1 5137 150 POTENTIAL MECHANISMS OF NON-SUICIDAL SELF-INJURY (NSSI) IN MAJOR DEPRESSIVE DISORDER: A SYSTEMATIC REVIEW. BACKGROUND: NON-SUICIDAL SELF-INJURY (NSSI) IS A FREQUENT AND PROMINENT PHENOMENON IN MAJOR DEPRESSIVE DISORDER (MDD). EVEN THOUGH ITS PREVALENCE AND RISK FACTORS ARE RELATIVELY WELL UNDERSTOOD, THE POTENTIAL MECHANISMS OF NSSI IN MDD REMAIN ELUSIVE. AIMS: TO REVIEW PRESENT EVIDENCE RELATED TO THE POTENTIAL MECHANISMS OF NSSI IN MDD. METHODS: ACCORDING TO PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES 2020 GUIDELINES, ARTICLES FOR THIS SYSTEMATIC REVIEW WERE SEARCHED ON MEDLINE (THROUGH PUBMED), EMBASE (THROUGH ELSEVIER), PSYCINFO (THROUGH OVID) AND WEB OF SCIENCE DATABASES FOR ENGLISH ARTICLES, AS WELL AS CHINA NATIONAL KNOWLEDGE INFRASTRUCTURE (CNKI), SINOMED, WANFANG DATA, AND THE CHONGQING VIP CHINESE SCIENCE AND TECHNOLOGY PERIODICAL (VIP) DATABASES FOR CHINESE ARTICLES PUBLISHED FROM THE DATE OF INCEPTION TO 2 AUGUST 2022. TWO RESEARCHERS (BW, HZ) INDEPENDENTLY SCREENED STUDIES BASED ON INCLUSION AND EXCLUSION CRITERIA AND ASSESSED THEIR QUALITY. RESULTS: A TOTAL OF 25 157 STUDIES WERE SEARCHED. ONLY 25 OF THEM WERE ULTIMATELY INCLUDED, CONTAINING 3336 SUBJECTS (1535 PATIENTS WITH MDD AND NSSI, 1403 PATIENTS WITH MDD WITHOUT NSSI AND 398 HCS). INCLUDED STUDIES WERE DIVIDED INTO 6 CATEGORIES: PSYCHOSOCIAL FACTORS (11 STUDIES), NEUROIMAGING (8 STUDIES), STRESS AND HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS (2 STUDIES), PAIN PERCEPTION (1 STUDY), ELECTROENCEPHALOGRAM (EEG) (2 STUDIES) AND EPIGENETICS (1 STUDY). CONCLUSIONS: THIS SYSTEMATIC REVIEW INDICATES THAT PATIENTS WITH MDD AND NSSI MIGHT HAVE SPECIFIC PSYCHOSOCIAL FACTORS, ABERRANT BRAIN FUNCTIONS AND NEUROCHEMICAL METABOLISMS, HPA AXIS DYSFUNCTIONS, ABNORMAL PAIN PERCEPTIONS AND EPIGENETIC ALTERATIONS. 2023 2 6351 33 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES. 2023 3 6433 27 THE VINDICATION OF LAMARCK? EPIGENETICS AT THE INTERSECTION OF LAW AND MENTAL HEALTH. RESEARCH ON EPIGENETIC MECHANISMS IS GAINING TRACTION, YET IS POORLY UNDERSTOOD BY CRIMINOLOGISTS AND BEHAVIORAL SCIENTISTS. THE CURRENT OBJECTIVE IS TO REVIEW RELEVANT STUDIES OF INTEREST TO BEHAVIORAL SCIENTISTS WHO STUDY CRIME, AND TO TRANSLATE ADMITTEDLY CHALLENGING SCIENTIFIC INFORMATION INTO TEXT THAT IS DIGESTIBLE TO THE AVERAGE CRIMINOLOGIST. USING SYSTEMATIC SEARCH PROCEDURES THE AUTHORS IDENTIFIED AND REVIEWED 41 STUDIES OF EPIGENETIC MECHANISMS IN PSYCHIATRIC AND BEHAVIORAL PHENOTYPES AMONG HUMANS. FINDINGS REVEALED SIGNIFICANT EPIGENETIC EFFECTS IN AN ASSORTMENT OF GENES THAT ARE IMPLICATED IN THE ETIOLOGY OF DEPRESSION, SUICIDALITY, CALLOUS-UNEMOTIONAL TRAITS, AND CHRONIC AND INTERGENERATIONAL AGGRESSIVE BEHAVIOR. SEVERAL POLYMORPHISMS THAT MEDIATE THE HPA AXIS, NEUROTRANSMISSION, IMMUNE RESPONSE, BRAIN DEVELOPMENT, SEROTONIN SYNTHESIS, AND OTHER PROCESSES WERE FOUND. ALTHOUGH PRESCRIPTIVE KNOWLEDGE BASED ON EPIGENETIC FINDINGS TO DATE IS PREMATURE, EPIGENETICS IS A NEW AND EXCITING SCIENTIFIC FRONTIER NOT TOO DIFFERENT IN SPIRIT FROM LAMARCK'S OBSERVATIONS CENTURIES AGO. 2015 4 6911 22 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 5 1145 37 CONCURRENT DIAGNOSIS OF ADENOMYOSIS AND CONGENITAL UTERINE ANOMALIES: A REVIEW. BACKGROUND: ADENOMYOSIS AND CONGENITAL UTERINE ANOMALIES (CUAS) CAN COMPROMISE REPRODUCTIVE POTENTIAL AND MAY COEXIST IN THE SAME PATIENT, ESPECIALLY IN CASES OF INFERTILITY. THIS REVIEW (CRD42022382850) AIMS TO EVALUATE THE PUBLISHED CASES OF CONCURRENT ADENOMYOSIS AND SYNDROMIC AND NONSYNDROMIC CUAS. METHODS: A LITERATURE SEARCH FOR SUITABLE ARTICLES PUBLISHED IN THE ENGLISH LANGUAGE WAS PERFORMED USING THE FOLLOWING DATABASES FROM INCEPTION TO 30 NOVEMBER 2022: MEDLINE, EMBASE, GLOBAL HEALTH, THE COCHRANE LIBRARY, HEALTH TECHNOLOGY ASSESSMENT DATABASE, AND WEB OF SCIENCE. ARTICLES INCLUDING BOTH CUAS AND ADENOMYOSIS, WITH DATA ABOUT THEIR POTENTIAL RELATIONSHIP, WERE INCLUDED. RESULTS: THE LITERATURE SEARCH RETRIEVED 14 ARTICLES THAT MET THE PURPOSE OF THIS REVIEW AND SUMMARIZED THE MOST RECENT FINDINGS REGARDING THE CONCURRENT DIAGNOSIS OF ADENOMYOSIS AND CUAS. CONCLUSIONS: ADENOMYOSIS CAN BE FOUND IN BOTH SYNDROMIC AND NONSYNDROMIC CUAS, AND MAY ARISE FROM SEVERAL ETIOLOGIES. THE HYPOTHESIS THAT OBSTRUCTIONS IN CUAS INCREASE UTERINE PRESSURE AND PROMOTE THE DEVELOPMENT OF ADENOMYOSIS REMAINS TO BE FURTHER ELUCIDATED, AND ADDITIONAL FINDINGS MAY ALSO PLAY A ROLE. THE PATIENT'S GENETIC, EPIGENETIC, AND HORMONAL PATTERNS, AS WELL AS NORMAL PHYSIOLOGICAL PROCESSES, SUCH AS PREGNANCY, MAY INFLUENCE THE GROWTH OF ADENOMYOSIS. 2023 6 6914 30 [VITAMIN D DEFICIENCY IN PREGNANCY AND ITS IMPACT ON THE FETUS, THE NEWBORN AND IN CHILDHOOD]. OBJECTIVE: VITAMIN D DEFICIENCY (VDD) IN PREGNANT WOMEN AND THEIR CHILDREN IS AN IMPORTANT HEALTH PROBLEM WITH SEVERE CONSEQUENCES FOR THE HEALTH OF BOTH. THUS, THE OBJECTIVES OF THIS REVIEW WERE TO REASSESS THE MAGNITUDE AND CONSEQUENCES OF VDD DURING PREGNANCY, LACTATION AND INFANCY, ASSOCIATED RISK FACTORS, PREVENTION METHODS, AND TO EXPLORE EPIGENETIC MECHANISMS IN EARLY FETAL LIFE CAPABLE OF EXPLAINING MANY OF THE NON-SKELETAL BENEFITS OF VITAMIN D (VID). DATA SOURCE: ORIGINAL AND REVIEW ARTICLES, AND CONSENSUS DOCUMENTS WITH ELEVATED LEVEL OF EVIDENCE FOR VDD-RELATED CLINICAL DECISIONS ON THE HEALTH OF PREGNANT WOMEN AND THEIR CHILDREN, AS WELL AS ARTICLES ON THE INFLUENCE OF VID ON EPIGENETIC MECHANISMS OF FETAL PROGRAMMING OF CHRONIC DISEASES IN ADULTHOOD WERE SELECTED AMONG ARTICLES PUBLISHED ON PUBMED OVER THE LAST 20 YEARS, USING THE SEARCH TERM VITD STATUS, IN COMBINATION WITH PREGNANCY, OFFSPRING HEALTH, CHILD OUTCOMES, AND PROGRAMMING. DATA SYNTHESIS: THE FOLLOWING ITEMS WERE ANALYZED: VID PHYSIOLOGY AND METABOLISM, RISK FACTORS FOR VDD AND IMPLICATIONS IN PREGNANCY, LACTATION AND INFANCY, CONCENTRATION CUTOFF TO DEFINE VDD, THE VARIABILITY OF METHODS FOR VDD DETECTION, RECOMMENDATIONS ON VID REPLACEMENT IN PREGNANT WOMEN, THE NEWBORN AND THE CHILD, AND THE EPIGENETIC INFLUENCE OF VID. CONCLUSIONS: VDD IS A COMMON CONDITION AMONG HIGH-RISK PREGNANT WOMEN AND THEIR CHILDREN. THE ROUTINE MONITORING OF SERUM 25(OH)D3 LEVELS IN ANTENATAL PERIOD IS MANDATORY. EARLY PREVENTIVE MEASURES SHOULD BE TAKEN AT THE SLIGHTEST SUSPICION OF VDD IN PREGNANT WOMEN, TO REDUCE MORBIDITY DURING PREGNANCY AND LACTATION, AS WELL AS ITS SUBSEQUENT IMPACT ON THE FETUS, THE NEWBORN AND THE CHILD. 2015 7 2967 29 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES. 2022 8 3899 22 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 9 815 29 CHANGES IN THE EXPRESSION OF INFLAMMATORY AND EPIGENETIC-MODULATORY GENES AFTER AN INTENSIVE MEDITATION RETREAT. BACKGROUND: MEDITATION RETREATS ARE CHARACTERIZED BY INTENSIVE OR CONCENTRATED PERIODS OF MEDITATION PRACTICE, COMMONLY UNDERTAKEN IN A RESIDENTIAL SETTING. ALTHOUGH RESEARCH INDICATES THAT MEDITATION TRAINING CAN POSITIVELY INFLUENCE PHYSICAL AND MENTAL HEALTH OUTCOMES, THE BIOLOGICAL CONSEQUENCES OF MEDITATION RETREAT INTERVENTIONS ARE RELATIVELY UNDERSTUDIED. IN THIS STUDY, WE EXAMINED THE INFLUENCE OF A MONTH-LONG, SILENT MEDITATION RETREAT ON THE EXPRESSION OF GENES INVOLVED IN EPIGENETIC MODULATION AND IMMUNE PROCESSES. METHOD: WE ASSESSED GENE EXPRESSION CHANGES IN EXPERIENCED MEDITATORS ATTENDING A MONTH-LONG INSIGHT MEDITATION RETREAT (N = 28), AS COMPARED TO A COMMUNITY CONTROL GROUP (N = 34) OF EXPERIENCED PRACTITIONERS LIVING THEIR EVERYDAY LIVES. BLOOD SAMPLES WERE COLLECTED ON DAY TWO OF THE RETREAT (TIME 1) AND AGAIN 3 WEEKS LATER (TIME 2). CONTROL PARTICIPANTS WERE ALSO ASSESSED ACROSS A 3-WEEK INTERVAL, DURING WHICH THEY MAINTAINED THEIR REGULAR DAILY ROUTINES. RESULTS: AS COMPARED TO CONTROLS, RETREAT PARTICIPANTS SHOWED DIFFERENTIAL CHANGES IN THE EXPRESSION OF SEVERAL GENES INVOLVED IN CHROMATIN MODULATION AND INFLAMMATION. THE MOST SUBSTANTIVE FINDING WAS DOWNREGULATION OF THE TNF PATHWAY IN RETREAT PARTICIPANTS, WHICH WAS NOT OBSERVED IN CONTROLS. CONCLUSIONS: THESE FINDINGS INDICATE THAT MEDITATION RETREAT PARTICIPATION MAY INFLUENCE SOME OF THE INFLAMMATORY MECHANISMS INVOLVED IN THE DEVELOPMENT OF CHRONIC DISEASES, AND THAT THIS STYLE OF PSYCHOSOCIAL INTERVENTION MAY HAVE THERAPEUTIC POTENTIAL, PARTICULARLY IN EXPERIENCED PRACTITIONERS. 2022 10 4834 30 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS. 2022 11 3146 47 GLOBAL RESEARCH TRENDS ON EPIGENETICS AND NEUROPATHIC PAIN: A BIBLIOMETRIC ANALYSIS. OBJECTIVE: NEUROPATHIC PAIN (NP) IS A COMMON DISEASE THAT MANIFESTS WITH PATHOLOGICAL CHANGES IN THE SOMATOSENSORY SYSTEM. IN RECENT YEARS, THE INTERACTIONS OF NP WITH THE EPIGENETIC MECHANISM HAVE BEEN INCREASINGLY ELUCIDATED. HOWEVER, ONLY A FEW STUDIES HAVE USED BIBLIOMETRIC TOOLS TO SYSTEMATICALLY ANALYZE KNOWLEDGE IN THIS FIELD. THE OBJECTIVE OF THIS STUDY IS TO VISUALLY ANALYZE THE TRENDS, HOTSPOTS, AND FRONTIERS IN EPIGENETICS AND NP RESEARCH BY USING A BIBLIOMETRIC METHOD. METHODS: STUDIES RELATED TO EPIGENETICS AND NP WERE SEARCHED FROM THE SCIENCE CITATION INDEX-EXPANDED OF THE WEB OF SCIENCE CORE COLLECTION DATABASE. SEARCH TIME IS FROM INCEPTION TO NOVEMBER 30, 2022. NO RESTRICTIONS WERE PLACED ON LANGUAGE. ONLY ARTICLES AND REVIEWS WERE INCLUDED AS DOCUMENT TYPES. DATA ON INSTITUTIONS, COUNTRIES, AUTHORS, JOURNAL DISTRIBUTION, AND KEYWORDS WERE IMPORTED INTO CITESPACE SOFTWARE FOR VISUAL ANALYSIS. RESULTS: A TOTAL OF 867 PUBLICATIONS MET THE INCLUSION CRITERIA, WHICH SPANNED THE PERIOD FROM 2000 TO 2022. OVER THE YEARS, THE NUMBER OF PUBLICATIONS AND THE FREQUENCY OF CITATIONS EXHIBITED A CLEAR UPWARD TREND IN GENERAL, REACHING A PEAK IN 2021. THE MAJOR CONTRIBUTING COUNTRIES IN TERMS OF THE NUMBER OF PUBLICATIONS WERE CHINA, THE UNITED STATES, AND JAPAN. THE TOP THREE INSTITUTIONS WERE RUTGERS STATE UNIVERSITY, XUZHOU MEDICAL UNIVERSITY, AND NANJING MEDICAL UNIVERSITY. MOLECULAR PAIN, PAIN, AND JOURNAL OF NEUROINFLAMMATION CONTRIBUTED SIGNIFICANTLY TO THE VOLUME OF ISSUES. AMONG THE TOP 10 AUTHORS IN TERMS OF THE NUMBER OF PUBLICATIONS, TAO YUAN-XIANG CONTRIBUTED 30 ENTRIES, FOLLOWED BY ZHANG YI WITH 24 AND WU SHAO-GEN WITH 20. ON THE BASIS OF THE BURST AND CLUSTERS OF KEYWORDS, "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA," AND "MICROGLIA" ARE GLOBAL HOTSPOTS IN THE FIELD. CONCLUSION: THE BIBLIOMETRIC ANALYSIS INDICATES THAT THE NUMBER OF PUBLICATIONS RELATED TO EPIGENETICS AND NP IS EXHIBITING A RAPID INCREASE. KEYWORD ANALYSIS SHOWS THAT "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA" AND "MICROGLIA" ARE THE MOST INTERESTING TERMS FOR RESEARCHERS IN THE FIELD. MORE RIGOROUS CLINICAL TRIALS AND ADDITIONAL STUDIES THAT EXPLORE RELEVANT MECHANISMS ARE REQUIRED IN THE FUTURE. 2023 12 6127 39 THE EPIGENETIC OVERLAP BETWEEN OBESITY AND MOOD DISORDERS: A SYSTEMATIC REVIEW. (1) BACKGROUND: OBESITY AND MOOD DISORDERS ARE CONSIDERED AS THE MOST PREVALENT MORBIDITIES IN MANY COUNTRIES. WE SUPPOSE THAT EPIGENETIC MECHANISMS MAY INDUCE HIGHER RATES OF OBESITY IN SUBJECTS WHO SUFFER FROM MOOD DISORDERS. IN THIS SYSTEMATIC REVIEW, WE FOCUSED ON THE POTENTIAL ROLES OF DNA METHYLATION ON MOOD DISORDERS AND OBESITY DEVELOPMENT. (2) METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED IN ACCORDANCE WITH THE PRISMA STATEMENT AND REGISTERED IN PROSPERO. A SYSTEMATIC SEARCH WAS CONDUCTED IN MEDLINE, SCOPUS, WEB OF SCIENCE, COCHRANE CENTRAL DATABASE, EMBASE, AND CINHAL. WE ALSO CONDUCTED A GREY LITERATURE SEARCH, SUCH AS GOOGLE SCHOLAR. (3) RESULTS: AFTER DEDUPLICATION, WE IDENTIFIED 198 POTENTIALLY RELATED CITATIONS. FINALLY, TEN UNIQUE STUDIES MET OUR INCLUSION CRITERIA. WE HAVE FOUND THREE OVERLAP GENES THAT SHOW SIGNIFICANT DNA METHYLATION CHANGES, BOTH IN OBESITY AND DEPRESSION. PATHWAY ANALYSIS INTERACTION FOR TAPBP, BDNF, AND SORBS2 CONFIRMED THE RELATION OF THESE GENES IN BOTH OBESITY AND MOOD DISORDERS. (4) CONCLUSIONS: WHILE MECHANISMS LINKING BOTH OBESITY AND MOOD DISORDERS TO EPIGENETIC RESPONSE ARE STILL UNKNOWN, WE HAVE ALREADY KNOWN CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM. AS THE RESULTS OF GENE ENRICHMENT, PATHWAYS ANALYSIS SHOWED THAT TAPBP, BDNF, AND SORBS2 LINKED TOGETHER BY INFLAMMATORY PATHWAYS. HYPERMETHYLATION IN THESE GENES MIGHT PLAY A CRUCIAL RULE IN THE CO-OCCURRENCE OF OBESITY AND MOOD DISORDERS. 2020 13 181 22 ACCELERATED EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN VITAMIN D LEVELS AND KNEE PAIN IN COMMUNITY-DWELLING INDIVIDUALS. OBJECTIVES: TO EXAMINE THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND PAIN INTENSITY AND DISABILITY IN INDIVIDUALS WITH AND WITHOUT KNEE PAIN, AND TO EXAMINE THE ROLE OF EPIGENETICS IN THIS RELATIONSHIP. DESIGN: CROSS-SECTIONAL ANALYSIS OF DATA FROM THE UPLOAD-2 STUDY (UNDERSTANDING PAIN AND LIMITATIONS IN OSTEOARTHRITIC DISEASE-2). PARTICIPANTS: 189 INDIVIDUALS AGED 45-65 YEARS AND OLDER. MEASUREMENTS: SERUM VITAMIN D LEVELS, PAIN RELATED INTERFERENCE AND CHARACTERISTIC PAIN INTENSITY MEASURES, AND THE EPIGENETIC CLOCK GRIMAGE DERIVED FROM BLOOD ANALYSES. RESULTS: LOWER VITAMIN D WAS ASSOCIATED WITH ADVANCED EPIGENETIC AGING (AGEACCELGRIM), GREATER PAIN AND DISABILITY AND THAT (AGEACCELGRIM) MEDIATED THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND SELF-REPORTED PAIN (AB = -0.0799; CI [-0.1492, -0.0237]) AND DISABILITY (AB = -0.0669; CI [-0.1365, -0.0149]) OUTCOMES. CONCLUSION: THESE DATA SUPPORT THE NOTION THAT LIFESTYLE FACTORS SUCH AS NUTRITION STATUS PLAY A KEY ROLE IN AGING PROCESS, AS WELL AS THE DEVELOPMENT AND MAINTENANCE OF AGE-RELATED DISEASES SUCH AS PAIN. MODIFYING NUTRITION STATUS COULD HELP PROMOTE HEALTHY AGING AND REDUCE PAIN. 2022 14 5213 22 PRESYMPTOMATIC RISK ASSESSMENT FOR CHRONIC NON-COMMUNICABLE DISEASES. THE PREVALENCE OF COMMON CHRONIC NON-COMMUNICABLE DISEASES (CNCDS) FAR OVERSHADOWS THE PREVALENCE OF BOTH MONOGENIC AND INFECTIOUS DISEASES COMBINED. ALL CNCDS, ALSO CALLED COMPLEX GENETIC DISEASES, HAVE A HERITABLE GENETIC COMPONENT THAT CAN BE USED FOR PRE-SYMPTOMATIC RISK ASSESSMENT. COMMON SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT TAG RISK HAPLOTYPES ACROSS THE GENOME CURRENTLY ACCOUNT FOR A NON-TRIVIAL PORTION OF THE GERM-LINE GENETIC RISK AND WE WILL LIKELY CONTINUE TO IDENTIFY THE REMAINING MISSING HERITABILITY IN THE FORM OF RARE VARIANTS, COPY NUMBER VARIANTS AND EPIGENETIC MODIFICATIONS. HERE, WE DESCRIBE A NOVEL MEASURE FOR CALCULATING THE LIFETIME RISK OF A DISEASE, CALLED THE GENETIC COMPOSITE INDEX (GCI), AND DEMONSTRATE ITS PREDICTIVE VALUE AS A CLINICAL CLASSIFIER. THE GCI ONLY CONSIDERS SUMMARY STATISTICS OF THE EFFECTS OF GENETIC VARIATION AND HENCE DOES NOT REQUIRE THE RESULTS OF LARGE-SCALE STUDIES SIMULTANEOUSLY ASSESSING MULTIPLE RISK FACTORS. COMBINING GCI SCORES WITH ENVIRONMENTAL RISK INFORMATION PROVIDES AN ADDITIONAL TOOL FOR CLINICAL DECISION-MAKING. THE GCI CAN BE POPULATED WITH HERITABLE RISK INFORMATION OF ANY TYPE, AND THUS REPRESENTS A FRAMEWORK FOR CNCD PRE-SYMPTOMATIC RISK ASSESSMENT THAT CAN BE POPULATED AS ADDITIONAL RISK INFORMATION IS IDENTIFIED THROUGH NEXT-GENERATION TECHNOLOGIES. 2010 15 6156 21 THE GENETIC INFLUENCE ON THE CORTICAL PROCESSING OF EXPERIMENTAL PAIN AND THE MODERATING EFFECT OF PAIN STATUS. BACKGROUND: RESEARCH SUGGESTS THAT THE COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS MODERATE THE EXPERIENCE OF PAIN. IN ORDER TO OBTAIN EXPERIMENTAL CONFIRMATION AND EXTENSION OF FINDINGS, CORTICAL PROCESSING OF EXPERIMENTALLY-INDUCED PAIN WAS USED. METHOD: A SAMPLE OF 78 INDIVIDUALS WITH CHRONIC LOW BACK PAIN COMPLAINTS AND 37 HEALTHY CONTROLS UNDERWENT EEG REGISTRATION. EVENT-RELATED POTENTIALS WERE MEASURED IN RESPONSE TO ELECTRICAL NOCICEPTIVE STIMULI AND MODERATION BY COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS WAS ASSESSED. RESULTS: GENETIC VARIATION DID NOT HAVE A DIRECT EFFECT ON CORTICAL PROCESSING OF EXPERIMENTAL PAIN. HOWEVER, GENETIC EFFECTS (COMT VAL(158)MET AND BDNF VAL(66)MET) ON EXPERIMENTAL PAIN WERE MODERATED BY THE PRESENCE OF CHRONIC PAIN. IN THE PRESENCE OF CHRONIC PAIN, THE COMT MET ALLELE AND THE BDNF MET ALLELE AUGMENTED CORTICAL PAIN PROCESSING, WHILST REDUCING PAIN PROCESSING IN PAIN-FREE CONTROLS. NO SIGNIFICANT EFFECTS WERE FOUND CONCERNING THE OPRM1 A(118)G POLYMORPHISM. CONCLUSIONS: THE CURRENT STUDY SUGGESTS THAT CHRONIC EXPERIENCE OF PAIN ENHANCES GENETIC SENSITIVITY TO EXPERIMENTALLY INDUCED MILDLY PAINFUL STIMULI, POSSIBLY THROUGH A PROCESS OF EPIGENETIC MODIFICATION. 2010 16 486 35 ASENAPINE TRANSDERMAL PATCH FOR THE MANAGEMENT OF SCHIZOPHRENIA. PURPOSE OF REVIEW: THIS IS A COMPREHENSIVE REVIEW OF THE LITERATURE REGARDING THE USE OF ASENAPINE FOR THE TREATMENT OF SCHIZOPHRENIA (SZ) IN ADULTS. IT COVERS AN INTRODUCTION, EPIDEMIOLOGY, RISK FACTORS, PATHOPHYSIOLOGY, AND CURRENT TREATMENT MODALITIES REGARDING SZ, PROVIDES A BACKGROUND ON THE MECHANISM OF ACTION OF ASENAPINE, AND THEN REVIEWS THE EXISTING EVIDENCE FOR USE OF ASENAPINE IN BOTH ITS SUBLINGUAL AND TRANSDERMAL FORMULATION IN THE TREATMENT OF SZ. RECENT FINDINGS: SZ IS A COMPLEX AND MULTIFACTORIAL MENTAL DISORDER WHICH IS THOUGHT TO COMBINE SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CAUSING ABNORMALITIES IN THE DOPAMINERGIC SYSTEM. SYMPTOMS ARE CATEGORIZED IN DELUSIONS, HALLUCINATIONS, DISORGANIZATION, AND NEGATIVE PRESENTATIONS LIKE AFFECTIVE FLATTENING AND APATHY. CURRENT TREATMENT FOCUSES ON ANTIPSYCHOTIC MEDICATIONS BY MEANS OF ORAL ADMINISTRATION OR LONG-ACTING INJECTION. ASENAPINE IS A SECOND-GENERATION ANTIPSYCHOTIC WITH 5HT-2A ANTAGONIST AND 5HT-1A/1B PARTIAL AGONIST PROPERTIES, WHICH PROVIDES A FAVORABLE PROFILE IN TARGETING SCHIZOPHRENIC SYMPTOMS, WHILE REDUCING MOTOR SIDE EFFECTS AND IMPROVING MOOD AND COGNITION. ASENAPINE IN ITS SUBLINGUAL FORMULATION WAS FDA APPROVED FOR TREATMENT OF SZ AND BIPOLAR I DISORDER IN ADULTS IN AUGUST OF 2009 AND HAS BEEN PROVEN TO BE BOTH EFFECTIVE AND SAFE. TRANSDERMAL PATCH OF ASENAPINE (SECUADO) WAS FDA APPROVED IN OCTOBER OF 2019, THE FIRST AND ONLY FDA APPROVED PATCH FOR SZ IN ADULTS, WHICH OFFERS ANOTHER STRATEGY FOR TREATMENT TO IMPROVE COMPLIANCE AND EASE OF ADMINISTRATION. SUMMARY: SZ IS A CHRONIC AND DEBILITATING DISEASE WHICH IS STILL NOT WELL UNDERSTOOD AND COMES AT GREAT COST WITH REGARDS TO THE QUALITY OF LIFE FOR PATIENTS. MEDICATION SIDE-EFFECTS AND COMPLIANCE ARE ENORMOUS ISSUES WHICH TAKE A TOLL ON HEALTH CARE SYSTEMS IN INDUSTRIALIZED NATIONS AND KEEP PATIENTS FROM ACHIEVING STABILITY WITH THEIR DISEASE. TRANSDERMAL ASENAPINE IS A NEW FIRST-IN-CLASS DOSAGE FORM AND PROVIDES A NOVEL MODALITY OF ADMINISTRATION. IT HAS BEEN SHOWN TO BE EFFECTIVE IN REDUCING POSITIVE, AS WELL AS NEGATIVE SYMPTOMS, WHILE STILL MAINTAINING A FAVORABLE SIDE-EFFECT PROFILE. 2020 17 4509 29 MSELENI JOINT DISEASE: A POTENTIAL MODEL OF EPIGENETIC CHONDRODYSPLASIA. OBJECTIVE: IN THIS PAPER PAST RESEARCH ON THE NATURAL HISTORY OF MSELENI JOINT DISEASE, A CRIPPLING ENDEMIC OSTEOARTHRITIS, ITS SOCIO-ECONOMIC IMPACTS, THE DEMOGRAPHICS, DIET, GEOLOGY AND THE GENETIC BACKGROUND OF AFFECTED PEOPLE ARE REVIEWED. IN ADDITION, SOME NEW RESEARCH IDEAS ARE SUGGESTED TO CONTINUE THE SEARCH FOR ETIOLOGICAL AVENUES FOR THIS DISEASE SUCH AS STABLE ISOTOPE ANALYSIS AND EPIGENETIC MECHANISMS. RESULTS: MSELENI JOINT DISEASE IS A CHONDRODYSPLASIA FIRST DESCRIBED IN 1970. IT IS GEOGRAPHICALLY CONFINED TO A REMOTE AREA IN THE MAPUTALAND REGION IN NORTHERN KWAZULU NATAL, SOUTH AFRICA. THIS DISEASE AFFECTS MOST JOINTS BUT PRIMARILY THOSE OF THE HIP; IT IS A PROGRESSIVE CONDITION BEGINNING WITH PAIN AND STIFFNESS UNTIL THE PATIENT'S ABILITY TO WALK BECOMES COMPROMISED. MSELENI JOINT DISEASE IS CHARACTERIZED BY TWO DISTINCT ABNORMALITIES, PROTRUSIO ACETABULI THAT MAINLY AFFECTS FEMALES AND INCREASES IN FREQUENCY WITH AGE, AND HIP DYSPLASIA THAT IS MORE FREQUENT WITH AGE. MUCH RESEARCH HAS BEEN CONDUCTED ON THE PEOPLE WITH THE DISEASE AND THEIR SURROUNDING ENVIRONMENT. CONCLUSION: DESPITE INTENSIVE INVESTIGATIONS INTO THE ETIOLOGY OF MSELENI JOINT DISEASE, IT REMAINS UNKNOWN. AS A RESULT THE EXAMINATION OF EPIGENETIC MECHANISMS AND STABLE ISOTOPE ANALYSIS OF TEETH ARE SUGGESTED AS A MEANS OF PROVIDING INFORMATION ON THE ETIOLOGY OF THE DISEASE. THESE METHODS CAN ALSO BE APPLIED TO OTHER CHONDROPLASIAS OF UNKNOWN ETIOLOGY. 2010 18 5464 21 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS. 2021 19 645 25 BIRTH DEFECTS IN GAZA: PREVALENCE, TYPES, FAMILIARITY AND CORRELATION WITH ENVIRONMENTAL FACTORS. THIS IS THE FIRST REPORT OF REGISTRATION AT BIRTH, AND OF INCIDENCE OF MAJOR STRUCTURAL BIRTH DEFECTS (BD) OBTAINED IN GAZA AT AL SHIFA HOSPITAL, WHERE 28% OF TOTAL BIRTHS IN GAZA STRIP OCCUR. DOCTORS REGISTERED 4,027 DELIVERIES, WITH A PROTOCOL COMPREHENSIVE OF CLINICAL, DEMOGRAPHIC, KIN AND ENVIRONMENTAL QUESTIONS. PREVALENCE OF BD IS 14/1,000, WITHOUT ASSOCIATION WITH INTERMARRIAGE OR GENDER OF THE CHILD. PREVALENCE OF LATE MISCARRIAGES AND STILL BIRTHS ARE RESPECTIVELY 23.3/1,000 AND 7.4/1,000, AND OF PREMATURE BIRTHS 19.6/1,000. COUPLES WITH A BD CHILD HAVE ABOUT 10 TIMES HIGHER FREQUENCY OF RECURRENCE OF A BD IN THEIR PROGENY THAN THOSE WITH NORMAL CHILDREN, BUT NONE OF THEIR 694 SIBLINGS AND ONLY 10/1,000 OF THEIR 1,423 PROGENY HAD BD, SIMILAR TO THE FREQUENCY IN GENERAL POPULATION. THESE DATA SUGGEST OCCURRENCE OF NOVEL GENETIC AND EPIGENETIC EVENTS IN DETERMINATION OF BD. CHILDREN WITH BD WERE BORN WITH HIGHER FREQUENCY (P < 0 001) IN FAMILIES WHERE ONE OR BOTH PARENTS WERE UNDER "WHITE PHOSPHORUS" ATTACK, THAT IN THE GENERAL POPULATION. BOMBING OF THE FAMILY HOME AND REMOVAL OF THE RUBBLE WERE ALSO FREQUENTLY REPORTED BY COUPLES WITH BD OCCURRENCE. THESE DATA SUGGESTS A CAUSATIVE/FAVORING ROLE OF ACUTE EXPOSURE OF PARENTS TO THE WEAPONS-ASSOCIATED CONTAMINANTS, AND/OR OF THEIR CHRONIC EXPOSURE FROM THEIR PERSISTENCE IN THE ENVIRONMENT ON THE EMBRYONIC DEVELOPMENT OF THEIR CHILDREN. 2012 20 6484 24 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998