1  4523 443 MULTIDISCIPLINARY APPROACH TO PROSTATITIS. THE MODERN CLINICAL RESEARCH ON PROSTATITIS STARTED WITH THE WORK OF STAMEY AND COWORKERS WHO DEVELOPED THE BASIC PRINCIPLES WE ARE STILL USING. THEY ESTABLISHED THE SEGMENTED CULTURE TECHNIQUE FOR LOCALIZING THE INFECTIONS IN THE MALES TO THE URETHRA, THE BLADDER, OR THE PROSTATE AND TO DIFFERENTIATE THE MAIN CATEGORIES OF PROSTATITIS. SUCH CATEGORIES WITH SLIGHT MODIFICATIONS ARE STILL USED ACCORDING TO THE NIH CLASSIFICATION: ACUTE BACTERIAL PROSTATITIS, CHRONIC BACTERIAL PROSTATITIS, CHRONIC PELVIC PAIN SYNDROME (CPPS) AND ASYMPTOMATIC PROSTATITIS. PROSTATIC INFLAMMATION IS CONSIDERED AN IMPORTANT FACTOR IN INFLUENCING BOTH PROSTATIC GROWTH AND PROGRESSION OF SYMPTOMS OF BENIGN PROSTATIC HYPERPLASIA AND PROSTATITIS. CHRONIC INFLAMMATION/NEUROINFLAMMATION IS A RESULT OF A DEREGULATED ACUTE PHASE RESPONSE OF THE INNATE IMMUNE SYSTEM AFFECTING SURROUNDING NEURAL TISSUE AT MOLECULAR, STRUCTURAL AND FUNCTIONAL LEVELS. CLINICAL OBSERVATIONS SUGGEST THAT CHRONIC INFLAMMATION CORRELATES WITH CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) AND BENIGN PROSTATIC HYPERPLASIA (BPH) AND AN HISTORY OF CLINICAL CHRONIC PROSTATITIS SIGNIFICANTLY INCREASES THE ODDS FOR PROSTATE CANCER. THE NIHNIDDK CLASSIFICATION BASED ON THE USE OF THE MICROBIOLOGICAL 4- GLASSES LOCALIZATION TEST OR SIMPLIFIED 2-GLASSES TEST, IS CURRENTLY ACCEPTED WORLDWIDE. THE UPOINT SYSTEM IDENTIFIES GROUPS OF CLINICIANS WITH HOMOGENEOUS CLINICAL PRESENTATION AND IS USED TO RECOGNIZE PHENOTYPES TO BE SUBMITTED TO SPECIFIC TREATMENTS. THE UPOINTS ALGORITHM IMPLEMENTED THE ORIGINAL UPOINT ADDING TO THE URINARY DOMAINS (U), PSYCHO-SOCIAL (P), ORGANSPECIFIC (O), INFECTION (I), NEUROLOGICAL (N), MUSCLE TENSION AND TENDERNESS (T) A FURTHER DOMAIN RELATED TO SEXUALITY (S). IN FACT SEXUAL DYSFUNCTION (ERECTILE, EJACULATORY, LIBIDO LOSS) HAS BEEN DESCRIBED IN 46-92% OF CASES WITH A HIGH IMPACT ON THE QUALITY OF LIFE OF PATIENTS WITH CP/CPPS. PROSTATIC ULTRASOUND REPRESENTS THE MOST POPULAR IMAGING TEST IN THE WORK-UP OF EITHER ACUTE AND CHRONIC PROSTATITIS ALTHOUGH NO SPECIFIC HYPO-HYPERECHOIC PATTERN HAS BEEN CLEARLY ASSOCIATED WITH CHRONIC BACTERIAL PROSTATITIS AND CPPS. USE OF A DIGITAL-PROCESSING SOFTWARE TO CALCULATE THE EXTENSION OF PROSTATIC CALCIFICATION AREA AT ULTRASOUND DEMONSTRATED A HIGHER PERCENTAGE OF PROSTATIC CALCIFICATION IN PATIENTS WITH CHRONIC BACTERIAL PROSTATITIS. MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING (MPMRI) IS THE CURRENT STATE-OF-THE ART IMAGING MODALITY IN THE ASSESSMENT OF PATIENTS WITH PROSTATE CANCER ALTHOUGH A VARIETY OF BENIGN CONDITIONS, INCLUDING INFLAMMATION, MAY MIMIC PROSTATE CANCER AND ACT AS CONFOUNDING FACTORS IN THE DISCRIMINATION BETWEEN NEOPLASTIC AND NON-NEOPLASTIC LESIONS. BACTERIA CAN INFECT PROSTATE GLAND BY: ASCENDING THE URETHRA, REFLUX OF URINE INTO THE PROSTATIC DUCTS, DIRECT INOCULATION OF BACTERIA THROUGH INSERTED BIOPSY NEEDLES OR HEMATOGENOUS SEEDING. ENTEROBACTERIACEAE ARE THE PREDOMINANT PATHOGENS IN ACUTE AND CHRONIC BACTERIAL PROSTATITIS, BUT AN INCREASING ROLE OF ENTEROCOCCI HAS BEEN REPORTED. MANY STRAINS OF THESE UROPATHOGENS EXHIBIT THE ABILITY TO FORM BIOFILM AND MULTIDRUG- RESISTANCE. SEXUALLY TRANSMITTED INFECTIONS (STI) AGENTS, IN PARTICULAR CHLAMYDIA TRACHOMATIS AND MYCOPLASMA GENITALIUM, HAVE BEEN ALSO CONSIDERED AS CAUSATIVE PATHOGENS OF CHRONIC BACTERIAL PROSTATITIS. ON THE CONTRARY THE EFFECTIVE ROLE IN GENITAL DISEASES OF OTHER "GENITAL MYCOPLASMAS" IS STILL A MUCH DEBATED ISSUE. SEXUALLY TRANSMITTED INFECTIONS AGENTS SHOULD BE INVESTIGATED BY MOLECULAR METHODS IN BOTH PATIENT AND SEXUAL PARTNER. "NEXT GENERATION" INVESTIGATIONS, SUCH AS CYTOKINE ANALYSIS, CYTOLOGICAL TYPING OF IMMUNE CELLS COULD HELP STRATIFYING THE IMMUNE RESPONSE. EPIGENETIC DYSREGULATION OF INFLAMMATORY FACTORS SHOULD BE INVESTIGATED ACCORDING TO SYSTEMIC AND COMPARTMENT-SPECIFIC SIGNALS. THE SEARCH FOR BIOMARKERS SHOULD ALSO INCLUDE EVALUATION OF HORMONAL PATHWAYS, AS MEASUREMENT OF ESTROGEN LEVELS IN SEMEN. ANTIMICROBIALS ARE THE FIRST LINE AGENTS FOR THE TREATMENT OF BACTERIAL PROSTATITIS. THE SUCCESS OF ANTIMICROBIAL TREATMENT DEPENDS ON THE ANTIBACTERIAL ACTIVITY AND THE PHARMACOKINETIC CHARACTERISTICS OF THE DRUG WHICH MUST REACH HIGH CONCENTRATIONS IN PROSTATE SECRETION AND PROSTATE TISSUE. ACUTE BACTERIAL PROSTATITIS CAN BE A SERIOUS INFECTION WITH A POTENTIAL RISK FOR UROSEPSIS FOR IINITIAL TREATMENT OF SEVERELY ILL PATIENTS, INTRAVENOUS ADMINISTRATION OF HIGH DOSES OF BACTERICIDAL ANTIMICROBIALS, SUCH AS BROAD-SPECTRUM PENICILLINS, THIRD-GENERATION CEPHALOSPORINS OR FLUOROQUINOLONES, IS RECOMMENDED IN COMBINATION WITH AN AMINOGLYCOSIDE. USE OF PIPERACILLIN-TAZOBACTAM AND MEROPENEM IS JUSTIFIED IN PRESENCE OF MULTIRESISTANT GRAMNEGATIVE PATHOGENS. THE ANTIBIOTIC TREATMENT OF CHRONIC PROSTATITIS IS CURRENTLY BASED ON THE USE OF FLUOROQUINOLONES THAT, GIVEN FOR 2 TO 4 WEEKS, CURED ABOUT 70% OF MEN WITH CHRONIC BACTERIAL PROSTATITIS. FOR THE TREATMENT OF CHLAMYDIAL PROSTATITIS MACROLIDES WERE SHOWN TO BE MORE EFFECTIVE THAN FLUOROQUINOLONES, WHEREAS NO DIFFERENCES WERE OBSERVED IN MICROBIOLOGICAL AND CLINICAL EFFICACY BETWEEN MACROLIDES AND TETRACYCLINES FOR THE TREATMENT OF INFECTIONS CAUSED BY INTRACELLULAR PATHOGENS. AMINOGLYCOSIDES AND FOSFOMYCIN COULD BE CONSIDERED AS A THERAPEUTIC ALTERNATIVE FOR THE TREATMENT OF QUINOLONE RESISTANT PROSTATITIS. USE OF ALPHA-BLOCKERS IN CP/CPPS PATIENTS WITH URINARY SYMPTOMS AND ANALGESICS +/- NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID), IN PRESENCE OF PAIN DEMONSTRATED A REDUCTION OF SYMPTOMS REDUCTION AND AN IMPROVEMENT OF QUALITY OF LIFE, ALTHOUGH LONG TERM USE OF NSAID IS LIMITED BY SIDE EFFECT PROFILE. HOWEVER, THE MULTIMODAL THERAPEUTIC REGIMEN BY CONTEMPORARY USE OF ALPHABLOCKERS, ANTIBIOTICS AND ANTI-INFLAMMATORY SHOWED A BETTER CONTROL OF PROSTATITIS SYMPTOMS THAN SINGLE DRUG TREATMENT. NOVEL THERAPEUTIC SUBSTANCES FOR THE TREATMENT OF PAIN, SUCH AS THE CANNABINOID ANANDAMIDE WOULD BE HIGHLY INTERESTING TO TEST. AN ALTERNATIVE FOR THE TREATMENT OF CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME IS PHYTOTHERAPY, AS PRIMARY THERAPY OR IN ASSOCIATION WITH OTHER DRUGS. QUERCETIN, POLLEN EXTRACT, EXTRACT OF SERENOA REPENS AND OTHER MIXTURES OF HERBAL EXTRACTS SHOWED A POSITIVE EFFECT ON SYMPTOMS AND QUALITY OF LIFE WITHOUT SIDE EFFECTS. THE ASSOCIATION OF CP/CPPS WITH ALTERATIONS OF INTESTINAL FUNCTION HAS BEEN DESCRIBED. DIET HAS ITS EFFECTS ON INFLAMMATION BY REGULATION OF THE COMPOSITION OF INTESTINAL FLORA AND DIRECT ACTION ON THE INTESTINAL CELLS (STERILE INFLAMMATION). INTESTINAL BACTERIA (MICROBIOTA) INTERACTS WITH FOOD INFLUENCING THE METABOLIC, IMMUNE AND INFLAMMATORY RESPONSE OF THE ORGANISM. THE INTESTINAL MICROBIOTA HAS PROTECTIVE FUNCTION AGAINST PATHOGENIC BACTERIA, METABOLIC FUNCTION BY SYNTHESIS OF VITAMINS, DECOMPOSITION OF BILE ACIDS AND PRODUCTION OF TROPHIC FACTORS (BUTYRATE), AND MODULATION OF THE INTESTINAL IMMUNE SYSTEM. THE ALTERATION OF THE MICROBIOTA IS CALLED "DYSBIOSIS" CAUSING INVASIVE INTESTINAL DISEASES PATHOLOGIES (LEAKY GUT SYNDROME AND FOOD INTOLERANCES, IRRITABLE BOWEL SYNDROME OR CHRONIC INFLAMMATORY BOWEL DISEASES) AND CORRELATING WITH NUMEROUS SYSTEMIC DISEASES INCLUDING ACUTE AND CHRONIC PROSTATITIS. ADMINISTRATION OF LIVE PROBIOTICS BACTERIA CAN BE USED TO REGULATE THE BALANCE IF INTESTINAL FLORA. SESSIONS OF HYDROCOLONTHERAPY CAN REPRESENT AN INTEGRATION TO THIS THERAPEUTIC APPROACH. FINALLY, MICROBIOLOGICAL EXAMINATION OF SEXUAL PARTNERS CAN OFFER SUPPLEMENTARY INFORMATION FOR TREATMENT.	2019	

2  6489  47 TRACHOMA AND OCULAR CHLAMYDIAL INFECTION IN THE ERA OF GENOMICS. TRACHOMA IS A BLINDING DISEASE USUALLY CAUSED BY INFECTION WITH CHLAMYDIA TRACHOMATIS (CT) SEROVARS A, B, AND C IN THE UPPER TARSAL CONJUNCTIVA. INDIVIDUALS IN ENDEMIC REGIONS ARE REPEATEDLY INFECTED WITH CT THROUGHOUT CHILDHOOD. A PROPORTION OF INDIVIDUALS EXPERIENCE PROLONGED OR SEVERE INFLAMMATORY EPISODES THAT ARE KNOWN TO BE SIGNIFICANT RISK FACTORS FOR OCULAR SCARRING IN LATER LIFE. CONTINUED SCARRING OFTEN LEADS TO TRICHIASIS AND IN-TURNING OF THE EYELASHES, WHICH CAUSES PAIN AND CAN EVENTUALLY CAUSE BLINDNESS. THE MECHANISMS DRIVING THE CHRONIC IMMUNOPATHOLOGY IN THE CONJUNCTIVA, WHICH LARGELY PROGRESSES IN THE ABSENCE OF DETECTABLE CT INFECTION IN ADULTS, ARE LIKELY TO BE MULTIFACTORIAL. SOCIOECONOMIC STATUS, EDUCATION, AND BEHAVIOR HAVE BEEN IDENTIFIED AS CONTRIBUTING TO THE RISK OF SCARRING AND INFLAMMATION. WE FOCUS ON THE CONTRIBUTION OF HOST AND PATHOGEN GENETIC VARIATION, BACTERIAL ECOLOGY OF THE CONJUNCTIVA, AND HOST EPIGENETIC IMPRINTING INCLUDING SMALL RNA REGULATION BY BOTH HOST AND PATHOGEN IN THE DEVELOPMENT OF OCULAR PATHOLOGY. EACH OF THESE FACTORS OR PROCESSES CONTRIBUTES TO PATHOGENIC OUTCOMES IN OTHER INFLAMMATORY DISEASES AND WE OUTLINE THEIR POTENTIAL ROLE IN TRACHOMA.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  4430  51 MOLECULAR BIOLOGY OF ONCOGENIC INFLAMMATORY PROCESSES. I. NON-ONCOGENIC AND ONCOGENIC PATHOGENS, INTRINSIC INFLAMMATORY REACTIONS WITHOUT PATHOGENS, AND MICRORNA/DNA INTERACTIONS (REVIEW). IN SOME INFLAMMASOMES TUMOR CELLS ARE GENERATED. THE INTERNAL ENVIRONMENT OF THE INFLAMMASOME IS CONDUCIVE TO THE INDUCTION OF MALIGNANT TRANSFORMATION. EPIGENETIC CHANGES INITIATE THIS PROCESS. THE SUBVERTED STROMAL CONNECTIVE TISSUE CELLS ACT TO PROMOTE AND SUSTAIN THE PROCESS OF MALIGNANT TRANS-FORMATION. IN ITS EARLY STAGES, THE PREMALIGNANT CELLS DEPEND ON PARACRINE CIRCUITRIES FOR THE RECEPTION OF GROWTH FACTORS. THE LIGANDS ARE DERIVED FROM THE CONNECTIVE TISSUE, AND THE RECEPTORS ARE EXPRESSED ON THE RECIPIENT PREMALIGNANT CELLS. THE INITIAL EVENTS ARE NOT A DIRECT ATTACK ON THE PROTO-ONCOGENES, AND THUS IT MAY BE ENTIRELY REVERSIBLE. EPIGENETIC PROCESSES OF HYPERMETHYLATION OF THE GENES AT THE PROMOTERS OF TUMOR SUPPRESSOR GENES (TO SILENCE THEM), AND DEACETYLATION OF THE HISTONES AIMED AT THE PROMOTERS OF PROTO-ONCOGENES (TO ACTIVATE THEM) ARE ON-GOING. A LARGE NUMBER OF SHORT RNA SEQUENCES (INTERFERING, MICRO-, SHORT HAIRPIN, NON-CODING RNAS) SILENCE TUMOR SUPPRESSOR GENES, BY NEUTRALIZING THEIR MRNAS. IN A SERIAL SEQUENCE ONCOGENES UNDERGO AMPLIFICATIONS, POINT-MUTATIONS, TRANSLOCATIONS AND FUSIONS. IN ITS EARLIEST STAGE, THE PROCESS IS REVERSIBLE BY DEMETHYLATION OF THE SILENCED SUPPRESSOR GENE PROMOTERS (TO REACTIVATE THEM), OR RE-ACETYLATION OF THE HISTONES OF THE ONCOGENE PROMOTERS, THUS DE-ACTIVATING THEM. THE EXTERNAL ADMINISTRATION OF HISTONE DEACETYLASE INHIBITORS USUALLY LEADS TO THE RESTORATION OF HISTONE ACETYLATION. IN TIME, THE UNCORRECTED PROCESSES SOLIDIFY INTO CONSTITUTIVE AND IRREVERSIBLE GENE MUTATIONS. SOME OF THE PATHOGENS INDUCING INFLAMMATIONS WITH CONSQUENTIAL MALIGNANT TRANSFORMATION CONTAIN ONCOGENIC GENE SEQUENCES (PAPILLOMA VIRUSES, EPSTEIN-BARR VIRUS, KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS, HEPATITIS B AND C VIRUSES, MERKEL CELL POLYOMA VIRUS, HELICOBACTER PYLORI, ENTEROTOXIGENIC BACTEROIDES FRAGILIS). THESE INDUCED MALIGNANCIES MAY BE MULTIFOCAL. OTHER PATHOGENS ARE DEVOID OF ANY KNOWN ONCOGENIC GENOMIC SEQUENCES (MYCOPLASMA VAV-CARCINOGENESIS, CHLAMYDIA MALT-LYMPHOMA GENESIS). IN THESE CASES THE HOST'S INFLAMMATORY REACTIONS INDUCE THE MALIGNANT TRANSFORMATION IN SERIAL SEQUENCES OF GENE ALTERATIONS INITIATED BY HYPOXIA AND REACTIVE OXYGEN AND NITROGEN SPECIES GENERATION. CARCINOGENIC INTRINSIC INFLAMMATORY PROCESSES ENDOGENOUSLY INITIATED WITHOUT A PATHOGEN ARE RECOGNIZED. CHRONIC INFLAMMATORY PROCESSES SIGNAL THE RNA/DNA COMPLEX. IN RESPONSE, THE DNA MAY REVERT INTO ITS ANCIENT PRIMORDIAL 'IMMORTAL' FORMAT, WHICH THE CLINICS RECOGNIZE AS 'ONCOGENESIS'. THE DNA REMAINS THE ULTIMATE MASTER OF BIOENGINEERING IN ORDER TO SUSTAIN LIFE. A DISCUSSION ON THE MOST VERSATILE AND RESISTANT PRIMORDIAL RNA/DNA COMPLEX AND THE PRE-, PROTO-, AND UNICELLULAR WORLD IN WHICH THEY CO-EXISTED IS INCLUDED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4   983  59 CHRONIC PROSTATITIS AFFECTS MALE REPRODUCTIVE HEALTH AND IS ASSOCIATED WITH SYSTEMIC AND LOCAL EPIGENETIC INACTIVATION OF C-X-C MOTIF CHEMOKINE 12 RECEPTOR C-X-C CHEMOKINE RECEPTOR TYPE 4. BACKGROUND/AIMS/OBJECTIVES: CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) HAS DETRIMENTAL EFFECTS ON THE QUALITY OF LIFE INCLUDING THE ASPECT OF SEXUAL DYSFUNCTION. THE AIM OF THE STUDY WAS TO IDENTIFY IF THERE WAS AN ADVERSE EFFECT ON THE MALE GENITAL COMPARTMENT AND IF THERE ARE SYSTEMIC OR COMPARTMENT-SPECIFIC LOCAL SIGNALS FOR EPIGENETIC DYSREGULATION OF INFLAMMATORY FACTORS IN CP/CPPS PATIENTS. METHODS: ONE HUNDRED FIVE NIH IIIB CP/CPPS PATIENTS AND 41 HEALTHY MEN WERE RECRUITED AND UNDERWENT INVESTIGATIONS OF URINES, SEMEN AND BLOOD. PROMOTER METHYLATION AND EXPRESSION OF THE CHEMOKINE C-X-C MOTIF CHEMOKINE 12 AND ITS RECEPTOR C-X-C CHEMOKINE RECEPTOR TYPE 4 (CXCR4) (INVOLVED IN THE RECRUITMENT OF MAST CELLS) WERE ANALYZED IN PROSTATE EPITHELIAL CELL LINES AND IN HEALTHY VOLUNTEERS' AND PATIENTS' BLOOD, EJACULATE CELL PELLETS, AND SEPARATED EJACULATE FRACTIONS (SPERM AND SEMINAL SOMATIC CELLS). RESULTS: INDEPENDENTLY FROM AGE, CP/CPPS NIH IIIB WAS ASSOCIATED WITH SIGNIFICANT IMPAIRMENT OF SPERM MOTILITY, MORPHOLOGY AND SEMEN PH (P < 0.001). PATIENTS OLDER THAN 33 YEARS SHOWED SIGNIFICANTLY INCREASED SEMINAL INTERLEUKIN-8 AND SERUM PROSTATE SPECIFIC ANTIGEN VALUES. IN PATIENTS, THE CXCR4 MRNA-EXPRESSION WAS SIGNIFICANTLY DECREASED IN WHOLE BLOOD AND EJACULATE CELL PELLETS DUE TO PROMOTER HYPERMETHYLATION. ANALYSES ON SEPARATED FRACTIONS OF SPERM AND SEMINAL SOMATIC CELLS REVEALED THAT SPERM DNA WAS UNAFFECTED, WHEREAS SOMATIC CELL DNA WAS DIFFERENTIALLY METHYLATED. CONCLUSIONS: NIH IIIB CP/CPPS HAS NEGATIVE EFFECTS ON SURROGATE PARAMETERS OF MALE FERTILITY AND IS ASSOCIATED SIGNIFICANTLY WITH SYSTEMIC AND LOCAL EPIGENETIC INACTIVATION OF CXCR4.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5   537  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  3934  97 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS.	1982	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  5786  49 SPORT AND MALE SEXUALITY. THE RELATIONSHIPS BETWEEN SPORT AND SEXUALITY IN MALES ARE OF GREAT SOCIAL AND CLINICAL INTEREST, BECAUSE OF SPORTS AND MOTOR ACTIVITIES THAT HIGHLY PROMOTE SOCIAL AND SEXUAL RELATIONSHIPS. EVEN IF FEW LITERATURE EXIST, TWO MAIN QUESTIONS SHOULD BE TAKEN INTO ACCOUNT: WHETHER AND HOW PHYSICAL EXERCISE AND SPORT POSITIVELY OR NEGATIVELY INFLUENCE SEXUAL HEALTH AND BEHAVIOR AND/OR WHETHER AND HOW SEXUAL BEHAVIOR MAY AFFECT A SUB-SEQUENT SPORT PERFORMANCE. PHYSICAL EXERCISE AND SPORT PER SE CAN INFLUENCE, POSITIVELY OR NEGATIVELY, THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FUNCTION AND, CONSEQUENTLY, THE INDIVIDUAL'S REPRODUCTIVE AND/OR SEXUAL HEALTH. THIS DEPENDS ON INDIVIDUAL FACTORS SUCH AS GENETIC AND EPIGENETIC ONES AND ON DIFFERENT VARIABLES INVOLVED IN THE PRACTICE OF SPORT ACTIVITIES (TYPE OF SPORT, INTENSITY AND DURATION OF TRAINING, DOPING AND DRUG USE AND ABUSE, NUTRITION, SUPPLEMENTS, PSYCHOLOGICAL STRESS, ALLOSTATIC LOAD, ETC.). IF WELL CONDUCTED, MOTOR AND SPORT ACTIVITIES COULD HAVE BENEFICIAL EFFECTS ON SEXUAL HEALTH IN MALES. AMONG DIFFERENT LIFESTYLE CHANGES, INFLUENCING SEXUAL HEALTH, REGULAR PHYSICAL ACTIVITY IS FUNDAMENTAL TO ANTAGONIZE THE ONSET OF ERECTILE DYSFUNCTION (ED). HOWEVER, COMPETITIVE SPORT CAN LEAD BOTH REPRODUCTIVE AND/OR SEXUAL TRACT DAMAGES AND DYSFUNCTIONS, TRANSIENT (GENITAL PAIN, HYPOESTHESIA OF THE GENITALIA, HYPOGONADISM, DE, ALTERED SEXUAL DRIVE, ETC.) OR PERMANENT (HYPOGONADISM, DE, ETC.), BY ACTING DIRECTLY (TRAUMAS OF THE EXTERNAL GENITALIA, SADDLE-RELATED DISORDERS IN CYCLISTS, ETC.) OR INDIRECTLY (EXERCISE-RELATED HYPOGONADISM, DRUG ABUSE, DOPING, STRESS, ETC.). SEXUAL ACTIVITIES SHORTLY PERFORMED BEFORE A SPORT COMPETITION COULD DIFFERENTLY INFLUENCE SPORT PERFORMANCE. DUE TO THE FEW EXISTING DATA, IT IS ADVISABLE TO AVOID AN ABSOLUTE PRE-COMPETITION SEXUAL ABSTINENCE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  1854  61 ELEVATED SEMINAL PLASMA ESTRADIOL AND EPIGENETIC INACTIVATION OF ESR1 AND ESR2 IS ASSOCIATED WITH CP/CPPS. CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) IS ASSOCIATED WITH URINARY TRACT SYMPTOMS AND HORMONAL IMBALANCES AMONGST OTHERS. THE HETEROGENEOUS CLINICAL PRESENTATION, UNEXPLORED MOLECULAR BACKGROUND AND LACK OF PROSTATE BIOPSIES COMPLICATE THERAPY. HERE, USING LIQUID BIOPSIES, WE PERFORMED A COMPREHENSIVE TRANSLATIONAL STUDY ON MEN DIAGNOSED WITH CP/CPPS TYPE III (N= 50; MEDIAN AGE 39.8, RANGE 23-65) AND AGE-MATCHED CONTROLS (N= 61; MEDIAN AGE 36.8, RANGE 20-69), CONSIDERING BIOCHEMICAL PARAMETERS OF BLOOD AND EJACULATES, AND EPIGENETIC REGULATION OF THE ESTROGEN RECEPTOR GENES (ESR1 AND ESR2) IN LEUKOCYTES ISOLATED FROM BLOOD (SYSTEMIC REGULATION) AND IN SOMATIC CELLS ISOLATED FROM EJACULATES (LOCAL REGULATION). WE FOUND ELEVATED 17BETA-ESTRADIOL (E(2)) LEVELS IN SEMINAL PLASMA, BUT NOT IN BLOOD PLASMA, THAT WAS SIGNIFICANTLY ASSOCIATED WITH CP/CPPS AND IMPAIRED URINARY TRACT SYMPTOMS. IN EJACULATED SOMATIC CELLS OF CP/CPPS PATIENTS WE FOUND THAT ESR1 AND ESR2 WERE BOTH SIGNIFICANTLY HIGHER METHYLATED IN CPG-PROMOTERS AND EXPRESSIONALLY DOWN-REGULATED IN COMPARISON TO CONTROLS. MAST CELLS ARE REPORTED TO CONTRIBUTE TO CP/CPPS AND ARE ESTROGEN RESPONSIVE. CONSISTENT WITH THIS, WE FOUND THAT E(2) -TREATMENT OF HUMAN MAST CELL LINES (HMC-1 AND LAD2) RESULTED IN ALTERED CYTOKINE AND CHEMOKINE EXPRESSION. INTERESTINGLY, IN HMC-1 CELLS, POSSESSING EPIGENETICALLY INACTIVATED ESR1 AND ESR2, E(2) -TREATMENT LED TO A REDUCED TRANSCRIPTION OF A NUMBER OF INFLAMMATORY GENES. OVERALL, THESE DATA SUGGEST THAT ELEVATED LOCAL E(2) LEVELS ASSOCIATE WITH AN EPIGENETIC DOWN-REGULATION OF THE ESTROGEN RECEPTORS AND HAVE A PROMINENT ROLE IN CP/CPPS. INVESTIGATING E(2) LEVELS IN SEMEN COULD THEREFORE SERVE AS A PROMISING BIOMARKER TO SELECT PATIENTS FOR ESTROGEN TARGETED THERAPY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9   107  63 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  4015  65 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  6742  67 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12   244  62 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  1887  82 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  6743  76 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. 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.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  6406  55 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  2772  65 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  5451  54 REPROGRAMMING CELLS FROM GULF WAR VETERANS INTO NEURONS TO STUDY GULF WAR ILLNESS. GULF WAR ILLNESS (GWI), WHICH AFFLICTS AT LEAST 25% OF VETERANS WHO SERVED IN THE 1990-1991 WAR IN THE PERSIAN GULF, IS THOUGHT TO BE CAUSED BY DEPLOYMENT EXPOSURES TO VARIOUS NEUROTOXICANTS, INCLUDING PESTICIDES, ANTI-NERVE GAS PILLS, AND LOW-LEVEL NERVE AGENTS INCLUDING SARIN/CYCLOSARIN. GWI IS A MULTISYMPTOM DISORDER CHARACTERIZED BY FATIGUE, JOINT PAIN, COGNITIVE PROBLEMS, AND GASTROINTESTINAL COMPLAINTS. THE MOST PROMINENT SYMPTOMS OF GWI (MEMORY PROBLEMS, POOR ATTENTION/CONCENTRATION, CHRONIC HEADACHES, MOOD ALTERATIONS, AND IMPAIRED SLEEP) SUGGEST THAT THE DISEASE PRIMARILY AFFECTS THE CNS. DEVELOPMENT OF URGENTLY NEEDED TREATMENTS DEPENDS ON EXPERIMENTAL MODELS APPROPRIATE FOR TESTING MECHANISTIC HYPOTHESES AND FOR SCREENING THERAPEUTIC COMPOUNDS. RODENT MODELS HAVE BEEN USEFUL THUS FAR, BUT ARE LIMITED BY THEIR INABILITY TO ASSESS THE CONTRIBUTION OF GENETIC OR EPIGENETIC BACKGROUND TO THE DISEASE, AND BECAUSE DISEASE-VULNERABLE PROTEINS AND PATHWAYS MAY BE DIFFERENT IN HUMANS RELATIVE TO RODENTS. AS OF YET, NO POSTMORTEM TISSUE FROM THE VETERANS HAS BECOME AVAILABLE FOR RESEARCH. WE ARE MOVING FORWARD WITH A PARADIGM SHIFT IN THE STUDY OF GWI, WHICH UTILIZES CONTEMPORARY STEM CELL TECHNOLOGY TO CONVERT SOMATIC CELLS FROM GULF WAR VETERANS INTO PLURIPOTENT CELL LINES THAT CAN BE DIFFERENTIATED INTO VARIOUS CELL TYPES, INCLUDING NEURONS, GLIA, MUSCLE, OR OTHER RELEVANT CELL TYPES. SUCH CELL LINES ARE IMMORTAL AND WILL BE A RESOURCE FOR GWI RESEARCHERS TO PURSUE MECHANISTIC HYPOTHESES AND THERAPEUTICS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  3630  67 INCLUSION OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH TO ADVANCE UNDERSTANDING OF THEIR INFLUENCE ON THE BIOLOGY OF CHRONIC DISEASE. SOCIAL DETERMINANTS OF HEALTH (SDOH) CONSIDER SOCIAL, POLITICAL, AND ECONOMIC FACTORS THAT CONTRIBUTE TO HEALTH DISPARITIES IN PATIENTS AND POPULATIONS. THE MOST COMMON HEALTH-RELATED SDOH EXPOSURES ARE FOOD AND HOUSING INSECURITY, FINANCIAL INSTABILITY, TRANSPORTATION NEEDS, LOW LEVELS OF EDUCATION, AND PSYCHOSOCIAL STRESS. THESE DOMAINS DESCRIBE RISKS THAT CAN IMPACT HEALTH OUTCOMES MORE THAN HEALTH CARE. EPIDEMIOLOGIC AND TRANSLATIONAL RESEARCH DEMONSTRATES THAT SDOH FACTORS REPRESENT EXPOSURES THAT PREDICT HARM AND IMPACT THE HEALTH OF INDIVIDUALS. INTERNATIONAL AND NATIONAL GUIDELINES URGE HEALTH PROFESSIONALS TO ADDRESS SDOH IN CLINICAL PRACTICE AND PUBLIC HEALTH. THE FURTHER IMPLEMENTATION OF THESE RECOMMENDATIONS INTO BASIC AND TRANSLATIONAL RESEARCH, HOWEVER, IS LAGGING. HEREIN, WE CONSIDER A PRECISION HEALTH FRAMEWORK TO DESCRIBE HOW SDOH CONTRIBUTES TO THE EXPOSOME AND EXACERBATES PHYSIOLOGIC PATHWAYS THAT LEAD TO CHRONIC DISEASE. SDOH FACTORS ARE ASSOCIATED WITH VARIOUS FORMS OF STRESSORS THAT IMPACT PHYSIOLOGICAL PROCESSES THROUGH EPIGENETIC, INFLAMMATORY, AND REDOX REGULATION. MANY SDOH EXPOSURES MAY ADD TO OR POTENTIATE THE PATHOLOGIC EFFECTS OF ADDITIONAL ENVIRONMENTAL EXPOSURES. THIS OVERVIEW AIMS TO INFORM BASIC LIFE SCIENCE AND TRANSLATIONAL RESEARCHERS ABOUT SDOH EXPOSURES THAT CAN CONFOUND ASSOCIATIONS BETWEEN CLASSIC BIOMEDICAL DETERMINANTS OF DISEASE AND HEALTH OUTCOMES. TO ADVANCE THE STUDY OF TOXICOLOGY THROUGH EITHER QUALITATIVE OR QUANTITATIVE ASSESSMENT OF EXPOSURES TO CHEMICAL AND BIOLOGICAL SUBSTANCES, A MORE COMPLETE ENVIRONMENTAL EVALUATION SHOULD INCLUDE SDOH EXPOSURES. WE DISCUSS COMMON APPROACHES TO MEASURE SDOH FACTORS AT INDIVIDUAL AND POPULATION LEVELS AND REVIEW THE ASSOCIATIONS BETWEEN SDOH RISK FACTORS AND PHYSIOLOGIC MECHANISMS THAT INFLUENCE CHRONIC DISEASE. WE PROVIDE CLINICAL AND POLICY-BASED MOTIVATION TO ENCOURAGE RESEARCHERS TO CONSIDER THE IMPACT OF SDOH EXPOSURES ON STUDY RESULTS AND DATA INTERPRETATION. WITH VALID MEASURES OF SDOH FACTORS INCORPORATED INTO STUDY DESIGN AND ANALYSES, FUTURE TOXICOLOGICAL RESEARCH MAY CONTRIBUTE TO AN EVIDENCE BASE THAT CAN BETTER INFORM PREVENTION AND TREATMENT OPTIONS, TO IMPROVE EQUITABLE CLINICAL CARE AND POPULATION HEALTH. (C) 2022 WILEY PERIODICALS LLC.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19   367  45 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20   105  60 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS.	2018