1 4858 90 ORAL ANTIBIOTIC USE AND CHRONIC DISEASE: LONG-TERM HEALTH IMPACT BEYOND ANTIMICROBIAL RESISTANCE AND CLOSTRIDIOIDES DIFFICILE. WE RECENTLY REPORTED AN INCREASED COLON CANCER RISK ASSOCIATED WITH ORAL ANTIBIOTIC USE IN A LARGE UNITED KINGDOM POPULATION. THIS ASSOCIATION BETWEEN ANTIBIOTIC EXPOSURE AND CANCER RISK ADDS TO A GROWING BODY OF EVIDENCE THAT ANTIBIOTIC USE HAS UNINTENDED OFF-TARGET LONG-TERM HEALTH CONSEQUENCES. THIS ADDENDUM HIGHLIGHTS MAJOR STUDIES LINKING ANTIBIOTIC USE AND CHRONIC DISEASE IN PEDIATRIC AND ADULT POPULATIONS. MICROBIOTA DYSBIOSIS IS THE KEY PROPOSED MECHANISM UNDERLYING ANTIBIOTIC:DISEASE ASSOCIATIONS, RESULTING IN ALTERATIONS IN GENE EXPRESSION, EPIGENETIC MODIFICATION, COLONIZATION BY PATHOGENIC BACTERIA, INSTIGATION OF BIOFILMS, AND IMMUNE REGULATION AND INFLAMMATION. THESE ADVERSE OUTCOMES OF ANTIBIOTIC EXPOSURE UNDERSCORE THE NEED FOR DIAGNOSTIC AND ANTIBIOTIC STEWARDSHIP, AS WELL AS THE URGENCY FOR FURTHER DEVELOPMENT OF NON-ANTIBIOTIC THERAPIES FOR BACTERIAL INFECTIONS. 2020 2 4827 32 OFF-TARGET DRUG EFFECTS RESULTING IN ALTERED GENE EXPRESSION EVENTS WITH EPIGENETIC AND "QUASI-EPIGENETIC" ORIGINS. THIS REVIEW SYNTHESIZES EXAMPLES OF PHARMACOLOGICAL AGENTS WHO HAVE OFF-TARGET EFFECTS OF AN EPIGENETIC NATURE. WE EXPAND UPON THE PARADIGM OF EPIGENETICS TO INCLUDE "QUASI-EPIGENETIC" MECHANISMS. QUASI-EPIGENETICS INCLUDES MECHANISMS OF DRUGS ACTING UPSTREAM OF EPIGENETIC MACHINERY OR MAY THEMSELVES IMPACT TRANSCRIPTION FACTOR REGULATION ON A MORE GLOBAL SCALE. WE EXPLORE THESE AVENUES WITH FOUR EXAMPLES OF CONVENTIONAL PHARMACEUTICALS AND THEIR UNINTENDED, BUT NOT NECESSARILY ADVERSE, BIOLOGICAL EFFECTS. THE QUASI-EPIGENETIC DRUGS IDENTIFIED IN THIS REVIEW INCLUDE THE USE OF BETA-LACTAM ANTIBIOTICS TO ALTER GLUTAMATE RECEPTOR ACTIVITY AND THE ACTION OF CYCLOSPORINE ON MULTIPLE TRANSCRIPTION FACTORS. IN ADDITION, WE REPORT ON MORE CANONICAL EPIGENOME CHANGES ASSOCIATED WITH PHARMACOLOGICAL AGENTS SUCH AS LITHIUM IMPACTING AUTOPHAGY OF ABERRANT PROTEINS, AND OPIOID DRUGS WHOSE CHRONIC USE INCREASES THE EXPRESSION OF GENES ASSOCIATED WITH ADDICTIVE PHENOTYPES. BY EXPANDING OUR APPRECIATION OF TRANSCRIPTOMIC REGULATION AND THE EFFECTS THESE DRUGS HAVE ON THE EPIGENOME, IT IS POSSIBLE TO ENHANCE THERAPEUTIC APPLICATIONS BY EXPLOITING OFF-TARGET EFFECTS AND EVEN REPURPOSING ESTABLISHED PHARMACEUTICALS. THAT IS, EXPLORATION OF "PHARMACOEPIGENETIC" MECHANISMS CAN EXPAND THE BREADTH OF THE USEFUL ACTIVITY OF A DRUG BEYOND THE TRADITIONAL DRUG TARGETS SUCH AS RECEPTORS AND ENZYMES. 2016 3 1893 33 ENDOMETRIOSIS: NEW PERSPECTIVE FOR THE DIAGNOSIS OF CERTAIN CYTOKINES IN WOMEN AND ADOLESCENT GIRLS, AS WELL AS THE PROGRESSION OF DISEASE OUTGROWTH: A SYSTEMATIC REVIEW. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGICAL DISORDER THAT UNDOUBTEDLY IMPACTS ON QUALITY OF LIFE, AND IS ONE OF THE MORE COMPLEX AND MYSTERIOUS ILLNESSES OF OUR CENTURY, WHICH IS ASSOCIATED WITH THE IMPROPER GROWTH OF ENDOMETRIAL TISSUE OUTSIDE OF THE UTERINE CAVITY. THIS PATHOLOGICALLY IMPLANTED TISSUE CAN BE FOUND MOST FREQUENTLY IN THE MINOR PELVIS, BUT ALSO IN THE PERITONEAL CAVITY, AND CAN AFFECT MANY ORGANS, LEADING TO CHRONIC PELVIC PAIN SYNDROME, INFERTILITY, AND DYSMENORRHEA. ENDOMETRIAL TISSUE IS A PARTICULARLY DYNAMIC TISSUE THAT HAS A DIRECT IMPACT ON THE PROGRESSION OF THE DISEASE, WITH ALTERED IMMUNITY, AS WELL AS CYTOKINE STORMS WITHIN THE METAPLASTIC ENDOMETRIOTIC SITE, AS POSSIBLE KEY FACTORS. CURRENTLY, DIAGNOSIS OF THIS MYSTERIOUS CHRONIC ILLNESS RELIES ON PERFORMING A LAPAROSCOPIC PROCEDURE WITH TISSUE SAMPLING. ONE OF THE MOST TROUBLESOME OUTCOMES OF THIS UNINTENDED PROGRESSION IS THAT WE LACK ANY SPECIFIC, SENSITIVE, NON-INVASIVE DIAGNOSTIC TOOLS. CURRENTLY, THE VAST MAJORITY OF REGIME STEWARDSHIP OPTIONS RELY ON ANTI-CONTRACEPTIVE DRUGS, OR OTHER REMEDIES THAT SUPPRESS THE RELEASE OF ESTROGEN THROUGH THE GONADS-ALTHOUGH IN MOST CLINICAL TRIALS, ENDOMETRIOSIS IS A CHRONIC PROGRESSIVE DISORDER THAT DEPENDS MOSTLY ON THE HIGH CONCENTRATION OF ESTROGEN. MOREOVER, MANY SPECIFIC TRIALS HAVE DEMONSTRATED THAT THE EUTOPIC ENDOMETRIAL CELLS IN INDIVIDUALS WITH ENDOMETRIOSIS REMAIN MUCH MORE RESISTANT TO THE IMMUNOLOGICAL ANNIHILATION PROCESS CAUSED BY CERTAIN ELEMENTS OF THE IMMUNE SYSTEM. NEVERTHELESS, EUTOPIC ENDOMETRIAL CELLS HAVE THE POTENTIAL TO SIMILARLY ESCALATE THE EXPRESSION OF AROMATASE RECEPTORS ON THE SURFACE OF THE PATHOLOGICAL CELLS, WHICH IN THE FINAL CASCADE CAUSE AN INCREASE IN THE CONCENTRATION OF ESTROGEN, AS WELL AS OTHER INFLAMMATORY PROTEINS THAT CONTRIBUTE TO PATHOLOGICAL OUTGROWTH. DATA REVEAL OCCURRENCE AMONG FIRST-DEGREE RELATIVES, SUGGESTING THAT THE SPECIFIC CASCADE COULD BE RELATED TO INHERITED AS WELL AS EPIGENETIC (ACQUIRED) MECHANISMS. IN WOMEN WITH THE DISEASE, CONFIRMED BY LAPAROSCOPIC PROCEDURES, DIAGNOSIS OF ENDOMETRIOSIS CAN BE ESTABLISHED ALSO VIA DETECTION BY GENE POLYMORPHISM IN THE GENES WHICH ARE RESPONSIBLE FOR RESPONSIBLE FOR THE DETOXIFICATION PHASE OF ESTROGEN RECEPTORS AND OTHER IMMUNOMODULATOR COMPONENTS. A RECENT PUBLICATION AIMS TO REVEAL A NEW PROSPECT FOR THE NON-INVASIVE DIAGNOSIS, DETECTION, AND ESTIMATION OF CERTAIN BIOMARKERS FOR MUCH MORE SPECIFIC INVESTIGATION OF THE DISEASE'S PROGRESSION. 2021 4 6634 14 UNINTEGRATED TWO-LONG TERMINAL REPEAT CIRCULAR HUMAN T LYMPHOTROPIC VIRUS DNA ACCUMULATION DURING CHRONIC HTLV INFECTION. ACCUMULATION OF UNINTEGRATED HUMAN T LYMPHOTROPIC VIRUS (HTLV) DNA WAS ANALYZED IN LONG-TERM T CELL LINES INFECTED WITH HTLV TYPE I (HTLV-I) OR TYPE II (HTLV-II). BY USING A POLYMERASE CHAIN REACTION-BASED ASSAY, AMPLIFIED PRODUCTS OF EXPECTED SIZE WERE OBTAINED IN ALL OF THE HTLV-I-INFECTED (N = 7) AND HTLV-II-INFECTED (N = 8) CELL LINES. THE SIGNAL INTENSITIES OF THE HYBRIDIZING BAND VARIED GREATLY AMONG THE CELL LINES AND DID NOT CORRELATE WITH HTLV P24GAG ANTIGEN PRODUCTION. FURTHER ANALYSIS OF HTLV-I-INFECTED CLONES DEMONSTRATED CONSIDERABLE VARIABILITY IN THE UNINTEGRATED DNA ACCUMULATION, SUGGESTING THAT EITHER THE EPIGENETIC STATUS OF THE HOST CELL OR SOME ENVIRONMENTAL FACTOR DETERMINES THE OCCURRENCE OF UNINTEGRATED DNA. THE PRESENCE OF LOWER LEVELS OF UNINTEGRATED DNA IN MOST OF THE HTLV-INFECTED, LONG-TERM CELL LINES PRESUMABLY RESULTS IN PERSISTENT NONCYTOPATHIC INFECTION. 1993 5 792 23 CELLULAR MECHANISMS PROMOTING CACHEXIA AND HOW THEY ARE OPPOSED BY SIRTUINS (1). MANY CHRONIC DISEASES ARE ASSOCIATED WITH UNINTENTIONAL LOSS OF BODY WEIGHT, WHICH IS TERMED "CACHEXIA". CACHEXIA IS A COMPLEX MULTIFACTORIAL SYNDROME ASSOCIATED WITH THE UNDERLYING PRIMARY DISEASE, AND CHARACTERIZED BY LOSS OF SKELETAL MUSCLE WITH OR WITHOUT LOSS OF FAT TISSUE. PATIENTS WITH CACHEXIA FACE DIRE SYMPTOMS LIKE DYSPNEA, FATIGUE, EDEMA, EXERCISE INTOLERANCE, AND LOW RESPONSIVENESS TO MEDICAL THERAPY, WHICH WORSEN QUALITY OF LIFE. BECAUSE CACHEXIA IS NOT A STAND-ALONE DISORDER, TREATING PRIMARY DISEASE - SUCH AS CANCER - TAKES PRECEDENCE FOR THE PHYSICIAN, AND IT REMAINS MOSTLY A NEGLECTED ILLNESS. EXISTING CLINICAL TRIALS HAVE DEMONSTRATED LIMITED SUCCESS MOSTLY BECAUSE OF THEIR MONOTHERAPEUTIC APPROACH AND LATE DETECTION OF THE SYNDROME. TO CONQUER CACHEXIA, IT IS ESSENTIAL TO IDENTIFY AS MANY MOLECULAR TARGETS AS POSSIBLE USING THE LATEST TECHNOLOGIES WE HAVE AT OUR DISPOSAL. IN THIS REVIEW, WE HAVE DISCUSSED DIFFERENT ASPECTS OF CACHEXIA, WHICH INCLUDE VARIOUS DISEASE SETTINGS, ACTIVE MOLECULAR PATHWAYS, AND RECENT NOVEL ADVANCES MADE IN THIS FIELD TO UNDERSTAND CONSEQUENCES OF THIS ILLNESS. WE ALSO DISCUSS ROLES OF THE SIRTUINS, THE NAD(+)-DEPENDENT LYSINE DEACETYLASES, MICRORNAS, CERTAIN DIETARY OPTIONS, AND EPIGENETIC DRUGS AS POTENTIAL APPROACHES, WHICH CAN BE USED TO TACKLE CACHEXIA AS EARLY AS POSSIBLE IN ITS COURSE. 2019 6 1098 19 COLLATERAL DAMAGE: MATERNAL OBESITY DURING PREGNANCY CONTINUES TO RISE. IMPORTANCE: THE PANDEMIC OF OBESITY DURING PREGNANCY NOW AFFLICTS 1 OUT OF EVERY 2 PREGNANT WOMEN IN THE UNITED STATES. EVEN THOUGH UNINTENDED PREGNANCY HAS DECREASED TO 45% OF ALL PREGNANCIES, 50% OF THOSE UNINTENDED PREGNANCIES OCCUR IN OBESE WOMEN. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY WHY CURRENT LIFESTYLE INTERVENTIONS FOR OBESE PREGNANCY ARE NOT EFFECTIVE AND WHAT THE NEWER COMPLICATIONS ARE FOR OBESITY DURING PREGNANCY. EVIDENCE ACQUISITION: AVAILABLE LITERATURES ON CURRENT TREATMENTS FOR MATERNAL OBESITY WERE REVIEWED FOR EFFECTIVENESS. EMERGING MATERNAL AND INFANT COMPLICATIONS FROM OBESITY DURING PREGNANCY WERE EXAMINED FOR SIGNIFICANCE. RESULTS: LIMITATIONS IN SUCCESSFUL INTERVENTIONS FELL INTO 3 BASIC CATEGORIES TO INCLUDE THE FOLLOWING: (1) PRECONCEPTION WEIGHT LOSS; (2) BARIATRIC SURGERY BEFORE PREGNANCY; AND (3) PREVENTION OF EXCESSIVE GESTATIONAL WEIGHT GAIN DURING PREGNANCY. EMERGING SIGNIFICANT PHYSIOLOGICAL CHANGES FROM MATERNAL OBESITY IS COMPOSED OF INFLAMMATION (PLACENTA AND HUMAN MILK), METABOLISM (HORMONES, MICROBIOME, FATTY ACIDS), AND OFFSPRING OUTCOMES (BODY COMPOSITION, CONGENITAL MALFORMATIONS, CHRONIC KIDNEY DISEASE, ASTHMA, NEURODEVELOPMENT, AND BEHAVIOR). CONCLUSIONS AND RELEVANCE: ARE CURRENT PREPREGNANCY LIFESTYLE AND BEHAVIORAL INTERVENTIONS FEASIBLE TO PREVENT MATERNAL OBESITY COMPLICATIONS? EPIGENETIC AND METABOLOMIC RESEARCH WILL BE CRITICAL TO DETERMINE WHAT IS NEEDED TO BLUNT THE EFFECTS OF MATERNAL OBESITY AND TO DISCOVER SUCCESSFUL TREATMENT. 2020 7 4541 35 MULTISYSTEMIC ALTERATIONS IN HUMANS INDUCED BY BISPHENOL A AND PHTHALATES: EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES REVEAL THE NEED TO CHANGE HEALTH POLICIES. A VAST AMOUNT OF EVIDENCE INDICATES THAT BISPHENOL A (BPA) AND PHTHALATES ARE WIDELY DISTRIBUTED IN THE ENVIRONMENT SINCE THESE COMPOUNDS ARE MASS-PRODUCED FOR THE MANUFACTURE OF PLASTICS AND PLASTICIZERS. THESE COMPOUNDS BELONG TO A LARGE GROUP OF SUBSTANCES TERMED ENDOCRINE-DISRUPTING CHEMICALS (EDC). IT IS WELL KNOWN THAT HUMANS AND LIVING ORGANISMS ARE UNAVOIDABLY AND UNINTENTIONALLY EXPOSED TO BPA AND PHTHALATES FROM FOOD PACKAGING MATERIALS AND MANY OTHER EVERYDAY PRODUCTS. BPA AND PHTHALATES EXERT THEIR EFFECT BY INTERFERING WITH HORMONE SYNTHESIS, BIOAVAILABILITY, AND ACTION, THEREBY ALTERING CELLULAR PROLIFERATION AND DIFFERENTIATION, TISSUE DEVELOPMENT, AND THE REGULATION OF SEVERAL PHYSIOLOGICAL PROCESSES. IN FACT, THESE EDC CAN ALTER FETAL PROGRAMMING AT AN EPIGENETIC LEVEL, WHICH CAN BE TRANSGENERATIONAL TRANSMITTED AND MAY BE INVOLVED IN THE DEVELOPMENT OF VARIOUS CHRONIC PATHOLOGIES LATER IN THE ADULTHOOD, INCLUDING METABOLIC, REPRODUCTIVE AND DEGENERATIVE DISEASES, AND CERTAIN TYPES OF CANCER. IN THIS REVIEW, WE DESCRIBE THE MOST RECENT PROPOSED MECHANISMS OF ACTION OF THESE EDC AND OFFER A COMPELLING SELECTION OF EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES, WHICH SHOW EVIDENCE OF HOW EXPOSURE TO THESE POLLUTANTS AFFECTS OUR HEALTH DURING DEVELOPMENT, AND THEIR ASSOCIATION WITH A WIDE RANGE OF REPRODUCTIVE, METABOLIC AND NEUROLOGICAL DISEASES, AS WELL AS HORMONE-RELATED CANCERS. WE STRESS THE IMPORTANCE OF CONCERN IN THE GENERAL POPULATION AND THE URGENT NEED FOR THE MEDICAL HEALTH CARE SYSTEM TO CLOSELY MONITOR EDC LEVELS IN THE POPULATION DUE TO UNAVOIDABLE AND INVOLUNTARY EXPOSURE TO THESE POLLUTANTS AND THEIR IMPACT ON HUMAN HEALTH. 2021 8 1857 26 ELIMINATION OF PERSISTENT TOXICANTS FROM THE HUMAN BODY. THERE IS COMPELLING EVIDENCE THAT VARIOUS CHEMICAL AGENTS ARE IMPORTANT DETERMINANTS OF MYRIAD HEALTH AFFLICTIONS--SEVERAL XENOBIOTICS HAVE THE POTENTIAL TO DISRUPT REPRODUCTIVE, DEVELOPMENTAL, AND NEUROLOGICAL PROCESSES AND SOME AGENTS IN COMMON USE HAVE CARCINOGENIC, EPIGENETIC, ENDOCRINE-DISRUPTING, AND IMMUNE-ALTERING ACTION. SOME TOXICANTS APPEAR TO HAVE BIOLOGICAL EFFECT AT MINISCULE LEVELS AND CERTAIN CHEMICAL COMPOUNDS ARE PERSISTENT AND BIOACCUMULATIVE WITHIN THE HUMAN BODY. DESPITE ESCALATING PUBLIC HEALTH MEASURES TO PRECLUDE FURTHER EXPOSURES, MANY PEOPLE THROUGHOUT THE WORLD HAVE ALREADY ACCRUED A SIGNIFICANT BODY BURDEN OF TOXICANTS, PLACING THEM AT POTENTIAL HEALTH RISK. AS A RESULT, INCREASING DISCUSSION IS UNDERWAY ABOUT POSSIBLE INTERVENTIONS TO FACILITATE ELIMINATION OF PERSISTENT TOXICANTS FROM THE HUMAN ORGANISM IN ORDER TO OBVIATE HEALTH AFFLICTION AND TO POTENTIALLY AMELIORATE CHRONIC DEGENERATIVE ILLNESS. AN OVERVIEW OF THE CLINICAL ASPECTS OF DETOXIFICATION IS PRESENTED WITH DISCUSSION OF ESTABLISHED AND EMERGING INTERVENTIONS FOR THE ELIMINATION OF PERSISTENT XENOBIOTICS. POTENTIAL THERAPIES TO CIRCUMVENT ENTEROHEPATIC RECIRCULATION AND A CASE REPORT HIGHLIGHTING A CLINICAL OUTCOME ASSOCIATED WITH DETOXIFICATION ARE ALSO PRESENTED FOR CONSIDERATION. 2011 9 3404 36 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 10 3820 18 INTRODUCTION TO PRECLINICAL EVIDENCE FROM ANIMAL MODELS OF ENDOMETRIOSIS. ENDOMETRIOSIS, THE PRESENCE AND GROWTH OF UTERINE ENDOMETRIAL GLANDULAR EPITHELIAL AND STROMA CELLS OUTSIDE THE UTERINE CAVITY, CAUSES PAIN AND INFERTILITY IN WOMEN AND GIRLS OF REPRODUCTIVE AGE. AS RANDOMIZED, DOUBLE-BLINDED, CONTROLLED STUDIES OF ENDOMETRIOSIS IN WOMEN ARE IMPRACTICAL AND AT TIMES ETHICALLY PROHIBITIVE, ANIMAL MODELS FOR ENDOMETRIOSIS AROSE AS AN IMPORTANT ADJUNCT TO GAIN MECHANISTIC INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGICAL MECHANISMS OF THIS PERPLEXING DISORDER. A MORE THOROUGH UNDERSTANDING OF ENDOMETRIOSIS IN WOMEN MAY HELP DEVELOP NOVEL NONINVASIVE DIAGNOSTICS, CLASSIFICATION SYSTEMS, THERAPEUTIC REGIMES, AND EVEN PREVENTATIVE METHODS FOR THE MANAGEMENT OF ENDOMETRIOSIS. THIS CHAPTER IS INTENDED TO INTRODUCE A BRIEF HISTORICAL BACKGROUND, BIOLOGICAL AND EPIDEMIOLOGICAL ASPECTS, THE MAJOR SYMPTOMS, THE EFFECTS OF ENDOCRINE-DISRUPTING CHEMICALS, AND AN EXAMPLE OF AN EPIGENETIC FACTOR OF ENDOMETRIOSIS IN WOMEN. 2020 11 1915 31 ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE OF METALS AND FEMALE REPRODUCTIVE HEALTH. UNTAINTED ENVIRONMENT PROMOTES HEALTH, BUT THE LAST FEW DECADES EXPERIENCED STEEP UPSURGE IN ENVIRONMENTAL CONTAMINANTS POSING DETRIMENTAL PHYSIOLOGICAL IMPACT. THE RESPONSIBLE FACTORS MAINLY INCLUDE THE EXPONENTIAL GROWTH OF HUMAN POPULATION, HAVOC RISE IN INDUSTRIALIZATION, POORLY PLANNED URBANIZATION, AND SLAPDASH ENVIRONMENT MANAGEMENT. ENVIRONMENTAL DEGRADATION CAN INCREASE THE LIKELIHOOD OF HUMAN EXPOSURE TO HEAVY METALS, RESULTING IN HEALTH CONSEQUENCES SUCH AS REPRODUCTIVE PROBLEMS. AS A RESULT, RESEARCH INTO METAL-INDUCED CAUSES OF REPRODUCTIVE IMPAIRMENT AT THE GENETIC, EPIGENETIC, AND BIOCHEMICAL LEVELS MUST BE STRENGTHENED FURTHER. THESE METALS IMPACT UPON THE FEMALE REPRODUCTION AT ALL STRATA OF ITS REGULATION AND FUNCTIONS, BE IT DEVELOPMENT, MATURATION, OR ENDOCRINE FUNCTIONS, AND ARE LINKED TO AN INCREASE IN THE CAUSES OF INFERTILITY IN WOMEN. CHRONIC EXPOSURES TO THE HEAVY METALS MAY LEAD TO BREAST CANCER, ENDOMETRIOSIS, ENDOMETRIAL CANCER, MENSTRUAL DISORDERS, AND SPONTANEOUS ABORTIONS, AS WELL AS PRE-TERM DELIVERIES, STILLBIRTHS. FOR EXAMPLE, ENDOMETRIOSIS, ENDOMETRIAL CANCER, AND SPONTANEOUS ABORTIONS ARE ALL CAUSED BY THE METALLOESTROGEN CADMIUM (CD); LEAD (PB) LEVELS OVER A CERTAIN THRESHOLD CAN CAUSE SPONTANEOUS ABORTION AND HAVE A TERATOGENIC IMPACT; TOXIC AMOUNTS OF MERCURY (HG) HAVE AN INFLUENCE ON THE MENSTRUAL CYCLE, WHICH CAN LEAD TO INFERTILITY. IMPACT OF ENVIRONMENTAL EXPOSURE TO HEAVY METALS ON FEMALE FERTILITY IS THEREFORE A WELL-KNOWN FACT. THUS, THE UNDERLYING MECHANISMS MUST BE EXPLAINED AND PERIODICALLY UPDATED, GIVEN THE GROWING EVIDENCE ON THE INFLUENCE OF INCREASING ENVIRONMENTAL HEAVY METAL LOAD ON FEMALE FERTILITY. THE PURPOSE OF THIS REVIEW IS TO GIVE A CONCISE OVERVIEW OF HOW HEAVY METAL AFFECTS FEMALE REPRODUCTIVE HEALTH. 2022 12 3821 19 INTRODUCTION: FROM PATHOGENESIS TO THERAPY, DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. A NUMBER OF THEORIES MAY EXPLAIN ITS PATHOGENESIS AND MANY ARGUMENTS SUPPORT THE HYPOTHESIS THAT GENETIC OR EPIGENETIC CHANGES ARE A PREREQUISITE FOR DEVELOPMENT OF LESIONS INTO DEEP ENDOMETRIOSIS. DEEP ENDOMETRIOSIS IS FREQUENTLY RESPONSIBLE FOR PELVIC PAIN, DYSMENORRHEA, AND/OR DEEP DYSPAREUNIA, BUT CAN ALSO CAUSE OBSTETRICAL COMPLICATIONS. DIAGNOSIS MAY BE IMPROVED BY HIGH-QUALITY IMAGING. THERAPEUTIC APPROACHES ARE A SOURCE OF CONTENTION AS WELL. IN THIS ISSUE'S VIEWS AND REVIEWS, MEDICAL AND SURGICAL STRATEGIES ARE DISCUSSED, AND IT IS EMPHASIZED THAT TREATMENT SHOULD BE DESIGNED ACCORDING TO A PATIENT'S SYMPTOMS AND INDIVIDUAL NEEDS. IT IS ALSO VITAL THAT REFERRAL CENTERS HAVE THE KNOWLEDGE AND EXPERIENCE TO TREAT DEEP ENDOMETRIOSIS MEDICALLY AND/OR SURGICALLY. THE DEBATE MUST CONTINUE BECAUSE EMERGING TRENDS IN THERAPY NEED TO BE FOLLOWED AND INVESTIGATED FOR OPTIMAL MANAGEMENT. 2017 13 367 21 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 14 4871 25 OUR GENES ARE NOT OUR DESTINY: INCORPORATING MOLECULAR MEDICINE INTO CLINICAL PRACTICE. IN MANY DEVELOPED NATIONS, THE STATE OF PUBLICLY ADMINISTERED HEALTH CARE IS INCREASINGLY PRECARIOUS AS A RESULT OF ESCALATING NUMBERS OF CHRONICALLY ILL PATIENTS, INADEQUATE MEDICAL PERSONNEL AND HOSPITAL FACILITIES, AS WELL AS SPARSE FUNDING FOR ONGOING UPGRADES TO STATE-OF-THE-ART DIAGNOSTIC AND THERAPEUTIC TECHNOLOGY - AN INCREASED EMPHASIS ON AETIOLOGY-CENTRED MEDICINE SHOULD BE CONSIDERED IN ORDER TO ACHIEVE IMPROVED HEALTH FOR PATIENTS AND POPULATIONS. MEDICAL PRACTICE PATTERNS WHICH ARE DESIGNED TO PROVIDE QUICK AND EFFECTIVE AMELIORATION OF SIGNS AND SYMPTOMS ARE FREQUENTLY NOT AN ENDURING SOLUTION TO MANY HEALTH AFFLICTIONS AND CHRONIC DISEASE STATES. RECENT SCIENTIFIC DISCOVERY HAS RENDERED THE DRUG-ORIENTED ALGORITHMIC PARADIGM COMMONLY FOUND IN CONTEMPORARY EVIDENCE-BASED MEDICINE TO BE A REDUCTIONIST APPROACH TO CLINICAL PRACTICE. UNFOLDING EVIDENCE APPEARS TO SUPPORT A GENETIC PREDISPOSITION MODEL OF HEALTH AND ILLNESS RATHER THAN A FATALISTIC PREDESTINATION CONSTRUCT - MODIFIABLE EPIGENETIC AND ENVIRONMENTAL FACTORS HAVE ENORMOUS POTENTIAL TO INFLUENCE CLINICAL OUTCOMES. BY UNDERSTANDING AND APPLYING FUNDAMENTAL CLINICAL PRINCIPLES RELATING TO THE EMERGING FIELDS OF MOLECULAR MEDICINE, NUTRIGENOMICS AND HUMAN EXPOSURE ASSESSMENT, DOCTORS WILL BE EMPOWERED TO ADDRESS CAUSALITY OF AFFLICTION WHEN POSSIBLE AND ACHIEVE SUSTAINED REPRIEVE FOR MANY SUFFERING PATIENTS. 2008 15 6792 18 [DOHAD AND EPIGENETIC INFORMATION: SOCIETAL CHALLENGES]. THE CONCEPT OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) ALTERS OUR UNDERSTANDING OF WHAT CONSTITUTES "HEALTH" OR "DISEASE" INTENDED AS CHRONIC, NON-COMMUNICABLE DISEASES, WHICH DEVELOP OVER THE LIFE COURSE IN HIGH INCOME AND EMERGING COUNTRIES. IT IMPLIES A CHANGE IN PARADIGM FORMING A BASIS FOR PREVENTION POLICIES ACROSS THE GLOBE. IT ALSO IMPACTS PSYCHOLOGICAL, SOCIAL, ECONOMIC, ETHICAL AND LEGAL SCIENCES. IN LINE WITH THE UNANTICIPATED UNDERPINNING EPIGENETIC MECHANISMS ARE ALSO THE SOCIAL ISSUES (INCLUDING PUBLIC POLICIES) THAT COULD BE PRODUCED BY THE KNOWLEDGE RELATED TO DOHAD THAT OPENS A WIDE FIELD OF INQUIRY. THE INFORMATION UNVEILED BY EPIGENETICS COUPLED WITH INFORMATION ON LIFESTYLE INCLUDING DURING THE DEVELOPMENT PHASE, IS OF UNFORESEEN NATURE, RAISING ISSUES OF DIFFERENT NATURE. THEREFORE IT REQUIRES SPECIFIC ATTENTION AND RESEARCH, AND A SPECIFIC SUPPORT BY A PLURIDISCIPLINARY REFLECTION SINCE THE VERY BEGINNING OF ITS PRODUCTION, TO ANTICIPATE THE QUESTIONS THAT MIGHT BE RAISED IN THE FUTURE. 2016 16 421 27 ANIMAL MODELS IN EPIGENETIC RESEARCH: INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE CONSIDERATIONS ACROSS THE LIFESPAN. THE RAPID EXPANSION AND EVOLUTION OF EPIGENETICS AS A CORE SCIENTIFIC DISCIPLINE HAVE RAISED NEW QUESTIONS ABOUT HOW ENDOGENOUS AND ENVIRONMENTAL FACTORS CAN INFORM THE MECHANISMS THROUGH WHICH BIOLOGICAL FORM AND FUNCTION ARE REGULATED. EXISTING AND PROPOSED ANIMAL MODELS USED FOR EPIGENETIC RESEARCH HAVE TARGETED A MYRIAD OF HEALTH AND DISEASE ENDPOINTS THAT MAY BE ACUTE, CHRONIC, AND TRANSGENERATIONAL IN NATURE. INITIATING EVENTS AND OUTCOMES MAY EXTEND ACROSS THE ENTIRE LIFESPAN TO ELICIT UNANTICIPATED PHENOTYPES THAT ARE OF PARTICULAR CONCERN TO INSTITUTIONAL ANIMAL CARE AND USE COMMITTEES (IACUCS). THE DYNAMICS AND PLASTICITY OF EPIGENETIC MECHANISMS PRODUCE EFFECTS AND CONSEQUENCES THAT ARE MANIFEST DIFFERENTIALLY WITHIN DISCREET SPATIAL AND TEMPORAL CONTEXTS, INCLUDING PRENATAL DEVELOPMENT, STEM CELLS, ASSISTED REPRODUCTIVE TECHNOLOGIES, PRODUCTION OF SEXUAL DIMORPHISMS, SENESCENCE, AND OTHERS. MANY DIETARY AND NUTRITIONAL INTERVENTIONS HAVE ALSO BEEN SHOWN TO HAVE A SIGNIFICANT IMPACT ON BIOLOGICAL FUNCTIONS AND DISEASE SUSCEPTIBILITIES THROUGH ALTERED EPIGENETIC PROGRAMMING. THE ENVIRONMENTAL, CHEMICAL, TOXIC, THERAPEUTIC, AND PSYCHOSOCIAL STRESSORS USED IN ANIMAL STUDIES TO ELICIT EPIGENETIC CHANGES CAN BECOME EXTREME AND SHOULD RAISE IACUC CONCERNS FOR THE WELL-BEING AND PROPER CARE OF ALL RESEARCH ANIMALS INVOLVED. EPIGENETICS RESEARCH IS RAPIDLY BECOMING AN INTEGRAL PART OF THE SEARCH FOR MECHANISMS IN EVERY MAJOR AREA OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND WILL FOSTER THE CONTINUED DEVELOPMENT OF NEW ANIMAL MODELS. FROM THE IACUC PERSPECTIVE, CARE MUST BE TAKEN TO ACKNOWLEDGE THE PARTICULAR NEEDS AND CONCERNS CREATED BY SUPERIMPOSITION OF EPIGENETIC MECHANISMS OVER DIVERSE FIELDS OF INVESTIGATION TO ENSURE THE PROPER CARE AND USE OF ANIMALS WITHOUT IMPEDING SCIENTIFIC PROGRESS. 2012 17 1892 15 ENDOMETRIOSIS: EPIDEMIOLOGY, CLASSIFICATION, PATHOGENESIS, TREATMENT AND GENETICS (REVIEW OF LITERATURE). ENDOMETRIOSIS IS A "MYSTERIOUS" DISEASE AND ITS EXACT CAUSE HAS NOT YET BEEN ESTABLISHED. AMONG THE ETIOLOGICAL FACTORS, CONGENITAL, ENVIRONMENTAL, EPIGENETIC, AUTOIMMUNE AND ALLERGIC FACTORS ARE LISTED. IT IS BELIEVED THAT THE PRIMARY MECHANISM OF THE FORMATION OF ENDOMETRIOSIS FOCI IS RETROGRADE MENSTRUATION, I.E., THE PASSAGE OF MENSTRUAL BLOOD THROUGH THE FALLOPIAN TUBES INTO THE PERITONEAL CAVITY AND IMPLANTATION OF EXFOLIATED ENDOMETRIAL CELLS. HOWEVER, SINCE THIS MECHANISM IS ALSO OBSERVED IN HEALTHY WOMEN, OTHER FACTORS MUST ALSO BE INVOLVED IN THE FORMATION OF ENDOMETRIOSIS FOCI. ENDOMETRIOSIS IS IN MANY WOMEN THE CAUSE OF INFERTILITY, CHRONIC PAIN AND THE DETERIORATION OF THE QUALITY OF LIFE. IT ALSO REPRESENTS A SIGNIFICANT FINANCIAL BURDEN ON HEALTH SYSTEMS. THE ARTICLE PRESENTS A REVIEW OF THE LITERATURE ON ENDOMETRIOSIS-A DISEASE AFFECTING WOMEN THROUGHOUT THE WORLD. 2021 18 6833 26 [HYPOTHETICAL LINK BETWEEN ENDOMETRIOSIS AND XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD]. ENDOMETRIOSIS IS AN OESTROGEN-DEPENDENT INFLAMMATORY DISEASE AFFECTING 10 % OF REPRODUCTIVE-AGED WOMEN. OFTEN ACCOMPANIED BY CHRONIC PELVIC PAIN AND INFERTILITY, ENDOMETRIOSIS RIGOROUSLY INTERFERES WITH WOMEN'S QUALITY OF LIFE. ALTHOUGH THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS REMAINS UNCLEAR, A GROWING BODY OF EVIDENCE POINTS TO THE IMPLICATION OF ENVIRONMENTAL TOXICANTS. OVER THE LAST DECADE, AN INCREASE IN THE INCIDENCE OF ENDOMETRIOSIS HAS BEEN REPORTED AND COINCIDES WITH THE INTRODUCTION OF GENETICALLY MODIFIED FOODS IN OUR DIET. EVEN THOUGH ASSESSMENTS OF GENETICALLY MODIFIED FOOD RISK HAVE NOT INDICATED ANY HAZARD ON HUMAN HEALTH, XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS PESTICIDES RESIDUES AND XENOPROTEINS, COULD BE HARMFUL IN THE LONG-TERM. THE "LOW-DOSE HYPOTHESIS", ACCUMULATION AND BIOTRANSFORMATION OF PESTICIDES-ASSOCIATED GENETICALLY MODIFIED FOOD AND THE MULTIPLIED TOXICITY OF PESTICIDES-FORMULATION ADJUVANTS SUPPORT THIS HYPOTHESIS. THIS REVIEW SUMMARIZES TOXIC EFFECTS (IN VITRO AND ON ANIMAL MODELS) OF SOME XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS GLYPHOSATE AND CRY1AB PROTEIN, AND EXTRAPOLATES ON THEIR POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. THEIR ROLES AS IMMUNE TOXICANTS, PRO-OXIDANTS, ENDOCRINE DISRUPTORS AND EPIGENETIC MODULATORS ARE DISCUSSED. 2010 19 4006 24 LOST AMONG THE TREES? THE AUTONOMIC NERVOUS SYSTEM AND PAEDIATRICS. THE AUTONOMIC NERVOUS SYSTEM (ANS) HAS BEEN STRIKINGLY NEGLECTED IN WESTERN MEDICINE. DESPITE ITS PROFOUND IMPORTANCE FOR REGULATION, ADJUSTMENT AND COORDINATION OF BODY SYSTEMS, IT LACKS PRIORITY IN TRAINING AND PRACTICE AND RECEIVES SCANT ATTENTION IN NUMEROUS MAJOR TEXTBOOKS. THE ANS IS INTEGRAL TO MANIFESTATIONS OF ILLNESS, UNDERLYING FAMILIAR PHYSICAL AND PSYCHOLOGICAL SYMPTOMS. WHEN ANS ACTIVITY IS ITSELF DYSFUNCTIONAL, USUAL INDICATORS OF ACUTE ILLNESS MAY PROVE DECEPTIVE. RECOGNISING THE RELEVANCE OF THE ANS CAN INVOLVE SEEING THE FAMILIAR THROUGH FRESH EYES, CHALLENGING ASSUMPTIONS IN CLINICAL ASSESSMENT AND IN APPROACHES TO PRACTICE. ITS IMPORTANCE EXTENDS FROM PHYSICAL AND PSYCHOLOGICAL WELL-BEING TO PARENTING AND SAFEGUARDING, PUBLIC SERVICES AND THE FUNCTIONING OF SOCIETY. EXPLORATION OF ITS ROLE IN CONDITIONS RANGING FROM NEUROLOGICAL, GASTROINTESTINAL AND CONNECTIVE TISSUE DISORDERS, DIABETES AND CHRONIC FATIGUE SYNDROME, TO AUTISM, BEHAVIOURAL AND MENTAL HEALTH DIFFICULTIES MAY OPEN THERAPEUTIC AVENUES. THE ANS OFFERS A MECHANISM FOR SO-CALLED FUNCTIONAL ILLNESSES AND ILLUSTRATES THE IMPORTANCE OF RECOGNISING THAT 'STRESS' TAKES MANY FORMS, PHYSICAL, PSYCHOLOGICAL AND ENVIRONMENTAL, DESIRABLE AND OTHERWISE. EVIDENCE OF INTRAUTERINE AND POST-NATAL PROGRAMMING OF ANS REACTIVITY SUGGESTS THAT NEONATAL CARE AND SAFEGUARDING PRACTICE MAY OFFER PREVENTIVE OPPORTUNITY, AS MAY GREATER UNDERSTANDING OF EPIGENETIC CHANGE OF ANS ACTIVITY THROUGH, FOR EXAMPLE, ACCIDENTAL OR PSYCHOLOGICAL TRAUMA OR INFECTION. THE AIM OF THIS ARTICLE IS TO ACCELERATE RECOGNITION OF THE IMPORTANCE OF THE ANS THROUGHOUT PAEDIATRICS, AND OF THE POTENTIAL PHYSICAL AND PSYCHOLOGICAL COST OF NEGLECTING IT. 2014 20 2869 28 FUNCTIONAL FOODS AND HEALTH EFFECTS: A NUTRITIONAL BIOCHEMISTRY PERSPECTIVE. BACKGROUND: INCREASED CONSUMER S INTEREST IN HEALTH HAS DRIVEN THE DEVELOPMENT OF FOODS THAT OFFER SPECIFIC BENEFICIAL EFFECTS. THE LIST OF FOODS AND INGREDIENTS INCLUDES ESSENTIAL AND NON-ESSENTIAL NUTRIENTS, PLANT AND MARINE COMPONENTS, WHOLE FOODS, MICROORGANISMS, MICROALGAE AND TECHNOLOGICAL APPROACHES. TRADITIONALLY, HEALTH OUTCOMES FOCUSSED ON THE PREVENTION OF CHRONIC DISEASES BUT HEALTH TARGETS HAVE EXPANDED TO COVER AREAS SUCH AS BRAIN HEALTH, INFLAMMATION, EYE HEALTH, WOMEN S HEALTH, HEALTHY AGEING AND BEAUTY. OBJECTIVE: THIS REVIEW HIGHLIGHTS, FROM A NUTRITIONAL BIOCHEMISTRY PERSPECTIVE, DIFFERENTIAL ASPECTS ON DESIGNING AND INTERPRETING HUMAN STUDIES TO SUPPORT THE HEALTH EFFECTS OF FUNCTIONAL FOODS. RESULTS: DESPITE THE AVAILABLE EVIDENCE FROM IN VITRO, ANIMAL AND OBSERVATIONAL STUDIES, WELLDESIGNED HUMAN STUDIES ARE NECESSARY TO SUPPORT THE HEALTH EFFECTS OF FUNCTIONAL FOODS. INTERVENTION TRIALS WITH FOODS ARE COMPLEX AS THEY IMPLY LIMITATIONS DUE TO METHODOLOGICAL, FOOD-RELATED AND HOST-RELATED FACTORS. THE USE OF RESPONSIVE, VALIDATED AND CLINICALLY RELEVANT MARKERS BECOMES ESSENTIAL EVEN THOUGH THERE IS A LACK OF RELIABLE BIOMARKERS OF EXPOSURE FOR MANY BIOACTIVES. FURTHERMORE, THE EFFECT OF MODULATING FACTORS SUCH AS SUBCLINICAL INFLAMMATION, GUT MICROBIOTA AND GENETIC VARIABILITY SHOULD BE TAKEN INTO ACCOUNT. MULTIPLE INDICATORS MAY PROVIDE A MORE RELIABLE ALTERNATIVE TO ASSESS PHYSIOLOGICAL PROCESSES WHILE EMERGING BIOMARKERS (MICRORNAS, EPIGENETIC CHANGES) CONSTITUTE A PROMISING APPROACH. ADDITIONALLY, THE MAGNITUDE OF THE CHANGE IS CRITICAL TO SUPPORT ANY HEALTH EFFECT ALTHOUGH INTERVENTIONS MAY HAVE A LIMITED CLINICAL IMPACT BUT BE EPIDEMIOLOGICALLY RELEVANT. ALSO, BASED ON THE AVAILABLE DATA, THE PREMISE THAT BIOACTIVESCONTAINING FOODS ARE SAFE MAY BE QUESTIONABLE. CONCLUSION: AN INTEGRATED APPROACH INCLUDING MULTIPLE BIOMARKERS, GENETIC VARIABILITY, EFFECT OF GUT MICROBIOTA AND RISK/BENEFIT ASSESSMENT SHOULD BE USED TO SUPPORT THE POTENTIAL HEALTH EFFECTS OF FUNCTIONAL FOODS. 2016