1 5106 82 POLYCYSTIC OVARY SYNDROME IN ADULT WOMEN. POLYCYSTIC OVARY SYNDROME IS THE MOST PREVALENT ENDOCRINE-METABOLIC PATHOLOGY IN PRE-MENOPAUSAL WOMEN. ITS ETIOPATHOGENESIS IS COMPLEX, MULTIFACTORIAL AND HETEROGENEOUS, INCLUDING THE INTERACTION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ANDROGENIC EXCESS CONSTITUTES THE DISEASE'S MAIN PHYSIOPATHOLOGICAL MECHANISM AND RESULTS IN REPRODUCTIVE, METABOLIC AND COSMETIC ALTERATIONS WHICH NEGATIVELY IMPACT THESE PATIENTS' QUALITY OF LIFE. THE CRITERIA ESTABLISHED IN THE ROTTERDAM CONSENSUS AND THEIR CORRECT APPLICATION FORM THE NECESSARY BASIS FOR THIS SYNDROME'S PROPER DIAGNOSIS. IN THE ABSENCE OF AN AETIOLOGICAL TREATMENT, THE AIM IS TO IMPROVE THE CLINICAL SIGNS AND SYMPTOMS DERIVED FROM HYPERANDROGENISM, OVARIAN DYSFUNCTION AND EXISTING METABOLIC COMPLICATIONS, AND, THEREFORE, THEY MUST BE CHRONIC AND INDIVIDUALISED. 2019 2 5105 32 POLYCYSTIC OVARIAN SYNDROME: A COMPLEX DISEASE WITH A GENETICS APPROACH. POLYCYSTIC OVARIAN SYNDROME (PCOS) IS A COMPLEX ENDOCRINE DISORDER AFFECTING FEMALES IN THEIR REPRODUCTIVE AGE. THE EARLY DIAGNOSIS OF PCOS IS COMPLICATED AND COMPLEX DUE TO OVERLAPPING SYMPTOMS OF THIS DISEASE. THE MOST ACCEPTED DIAGNOSTIC APPROACH TODAY IS THE ROTTERDAM CONSENSUS (2003), WHICH SUPPORTS THE POSITIVE DIAGNOSIS OF PCOS WHEN PATIENTS PRESENT TWO OUT OF THE FOLLOWING THREE SYMPTOMS: BIOCHEMICAL AND CLINICAL SIGNS OF HYPERANDROGENISM, OLIGO, AND ANOVULATION, ALSO POLYCYSTIC OVARIAN MORPHOLOGY ON SONOGRAPHY. GENETIC VARIANCE, EPIGENETIC CHANGES, AND DISTURBED LIFESTYLE LEAD TO THE DEVELOPMENT OF PATHOPHYSIOLOGICAL DISTURBANCES, WHICH INCLUDE HYPERANDROGENISM, INSULIN RESISTANCE, AND CHRONIC INFLAMMATION IN PCOS FEMALES. AT THE MOLECULAR LEVEL, DIFFERENT PROTEINS AND MOLECULAR AND SIGNALING PATHWAYS ARE INVOLVED IN DISEASE PROGRESSION, WHICH LEADS TO THE FAILURE OF A SINGLE GENETIC DIAGNOSTIC APPROACH. THE GENETIC APPROACH TO ELUCIDATE THE MECHANISM OF PATHOGENESIS OF PCOS WAS RECENTLY DEVELOPED, WHEREBY FOUR PHENOTYPIC VARIANCES OF PCOS CATEGORIZE PCOS PATIENTS INTO CLASSIC, OVULATORY, AND NON-HYPERANDROGENIC TYPES. GENETIC STUDIES HELP TO IDENTIFY THE ROOT CAUSE FOR THE DEVELOPMENT OF THIS PCOS. PCOS GENETIC INHERITANCE IS AUTOSOMAL DOMINANT BUT THE LATEST INVESTIGATIONS REVEALED IT AS A MULTIGENE ORIGIN DISEASE. DIFFERENT GENETIC LOCI AND SPECIFIC GENES HAVE BEEN IDENTIFIED SO FAR AS BEING ASSOCIATED WITH THIS DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND RELATED GENETIC STUDIES HAVE CHANGED THE SCENARIO FOR THE DIAGNOSIS AND TREATMENT OF THIS REPRODUCTIVE AND METABOLIC CONDITION KNOWN AS PCOS. THIS REVIEW ARTICLE BRIEFLY DISCUSSES DIFFERENT GENES ASSOCIATED DIRECTLY OR INDIRECTLY WITH DISEASE DEVELOPMENT AND PROGRESSION. 2022 3 4403 35 MODULATION OF THE INFLAMMATORY RESPONSE IN POLYCYSTIC OVARY SYNDROME (PCOS)-SEARCHING FOR EPIGENETIC FACTORS. POLYCYSTIC OVARY SYNDROME (PCOS) IS THE MOST COMMON ENDOCRINE DISORDER IN WOMEN OF REPRODUCTIVE AGE. DESPITE ITS INCIDENCE, THE SYNDROME IS POORLY UNDERSTOOD AND REMAINS UNDERDIAGNOSED, AND FEMALE PATIENTS ARE DIAGNOSED WITH A DELAY. THE HETEROGENOUS NATURE OF THIS COMPLEX DISORDER RESULTS FROM THE COMBINED OCCURRENCE OF GENETIC, ENVIRONMENTAL, ENDOCRINE, AND BEHAVIORAL FACTORS. PRIMARY CLINICAL MANIFESTATIONS OF PCOS ARE DERIVED FROM THE EXCESS OF ANDROGENS (ANOVULATION, POLYCYSTIC OVARY MORPHOLOGY, LACK OF OR SCANTY, IRREGULAR MENSTRUAL PERIODS, ACNE AND HIRSUTISM), WHEREAS THE SECONDARY MANIFESTATIONS INCLUDE MULTIPLE METABOLIC, CARDIOVASCULAR, AND PSYCHOLOGICAL DISORDERS. DIETARY AND LIFESTYLE FACTORS PLAY IMPORTANT ROLES IN THE DEVELOPMENT AND COURSE OF PCOS, WHICH SUGGESTS STRONG EPIGENETIC AND ENVIRONMENTAL INFLUENCES. MANY STUDIES HAVE SHOWN A STRONG ASSOCIATION BETWEEN PCOS AND CHRONIC, LOW-GRADE INFLAMMATION BOTH IN THE OVARIAN TISSUE AND THROUGHOUT THE BODY. IN THE VAST MAJORITY OF PCOS PATIENTS, ELEVATED VALUES OF INFLAMMATORY MARKERS OR THEIR GENE MARKERS HAVE BEEN REPORTED. DEVELOPMENT OF THE VICIOUS CYCLE OF THE CHRONIC INFLAMMATORY STATE IN PCOS IS ADDITIONALLY STIMULATED BY HYPERINSULINEMIA AND OBESITY. CHANGES IN DNA METHYLATION, HISTONE ACETYLATION AND NONCODING RNA LEVELS ARE PRESENTED IN THIS REVIEW IN THE CONTEXT OF OXIDATIVE STRESS, REACTIVE OXYGEN SPECIES, AND INFLAMMATORY SIGNALING IN PCOS. EPIGENETIC MODULATION OF ANDROGENIC ACTIVITY IN RESPONSE TO INFLAMMATORY SIGNALING IS ALSO DISCUSSED. 2022 4 6870 25 [PATHOGENESIS OF THE METABOLIC SYNDROME]. AFTER AN INITIAL ATTEMPT BY THE WHO TO DEFINE METABOLIC SYNDROME (MS) ON A PATHOPHYSIOLOGICALLY ORIENTED APPROACH REQUIRING THE ASSESSMENT OF INSULIN RESISTANCE MARKERS, THE NCEP-ATPIII AND MORE RECENTLY THE IDF PROPOSED MORE CLINICALLY ORIENTED CRITERIA TO HELP, TOWARD A PREVENTIVE MEDICINE GOAL, TO IDENTIFY PATIENTS WHO ARE LIKELY TO HAVE FEATURES OF THE MS AND BE AT INCREASED RISK OF TYPE 2 DIABETES AND CARDIO VASCULAR DISEASE. THE NOTION OF MS IS BUILT AROUND ABNORMALITIES OF THE METABOLISM OF LIPIDS AND CARBON HYDRATES, A RISE OF BLOOD PRESSURE, AND VISCERAL OBESITY OF ABDOMINAL LOCALIZATION. THESE PARAMETERS REPORT ONLY PARTIALLY ON MECHANISMS LEADING TO THE DEVELOPMENT OF THE MS. THE PHYSIOPATHOLOGY OF MS IS PARTIALLY UNDERSTOOD EVEN TODAY AND LIKELY RESULTS FROM THE COMBINATION OF ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS. ABDOMINAL VISCERAL OBESITY, A STATE OF LOW-GRADE CHRONIC INFLAMMATION AND INSULIN RESISTANCE ARE THE MAIN PROCESSES SUSCEPTIBLE TO EXPLAIN THE VARIOUS CONSTITUENTS OF THIS SYNDROME. 2008 5 1935 25 ENVIRONMENTAL RISK FACTORS AND EPIGENETIC ALTERNATIONS IN PSORIASIS. INTRODUCTION AND OBJECTIVE: PSORIASIS ISA QUITE COMMON, CHRONIC AND IMMUNE-MEDIATED SKIN DISORDER. THE PREVALENCE OF PSORIASIS DIFFERS IN VARIOUS COUNTRIES, BUT IT IS SAID TO AFFECT 2% OF THE WORLD'S POPULATION IN GENERAL. PSORIASIS HAS MANY DIFFERENT CLINICAL FEATURES BUT ALL LESIONS HAVE THE SAME CHARACTERISTIC: ERYTHEMA, THICKENING AND SCALE, ALTHOUGH OTHER CLINICAL FEATURES ARE ALSO CONNECTED, SUCH AS PSORIATIC ARTHRITIS, OBESITY AND METABOLIC SYNDROME. ALL OF THESE MAY LEAD TO CONDITIONS IMPAIRING THE QUALITY OF LIFE. THIS REVIEW IS AN ATTEMPT TO SUMMARIZE RECENT DATA REGARDING ENVIRONMENTAL FACTORS, TOGETHER WITH EPIGENETIC MARKERS AND PROCESSES PLAYING AN IMPORTANT ROLE IN PSORIASIS. STATE OF KNOWLEDGE: MANY DIFFERENT ENVIRONMENTAL FACTORS PLAY A ROLE IN GENETICALLY PREDISPOSED PATIENTS. THIS IS CAUSES EPIGENETIC ALTERNATIONS WHICH MAY BE A LINKING PART IN THE WHOLE PROCESS. MANY STUDIES HAVE INDICATED A CONNECTION BETWEEN PSORIASIS AND VARIOUS GENES AND ANTIGENS. THE PRESENCE OF HLA-CW6 IS COMMON AS WELL A STRONG LINK BETWEEN ITS PRESENCE AND THE ONSET OF PSORIASIS BEING OBSERVED. THE MAIN ALTERNATIONS ARE DNA METHYLATION, HISTONE'S MODIFICATIONS AND THE ROLE OF MICRORNA. EXCESSIVE REACTION IS USUALLY NOT PRESENT WITHOUT A TRIGGERING FACTOR. ENVIRONMENTAL FACTORS ARE MOSTLY RATED, SUCH AS DRUGS, LIFE STYLE AND HABITS (SMOKING, ALCOHOL), DIET, PHYSICAL TRAUMA (SKIN INJURY PROVOKING KOEBNER PHENOMENON), STRESS, MICROORGANISM AND INFECTIONS. CONCLUSIONS: THE CORRELATION BETWEEN PATHOGENESIS OF PSORIASIS AND ENVIRONMENTAL RISK FACTORS, TOGETHER WITH EPIGENETIC ALTERNATIONS STILL REQUIRE MORE INVESTIGATION. EDUCATION ABOUT DIET HABITS, NUTRITION, WEIGHT LOSS AND HEALTHY LIFESTYLE SEEMS TO BE IMPORTANT DURING THE TREATMENT OF PSORIASIS. 2020 6 6863 25 [ONE AUTISM, SEVERAL AUTISMS. PHENOTYPICAL VARIABILITY IN AUTISM SPECTRUM DISORDERS]. INTRODUCTION: AUTISM SPECTRUM DISORDERS (ASD) ARE A HETEROGENEOUS GROUP OF DISORDERS THAT BEGIN IN THE EARLY MONTHS OF LIFE AND FOLLOW A CHRONIC PROGRESSION. THEY HAVE A BIOLOGICAL ORIGIN, WITH COMPLEX AETIOLOGICAL FACTORS THAT INVOLVE DIFFERENT GENETIC, EPIGENETIC AND ENVIRONMENTAL MECHANISMS THAT INTERACT WITH ONE ANOTHER. AIM: TO REVIEW THE MAIN FACTORS THAT VARY THE PRESENTATION OF AUTISM TAKING INTO ACCOUNT THE MOST RECENT SCIENTIFIC EVIDENCE. DEVELOPMENT: ASPECTS RELATED WITH THE DEVELOPMENT OF SYMPTOMS, GENDER, COMORBIDITY, AGE AND AETIOLOGY DETERMINE THE VARIABILITY IN THE CLINICAL PRESENTATION OF ASD. CONCLUSIONS: AUTISM IS HIGHLY HETEROGENEOUS AND IS PHENOTYPICALLY RELATED, AT LEAST IN PART, WITH A WIDE RANGE OF CAUSATIONS, WHICH RESEARCHERS HAVE BEGUN TO UNRAVEL BUT WHICH ARE STILL LARGELY UNKNOWN. AETIOLOGICAL RESEARCH, ESPECIALLY IN THE AREA OF GENETICS, WILL MAKE IT POSSIBLE TO IDENTIFY DIFFERENT HOMOGENEOUS SUBGROUPS WITH THEIR CORRESPONDING PHENOTYPES, WHILE ALSO OPENING UP THE WAY TO POSSIBLE THERAPEUTIC ALTERNATIVES IN THE FUTURE. 2016 7 259 22 ADVANCES IN PCOS PATHOGENESIS AND PROGRESSION-MITOCHONDRIAL MUTATIONS AND DYSFUNCTION. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON FEMALE ENDOCRINE DISORDER, WHICH STILL REMAINS LARGELY UNSOLVED IN TERMS OF ETIOLOGY AND PATHOGENESIS DESPITE IMPORTANT ADVANCES IN OUR UNDERSTANDING OF ITS GENETIC, EPIGENETIC, OR ENVIRONMENTAL FACTOR IMPLICATIONS. IT IS A HETEROGENEOUS DISEASE, FREQUENTLY ASSOCIATED WITH INSULIN RESISTANCE, CHRONIC INFLAMMATION, AND OXIDATIVE STRESS AND PROBABLY ACCOMPANIED WITH SUBCLINICAL CARDIOVASCULAR DISEASE (CVD) AND SOME MALIGNANT LESIONS AS WELL, SUCH AS ENDOMETRIAL CANCER. DISCREPANCIES IN THE CLINICAL PHENOTYPE AND PROGRESSION OF PCOS EXIST BETWEEN DIFFERENT POPULATION GROUPS, WHICH NUCLEAR GENETIC STUDIES HAVE SO FAR FAILED TO EXPLAIN. OVER THE LAST YEARS, MITOCHONDRIAL DYSFUNCTION HAS BEEN INCREASINGLY RECOGNIZED AS AN IMPORTANT CONTRIBUTOR TO AN ARRAY OF DISEASES. BECAUSE MITOCHONDRIA ARE UNDER THE DUAL GENETIC CONTROL OF BOTH THE MITOCHONDRIAL AND NUCLEAR GENOMES, MUTATIONS WITHIN EITHER DNA MOLECULE MAY RESULT IN DEFICIENCY IN RESPIRATORY CHAIN FUNCTION THAT LEADS TO A REDUCED ABILITY TO PRODUCE CELLULAR ADENOSINE-5'-TRIPHOSPHATE AND TO AN EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES. HOWEVER, THE ASSOCIATION BETWEEN VARIANTS IN MITOCHONDRIAL GENOME, MITOCHONDRIAL DYSFUNCTION, AND PCOS HAS BEEN INVESTIGATED TO A LESSER EXTENT. MAY MUTATIONS IN MITOCHONDRIAL DNA (MTDNA) BECOME AN ADDITIONAL TARGET OF INVESTIGATIONS ON THE MISSING PCOS HERITABILITY? ARE MUTATIONS IN MTDNA IMPLICATED IN THE INITIATION AND PROGRESSION OF PCOS COMPLICATIONS, E.G., CVDS, DIABETES MELLITUS, CANCERS? 2018 8 5670 31 SHARED (EPI)GENOMIC BACKGROUND CONNECTING NEURODEGENERATIVE DISEASES AND TYPE 2 DIABETES. THE PROGRESSIVE AGING OF POPULATIONS HAS RESULTED IN AN INCREASED PREVALENCE OF CHRONIC PATHOLOGIES, ESPECIALLY OF METABOLIC, NEURODEGENERATIVE AND MOVEMENT DISORDERS. IN PARTICULAR, TYPE 2 DIABETES (T2D), ALZHEIMER'S DISEASE (AD) AND PARKINSON'S DISEASE (PD) ARE AMONG THE MOST PREVALENT AGE-RELATED, MULTIFACTORIAL PATHOLOGIES THAT DESERVE PARTICULAR ATTENTION, GIVEN THEIR DRAMATIC IMPACT ON PATIENT QUALITY OF LIFE, THEIR ECONOMIC AND SOCIAL BURDEN AS WELL THE ETIOPATHOGENETIC MECHANISMS, WHICH MAY OVERLAP IN SOME CASES. INDEED, THE EXISTENCE OF COMMON TRIGGERING FACTORS REFLECTS THE CONTRIBUTION OF MUTUAL GENETIC, EPIGENETIC AND ENVIRONMENTAL FEATURES IN THE ETIOPATHOGENETIC MECHANISMS UNDERLYING T2D AND AD/PD. ON THIS SUBJECT, THIS REVIEW WILL SUMMARIZE THE SHARED (EPI)GENOMIC FEATURES THAT CHARACTERIZE THESE COMPLEX PATHOLOGIES. IN PARTICULAR, GENETIC VARIANTS AND GENE EXPRESSION PROFILES ASSOCIATED WITH T2D AND AD/PD WILL BE DISCUSSED AS POSSIBLE CONTRIBUTORS TO DETERMINE THE SUSCEPTIBILITY AND PROGRESSION TO THESE DISORDERS. MOREOVER, POTENTIAL SHARED EPIGENETIC MODIFICATIONS AND FACTORS AMONG T2D, AD AND PD WILL ALSO BE ILLUSTRATED. OVERALL, THIS REVIEW SHOWS THAT FINDINGS FROM GENOMIC STUDIES STILL DESERVES FURTHER RESEARCH TO EVALUATE AND IDENTIFY GENETIC FACTORS THAT DIRECTLY CONTRIBUTE TO THE SHARED ETIOPATHOGENESIS. MOREOVER, A COMMON EPIGENETIC BACKGROUND STILL NEEDS TO BE INVESTIGATED AND CHARACTERIZED. THE EVIDENCES DISCUSSED IN THIS REVIEW UNDERLINE THE IMPORTANCE OF INTEGRATING LARGE-SCALE (EPI)GENOMIC DATA WITH ADDITIONAL MOLECULAR INFORMATION AND CLINICAL AND SOCIAL BACKGROUND IN ORDER TO FINELY DISSECT THE COMPLEX ETIOPATHOGENIC NETWORKS THAT BUILD UP THE "DISEASE INTERACTOME" CHARACTERIZING T2D, AD AND PD. 2020 9 6204 27 THE INFLUENCE OF EPIGENETICS AND INFLAMMATION ON CARDIOMETABOLIC RISKS. CARDIOMETABOLIC DISEASES INCLUDE METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES MELLITUS, AND HYPERTENSION. EPIGENETIC MODIFICATIONS PARTICIPATE IN CARDIOMETABOLIC DISEASES THROUGH SEVERAL PATHWAYS, INCLUDING INFLAMMATION, VASCULAR DYSFUNCTION, AND INSULIN RESISTANCE. EPIGENETIC MODIFICATIONS, WHICH ENCOMPASS ALTERATIONS TO GENE EXPRESSION WITHOUT MUTATING THE DNA SEQUENCE, HAVE GAINED MUCH ATTENTION IN RECENT YEARS, SINCE THEY HAVE BEEN CORRELATED WITH CARDIOMETABOLIC DISEASES AND MAY BE TARGETED FOR THERAPEUTIC INTERVENTIONS. EPIGENETIC MODIFICATIONS ARE GREATLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, CIGARETTE SMOKING, AND POLLUTION. SOME MODIFICATIONS ARE HERITABLE, INDICATING THAT THE BIOLOGICAL EXPRESSION OF EPIGENETIC ALTERATIONS MAY BE OBSERVED ACROSS GENERATIONS. MOREOVER, MANY PATIENTS WITH CARDIOMETABOLIC DISEASES PRESENT WITH CHRONIC INFLAMMATION, WHICH CAN BE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS. THE INFLAMMATORY ENVIRONMENT WORSENS THE PROGNOSIS OF CARDIOMETABOLIC DISEASES AND FURTHER INDUCES EPIGENETIC MODIFICATIONS, PREDISPOSING PATIENTS TO THE DEVELOPMENT OF OTHER METABOLISM-ASSOCIATED DISEASES AND COMPLICATIONS. A DEEPER UNDERSTANDING OF INFLAMMATORY PROCESSES AND EPIGENETIC MODIFICATIONS IN CARDIOMETABOLIC DISEASES IS NECESSARY TO IMPROVE OUR DIAGNOSTIC CAPABILITIES, PERSONALIZED MEDICINE APPROACHES, AND THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS. FURTHER UNDERSTANDING MAY ALSO ASSIST IN PREDICTING DISEASE OUTCOMES, ESPECIALLY IN CHILDREN AND YOUNG ADULTS. THIS REVIEW DESCRIBES EPIGENETIC MODIFICATIONS AND INFLAMMATORY PROCESSES UNDERLYING CARDIOMETABOLIC DISEASES, AND FURTHER DISCUSSES ADVANCES IN THE RESEARCH FIELD WITH A FOCUS ON SPECIFIC POINTS FOR INTERVENTIONAL THERAPY. 2023 10 1248 22 CURRENT EVIDENCE FOR BIOLOGICAL BIOMARKERS AND MECHANISMS UNDERLYING ACUTE TO CHRONIC PAIN TRANSITION ACROSS THE PEDIATRIC AGE SPECTRUM. CHRONIC PAIN IS HIGHLY PREVALENT IN THE PEDIATRIC POPULATION. MANY FACTORS ARE INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN. CURRENTLY, THERE ARE CONCEPTUAL MODELS PROPOSED, BUT THEY LACK A MECHANISTICALLY SOUND INTEGRATED THEORY CONSIDERING THE STAGES OF CHILD DEVELOPMENT. OBJECTIVE BIOMARKERS ARE CRITICALLY NEEDED FOR THE DIAGNOSIS, RISK STRATIFICATION, AND PROGNOSIS OF THE PATHOLOGICAL STAGES OF PAIN CHRONIFICATION. IN THIS ARTICLE, WE SUMMARIZE THE CURRENT EVIDENCE ON MECHANISMS AND BIOMARKERS OF ACUTE TO CHRONIC PAIN TRANSITIONS IN INFANTS AND CHILDREN THROUGH THE DEVELOPMENTAL LENS. THE GOAL IS TO IDENTIFY GAPS AND OUTLINE FUTURE DIRECTIONS FOR BASIC AND CLINICAL RESEARCH TOWARD A DEVELOPMENTALLY INFORMED THEORY OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. AT THE OUTSET, THE IMPORTANCE OF OBJECTIVE BIOMARKERS FOR CHRONIFICATION OF PAIN IN CHILDREN IS OUTLINED, FOLLOWED BY A SUMMARY OF THE CURRENT EVIDENCE ON THE MECHANISMS OF ACUTE TO CHRONIC PAIN TRANSITION IN ADULTS, IN ORDER TO CONTRAST WITH THE DEVELOPMENTAL MECHANISMS OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. EVIDENCE IS PRESENTED TO SHOW THAT CHRONIC PAIN MAY HAVE ITS ORIGIN FROM INSULTS EARLY IN LIFE, WHICH PRIME THE CHILD FOR THE DEVELOPMENT OF CHRONIC PAIN IN LATER LIFE. FURTHERMORE, AVAILABLE GENETIC, EPIGENETIC, PSYCHOPHYSICAL, ELECTROPHYSIOLOGICAL, NEUROIMAGING, NEUROIMMUNE, AND SEX MECHANISMS ARE DESCRIBED IN INFANTS AND OLDER CHILDREN. IN CONCLUSION, FUTURE DIRECTIONS ARE DISCUSSED WITH A FOCUS ON RESEARCH GAPS, TRANSLATIONAL AND CLINICAL IMPLICATIONS. UTILIZATION OF DEVELOPMENTAL MECHANISMS FRAMEWORK TO INFORM CLINICAL DECISION-MAKING AND STRATEGIES FOR PREVENTION AND MANAGEMENT OF ACUTE TO CHRONIC PAIN TRANSITIONS IN CHILDREN, IS HIGHLIGHTED. 2023 11 4973 26 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 12 2584 21 EPIGENETICS OF OBESITY. OBESITY IS A METABOLIC DISEASE, WHICH IS BECOMING AN EPIDEMIC HEALTH PROBLEM: IT HAS BEEN RECENTLY DEFINED IN TERMS OF GLOBAL PANDEMIC. OVER THE YEARS, THE APPROACHES THROUGH FAMILY, TWINS AND ADOPTION STUDIES LED TO THE IDENTIFICATION OF SOME CAUSAL GENES IN MONOGENIC FORMS OF OBESITY BUT THE ORIGINS OF THE PANDEMIC OF OBESITY CANNOT BE CONSIDERED ESSENTIALLY DUE TO GENETIC FACTORS, BECAUSE HUMAN GENOME IS NOT LIKELY TO CHANGE IN JUST A FEW YEARS. EPIGENETIC STUDIES HAVE OFFERED IN RECENT YEARS VALUABLE TOOLS FOR THE UNDERSTANDING OF THE WORLDWIDE SPREAD OF THE PANDEMIC OF OBESITY. THE INVOLVEMENT OF EPIGENETIC MODIFICATIONS-DNA METHYLATION, HISTONE TAILS, AND MIRNAS MODIFICATIONS-IN THE DEVELOPMENT OF OBESITY IS MORE AND MORE EVIDENT. IN THE EPIGENETIC LITERATURE, THERE ARE EVIDENCES THAT THE ENTIRE EMBRYO-FETAL AND PERINATAL PERIOD OF DEVELOPMENT PLAYS A KEY ROLE IN THE PROGRAMMING OF ALL HUMAN ORGANS AND TISSUES. THEREFORE, THE MOLECULAR MECHANISMS INVOLVED IN THE EPIGENETIC PROGRAMMING REQUIRE A NEW AND GENERAL PATHOGENIC PARADIGM, THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE THEORY, TO EXPLAIN THE CURRENT EPIDEMIOLOGICAL TRANSITION, THAT IS, THE WORLDWIDE INCREASE OF CHRONIC, DEGENERATIVE, AND INFLAMMATORY DISEASES SUCH AS OBESITY, DIABETES, CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES, AND CANCER. OBESITY AND ITS RELATED COMPLICATIONS ARE MORE AND MORE ASSOCIATED WITH ENVIRONMENTAL POLLUTANTS (OBESOGENS), GUT MICROBIOTA MODIFICATIONS AND UNBALANCED FOOD INTAKE, WHICH CAN INDUCE, THROUGH EPIGENETIC MECHANISMS, WEIGHT GAIN, AND ALTERED METABOLIC CONSEQUENCES. 2016 13 6459 11 TIME TO CHANGE FROM A SIMPLE LINEAR MODEL TO A COMPLEX SYSTEMS MODEL. A SIMPLE LINEAR MODEL TO TEST THE HYPOTHESIS BASED ON ONE-ON-ONE RELATIONSHIP HAS BEEN USED TO FIND THE CAUSATIVE FACTORS OF DISEASES. HOWEVER, WE NOW KNOW THAT NOT JUST ONE, BUT MANY FACTORS FROM DIFFERENT SYSTEMS SUCH AS CHEMICAL EXPOSURE, GENES, EPIGENETIC CHANGES, AND PROTEINS ARE INVOLVED IN THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS DIABETES MELLITUS. SO, WITH AVAILABILITY OF MODERN TECHNOLOGIES TO UNDERSTAND THE INTRICATE NATURE OF RELATIONS AMONG COMPLEX SYSTEMS, WE NEED TO MOVE FORWARD TO THE FUTURE BY TAKING COMPLEX SYSTEMS MODEL. 2016 14 6380 15 THE ROLE OF OBESITY AND DIABETES IN DEMENTIA. CHRONIC CONDITIONS SUCH AS OBESITY, DIABETES, AND DEMENTIA ARE INCREASING IN THE UNITED STATES (US) POPULATION. KNOWLEDGE OF THESE CHRONIC CONDITIONS, PREVENTATIVE MEASURES, AND PROPER MANAGEMENT TACTICS IS IMPORTANT AND CRITICAL TO PREVENTING DISEASE. THE OVERLAP BETWEEN OBESITY, DIABETES, AND DEMENTIA IS BECOMING FURTHER ELUCIDATED. THESE CONDITIONS SHARE A SIMILAR ORIGIN THROUGH THE COMPONENTS OF INCREASING AGE, GENDER, GENETIC AND EPIGENETIC PREDISPOSITIONS, DEPRESSION, AND A HIGH-FAT WESTERN DIET (WD) THAT ALL CONTRIBUTE TO THE INFLAMMATORY STATE ASSOCIATED WITH THE DEVELOPMENT OF OBESITY, DIABETES, AND DEMENTIA. THIS INFLAMMATORY STATE LEADS TO THE DYSREGULATION OF FOOD INTAKE AND INSULIN RESISTANCE. OBESITY IS OFTEN THE CORNERSTONE THAT LEADS TO THE DEVELOPMENT OF DIABETES AND, SUBSEQUENTLY, IN THE CASE OF TYPE 2 DIABETES MELLITUS (T2DM), PROGRESSION TO "TYPE 3 DIABETES MELLITUS (T3DM)". OBESITY AND DEPRESSION ARE CLOSELY ASSOCIATED WITH DIABETES. HOWEVER, DEMENTIA CAN BE AVOIDED WITH LIFESTYLE MODIFICATIONS, BY SWITCHING TO A PLANT-BASED DIET (E.G., A MEDITERRANEAN DIET (MD)), AND INCREASING PHYSICAL ACTIVITY. DIET AND EXERCISE ARE NOT THE ONLY TREATMENT OPTIONS. THERE ARE SEVERAL SURGICAL AND PHARMACOLOGICAL INTERVENTIONS AVAILABLE FOR PREVENTION. CURRENT AND FUTURE RESEARCH WITHIN EACH OF THESE FIELDS IS WARRANTED AND OFFERS THE CHANCE FOR NEW TREATMENT OPTIONS AND A BETTER UNDERSTANDING OF THE PATHOGENESIS OF EACH CONDITION. 2022 15 6116 20 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 16 6306 20 THE RECOGNITION AND TREATMENT OF GROWTH DISORDERS - A 50-YEAR RETROSPECTIVE. THE PAST 50 YEARS HAVE SEEN GREAT PROGRESS IN THE UNDERSTANDING AND TREATMENT OF CLASSIC GROWTH DISORDERS. ADVANCES SUCH AS THE RECOGNITION OF HORMONE RECEPTOR DEFECTS, THE DEVELOPMENT OF RECOMBINANT GROWTH HORMONE, AND THE EXPANDING AWARENESS OF EPIGENETIC PHENOMENA AFFECTING GROWTH ARE AMONG THESE GREAT ACHIEVEMENTS. YET GROWTH FAILURE REMAINS A PERVASIVE PROBLEM AMONG CHILDREN WITH COMPLEX HEALTH CONDITIONS, SUCH AS SURVIVORS OF CHILDHOOD CANCERS, PREMATURE INFANTS, ORGAN TRANSPLANT RECIPIENTS, AND CHILDREN WITH CYSTIC FIBROSIS. THE SIGNIFICANT INCREASES IN LIFE EXPECTANCY AMONG THESE GROUPS UNDERSCORES THE POTENTIAL CONSEQUENCES OF POOR GROWTH, WHETHER DUE TO THE UNDERLYING CONDITIONS OR MEDICAL TREATMENTS, AS THEY MAY HAVE LONG-LASTING EFFECTS INTO ADULTHOOD. THE ONGOING CONTRIBUTIONS OF HUMAN BIOLOGISTS TO THE STUDY OF HUMAN GROWTH REMAIN ESSENTIAL IN THE RECOGNITION AND TREATMENT OF GROWTH DISORDERS, BY DEFINING NORMAL PATTERNS OF GROWTH AND BODY COMPOSITION, THE INTERPLAY OF GROWTH AND MATURATION, THE ROLE OF ENVIRONMENTAL, BEHAVIORAL AND GENETIC FACTORS, AND THE LONG-TERM CONSEQUENCES OF GROWTH PATTERNS. EXAMPLES WILL BE GIVEN BASED ON TWO COMMON GENETIC DISORDERS, CYSTIC FIBROSIS AND SICKLE-CELL ANEMIA, TO HIGHLIGHT THE RELATIONSHIPS BETWEEN GROWTH FAILURE, SURVIVAL, AND MALNUTRITION. ALSO, A STUDY OF BONE MINERAL ACCRETION IN CHILDREN WITH CYSTIC FIBROSIS WILL ILLUSTRATE THE IMPORTANCE OF UNDERSTANDING PATTERNS OF GROWTH IN HEALTHY CHILDREN, AND THEIR APPLICATION IN THE DIAGNOSIS AND MANAGEMENT OF CHILDREN WITH CHRONIC DISEASE. THESE EXAMPLES ACCENTUATE THE NEED FOR CONTINUED PARTICIPATION OF HUMAN BIOLOGISTS IN THE STUDY OF GROWTH AND DEVELOPMENT AND THE CARE OF CHILDREN. 2009 17 3676 22 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 18 4892 29 OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: OXIDATIVE STRESS IN POLYCYSTIC OVARY SYNDROME. IN BRIEF: A GENETIC, EPIGENETIC, AND ENVIRONMENTAL ASSOCIATION EXISTS BETWEEN OXIDATIVE STRESS (OS) AND POLYCYSTIC OVARY SYNDROME (PCOS), EXPRESSED IN A MULTIFACETED CLINICAL PROFILE. THIS REVIEW SUMMARIZES AND DISCUSSES THE ROLE OF OS IN THE PATHOGENESIS OF PCOS SYNDROME, FOCUSING ON METABOLIC, REPRODUCTIVE, AND CANCER COMPLICATIONS. ABSTRACT: OXIDATIVE STRESS (OS), AN IMBALANCE BETWEEN OXIDANTS AND ANTIOXIDANTS IN CELLS, IS ONE OF MANY FACTORS PLAYING ESSENTIAL ROLES IN THE PATHOGENESIS OF POLYCYSTIC OVARY SYNDROME (PCOS). PCOS IS DESCRIBED MAINLY AS A DISPROPORTION OF REPRODUCTIVE HORMONES, LEADING TO CHRONIC ANOVULATION AND INFERTILITY IN WOMEN. INTERESTINGLY, OS IN PCOS MAY BE ASSOCIATED WITH MANY DISORDERS AND DISEASES. THIS REVIEW FOCUSES ON CHARACTERISTIC MARKERS OF OS IN PCOS AND THE RELATIONSHIP BETWEEN OS AND PCOS RELATED TO INSULIN RESISTANCE (IR), HYPERANDROGENEMIA, OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND CANCER. INTERESTINGLY, IN PATIENTS WITH PCOS, AN INCREASE IN OXIDATIVE STATUS AND INSUFFICIENT COMPENSATION OF THE INCREASE IN ANTIOXIDANT STATUS BEFORE ANY CARDIOVASCULAR COMPLICATIONS ARE OBSERVED. MOREOVER, FREE RADICALS PROMOTE CARCINOGENESIS IN PCOS PATIENTS. HOWEVER, DESPITE THESE DATA, IT HAS NOT BEEN ESTABLISHED WHETHER OXYGEN STRESS INFLUENCES PCOS DEVELOPMENT OR A SECONDARY DISORDER RESULTING FROM HYPERGLYCEMIA, IR, AND CARDIOVASCULAR AND CANCER COMPLICATIONS IN WOMEN. 2022 19 5076 20 PHYSIOLOGICAL AND ENVIRONMENTAL FACTORS AFFECTING CANCER RISK AND PROGNOSIS IN OBESITY. OBESITY RESULTS FROM A CHRONIC EXCESSIVE ACCUMULATION OF ADIPOSE TISSUE DUE TO A LONG-TERM IMBALANCE BETWEEN ENERGY INTAKE AND EXPENDITURE. AVAILABLE EPIDEMIOLOGICAL AND CLINICAL DATA STRONGLY SUPPORT THE LINKS BETWEEN OBESITY AND CERTAIN CANCERS. EMERGING CLINICAL AND EXPERIMENTAL FINDINGS HAVE IMPROVED OUR UNDERSTANDING OF THE ROLES OF KEY PLAYERS IN OBESITY-ASSOCIATED CARCINOGENESIS SUCH AS AGE, SEX (MENOPAUSE), GENETIC AND EPIGENETIC FACTORS, GUT MICROBIOTA AND METABOLIC FACTORS, BODY SHAPE TRAJECTORY OVER LIFE, DIETARY HABITS, AND GENERAL LIFESTYLE. IT IS NOW WIDELY ACCEPTED THAT THE CANCER-OBESITY RELATIONSHIP DEPENDS ON THE SITE OF CANCER, THE SYSTEMIC INFLAMMATORY STATUS, AND MICRO ENVIRONMENTAL PARAMETERS SUCH AS LEVELS OF INFLAMMATION AND OXIDATIVE STRESS IN TRANSFORMING TISSUES. WE HEREBY REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF CANCER RISK AND PROGNOSIS IN OBESITY WITH RESPECT TO THESE PLAYERS. WE HIGHLIGHT HOW THE LACK OF THEIR CONSIDERATION CONTRIBUTED TO THE CONTROVERSY OVER THE LINK BETWEEN OBESITY AND CANCER IN EARLY EPIDEMIOLOGICAL STUDIES. FINALLY, THE LESSONS AND CHALLENGES OF INTERVENTIONS FOR WEIGHT LOSS AND BETTER CANCER PROGNOSIS, AND THE MECHANISMS OF WEIGHT GAIN IN SURVIVORS ARE ALSO DISCUSSED. 2023 20 6823 23 [GENERAL CONCEPTS OF EPIGENETICS: PROJECTIONS IN PAEDIATRICS]. CURRENT EVIDENCE SUPPORTS THE NOTION THAT ALTERATIONS IN INTRAUTERINE GROWTH AND DURING THE FIRST YEARS OF LIFE HAVE A SUBSTANTIAL EFFECT ON THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE, WHICH IN SOME CASES IS EVEN HIGHER THAN THOSE DUE TO GENETIC FACTORS. THE PERSISTENCE AND REPRODUCIBILITY OF THE PHENOTYPES ASSOCIATED WITH ALTERED EARLY DEVELOPMENT SUGGEST THE PARTICIPATION OF MECHANISMS THAT WOULD RECORD ENVIRONMENTAL CUES, GENERATING A CELLULAR REPROGRAMMING (I.E., EPIGENETIC MECHANISMS). THIS REVIEW IS AN INTRODUCTION TO A SERIES OF FIVE ARTICLES FOCUSED ON THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF HIGHLY PREVALENT CHRONIC DISEASES (I.E., CARDIOVASCULAR, METABOLIC, ASTHMA/ALLERGIES AND CANCER) AND THEIR ORIGINS IN THE FOETAL AND NEONATAL PERIOD. THIS SERIES OF ARTICLES AIMS TO SHOW THE STATE OF THE ART IN THIS RESEARCH AREA AND PRESENT THE UPCOMING CLUES AND CHALLENGES, IN WHICH PAEDIATRICIANS HAVE A PROMINENT ROLE, DEVELOPING STRATEGIES FOR THE PREVENTION, EARLY DETECTION AND FOLLOW-UP. 2016