THIS ARTICLE IS TO ACCELERATE RECOGNITION OF THE IMPORTANCE OF THE ANS THROUGHOUT PAEDIATRICS, AND OF THE POTENTIAL PHYSICAL AND PSYCHOLOGICAL COST OF NEGLECTING IT. 2014 16 5719 22 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 17 225 35 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 18 6897 17 [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 19 357 30 ALTERNATIVE MODELS FOR TRANSGENERATIONAL EPIGENETIC INHERITANCE: MOLECULAR PSYCHIATRY BEYOND MICE AND MAN. MENTAL ILLNESS REMAINS THE GREATEST CHRONIC HEALTH BURDEN GLOBALLY WITH FEW IN-ROADS HAVING BEEN MADE DESPITE SIGNIFICANT ADVANCES IN GENOMIC KNOWLEDGE IN RECENT DECADES. THE FIELD OF PSYCHIATRY IS CONSTANTLY CHALLENGED TO BRING NEW APPROACHES AND TOOLS TO ADDRESS AND TREAT THE NEEDS OF VULNERABLE INDIVIDUALS AND SUBPOPULATIONS, AND THAT HAS TO BE SUPPORTED BY A CONTINUOUS GROWTH IN KNOWLEDGE. THE MAJORITY OF NEUROPSYCHIATRIC SYMPTOMS REFLECT COMPLEX GENE-ENVIRONMENT INTERACTIONS, WITH EPIGENETICS BRIDGING THE GAP BETWEEN GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL STRESSORS THAT TRIGGER DISEASE ONSET AND DRIVE THE ADVANCEMENT OF SYMPTOMS. IT HAS MORE RECENTLY BEEN DEMONSTRATED IN PRECLINICAL MODELS THAT EPIGENETICS UNDERPINS THE TRANSGENERATIONAL INHERITANCE OF STRESS-RELATED BEHAVIOURAL PHENOTYPES IN BOTH PATERNAL AND MATERNAL LINEAGES, PROVIDING FURTHER SUPPORTING EVIDENCE FOR HERITABILITY IN HUMANS. HOWEVER, UNBIASED PROSPECTIVE STUDIES OF THIS NATURE ARE PRACTICALLY IMPOSSIBLE TO CONDUCT IN HUMANS SO PRECLINICAL MODELS REMAIN OUR BEST OPTION FOR RESEARCHING THE MOLECULAR PATHOPHYSIOLOGIES UNDERLYING MANY NEUROPSYCHIATRIC CONDITIONS. WHILE RODENTS WILL REMAIN THE DOMINANT MODEL SYSTEM FOR PRECLINICAL STUDIES (ESPECIALLY FOR ADDRESSING COMPLEX BEHAVIOURAL PHENOTYPES), THERE IS SCOPE TO EXPAND CURRENT RESEARCH OF THE MOLECULAR AND EPIGENETIC PATHOLOGIES BY USING INVERTEBRATE MODELS. HERE, WE WILL DISCUSS THE UTILITY AND ADVANTAGES OF TWO ALTERNATIVE MODEL ORGANISMS-CAENORHABDITIS ELEGANS AND DROSOPHILA MELANOGASTER-AND SUMMARISE THE COMPELLING INSIGHTS OF THE EPIGENETIC REGULATION OF TRANSGENERATIONAL INHERITANCE THAT ARE POTENTIALLY RELEVANT TO HUMAN PSYCHIATRY. 2021 20 4966 25 PATHOGENOMICS OF ENDOMETRIOSIS DEVELOPMENT. FOR OVER 100 YEARS, ENDOMETRIOSIS, AS A CHRONIC, ESTROGEN-DEPENDENT, INFLAMMATORY, HERITABLE DISEASE AFFECTING APPROXIMATELY 5(-)10% OF WOMEN IN REPRODUCTIVE AGE HAS BEEN THE FOCUS OF CLINICIANS AND SCIENTISTS. IN SPITE OF NUMEROUS ENVIRONMENTAL, GENETIC, EPIGENETIC, ENDOCRINE, AND IMMUNOLOGICAL STUDIES, OUR KNOWLEDGE OF ENDOMETRIOSIS IS STILL FRAGMENTARY, AND ITS PRECISE PATHOPHYSIOLOGY AND PATHOGENOMICS REMAIN A MYSTERY. THE IMPLEMENTATION OF NEW TECHNOLOGIES HAS PROVIDED TREMENDOUS PROGRESS IN UNDERSTANDING THE MANY INTRINSIC MOLECULAR MECHANISMS IN THE DEVELOPMENT OF ENDOMETRIOSIS, WITH PROGENITOR AND STEM CELLS (SCS) OF THE EUTOPIC ENDOMETRIUM AS THE STARTING PLAYERS AND ENDOMETRIOTIC LESIONS AS THE FINAL PATHOMORPHOLOGICAL TRAIT. NOVEL DATA ON THE MOLECULAR, GENETIC, AND EPIGENETIC MECHANISMS OF THE DISEASE ARE BRIEFLY OUTLINED. WE HYPOTHESIZE THE EXISTENCE OF AN ENDOMETRIOSIS DEVELOPMENT GENETIC PROGRAM (EMDP) THAT GOVERNS THE ORIGIN OF ENDOMETRIUM STEM CELLS PROGRAMMED FOR ENDOMETRIOSIS (1), THEIR TRANSITION (METAPLASIA) INTO MESENCHYMAL SCS (2), AND THEIR INVASION OF THE PERITONEUM AND PROGRESSION TO ENDOMETRIOTIC LESIONS (3). THE PROS AND CONS OF THE RECENT UNIFYING THEORY OF ENDOMETRIOSIS ARE ALSO DISCUSSED. COMPLEX GENOMIC AND EPIGENETIC INTERACTIONS AT DIFFERENT STAGES OF THE ENDOMETRIOSIS PROCESS RESULT IN DIFFERENT FORMS OF THE DISEASE, WITH SPECIFIC FEATURES AND CLINICAL MANIFESTATIONS. THE SIGNIFICANCE OF THE EMDP IN ELABORATING A NEW STRATEGY FOR ENDOMETRIOSIS PREDICTION, PREVENTION, AND TREATMENT IS DISCUSSED. 2018