1   745 300 CANNABIS ALTERS EPIGENETIC INTEGRITY AND ENDOCANNABINOID SIGNALLING IN THE HUMAN FOLLICULAR NICHE. STUDY QUESTION: DO PHYTOCANNABINOIDS (PCS) AFFECT FOLLICULAR ENDOCANNABINOID SIGNALLING AND THE EPIGENOME IN THE SURROUNDING GRANULOSA CELLS (GCS)? SUMMARY ANSWER: EXPOSURE TO PCS INCREASES THE EXPRESSION OF ENDOCANNABINOID RECEPTORS AND REDUCES DNA METHYLATION ENZYME EXPRESSION AND GLOBAL DNA METHYLATION IN NAIVE GCS. WHAT IS KNOWN ALREADY: CANNABIS PLANT DERIVATIVES, KNOWN AS PCS, ARE USED FOR MEDICINAL AND RECREATIONAL PURPOSES. THE MAIN PC, TETRAHYDROCANNABINOL (THC), IS THE THIRD MOST COMMONLY USED SUBSTANCE BY WOMEN OF CHILDBEARING AGE, HENCE KNOWLEDGE OF THE EFFECT IT HAS ON REPRODUCTION IS OF UTMOST IMPORTANCE. THC EXERTS ITS EFFECTS VIA RECEPTORS OF THE ENDOCANNABINOID SYSTEM (ECS) AND CAN INTERFERE WITH FOLLICULOGENESIS, OOCYTE DEVELOPMENT AND OVULATION. ENDOCANNABINOIDS HAVE BEEN MEASURED IN FOLLICULAR FLUID (FF) OBTAINED DURING OOCYTE RETRIEVAL AND ARE IMPLICATED IN CONTROLLING FOLLICULOGENESIS. IT HAS BEEN ESTABLISHED THAT IN THE PLACENTA, PCS DISRUPT ENDOCANNABINOID HOMEOSTASIS VIA IMPAIRMENT OF THE SYNTHETIC AND DEGRADING ENZYMES, LEADING TO A NET INCREASE OF ENDOCANNABINOID LEVELS. FINALLY, PREVIOUS STUDIES HAVE SHOWN THAT THC ALTERS METHYLATION AND HISTONE MODIFICATIONS IN SPERM, BRAIN AND BLOOD CELLS. STUDY DESIGN, SIZE, DURATION: THIS STUDY INCLUDED AN IN VIVO COHORT ASSESSMENT OF CANNABIS EXPOSURE AND ITS EFFECTS ON THE FOLLICLE AND IN VITRO ASSAYS CONDUCTED TO VALIDATE THE IN VIVO FINDINGS AND TO EXPLORE POSSIBLE MECHANISMS OF ACTION. PARTICIPANTS/MATERIALS, SETTING, METHODS: A TOTAL OF 318 FF SAMPLES, FROM 261 PATIENTS UNDERGOING IVF TREATMENT AT A PRIVATE FERTILITY CLINIC WHO CONSENTED FOR BIOBANKING BIOLOGICAL WASTE MATERIAL BETWEEN JANUARY 2018 AND JULY 2019, WERE INCLUDED IN THIS STUDY. CONCENTRATIONS OF PCS AND ENDOCANNABINOIDS WERE ASSESSED IN FF BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS/MS). EXPOSURE TO PCS WAS DETERMINED BASED ON THESE MEASURED LEVELS. LEVELS OF BOTH ENDOCANNABINOID RECEPTORS (CB1R, CB2R) AND THE DE NOVO DNA METHYLATING ENZYME, DNMT3B, IN GCS WERE ASSESSED BY FLOW CYTOMETRY BOTH IN VITRO AND IN VIVO AND GLOBAL DNA METHYLATION WAS ASSESSED IN VITRO BY ELISA. IN VIVO EFFECTS WERE ASSESSED BY COMPARING SAMPLES POSITIVE FOR AT LEAST ONE PC, WITH SAMPLES NEGATIVE FOR ALL MEASURED PCS. IN VITRO EFFECTS WERE DETERMINED IN NAIVE GCS, OBTAINED CONCURRENTLY WITH FF SAMPLES THAT HAD TESTED NEGATIVE FOR ALL PCS. THESE GCS WERE TREATED WITH DIFFERENT COMBINATIONS OF THE MAIN THREE PCS. MAIN RESULTS AND THE ROLE OF CHANCE: OVERALL, 17 PATIENTS (6.4%) WERE POSITIVE FOR CANNABIS CONSUMPTION. FURTHERMORE, THE PREVALENCE OF CANNABIS POSITIVITY IN THE FF INCREASED FROM 4% OF THE TESTED SAMPLES THAT WERE COLLECTED PRIOR TO NATIONAL LEGALISATION IN OCTOBER 2018 TO 12% OF THOSE COLLECTED FOLLOWING LEGALISATION. OF NOTE, 59% OF PATIENTS WHO TESTED POSITIVE FOR PCS (10 OF 17) REPORTED PREVIOUS OR ONGOING EXPOSURE TO CANNABIS UPON THEIR INITIAL INTAKE. ENDOCANNABINOID LEVELS WERE NOT AFFECTED BY THE PRESENCE OF PCS. CB2R WAS MORE PREVALENT THAN CB1R IN GCS AND ITS EXPRESSION INCREASED FOLLOWING ACUTE AND CHRONIC IN VITRO EXPOSURE TO PCS. THE EXPRESSION OF DNMT3B AND GLOBAL METHYLATION DECREASED FOLLOWING EXPOSURE, SUGGESTING THAT CANNABIS MAY AFFECT THE EPIGENOME IN THE FOLLICULAR NICHE. THE ACUTE CHANGES WERE SUSTAINED THROUGHOUT CHRONIC TREATMENT. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: OUR STUDY IS LIMITED BY LACK OF DETAILS REGARDING MODE, FREQUENCY AND TIMING OF PC CONSUMPTION. MOREOVER, WE WERE NOT ABLE TO ADEQUATELY ASSESS THE EFFECT OF PCS ON IMMEDIATE OR LONG-TERM CLINICAL OUTCOMES, DUE TO THE SMALL SAMPLE SIZE AND THE LACK OF FOLLOW UP. FUTURE, LARGE-SCALE STUDIES SHOULD FOCUS ON ASSESS THE CLINICAL IMPLICATIONS OF CANNABIS EXPOSURE, VALIDATE OUR FINDINGS, AND DETERMINE TO WHAT EXTENT CANNABIS AFFECTS THE EPIGENOME OVARIAN FOLLICLE AND THE DEVELOPING OOCYTE. WIDER IMPLICATIONS OF THE FINDINGS: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY MEASURING PCS IN FF BY LC-MS/MS. WE SHOW THAT CONSUMING CANNABIS ALTERS THE ECS IN THE DEVELOPING FOLLICLE, AND DIRECTLY AFFECTS DNMT EXPRESSION AND GLOBAL DNA METHYLATION LEVELS. CANNABIS LEGALISATION AND USE IS INCREASING WORLDWIDE, THEREFORE FURTHER UNDERSTANDING ITS ROLE IN FEMALE FERTILITY AND FOLLICULOGENESIS IS CRITICAL. STUDY FUNDING/COMPETING INTEREST(S): ALL FUNDING WAS PROVIDED BY CREATE FERTILITY CENTRE THROUGH THE REINVESTMENT OF CLINICAL EARNINGS. THE AUTHORS DECLARE NO COMPETING INTERESTS.	2021	

2  3085  44 GENOME-WIDE SCREEN OF OVARY-SPECIFIC DNA METHYLATION IN POLYCYSTIC OVARY SYNDROME. OBJECTIVE: TO COMPARE GENOME-WIDE DNA METHYLATION PROFILES IN OVARY TISSUE FROM WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS) AND HEALTHY CONTROLS. DESIGN: CASE-CONTROL STUDY MATCHED FOR AGE AND BODY MASS INDEX. SETTING: UNIVERSITY-AFFILIATED HOSPITAL. PATIENT(S): TEN WOMEN WITH PCOS WHO UNDERWENT OVARIAN DRILLING TO INDUCE OVULATION AND 10 HEALTHY WOMEN WHO WERE UNDERGOING LAPAROSCOPIC STERILIZATION, HYSTERECTOMY FOR BENIGN CONDITIONS, DIAGNOSTIC LAPAROSCOPY FOR PELVIC PAIN, OR OOPHORECTOMY FOR NONOVARIAN INDICATIONS. INTERVENTION(S): NONE. MAIN OUTCOME MEASURE(S): GENOME-WIDE DNA METHYLATION PATTERNS DETERMINED BY IMMUNOPRECIPITATION AND MICROARRAY (MEDIP-CHIP) ANALYSIS. RESULT(S): THE METHYLATION LEVELS WERE STATISTICALLY SIGNIFICANTLY HIGHER IN CPG ISLAND SHORES (CGI SHORES), WHICH LIE OUTSIDE OF CORE PROMOTER REGIONS, AND LOWER WITHIN GENE BODIES IN WOMEN WITH PCOS RELATIVE TO THE CONTROLS. IN ADDITION, HIGH CPG CONTENT PROMOTERS WERE THE MOST FREQUENTLY HYPERMETHYLATED PROMOTERS IN PCOS OVARIES BUT WERE MORE OFTEN HYPOMETHYLATED IN CONTROLS. SECOND, 872 CGIS, SPECIFICALLY METHYLATED IN PCOS, REPRESENTED 342 GENES THAT COULD BE ASSOCIATED WITH VARIOUS MOLECULAR FUNCTIONS, INCLUDING PROTEIN BINDING, HORMONE ACTIVITY, AND TRANSCRIPTION REGULATOR ACTIVITY. FINALLY, METHYLATION DIFFERENCES WERE VALIDATED IN SEVEN GENES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THESE GENES CORRELATED TO SEVERAL FUNCTIONAL FAMILIES RELATED TO THE PATHOGENESIS OF PCOS AND MAY BE POTENTIAL BIOMARKERS FOR THIS DISEASE. CONCLUSION(S): OUR RESULTS DEMONSTRATED THAT EPIGENETIC MODIFICATION DIFFERS BETWEEN PCOS AND NORMAL OVARIES, WHICH MAY HELP TO FURTHER UNDERSTAND THE PATHOPHYSIOLOGY OF THIS DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  3750  29 INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME ACROSS VARIOUS TISSUES: AN UPDATED REVIEW OF PATHOGENESIS, EVALUATION, AND TREATMENT. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON ENDOCRINE DISORDER CHARACTERIZED BY CHRONIC OVULATION DYSFUNCTION AND OVERABUNDANCE OF ANDROGENS; IT AFFECTS 6-20% OF WOMEN OF REPRODUCTIVE AGE. PCOS INVOLVES VARIOUS PATHOPHYSIOLOGICAL FACTORS, AND AFFECTED WOMEN USUALLY HAVE SIGNIFICANT INSULIN RESISTANCE (IR), WHICH IS A MAJOR CAUSE OF PCOS. IR AND COMPENSATORY HYPERINSULINAEMIA HAVE DIFFERING PATHOGENESES IN VARIOUS TISSUES, AND IR VARIES AMONG DIFFERENT PCOS PHENOTYPES. GENETIC AND EPIGENETIC CHANGES, HYPERANDROGENAEMIA, AND OBESITY AGGRAVATE IR. INSULIN SENSITIZATION DRUGS ARE A NEW TREATMENT MODALITY FOR PCOS. WE SEARCHED PUBMED, GOOGLE SCHOLAR, ELSEVIER, AND UPTODATE DATABASES IN THIS REVIEW, AND FOCUSED ON THE PATHOGENESIS OF IR IN WOMEN WITH PCOS AND THE PATHOPHYSIOLOGY OF IR IN VARIOUS TISSUES. IN ADDITION, THE REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE CURRENT PROGRESS IN THE EFFICACY OF INSULIN SENSITIZATION THERAPY IN THE MANAGEMENT OF PCOS, PROVIDING THE LATEST EVIDENCE FOR THE CLINICAL TREATMENT OF WOMEN WITH PCOS AND IR.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  1891  46 ENDOMETRIOSIS. PELVIC ENDOMETRIOSIS IS A COMPLEX SYNDROME CHARACTERIZED BY AN ESTROGEN-DEPENDENT CHRONIC INFLAMMATORY PROCESS THAT AFFECTS PRIMARILY PELVIC TISSUES, INCLUDING THE OVARIES. IT IS CAUSED WHEN SHED ENDOMETRIAL TISSUE TRAVELS RETROGRADE INTO THE LOWER ABDOMINAL CAVITY. ENDOMETRIOSIS IS THE MOST COMMON CAUSE OF CHRONIC PELVIC PAIN IN WOMEN AND IS ASSOCIATED WITH INFERTILITY. THE UNDERLYING PATHOLOGIC MECHANISMS IN THE INTRACAVITARY ENDOMETRIUM AND EXTRAUTERINE ENDOMETRIOTIC TISSUE INVOLVE DEFECTIVELY PROGRAMMED ENDOMETRIAL MESENCHYMAL PROGENITOR/STEM CELLS. ALTHOUGH ENDOMETRIOTIC STROMAL CELLS, WHICH COMPOSE THE BULK OF ENDOMETRIOTIC LESIONS, DO NOT CARRY SOMATIC MUTATIONS, THEY DEMONSTRATE SPECIFIC EPIGENETIC ABNORMALITIES THAT ALTER EXPRESSION OF KEY TRANSCRIPTION FACTORS. FOR EXAMPLE, GATA-BINDING FACTOR-6 OVEREXPRESSION TRANSFORMS AN ENDOMETRIAL STROMAL CELL TO AN ENDOMETRIOTIC PHENOTYPE, AND STEROIDOGENIC FACTOR-1 OVEREXPRESSION CAUSES EXCESSIVE PRODUCTION OF ESTROGEN, WHICH DRIVES INFLAMMATION VIA PATHOLOGICALLY HIGH LEVELS OF ESTROGEN RECEPTOR-BETA. PROGESTERONE RECEPTOR DEFICIENCY CAUSES PROGESTERONE RESISTANCE. POPULATIONS OF ENDOMETRIAL AND ENDOMETRIOTIC EPITHELIAL CELLS ALSO HARBOR MULTIPLE CANCER DRIVER MUTATIONS, SUCH AS KRAS, WHICH MAY BE ASSOCIATED WITH THE ESTABLISHMENT OF PELVIC ENDOMETRIOSIS OR OVARIAN CANCER. IT IS NOT KNOWN HOW INTERACTIONS BETWEEN EPIGENOMICALLY DEFECTIVE STROMAL CELLS AND THE MUTATED GENES IN EPITHELIAL CELLS CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN IS MANAGED BY SUPPRESSION OF OVULATORY MENSES AND ESTROGEN PRODUCTION, CYCLOOXYGENASE INHIBITORS, AND SURGICAL REMOVAL OF PELVIC LESIONS, AND IN VITRO FERTILIZATION IS FREQUENTLY USED TO OVERCOME INFERTILITY. ALTHOUGH NOVEL TARGETED TREATMENTS ARE BECOMING AVAILABLE, AS ENDOMETRIOSIS PATHOPHYSIOLOGY IS BETTER UNDERSTOOD, PREVENTIVE APPROACHES SUCH AS LONG-TERM OVULATION SUPPRESSION MAY PLAY A CRITICAL ROLE IN THE FUTURE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  5107  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  6682  44 UTERINE LEIOMYOMA: AVAILABLE MEDICAL TREATMENTS AND NEW POSSIBLE THERAPEUTIC OPTIONS. CONTEXT: UTERINE LEIOMYOMAS (FIBROIDS OR MYOMAS) ARE BENIGN TUMORS OF THE UTERUS AND ARE CLINICALLY APPARENT IN UP TO 25% OF REPRODUCTIVE-AGE WOMEN. HEAVY OR ABNORMAL UTERINE BLEEDING, PELVIC PAIN OR PRESSURE, INFERTILITY, AND RECURRENT PREGNANCY LOSS ARE GENERALLY ASSOCIATED WITH LEIOMYOMA. ALTHOUGH SURGICAL AND RADIOLOGICAL THERAPIES ARE FREQUENTLY USED FOR THE MANAGEMENT OF THIS TUMOR, MEDICAL THERAPIES ARE CONSIDERED THE FIRST-LINE TREATMENT OF LEIOMYOMA. EVIDENCE ACQUISITION AND SYNTHESIS: A REVIEW WAS CONDUCTED OF ELECTRONIC AND PRINT DATA COMPRISING BOTH ORIGINAL AND REVIEW ARTICLES ON PATHOPHYSIOLOGY AND MEDICAL TREATMENTS OF UTERINE LEIOMYOMA RETRIEVED FROM THE PUBMED OR GOOGLE SCHOLAR DATABASE UP TO JUNE 2012. THESE RESOURCES WERE INTEGRATED WITH THE AUTHORS' KNOWLEDGE OF THE FIELD. CONCLUSION: TO DATE, SEVERAL PATHOGENETIC FACTORS SUCH AS GENETIC FACTORS, EPIGENETIC FACTORS, ESTROGENS, PROGESTERONE, GROWTH FACTORS, CYTOKINES, CHEMOKINES, AND EXTRACELLULAR MATRIX COMPONENTS HAVE BEEN IMPLICATED IN LEIOMYOMA DEVELOPMENT AND GROWTH. ON THE BASIS OF CURRENT HYPOTHESES, SEVERAL MEDICAL THERAPIES HAVE BEEN INVESTIGATED. GNRH AGONIST HAS BEEN APPROVED BY US FOOD AND DRUG ADMINISTRATION FOR REDUCING FIBROID VOLUME AND RELATED SYMPTOMS. IN ADDITION, THE FDA ALSO APPROVED AN INTRAUTERINE DEVICE, LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM (MIRENA), FOR ADDITIONAL USE TO TREAT HEAVY MENSTRUAL BLEEDING IN INTRAUTERINE DEVICE USERS ONLY. CURRENTLY, MIFEPRISTONE, ASOPRISNIL, ULIPRISTAL ACETATE, AND EPIGALLOCATECHIN GALLATE HAVE BEEN SHOWN TO BE EFFECTIVE FOR FIBROID REGRESSION AND SYMPTOMATIC IMPROVEMENT WHICH ARE ALL IN CLINICAL TRIAL. IN ADDITION, SOME SYNTHETIC AND NATURAL COMPOUNDS AS WELL AS GROWTH FACTOR INHIBITORS ARE NOW UNDER LABORATORY INVESTIGATION, AND THEY COULD SERVE AS FUTURE THERAPEUTIC OPTIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  3751  55 INTAKE OF NATURAL COMPOUNDS AND CIRCULATING MICRORNA EXPRESSION LEVELS: THEIR RELATIONSHIP INVESTIGATED IN HEALTHY SUBJECTS WITH DIFFERENT DIETARY HABITS. DIET HAS A STRONG INFLUENCE ON MANY PHYSIOLOGICAL PROCESSES, WHICH IN TURN HAVE IMPORTANT IMPLICATIONS ON A VARIETY OF PATHOLOGICAL CONDITIONS. IN THIS RESPECT, MICRORNAS (MIRNAS), A CLASS OF SMALL NON-CODING RNAS PLAYING A RELEVANT EPIGENETIC ROLE IN CONTROLLING GENE EXPRESSION, MAY REPRESENT MEDIATORS BETWEEN THE DIETARY INTAKE AND THE HEALTHY STATUS. DESPITE GREAT ADVANCES IN THE FIELD OF NUTRI-EPIGENOMICS, IT REMAINS UNCLEAR HOW MIRNA EXPRESSION IS MODULATED BY THE DIET AND, SPECIFICALLY, THE INTAKE OF SPECIFIC NUTRIENTS. WE INVESTIGATED THE WHOLE CIRCULATING MIRNOME BY SMALL RNA-SEQUENCING PERFORMED ON PLASMA SAMPLES OF 120 HEALTHY VOLUNTEERS WITH DIFFERENT DIETARY HABITS (VEGANS, VEGETARIANS, AND OMNIVORES). DIETARY INTAKES OF SPECIFIC NUTRIENTS WERE ESTIMATED FOR EACH SUBJECT FROM THE INFORMATION REPORTED IN THE FOOD-FREQUENCY QUESTIONNAIRE PREVIOUSLY VALIDATED IN THE EPIC STUDY. WE FOCUSED HEREBY ON THE INTAKE OF 23 NATURAL COMPOUNDS (NCS) OF THE CLASSES OF LIPIDS, MICRO-ELEMENTS, AND VITAMINS. WE IDENTIFIED 78 SIGNIFICANT CORRELATIONS (RHO > 0.300, P-VALUE < 0.05) AMONG THE ESTIMATED DAILY INTAKE OF 13 NCS AND THE EXPRESSION LEVELS OF 58 PLASMA MIRNAS. OVERALL, VITAMIN D, SODIUM, AND VITAMIN E CORRELATED WITH THE LARGEST NUMBER OF MIRNAS. ALL THE IDENTIFIED CORRELATIONS WERE CONSISTENT AMONG THE THREE DIETARY GROUPS AND 22 OF THEM WERE CONFIRMED AS SIGNIFICANT (P-VALUE < 0.05) BY AGE-, GENDER-, AND BODY-MASS INDEX-ADJUSTED GENERALIZED LINEAR REGRESSION MODEL ANALYSIS. MIR-23A-3P EXPRESSION LEVELS WERE RELATED WITH DIFFERENT NCS INCLUDING A SIGNIFICANT POSITIVE CORRELATION WITH SODIUM (RHO = 0.377) AND SIGNIFICANT NEGATIVE CORRELATIONS WITH LIPID-RELATED NCS AND VITAMIN E. CONVERSELY, THE ESTIMATED INTAKE OF VITAMIN D WAS NEGATIVELY CORRELATED WITH THE EXPRESSION OF THE HIGHEST NUMBER OF CIRCULATING MIRNAS, PARTICULARLY MIR-1277-5P (RHO = -0.393) AND MIR-144-3P (RHO = -0.393). FUNCTIONAL ANALYSIS OF THE TARGETS OF SODIUM INTAKE-CORRELATED MIRNAS HIGHLIGHTED TERMS RELATED TO CARDIAC DEVELOPMENT. A SIMILAR APPROACH ON TARGETS OF THOSE MIRNAS CORRELATED WITH VITAMIN D INTAKE SHOWED AN ENRICHMENT IN GENES INVOLVED IN HORMONE METABOLISMS, WHILE THE RESPONSE TO CHRONIC INFLAMMATION WAS AMONG THE TOP ENRICHED PROCESSES INVOLVING TARGETS OF MIRNAS NEGATIVELY RELATED WITH VITAMIN E INTAKE. OUR FINDINGS SHOW THAT NUTRIENTS THROUGH THE HABITUAL DIET INFLUENCE CIRCULATING MIRNA PROFILES AND HIGHLIGHT THAT THIS ASPECT MUST BE CONSIDERED IN THE NUTRI-EPIGENOMIC RESEARCH.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  1888  41 ENDOMETRIOSIS AND IN VITRO FERTILISATION. THE AIM OF THE PRESENT REVIEW WAS TO DISCUSS A MATTER OF CONCERN IN THE CLINICAL FIELD OF OBSTETRICS/GYNECOLOGY, NAMELY THE POTENCY OF IN VITRO FERTILIZATION (IVF) IN THE MANAGEMENT OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY. ENDOMETRIOSIS IS A MEDICAL CONDITION AFFECTING ONE TENTH OF WOMEN IN THEIR FERTILE YEARS, AND ACCOUNTS FOR UP TO 50% OF INFERTILE WOMEN. THUS, SUCH HIGH PREVALENCE HAS ESTABLISHED THE NECESSITY FOR INVESTIGATING THE EFFECTIVENESS OF AVAILABLE TECHNIQUES IN ERADICATING THE DISEASE AND CONSTRAINING INFERTILITY AS WELL AS THE ACCOMPANYING PAIN SYMPTOMS OF ENDOMETRIOSIS. THE UNDERLYING MECHANISMS CONNECTING ENDOMETRIOSIS WITH LOW FECUNDITY HAVE BEEN EXTENSIVELY STUDIED, BOTH IN TERMS OF GENETIC ALTERATIONS AND EPIGENETIC EVENTS THAT CONTRIBUTE TO THE MANIFESTATION OF AN INFERTILITY PHENOTYPE IN WOMEN WITH THE DISEASE. SEVERAL STUDIES HAVE DEALT WITH THE IMPACT OF IVF IN PREGNANCY RATES (PRS) ON PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY REGARDING WOMEN WHO WISH TO CONCEIVE. RESULTS RETRIEVED FROM STUDIES AND META-ANALYSES DEPICT A DIVERSE PATTERN OF IVF SUCCESS, UNDERLINING THE INVOLVEMENT OF INDIVIDUAL PARAMETERS IN THE CONFIGURATION OF THE FINAL OUTCOME. THE ULTIMATE DECISION ON UNDERGOING IVF TREATMENT SHOULD BE BASED ON OBJECTIVE CRITERIA AND CLINICIANS' EXPERIENCE, CUSTOMIZED ACCORDING TO PATIENTS' INDIVIDUAL NEEDS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  5104  23 POLYCYSTIC OVARIAN SYNDROME. WOMEN WITH PCOS PRESENT WITH SIGNS OF CHRONIC ANOVULATION, HYPERANDROGENISM, AND METABOLIC ABNORMALITIES. THE NIH RECENTLY EMBRACED THE ROTTERDAM CRITERIA TO BROADLY IDENTIFY ALL THE PHENOTYPES OF PCOS. WOMEN WITH PCOS ARE OFTEN OBESE WITH INSULIN RESISTANCE AND HENCE HAVE AN INCREASED SUSCEPTIBILITY TO GLUCOSE INTOLERANCE AND TYPE 2 DIABETES. FUTURE RESEARCH SHOULD FOCUS ON THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS OF PCOS TO DEVELOP NEW THERAPIES TO ADDRESS THE PREVENTION OF THIS DISORDER AND ITS LONG-TERM COMPLICATIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10   747  37 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  5105  41 POLYCYSTIC OVARIAN SYNDROME: A COMPLEX DISEASE WITH A GENETICS APPROACH. POLYCYSTIC OVARIAN SYNDROME (PCOS) IS A COMPLEX ENDOCRINE DISORDER AFFECTING FEMALES IN THEIR REPRODUCTIVE AGE. THE EARLY DIAGNOSIS OF PCOS IS COMPLICATED AND COMPLEX DUE TO OVERLAPPING SYMPTOMS OF THIS DISEASE. THE MOST ACCEPTED DIAGNOSTIC APPROACH TODAY IS THE ROTTERDAM CONSENSUS (2003), WHICH SUPPORTS THE POSITIVE DIAGNOSIS OF PCOS WHEN PATIENTS PRESENT TWO OUT OF THE FOLLOWING THREE SYMPTOMS: BIOCHEMICAL AND CLINICAL SIGNS OF HYPERANDROGENISM, OLIGO, AND ANOVULATION, ALSO POLYCYSTIC OVARIAN MORPHOLOGY ON SONOGRAPHY. GENETIC VARIANCE, EPIGENETIC CHANGES, AND DISTURBED LIFESTYLE LEAD TO THE DEVELOPMENT OF PATHOPHYSIOLOGICAL DISTURBANCES, WHICH INCLUDE HYPERANDROGENISM, INSULIN RESISTANCE, AND CHRONIC INFLAMMATION IN PCOS FEMALES. AT THE MOLECULAR LEVEL, DIFFERENT PROTEINS AND MOLECULAR AND SIGNALING PATHWAYS ARE INVOLVED IN DISEASE PROGRESSION, WHICH LEADS TO THE FAILURE OF A SINGLE GENETIC DIAGNOSTIC APPROACH. THE GENETIC APPROACH TO ELUCIDATE THE MECHANISM OF PATHOGENESIS OF PCOS WAS RECENTLY DEVELOPED, WHEREBY FOUR PHENOTYPIC VARIANCES OF PCOS CATEGORIZE PCOS PATIENTS INTO CLASSIC, OVULATORY, AND NON-HYPERANDROGENIC TYPES. GENETIC STUDIES HELP TO IDENTIFY THE ROOT CAUSE FOR THE DEVELOPMENT OF THIS PCOS. PCOS GENETIC INHERITANCE IS AUTOSOMAL DOMINANT BUT THE LATEST INVESTIGATIONS REVEALED IT AS A MULTIGENE ORIGIN DISEASE. DIFFERENT GENETIC LOCI AND SPECIFIC GENES HAVE BEEN IDENTIFIED SO FAR AS BEING ASSOCIATED WITH THIS DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND RELATED GENETIC STUDIES HAVE CHANGED THE SCENARIO FOR THE DIAGNOSIS AND TREATMENT OF THIS REPRODUCTIVE AND METABOLIC CONDITION KNOWN AS PCOS. THIS REVIEW ARTICLE BRIEFLY DISCUSSES DIFFERENT GENES ASSOCIATED DIRECTLY OR INDIRECTLY WITH DISEASE DEVELOPMENT AND PROGRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12   849  55 CHILDHOOD TRAUMATIZATION IS ASSOCIATED WITH DIFFERENCES IN TRPA1 PROMOTER METHYLATION IN FEMALE PATIENTS WITH MULTISOMATOFORM DISORDER WITH PAIN AS THE LEADING BODILY SYMPTOM. BACKGROUND: THE CONSTRUCT OF MULTISOMATOFORM DISORDER (MSD) IS A COMMON POINT OF REFERENCE FOR PATIENTS IN DIFFERENT SOMATIC AND PSYCHOSOMATIC SPECIALTIES AND THEREFORE USEFUL IN STUDYING LARGE WELL-CHARACTERIZED COHORTS OF A PROTOTYPE OF A SOMATOFORM DISORDER AND IN PARALLEL AS A FUNCTIONAL SOMATIC SYNDROME (FSS). THIS DISORDER IS CHARACTERIZED BY DISTRESSING AND FUNCTIONALLY DISABLING SOMATIC SYMPTOMS WITH CHRONIC PAIN AS THE MOST FREQUENT AND CLINICALLY RELEVANT COMPLAINT. PAIN IS PERCEIVED BY NOCICEPTIVE NERVE FIBERS AND TRANSFERRED THROUGH THE GENERATION OF ACTION POTENTIALS BY DIFFERENT RECEPTOR MOLECULES KNOWN TO DETERMINE PAIN SENSITIVITY IN PATHOPHYSIOLOGICAL PROCESSES. PREVIOUS STUDIES HAVE SHOWN THAT FOR THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), RECEPTOR METHYLATION OF A PARTICULAR CPG DINUCLEOTIDE IN THE PROMOTER REGION IS INVERSELY ASSOCIATED WITH BOTH HEAT PAIN AND PRESSURE PAIN THRESHOLDS. IN THIS STUDY, WE HYPOTHESIZED THAT TRPA1 PROMOTER METHYLATION REGULATES PAIN SENSITIVITY OF PATIENTS WITH MULTISOMATOFORM DISORDER (MSD). A COHORT OF 151 PATIENTS WITH MSD AND 149 MATCHED HEALTHY VOLUNTEERS WERE EVALUATED USING QUANTITATIVE SENSORY TESTING, CLINICAL AND PSYCHOMETRIC ASSESSMENT, AND METHYLATION ANALYSIS USING DNA ISOLATED FROM WHOLE BLOOD. RESULTS: WE FOUND CPG -628 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD AND CPG -411 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD IN FEMALE VOLUNTEERS, I.E., HIGHER METHYLATION LEVELS LEAD TO HIGHER PAIN THRESHOLDS. A NOVEL FINDING IS THAT METHYLATION LEVELS WERE SIGNIFICANTLY DIFFERENT BETWEEN PATIENTS WITH NO AND SEVERE LEVELS OF CHILDHOOD TRAUMA. CPG METHYLATION ALSO CORRELATED WITH PSYCHOMETRIC ASSESSMENT OF PAIN AND PAIN LEVELS RATED ON A VISUAL ANALOG SCALE. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT EPIGENETIC REGULATION OF TRPA1 PLAYS A ROLE IN MECHANICAL PAIN SENSITIVITIES IN HEALTHY VOLUNTEERS. THEY FURTHER PROVIDE EVIDENCE FOR THE POSSIBLE INFLUENCE OF CHILDHOOD TRAUMATIC EXPERIENCES ON THE EPIGENETIC REGULATION OF TRPA1 IN PATIENTS WITH MSD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  4892  39 OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: OXIDATIVE STRESS IN POLYCYSTIC OVARY SYNDROME. IN BRIEF: A GENETIC, EPIGENETIC, AND ENVIRONMENTAL ASSOCIATION EXISTS BETWEEN OXIDATIVE STRESS (OS) AND POLYCYSTIC OVARY SYNDROME (PCOS), EXPRESSED IN A MULTIFACETED CLINICAL PROFILE. THIS REVIEW SUMMARIZES AND DISCUSSES THE ROLE OF OS IN THE PATHOGENESIS OF PCOS SYNDROME, FOCUSING ON METABOLIC, REPRODUCTIVE, AND CANCER COMPLICATIONS. ABSTRACT: OXIDATIVE STRESS (OS), AN IMBALANCE BETWEEN OXIDANTS AND ANTIOXIDANTS IN CELLS, IS ONE OF MANY FACTORS PLAYING ESSENTIAL ROLES IN THE PATHOGENESIS OF POLYCYSTIC OVARY SYNDROME (PCOS). PCOS IS DESCRIBED MAINLY AS A DISPROPORTION OF REPRODUCTIVE HORMONES, LEADING TO CHRONIC ANOVULATION AND INFERTILITY IN WOMEN. INTERESTINGLY, OS IN PCOS MAY BE ASSOCIATED WITH MANY DISORDERS AND DISEASES. THIS REVIEW FOCUSES ON CHARACTERISTIC MARKERS OF OS IN PCOS AND THE RELATIONSHIP BETWEEN OS AND PCOS RELATED TO INSULIN RESISTANCE (IR), HYPERANDROGENEMIA, OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND CANCER. INTERESTINGLY, IN PATIENTS WITH PCOS, AN INCREASE IN OXIDATIVE STATUS AND INSUFFICIENT COMPENSATION OF THE INCREASE IN ANTIOXIDANT STATUS BEFORE ANY CARDIOVASCULAR COMPLICATIONS ARE OBSERVED. MOREOVER, FREE RADICALS PROMOTE CARCINOGENESIS IN PCOS PATIENTS. HOWEVER, DESPITE THESE DATA, IT HAS NOT BEEN ESTABLISHED WHETHER OXYGEN STRESS INFLUENCES PCOS DEVELOPMENT OR A SECONDARY DISORDER RESULTING FROM HYPERGLYCEMIA, IR, AND CARDIOVASCULAR AND CANCER COMPLICATIONS IN WOMEN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14   537  37 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  6076  52 THE DYNAMICS OF NUCLEAR RECEPTORS AND NUCLEAR RECEPTOR COREGULATORS IN THE PATHOGENESIS OF ENDOMETRIOSIS. BACKGROUND: ENDOMETRIOSIS IS DEFINED AS THE COLONIZATION AND GROWTH OF ENDOMETRIAL TISSUE AT ANATOMIC SITES OUTSIDE THE UTERINE CAVITY. UP TO 15% OF REPRODUCTIVE-AGED WOMEN IN THE USA SUFFER FROM PAINFUL SYMPTOMS OF ENDOMETRIOSIS, SUCH AS INFERTILITY, PELVIC PAIN, MENSTRUAL CYCLE ABNORMALITIES AND INCREASED RISK OF CERTAIN CANCERS. HOWEVER, MANY OF THE CURRENT CLINICAL TREATMENTS FOR ENDOMETRIOSIS ARE NOT SUFFICIENTLY EFFECTIVE AND YIELD UNACCEPTABLE SIDE EFFECTS. THERE IS CLEARLY AN URGENT NEED TO IDENTIFY NEW MOLECULAR MECHANISMS THAT CRITICALLY UNDERPIN THE INITIATION AND PROGRESSION OF ENDOMETRIOSIS IN ORDER TO DEVELOP MORE SPECIFIC AND EFFECTIVE THERAPEUTICS WHICH LACK THE SIDE EFFECTS OF CURRENT THERAPIES. THE AIM OF THIS REVIEW IS TO DISCUSS HOW NUCLEAR RECEPTORS (NRS) AND THEIR COREGULATORS PROMOTE THE PROGRESSION OF ENDOMETRIOSIS. UNDERSTANDING THE PATHOGENIC MOLECULAR MECHANISMS FOR THE GENESIS AND MAINTENANCE OF ENDOMETRIOSIS AS MODULATED BY NRS AND COREGULATORS CAN REVEAL NEW THERAPEUTIC TARGETS FOR ALTERNATIVE ENDOMETRIOSIS TREATMENTS. METHODS: THIS REVIEW WAS PREPARED USING PUBLISHED GENE EXPRESSION MICROARRAY DATA SETS OBTAINED FROM PATIENTS WITH ENDOMETRIOSIS AND PUBLISHED LITERATURE ON NRS AND THEIR COREGULATORS THAT DEAL WITH ENDOMETRIOSIS PROGRESSION. USING THE ABOVE OBSERVATIONS, OUR CURRENT UNDERSTANDING OF HOW NRS AND NR COREGULATORS ARE INVOLVED IN THE PROGRESSION OF ENDOMETRIOSIS IS SUMMARIZED. RESULTS: ABERRANT LEVELS OF NRS AND NR COREGULATORS IN ECTOPIC ENDOMETRIOSIS LESIONS ARE ASSOCIATED WITH THE PROGRESSION OF ENDOMETRIOSIS. AS AN EXAMPLE, ENDOMETRIOTIC CELL-SPECIFIC ALTERATIONS IN GENE EXPRESSION ARE CORRELATED WITH A DIFFERENTIAL METHYLATION STATUS OF THE GENOME COMPARED WITH THE NORMAL ENDOMETRIUM. THESE DIFFERENTIAL EPIGENETIC REGULATIONS CAN GENERATE FAVORABLE CELL-SPECIFIC NR AND COREGULATOR MILIEUS FOR ENDOMETRIOSIS PROGRESSION. GENETIC ALTERATIONS, SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS AND INSERTION/DELETION POLYMORPHISMS OF NR AND COREGULATOR GENES, ARE FREQUENTLY DETECTED IN ECTOPIC LESIONS COMPARED WITH THE NORMAL ENDOMETRIUM. THESE GENETIC VARIATIONS IMPART NEW MOLECULAR PROPERTIES TO NRS AND COREGULATORS TO INCREASE THEIR CAPACITY TO STIMULATE PROGRESSION OF ENDOMETRIOSIS. FINALLY, POST-TRANSLATIONAL MODIFICATIONS OF NR COREGULATORS, SUCH AS PROTEOLYTIC PROCESSING, GENERATE ENDOMETRIOSIS-SPECIFIC ISOFORMS. COMPARED WITH THE UNMODIFIED COREGULATORS, THESE COREGULATOR ISOFORMS HAVE UNIQUE FUNCTIONS THAT ENHANCE THE PATHOGENESIS OF ENDOMETRIOSIS. CONCLUSIONS: EPIGENETIC/GENETIC VARIATIONS AND POSTTRANSLATIONAL MODIFICATIONS OF NRS AND COREGULATORS ALTER THEIR ORIGINAL FUNCTION SO THAT THEY BECOME POTENT 'DRIVERS' OF ENDOMETRIOSIS PROGRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  1887  79 ENDOMETRIAL RECEPTIVITY IN WOMEN OF ADVANCED AGE: AN UNDERRATED FACTOR IN INFERTILITY. BACKGROUND: MODERN LIFESTYLE HAS LED TO AN INCREASE IN THE AGE AT CONCEPTION. ADVANCED AGE IS ONE OF THE CRITICAL RISK FACTORS FOR FEMALE-RELATED INFERTILITY. IT IS WELL KNOWN THAT MATERNAL AGE POSITIVELY CORRELATES WITH THE DETERIORATION OF OOCYTE QUALITY AND CHROMOSOMAL ABNORMALITIES IN OOCYTES AND EMBRYOS. THE EFFECT OF AGE ON ENDOMETRIAL FUNCTION MAY BE AN EQUALLY IMPORTANT FACTOR INFLUENCING IMPLANTATION RATE, PREGNANCY RATE, AND OVERALL FEMALE FERTILITY. HOWEVER, THERE ARE ONLY A FEW PUBLISHED STUDIES ON THIS TOPIC, SUGGESTING THAT THIS AREA HAS BEEN UNDER-EXPLORED. IMPROVING OUR KNOWLEDGE OF ENDOMETRIAL AGING FROM THE BIOLOGICAL (CELLULAR, MOLECULAR, HISTOLOGICAL) AND CLINICAL PERSPECTIVES WOULD BROADEN OUR UNDERSTANDING OF THE RISKS OF AGE-RELATED FEMALE INFERTILITY. OBJECTIVE AND RATIONALE: THE OBJECTIVE OF THIS NARRATIVE REVIEW IS TO CRITICALLY EVALUATE THE EXISTING LITERATURE ON ENDOMETRIAL AGING WITH A FOCUS ON SYNTHESIZING THE EVIDENCE FOR THE IMPACT OF ENDOMETRIAL AGING ON CONCEPTION AND PREGNANCY SUCCESS. THIS WOULD PROVIDE INSIGHTS INTO EXISTING GAPS IN THE CLINICAL APPLICATION OF RESEARCH FINDINGS AND PROMOTE THE DEVELOPMENT OF TREATMENT OPTIONS IN THIS FIELD. SEARCH METHODS: THE REVIEW WAS PREPARED USING PUBMED (MEDLINE) UNTIL FEBRUARY 2023 WITH THE KEYWORDS SUCH AS 'ENDOMETRIAL AGING', 'RECEPTIVITY', 'DECIDUALIZATION', 'HORMONE', 'SENESCENCE', 'CELLULAR', 'MOLECULAR', 'METHYLATION', 'BIOLOGICAL AGE', 'EPIGENETIC', 'OOCYTE RECIPIENT', 'OOCYTE DONATION', 'EMBRYO TRANSFER', AND 'PREGNANCY RATE'. ARTICLES IN A LANGUAGE OTHER THAN ENGLISH WERE EXCLUDED. OUTCOMES: IN THE AGING ENDOMETRIUM, ALTERATIONS OCCUR AT THE MOLECULAR, CELLULAR, AND HISTOLOGICAL LEVELS SUGGESTING THAT AGING HAS A NEGATIVE EFFECT ON ENDOMETRIAL BIOLOGY AND MAY IMPAIR ENDOMETRIAL RECEPTIVITY. ADDITIONALLY, ADVANCED AGE INFLUENCES CELLULAR SENESCENCE, WHICH PLAYS AN IMPORTANT ROLE DURING THE INITIAL PHASE OF IMPLANTATION AND IS A MAJOR OBSTACLE IN THE DEVELOPMENT OF SUITABLE SENOLYTIC AGENTS FOR ENDOMETRIAL AGING. AGING IS ALSO ACCOUNTABLE FOR CHRONIC CONDITIONS ASSOCIATED WITH INFLAMMAGING, WHICH EVENTUALLY CAN LEAD TO INCREASED PRO-INFLAMMATION AND TISSUE FIBROSIS. FURTHERMORE, ADVANCED AGE INFLUENCES EPIGENETIC REGULATION IN THE ENDOMETRIUM, THUS ALTERING THE RELATION BETWEEN ITS EPIGENETIC AND CHRONOLOGICAL AGE. THE STUDIES IN OOCYTE DONATION CYCLES TO DETERMINE THE EFFECT OF AGE ON ENDOMETRIAL RECEPTIVITY WITH RESPECT TO THE RATES OF IMPLANTATION, CLINICAL PREGNANCY, MISCARRIAGE, AND LIVE BIRTH HAVE REVEALED CONTRADICTORY INFERENCES INDICATING THE NEED FOR FUTURE RESEARCH ON THE MECHANISMS AND CORRESPONDING CAUSAL EFFECTS OF WOMEN'S AGE ON ENDOMETRIAL RECEPTIVITY. WIDER IMPLICATIONS: INCREASING AGE CAN BE ACCOUNTABLE FOR FEMALE INFERTILITY AND IVF FAILURES. BASED ON THE COMPLIED OBSERVATIONS AND SYNTHESIZED CONCLUSIONS IN THIS REVIEW, ADVANCED AGE HAS BEEN SHOWN TO HAVE A NEGATIVE IMPACT ON ENDOMETRIAL FUNCTIONING. THIS INFORMATION CAN PROVIDE RECOMMENDATIONS FOR FUTURE RESEARCH FOCUSING ON MOLECULAR MECHANISMS OF AGE-RELATED CELLULAR SENESCENCE, CELLULAR COMPOSITION, AND TRANSCRIPTOMIC CHANGES IN RELATION TO ENDOMETRIAL AGING. ADDITIONALLY, FURTHER PROSPECTIVE RESEARCH IS NEEDED TO EXPLORE NEWLY EMERGING THERAPEUTIC OPTIONS, SUCH AS THE SENOLYTIC AGENTS THAT CAN TARGET ENDOMETRIAL AGING WITHOUT AFFECTING DECIDUALIZATION. MOREOVER, CLINICAL TRIAL PROTOCOLS, FOCUSING ON OOCYTE DONATION CYCLES, WOULD BE BENEFICIAL IN UNDERSTANDING THE DIRECT CLINICAL IMPLICATIONS OF ENDOMETRIAL AGING ON PREGNANCY OUTCOMES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  6406  39 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18  1004  48 CHRONIC TREATMENT WITH HORMONAL CONTRACEPTIVES ALTERS HIPPOCAMPAL BDNF AND HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS BUT NOT LEARNING AND MEMORY IN FEMALE RATS. HORMONAL CONTRACEPTIVES PREVENT OVULATION WITH SUBSEQUENT REDUCTION IN ENDOGENOUS LEVELS OF ESTRADIOL, PROGESTERONE AND ITS NEUROACTIVE METABOLITE ALLOPREGNANOLONE. THESE NEUROSTEROIDS MODULATE SEVERAL BRAIN FUNCTIONS, INCLUDING NEURONAL PLASTICITY, COGNITION AND MEMORY. WE HYPOTHESIZED THAT HORMONAL CONTRACEPTIVES MIGHT AFFECT SYNAPTIC PLASTICITY, LEARNING AND MEMORY, AS A CONSEQUENCE OF SUPPRESSED ENDOGENOUS HORMONES LEVELS. FEMALE RATS WERE ORALLY TREATED WITH A COMBINATION OF ETHINYL ESTRADIOL (EE, 0.020 MG) AND LEVONORGESTREL (LNG, 0.060 MG) ONCE DAILY FOR FOUR WEEKS. DECREASED HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND ALTERED HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS (PTMS) WERE OBSERVED 14 DAYS AFTER DISCONTINUATION FROM CHRONIC EE-LNG TREATMENT. THESE EFFECTS WERE NOT ACCOMPANIED BY ALTERATIONS IN LONG-TERM PLASTICITY AT GLUTAMATERGIC SYNAPSES, RECOGNITION MEMORY IN THE NOVEL OBJECT AND NOVEL PLACE LOCATION TESTS, OR SPATIAL LEARNING, MEMORY, AND BEHAVIORAL FLEXIBILITY IN THE MORRIS WATER MAZE TEST. THUS, DECREASED BDNF CONTENT DOES NOT AFFECT SYNAPTIC PLASTICITY AND COGNITIVE PERFORMANCE; RATHER IT MIGHT BE RELEVANT FOR THE OCCURRENCE OF CERTAIN PSYCHIATRIC SYMPTOMS, REPORTED BY SOME WOMEN USING HORMONAL CONTRACEPTIVES. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF HIPPOCAMPAL EPIGENETIC CHANGES INDUCED BY HORMONAL CONTRACEPTIVES AND COMPLEMENT PREVIOUS STUDIES ON THE NEUROBIOLOGICAL ACTIONS OF HORMONAL CONTRACEPTIVES; THE FINDING THAT EFFECTS OF CHRONIC EE-LNG TREATMENT ON BDNF CONTENT AND HISTONE PTMS ARE OBSERVED 14 DAYS AFTER DRUG DISCONTINUATION WARRANTS FURTHER INVESTIGATION TO BETTER UNDERSTAND THE IMPLICATIONS OF SUCH LONG-TERM CONSEQUENCES FOR WOMEN'S HEALTH.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19   265  68 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  6742  49 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM.	2012