1 6917 80 [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 2 964 15 CHRONIC MYELOPROLIFERATIVE DISEASES WITH AND WITHOUT THE PH CHROMOSOME: SOME UNRESOLVED ISSUES. PH-POSITIVE CHRONIC MYELOID LEUKEMIA (CML) AND PH-NEGATIVE CHRONIC MYELOPROLIFERATIVE DISEASES (MPDS), CHARACTERIZED IN MANY CASES BY THE PRESENCE OF THE JAK2(V617F) MUTATION, HAVE MANY FEATURES IN COMMON AND YET ALSO SHOW FUNDAMENTAL DIFFERENCES. IN THIS REVIEW, WE POSE FIVE DISCRETE AND RELATED QUESTIONS RELEVANT TO BOTH CATEGORIES OF HEMATOLOGICAL MALIGNANCY, NAMELY: WHAT ARE THE MECHANISMS THAT UNDERLIE DISEASE PROGRESSION FROM A RELATIVELY BENIGN OR CHRONIC PHASE? BY WHAT THERAPEUTIC METHODS MIGHT ONE TARGET RESIDUAL LEUKEMIA STEM CELLS IN CML? IS JAK2(V617F) THE ORIGINAL MOLECULAR EVENT IN MPD? WHAT EPIGENETIC EVENTS MUST HAVE A ROLE IN DICTATING DISEASE PHENOTYPE IN MPDS? AND FINALLY, WILL THE BENEFITS CONFERRED BY CURRENT OR FUTURE JAK2(V617F) INHIBITORS EQUAL OR EVEN SURPASS THE CLINICAL SUCCESS THAT HAS RESULTED FROM THE USE OF TYROSINE KINASE INHIBITORS IN CML? THESE AND OTHERS QUESTIONS MUST BE ADDRESSED AND IN SOME CASES SHOULD BE ANSWERED IN THE FORESEEABLE FUTURE. 2009 3 6040 14 THE CHRONIC MYELOPROLIFERATIVE DISORDERS: CLONALITY AND CLINICAL HETEROGENEITY. THE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD), POLYCYTHEMIA VERA (PV), CHRONIC IDIOPATHIC MYELOFIBROSIS (IMF), ESSENTIAL THROMBOCYTOSIS (ET), AND CHRONIC MYELOGENOUS LEUKEMIA (CML), ARE THOUGHT TO BE CLONAL DISORDERS ARISING IN A MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL. HOWEVER, ESTABLISHING THE DIAGNOSIS OF AN MPD OTHER THAN CML IS PROBLEMATIC DUE TO A LACK OF CLINICALLY APPLICABLE CLONAL MARKERS. FURTHERMORE, IN SOME PATIENTS, IN WHOM A CLASSICAL MPD PHENOTYPE IS PRESENT, THE HEMATOPOIETIC STEM CELLS APPEAR TO BE POLYCLONAL, SUGGESTING THAT THE CHRONIC MPD OTHER THAN CML MAY ACTUALLY BE A GENETICALLY HETEROGENEOUS GROUP OF DISORDERS. FURTHERMORE, SINCE THE ABERRANT CLONE IS BELIEVED TO ARISE FROM A MULTIPOTENT HEMATOPOIETIC STEM CELL, THE NON-CML CHRONIC MPD-ET, PV, AND IMF-COULD BE RELATED. ADDITIONAL UNRESOLVED ISSUES REGARDING THE MPD INCLUDE: IDENTIFICATION OF THE MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL INVOLVED, THE MOLECULAR BASIS FOR THE CLINICAL HETEROGENEITY AMONGST THE INDIVIDUAL MPD, THE CLINICAL SIGNIFICANCE OF CLONALITY IN NON-CML MPD, AND RECONCILIATION OF THERAPY WITH THE CLONAL AND CLINICAL HETEROGENEITY OF THESE DISORDERS. DETERMINATION OF CLONALITY HAS LARGELY BEEN CARRIED OUT USING X CHROMOSOME-LINKED POLYMORPHISMS, BUT SUCH STUDIES ARE LIMITED TO WOMEN AND WITH INCREASING PATIENT AGE ARE COMPROMISED BY SKEWING OF ALLELIC EXPRESSION IN BOTH NEUTROPHILS AND T LYMPHOCYTES, MAKING THE RESULTS DIFFICULT TO INTERPRET. X CHROMOSOME-LINKED POLYMORPHISM STUDIES HAVE INDICATED THAT IN PV THE TARGET STEM CELL IS ONE THAT GIVES RISE TO BOTH LYMPHOID AND MYELOID PROGENITORS. RECENTLY, TWO EPIGENETIC MARKERS HAVE BEEN IDENTIFIED IN THE MPD: IMPAIRED EXPRESSION OF THE THROMBOPOIETIN RECEPTOR, MPL, IN PLATELETS AND MEGAKARYOCYTES, AND OVEREXPRESSION IN NEUTROPHILS OF THE MRNA OF A GENE DESIGNATED POLYCYTHEMIA RUBRA VERA-1 (PRV-1). THE ROLE OF THESE EPIGENETIC ABNORMALITIES IN THE DIAGNOSIS OF THE MPD REMAINS TO BE ESTABLISHED. CURRENTLY, GIVEN THE UNRESOLVED ISSUES WITH RESPECT TO THE CLINICAL AND CLONAL HETEROGENEITY OF THE MPD, TREATMENT NEEDS TO BE TAILORED INDIVIDUALLY IN PATIENTS WITH AN MPD. 2004 4 4959 13 PATHOGENESIS OF MYELOPROLIFERATIVE DISORDERS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A SET OF CHRONIC HEMATOPOIETIC NEOPLASMS WITH OVERLAPPING CLINICAL AND MOLECULAR FEATURES. RECENT YEARS HAVE WITNESSED CONSIDERABLE ADVANCES IN OUR UNDERSTANDING OF THEIR PATHOGENETIC BASIS. DUE TO THEIR PROTRACTED CLINICAL COURSE, THE EVOLUTION TO ADVANCED HEMATOLOGICAL MALIGNANCIES, AND THE ACCESSIBILITY OF NEOPLASTIC TISSUE, THE STUDY OF MPNS HAS PROVIDED A WINDOW INTO THE EARLIEST STAGES OF TUMORIGENESIS. WITH THE DISCOVERY OF MUTATIONS IN CALR, THE MAJORITY OF MPN PATIENTS NOW BEAR AN IDENTIFIABLE MARKER OF CLONAL DISEASE; HOWEVER, THE MECHANISM BY WHICH MUTATED CALR PERTURBS MEGAKARYOPOIESIS IS CURRENTLY UNRESOLVED. WE ARE BEGINNING TO UNDERSTAND BETTER THE ROLE OF JAK2(V617F) HOMOZYGOSITY, THE FUNCTION OF COMUTATIONS IN EPIGENETIC REGULATORS AND SPLICEOSOME COMPONENTS, AND HOW THESE MUTATIONS COOPERATE WITH JAK2(V617F) TO MODULATE MPN PHENOTYPE. 2016 5 1490 22 DNA DIRECTED PRO-DOPAMINE REGULATION COUPLING SUBLUXATION REPAIR, H-WAVE((R)) AND OTHER NEUROBIOLOGICALLY BASED MODALITIES TO ADDRESS COMPLEXITIES OF CHRONIC PAIN IN A FEMALE DIAGNOSED WITH REWARD DEFICIENCY SYNDROME (RDS): EMERGENCE OF INDUCTION OF "DOPAMINE HOMEOSTASIS" IN THE FACE OF THE OPIOID CRISIS. ADDICTION IS A COMPLEX MULTIFACTORIAL CONDITION. ESTABLISHED GENETIC FACTORS CAN PROVIDE CLEAR GUIDANCE IN ASSESSING THE RISK OF ADDICTION TO SUBSTANCES AND BEHAVIORS. CHRONIC STRESS CAN ACCUMULATE, FORMING DIFFICULT TO RECOGNIZE ADDICTION PATTERNS FROM BOTH GENETIC AND EPIGENETIC (ENVIRONMENTAL) FACTORS. FURTHERMORE, PSYCHOLOGICAL/PHYSICAL/CHEMICAL STRESSORS ARE TYPICALLY CATEGORIZED LINEARLY, DELAYING IDENTIFICATION AND TREATMENT. THE PATIENT IN THIS CASE REPORT IS A CAUCASIAN FEMALE, AGED 36, WHO PRESENTED WITH CHRONIC PAIN AND PARTIAL DISABILITY FOLLOWING A SURGICALLY REPAIRED TRIMALLEOLAR FRACTURE. THE PATIENT HAD A HISTORY OF UNRESOLVED ATTENTION DEFICIT DISORDER AND AN MRI SCAN OF HER BRAIN REVEALED ATROPHY AND FUNCTIONAL ASYMMETRY. IN 2018, THE PATIENT ENTERED THE BAJAJ CHIROPRACTIC CLINIC, WHERE INITIAL TREATMENT FOCUSED ON RE-ESTABLISHING INTEGRITY OF THE SPINE AND LOWER EXTREMITY BIOMECHANICS AND GRADUATED INTO COGNITIVE BEHAVIOR STABILIZATION ASSISTED BY DNA PRO-DOPAMINE REGULATION GUIDED BY GENETIC ADDICTION RISK SEVERITY TESTING. DURING TREATMENT (2018-2021), PROGRESS ACHIEVED INCLUDED: IMPROVED COGNITIVE CLARITY, FOCUS, SLEEP, ANXIETY, AND EMOTIONAL STABILITY IN ADDITION TO PAIN REDUCTION (75%); ELIMINATION OF POWERFUL ANALGESICS; AND REDUCED INTAKE OF PREVIOUSLY UNADDRESSED ALCOHOLISM. TO HELP REDUCE HEDONIC ADDICTIVE BEHAVIORS AND PAIN, COUPLING OF H-WAVE WITH CORRECTIVE CHIROPRACTIC CARE SEEMS PRUDENT. WE EMPHASIZE THE IMPORTANCE OF GENETIC ASSESSMENT ALONG WITH ATTEMPTS AT INDUCING REQUIRED DOPAMINERGIC HOMEOSTASIS VIA PRECISION KB220PAM. IT IS HYPOTHESIZED THAT FROM PREVENTIVE CARE MODELS, A NEW STANDARD IS EMERGING INCLUDING SELF-AWARENESS AND ACCOUNTABILITY FOR REWARD DEFICIENCY AS A FUNCTION OF HYPODOPAMINERGIA. THIS CASE STUDY DOCUMENTS THE PROGRESSION OF A PATIENT DEALING WITH THE COMPLEXITIES OF AN INJURY, PAIN MANAGEMENT, COGNITIVE IMPAIRMENT, ANXIETY, DEPRESSION, AND THE APPLICATION OF UNIVERSAL HEALTH PRINCIPLES TOWARDS CORRECTION VERSUS PALLIATIVE CARE. 2022 6 4568 14 MYELOID-DERIVED SUPPRESSOR CELLS (MDSC): WHEN GOOD INTENTIONS GO AWRY. MDSC ARE A HETEROGENEOUS POPULATION OF IMMATURE MYELOID CELLS THAT ARE RELEASED BY BIOLOGICAL STRESS SUCH AS TISSUE DAMAGE AND INFLAMMATION. CONVENTIONALLY, MDSC ARE KNOWN FOR THEIR DETRIMENTAL ROLE IN CHRONIC INFLAMMATION AND NEOPLASTIC CONDITIONS. HOWEVER, THEIR INTRINSIC FUNCTIONS IN IMMUNOREGULATION, WOUND HEALING, AND ANGIOGENESIS ARE INTENDED TO PROTECT FROM OVER-REACTIVE IMMUNE RESPONSES, MAINTENANCE OF IMMUNOTOLERANCE, TISSUE REPAIR, AND HOMEOSTASIS. PARADOXICALLY, UNDER CERTAIN CONDITIONS, MDSC CAN IMPAIR PROTECTIVE IMMUNE RESPONSES AND EXACERBATE THE DISEASE. THE TRANSITION FROM PROTECTIVE TO HARMFUL MDSC IS MOST LIKELY DRIVEN BY ENVIRONMENTAL AND EPIGENETIC MECHANISMS INDUCED BY PROLONGED EXPOSURE TO UNRESOLVED INFLAMMATORY TRIGGERS. HERE, WE REVIEW SEVERAL EXAMPLES OF THE DUAL IMPACT OF MDSC IN CONDITIONS SUCH AS MATERNAL-FETAL TOLERANCE, SELF-ANTIGENS IMMUNOTOLERANCE, OBESITY-ASSOCIATED CANCER, SEPSIS AND TRAUMA. MOREOVER, WE ALSO HIGHLIGHTED THE EVIDENCE INDICATING THAT MDSC HAVE A ROLE IN COVID-19 PATHOPHYSIOLOGY. FINALLY, WE HAVE SUMMARIZED THE EVIDENCE INDICATING EPIGENETIC MECHANISMS ASSOCIATED WITH MDSC FUNCTION. 2021 7 2993 14 GENETIC PAIN LOSS DISORDERS. GENETIC PAIN LOSS INCLUDES CONGENITAL INSENSITIVITY TO PAIN (CIP), HEREDITARY SENSORY NEUROPATHIES AND, IF AUTONOMIC NERVES ARE INVOLVED, HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSAN). THIS HETEROGENEOUS GROUP OF DISORDERS HIGHLIGHTS THE ESSENTIAL ROLE OF NOCICEPTION IN PROTECTING AGAINST TISSUE DAMAGE. PATIENTS WITH GENETIC PAIN LOSS HAVE RECURRENT INJURIES, BURNS AND POORLY HEALING WOUNDS AS DISEASE HALLMARKS. CIP AND HSAN ARE CAUSED BY PATHOGENIC GENETIC VARIANTS IN >20 GENES THAT LEAD TO DEVELOPMENTAL DEFECTS, NEURODEGENERATION OR ALTERED NEURONAL EXCITABILITY OF PERIPHERAL DAMAGE-SENSING NEURONS. THESE GENETIC VARIANTS LEAD TO HYPERACTIVITY OF SODIUM CHANNELS, DISTURBED HAEM METABOLISM, ALTERED CLATHRIN-MEDIATED TRANSPORT AND IMPAIRED GENE REGULATORY MECHANISMS AFFECTING EPIGENETIC MARKS, LONG NON-CODING RNAS AND REPETITIVE ELEMENTS. THERAPIES FOR PAIN LOSS DISORDERS ARE MAINLY SYMPTOMATIC BUT THE FIRST TARGETED THERAPIES ARE BEING TESTED. CONVERSELY, CHRONIC PAIN REMAINS ONE OF THE GREATEST UNRESOLVED MEDICAL CHALLENGES, AND THE GENES AND MECHANISMS ASSOCIATED WITH PAIN LOSS OFFER NEW TARGETS FOR ANALGESICS. GIVEN THE PROGRESS THAT HAS BEEN MADE, THE COMING YEARS ARE PROMISING BOTH IN TERMS OF TARGETED TREATMENTS FOR PAIN LOSS DISORDERS AND THE DEVELOPMENT OF INNOVATIVE PAIN MEDICINES BASED ON KNOWLEDGE OF THESE GENETIC DISEASES. 2022 8 1281 13 DECIPHERING NEURODEGENERATIVE DISEASES USING LONG-READ SEQUENCING. NEURODEGENERATIVE DISEASES EXHIBIT CHRONIC PROGRESSIVE LESIONS IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS WITH UNCLEAR CAUSES. THE SEARCH FOR PATHOGENIC MUTATIONS IN HUMAN NEURODEGENERATIVE DISEASES HAS BENEFITED FROM MASSIVELY PARALLEL SHORT-READ SEQUENCERS. HOWEVER, GENOMIC REGIONS, INCLUDING REPETITIVE ELEMENTS, ESPECIALLY WITH HIGH/LOW GC CONTENT, ARE FAR BEYOND THE CAPABILITY OF CONVENTIONAL APPROACHES. RECENTLY, LONG-READ SINGLE-MOLECULE DNA SEQUENCING TECHNOLOGIES HAVE EMERGED AND ENABLED RESEARCHERS TO STUDY GENOMES, TRANSCRIPTOMES, AND METAGENOMES AT UNPRECEDENTED RESOLUTIONS. THE IDENTIFICATION OF NOVEL MUTATIONS IN UNRESOLVED NEURODEGENERATIVE DISORDERS, THE CHARACTERIZATION OF CAUSATIVE REPEAT EXPANSIONS, AND THE DIRECT DETECTION OF EPIGENETIC MODIFICATIONS ON NAIVE DNA BY VIRTUE OF LONG-READ SEQUENCERS WILL FURTHER EXPAND OUR UNDERSTANDING OF NEURODEGENERATIVE DISEASES. IN THIS ARTICLE, WE REVIEW AND COMPARE 2 PREVAILING LONG-READ SEQUENCING TECHNOLOGIES, PACIFIC BIOSCIENCES AND OXFORD NANOPORE TECHNOLOGIES, AND DISCUSS THEIR APPLICATIONS IN NEURODEGENERATIVE DISEASES. 2021 9 6815 16 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES. 2011 10 4344 16 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 11 4975 20 PATHOPHYSIOLOGICAL MECHANISMS OF AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC DISORDERS CHARACTERIZED BY INFLAMMATORY REACTIONS AGAINST SELF-ANTIGENS THAT CAN BE EITHER SYSTEMIC OR ORGAN SPECIFIC. AIDS CAN DIFFER IN THEIR EPIDEMIOLOGIC FEATURES AND CLINICAL PRESENTATIONS, YET ALL SHARE A REMARKABLE COMPLEXITY. AIDS RESULT FROM AN INTERPLAY OF GENETIC AND EPIGENETIC FACTORS WITH ENVIRONMENTAL COMPONENTS THAT ARE ASSOCIATED WITH IMBALANCES IN THE IMMUNE SYSTEM. MANY OF THE PATHOGENIC MECHANISMS OF AIDS ARE ALSO IMPLICATED IN MYASTHENIA GRAVIS (MG), AN AID IN WHICH INFLAMMATION OF THE THYMUS LEADS TO A NEUROMUSCULAR DISORDER. OUR GOAL HERE IS TO HIGHLIGHT THE SIMILARITIES AND DIFFERENCES BETWEEN MG AND OTHER AIDS BY REVIEWING THE COMMON TRANSCRIPTOME SIGNATURES AND THE DEVELOPMENT OF GERMINAL CENTERS AND BY DISCUSSING SOME UNRESOLVED QUESTIONS ABOUT AUTOIMMUNE MECHANISMS. THIS REVIEW WILL PROPOSE HYPOTHESES TO EXPLAIN THE ORIGIN OF REGULATORY T (T(REG) ) CELL DEFECTS AND THE CAUSES OF CHRONICITY AND SPECIFICITY OF AIDS. 2018 12 421 18 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 13 1 13 ON DECEMBER 5, 2017, THE NATIONAL ACADEMIES OF SCIENCES, ENGINEERING, AND MEDICINE HOSTED A PUBLIC WORKSHOP TITLED NUTRIGENOMICS AND THE FUTURE OF NUTRITION IN WASHINGTON, DC, TO REVIEW CURRENT KNOWLEDGE IN THE FIELD OF NUTRIGENOMICS AS IT RELATES TO NUTRITION. WORKSHOP PARTICIPANTS EXPLORED THE INFLUENCE OF GENETIC AND EPIGENETIC EXPRESSION ON NUTRITIONAL STATUS AND THE POTENTIAL IMPACT OF PERSONALIZED NUTRITION ON HEALTH MAINTENANCE AND CHRONIC DISEASE PREVENTION. THIS PUBLICATION SUMMARIZES THE PRESENTATIONS AND DISCUSSIONS FROM THE WORKSHOP. 2018 14 6792 20 [DOHAD AND EPIGENETIC INFORMATION: SOCIETAL CHALLENGES]. THE CONCEPT OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) ALTERS OUR UNDERSTANDING OF WHAT CONSTITUTES "HEALTH" OR "DISEASE" INTENDED AS CHRONIC, NON-COMMUNICABLE DISEASES, WHICH DEVELOP OVER THE LIFE COURSE IN HIGH INCOME AND EMERGING COUNTRIES. IT IMPLIES A CHANGE IN PARADIGM FORMING A BASIS FOR PREVENTION POLICIES ACROSS THE GLOBE. IT ALSO IMPACTS PSYCHOLOGICAL, SOCIAL, ECONOMIC, ETHICAL AND LEGAL SCIENCES. IN LINE WITH THE UNANTICIPATED UNDERPINNING EPIGENETIC MECHANISMS ARE ALSO THE SOCIAL ISSUES (INCLUDING PUBLIC POLICIES) THAT COULD BE PRODUCED BY THE KNOWLEDGE RELATED TO DOHAD THAT OPENS A WIDE FIELD OF INQUIRY. THE INFORMATION UNVEILED BY EPIGENETICS COUPLED WITH INFORMATION ON LIFESTYLE INCLUDING DURING THE DEVELOPMENT PHASE, IS OF UNFORESEEN NATURE, RAISING ISSUES OF DIFFERENT NATURE. THEREFORE IT REQUIRES SPECIFIC ATTENTION AND RESEARCH, AND A SPECIFIC SUPPORT BY A PLURIDISCIPLINARY REFLECTION SINCE THE VERY BEGINNING OF ITS PRODUCTION, TO ANTICIPATE THE QUESTIONS THAT MIGHT BE RAISED IN THE FUTURE. 2016 15 6577 19 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 16 4375 21 MISREGULATED INFLAMMATION AS AN OUTCOME OF EARLY-LIFE EXPOSURE TO ENDOCRINE-DISRUPTING CHEMICALS. THIS REVIEW INTRODUCES A POTENTIAL UNIFYING CONCEPT INVOLVING THE RISK OF CHRONIC DISEASES IN WHICH EARLY-LIFE EXPOSURE TO ENDOCRINE-DISRUPTING CHEMICALS (EDCS) CAN PROGRAM HOST RESPONSES FOR MISREGULATED INFLAMMATION. INFLAMMATION IS A PART OF HOST DEFENSE AGAINST PATHOGENIC CHALLENGES AND ONE OF THE PROCESSES NECESSARY FOR NORMAL TISSUE HOMEOREGULATION AND FOR REPRODUCTION (E.G., IMPLANTATION, LABOR). DEVIATIONS FROM TIGHTLY REGULATED INFLAMMATION PRESENT A SIGNIFICANT HEALTH RISK BECAUSE UNRESOLVED INFLAMMATION CAN COMPROMISE TISSUE FUNCTION AND INCREASE THE RISK FOR LATER-LIFE CANCER IN THE AFFECTED TARGET TISSUE. THE CRITICAL WINDOWS OF INNATE IMMUNE VULNERABILITY DURING PRENATAL AND NEONATAL MATURATION ARE WHEN DEVELOPMENTAL PROGRAMMING AND THE TRAJECTORY FOR CHILDHOOD AND ADULT INFLAMMATORY RESPONSES ARE LARGELY ESTABLISHED. MISREGULATED INFLAMMATION IS A COMMON THREAD THAT LINKS MOST SIGNIFICANT CHRONIC DISEASES AND CONDITIONS ACROSS ALL PHYSIOLOGIC SYSTEMS AS WELL AS THE ASSOCIATED COMORBID CONDITIONS. AS A RESULT, CHRONIC DISEASES EXIST BOTH AS A MYRIAD OF CONDITIONS AND AS AN INTEGRATED, DYSFUNCTIONALLY CONNECTED UNIT. BECAUSE THE HORMONE MICROENVIRONMENT EXERTS A SIGNIFICANT EFFECT ON RESIDENT INNATE IMMUNE CELL FUNCTION, ENDOCRINE DISRUPTION IS LIKELY TO PRODUCE MISREGULATED INFLAMMATION IN TISSUES. AMONG THE FACTORS DETERMINING SPECIFIC HEALTH RISKS AND DISEASE OUTCOMES ACROSS A LIFETIME ARE THE AGE OF EXPOSURE, SEX, GENETIC BACKGROUND, AND TRANSGENERATIONAL EPIGENETIC EXPERIENCES. ADDITIONAL RESEARCH INTO EARLY-LIFE EDC EXPOSURE AND MISREGULATION OF INFLAMMATION APPEARS TO BE A USEFUL AVENUE FOR REDUCING ENVIRONMENTAL HEALTH RISKS. 2012 17 6825 18 [GENETIC AND EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME]. THE DEVELOPMENT OF POLYCYSTIC OVARY SYNDROME AND ITS EXACT PATHOPHYSIOLOGICAL MECHANISM IS STILL UNCLEAR, BUT ENVIRONMENTAL AND GENETIC FACTORS LIKELY PLAY A ROLE. EXPOSITION TO TERATOGENIC EFFECTS DURING THE PRENATAL DEVELOPMENT CAN LEAD TO CHRONIC DISEASES IN THE POSTNATAL PERIOD. THIS FINDING CONFIRMS THE COMMON FAMILIAL AGGREGATION AS WELL. A LITERATURE SEARCH WAS CONDUCTED UP TO JANUARY 1, 2016 FOR ARTICLES DEALING WITH THE GENETIC OR EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME. THIS REVIEW WILL DISCUSS THE CURRENT UNDERSTANDING OF THE GENETIC BASIS AND CLINICAL PRESENTATION OF THIS DISEASE. ORV. HETIL., 2016, 157(32), 1275-1281. 2016 18 5457 18 RESEARCH AND THE PROMOTION OF CHILD HEALTH: A POSITION PAPER OF THE EUROPEAN SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION. CHILDREN COMPRISE ONE-FIFTH OF EUROPE'S POPULATION. PROMOTING CHILD HEALTH AND DEVELOPMENT IS OF KEY IMPORTANCE FOR SOCIETY AND ITS FUTURE. THIS POSITION PAPER HIGHLIGHTS OPPORTUNITIES OF INVESTING IN GASTROINTESTINAL, LIVER, AND NUTRITIONAL RESEARCH TO PROMOTE CHILD HEALTH AND DELINEATES PRIORITIES FOR RESEARCH. INVESTING IN CHILD HEALTH PLAYS A KEY ROLE IN THE PROMOTION OF POPULATION HEALTH, WELL-BEING, AND DISEASE PREVENTION LIFELONG, WITH LARGE HEALTH ECONOMIC BENEFITS. MAJOR OPPORTUNITIES FOR IMPROVING KNOWLEDGE AND TRANSLATIONAL APPLICATION ARISE FROM RECENT SCIENTIFIC AND TECHNOLOGICAL DEVELOPMENTS, FOR EXAMPLE, THE LONG-TERM IMPACT OF EARLY ENVIRONMENTAL CUES INTERACTING WITH GENES. PERSONALISED APPROACHES TO THERAPY AND PREVENTION SHOULD BE ENHANCED. DECIPHERING THE MICROBIOME AND ITS EFFECTS ON FUNCTIONS CAN HELP IN PROMOTING LONG-TERM HEALTH. EPIGENETIC RESEARCH CAN HELP TO UNDERSTAND HOW EARLY ENVIRONMENTAL FACTORS INFLUENCE LATER GASTROINTESTINAL AND HEPATIC HEALTH AND DISEASE. A LINKED NUTRITION AND PHYSICAL ACTIVITY STRATEGY CAN PROMOTE HEALTH AND PREVENT NUTRITIONAL DEFICIENCIES, INACTIVITY, AND CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS DIABETES, TO ENSURE OPTIMAL HEALTH AND COGNITION. SPECIAL ATTENTION SHOULD BE DEVOTED TO POPULATIONS WITH LOW SOCIOECONOMIC STATUS, MIGRANT BACKGROUND, AND ETHNIC MINORITIES, AND TO CRITICAL LIFE PERIODS, INCLUDING PREGNANCY, LACTATION, INFANCY, AND CHILDHOOD. IMPROVED UNDERSTANDING OF OPTIMAL NUTRITION AND ON MAINTAINING GUT AND LIVER HOMEOSTASIS THROUGHOUT CHILDHOOD WILL HELP PREVENT CHRONIC DISEASES IN LATER LIFE. 2014 19 6784 16 [CHRONIC STRESS AND EPIGENETICS. RELATION BETWEEN ACADEMIC SCIENCES AND THEOLOGY]. THE AUTHOR GIVES A SHORT ACCOUNT ON THE PRINCIPLES OF SELYE'S STRESS THEORY, AND DISCUSSES SIMILARITIES AND DISSIMILARITIES OF ACUTE AND CHRONIC STRESS. BOTH THE EXTERNAL, AND THE INTERNAL ENVIRONMENT, AS WELL AS THE PSYCHO-MENTAL STATUS ARE INVOLVED IN THE NOTION OF THE ENVIRONMENT. BASIC PRINCIPLES OF EPIGENETICS ARE REVIEWED: INTERACTION BETWEEN ENVIRONMENT AND GENES, NEUROENDOCRINE AND ENZYMATIC MECHANISMS INVOLVED IN SILENCING AND ACTIVATION OF GENES, NOTIONS OF PHENOTYPIC PLASTICITY, AND EPIGENETIC REPROGRAMMING ARE DISCUSSED. EPIGENETIC MECHANISMS OF INTERRELATION BETWEEN PATHOLOGICAL CLINICAL STATES (DISEASES) AND THE CHARACTERISTIC PHENOTYPES, CAUSATIVE ROLE OF PSYCHO-MENTAL STATUS IN EVOKING PATHOLOGICAL SOMATIC ALTERATIONS, AND THE POTENTIAL THERAPEUTIC CONSEQUENCES ARE BRIEFLY DISCUSSED. THE ETIOLOGICAL ROLE OF CHRONIC, CIVILIZATION STRESS IN PRODUCING THE WORLDWIDE INCREMENT OF CARDIOVASCULAR MORBIDITY IS CITED, ARGUMENTATION AND CRITICISM OF THE CURRENT THERAPEUTICAL PRACTICE IS DISCUSSED. THE AUTHOR CONCLUDES THAT RECENT ADVANCES IN EPIGENETIC KNOWLEDGE SEEM TO SOLVE THE CONTROVERSY BETWEEN THE ACADEMIC AND THEOLOGICAL SCIENCES. 2012 20 1149 16 CONNECTING THE IMMUNE SYSTEM, SYSTEMIC CHRONIC INFLAMMATION AND THE GUT MICROBIOME: THE ROLE OF SEX. UNRESOLVED LOW GRADE SYSTEMIC INFLAMMATION REPRESENTS THE UNDERLYING PATHOLOGICAL MECHANISM DRIVING IMMUNE AND METABOLIC PATHWAYS INVOLVED IN AUTOIMMUNE DISEASES (AID). MECHANISTIC STUDIES IN ANIMAL MODELS OF AID AND OBSERVATIONAL STUDIES IN PATIENTS HAVE FOUND ALTERATIONS IN GUT MICROBIOTA COMMUNITIES AND THEIR METABOLITES, SUGGESTING A MICROBIAL CONTRIBUTION TO THE ONSET OR PROGRESSION OF AID. THE GUT MICROBIOTA AND ITS METABOLITES HAVE BEEN SHOWN TO INFLUENCE IMMUNE FUNCTIONS AND IMMUNE HOMEOSTASIS BOTH WITHIN THE GUT AND SYSTEMATICALLY. MICROBIAL DERIVED-SHORT CHAIN FATTY ACID (SCFA) AND BIO-TRANSFORMED BILE ACID (BA) HAVE BEEN SHOWN TO INFLUENCE THE IMMUNE SYSTEM ACTING AS LIGANDS SPECIFIC CELL SIGNALING RECEPTORS LIKE GPRCS, TGR5 AND FXR, OR VIA EPIGENETIC PROCESSES. SIMILARLY, INTESTINAL PERMEABILITY (LEAKY GUT) AND BACTERIAL TRANSLOCATION ARE IMPORTANT CONTRIBUTORS TO CHRONIC SYSTEMIC INFLAMMATION AND, WITHOUT REPAIR OF THE INTESTINAL BARRIER, MIGHT REPRESENT A CONTINUOUS INFLAMMATORY STIMULUS CAPABLE OF TRIGGERING AUTOIMMUNE PROCESSES. RECENT STUDIES INDICATE GENDER-SPECIFIC DIFFERENCES IN IMMUNITY, WITH THE GUT MICROBIOTA SHAPING AND BEING CONCOMITANTLY SHAPED BY THE HORMONAL MILIEU GOVERNING DIFFERENCES BETWEEN THE SEXES. A BI-DIRECTIONAL CROSS-TALK BETWEEN MICROBIOTA AND THE ENDOCRINE SYSTEM IS EMERGING WITH BACTERIA BEING ABLE TO PRODUCE HORMONES (E.G. SEROTONIN, DOPAMINE AND SOMATOSTATINE), RESPOND TO HOST HORMONES (E.G. ESTROGENS) AND REGULATE HOST HORMONES' HOMEOSTASIS (E.G BY INHIBITING GENE PROLACTIN TRANSCRIPTION OR CONVERTING GLUCOCORTICOIDS TO ANDROGENS). WE REVIEW HEREIN HOW GUT MICROBIOTA AND ITS METABOLITES REGULATE IMMUNE FUNCTION, INTESTINAL PERMEABILITY AND POSSIBLY AID PATHOLOGICAL PROCESSES. FURTHER, WE DESCRIBE THE DYSBIOSIS WITHIN THE GUT MICROBIOTA OBSERVED IN DIFFERENT AID AND SPECULATE HOW RESTORING GUT MICROBIOTA COMPOSITION AND ITS REGULATORY METABOLITES BY DIETARY INTERVENTION INCLUDING PREBIOTICS AND PROBIOTICS COULD HELP IN PREVENTING OR AMELIORATING AID. FINALLY, WE SUGGEST THAT, GIVEN CONSISTENT OBSERVATIONS OF MICROBIOTA DYSBIOSIS ASSOCIATED WITH AID AND THE ABILITY OF SCFA AND BA TO REGULATE INTESTINAL PERMEABILITY AND INFLAMMATION, FURTHER MECHANISTIC STUDIES, EXAMINING HOW DIETARY MICROBIOTA MODULATION CAN PROTECT AGAINST AID, HOLD CONSIDERABLE POTENTIAL TO TACKLE INCREASED INCIDENCE OF AID AT THE POPULATION LEVEL. 2018