1 6302 166 THE PUTATIVE ROLE OF VIRUSES, BACTERIA, AND CHRONIC FUNGAL BIOTOXIN EXPOSURE IN THE GENESIS OF INTRACTABLE FATIGUE ACCOMPANIED BY COGNITIVE AND PHYSICAL DISABILITY. PATIENTS WHO PRESENT WITH SEVERE INTRACTABLE APPARENTLY IDIOPATHIC FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY PRESENT A SIGNIFICANT THERAPEUTIC CHALLENGE. THE EFFECT OF PSYCHOLOGICAL COUNSELING IS LIMITED, WITH SIGNIFICANT BUT VERY SLIGHT IMPROVEMENTS IN PSYCHOMETRIC MEASURES OF FATIGUE AND DISABILITY BUT NO IMPROVEMENT ON SCIENTIFIC MEASURES OF PHYSICAL IMPAIRMENT COMPARED TO CONTROLS. SIMILARLY, EXERCISE REGIMES EITHER PRODUCE SIGNIFICANT, BUT PRACTICALLY UNIMPORTANT, BENEFIT OR PROVOKE SYMPTOM EXACERBATION. MANY SUCH PATIENTS ARE AFFORDED THE EXCLUSIONARY, NON-SPECIFIC DIAGNOSIS OF CHRONIC FATIGUE SYNDROME IF RUDIMENTARY TESTING FAILS TO DISCOVER THE CAUSE OF THEIR SYMPTOMS. MORE SOPHISTICATED INVESTIGATIONS OFTEN REVEAL THE PRESENCE OF A RANGE OF PATHOGENS CAPABLE OF ESTABLISHING LIFE-LONG INFECTIONS WITH SOPHISTICATED IMMUNE EVASION STRATEGIES, INCLUDING PARVOVIRUSES, HHV6, VARIANTS OF EPSTEIN-BARR, CYTOMEGALOVIRUS, MYCOPLASMA, AND BORRELIA BURGDORFERI. OTHER PATIENTS HAVE A HISTORY OF CHRONIC FUNGAL OR OTHER BIOTOXIN EXPOSURE. HEREIN, WE EXPLAIN THE EPIGENETIC FACTORS THAT MAY RENDER SUCH INDIVIDUALS SUSCEPTIBLE TO THE CHRONIC PATHOLOGY INDUCED BY SUCH AGENTS, HOW SUCH AGENTS INDUCE PATHOLOGY, AND, INDEED, HOW SUCH PATHOLOGY CAN PERSIST AND EVEN AMPLIFY EVEN WHEN INFECTIONS HAVE CLEARED OR WHEN BIOTOXIN EXPOSURE HAS CEASED. THE PRESENCE OF ACTIVE, REACTIVATED, OR EVEN LATENT HERPES VIRUS COULD BE A POTENTIAL SOURCE OF INTRACTABLE FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY IN SOME PATIENTS, AND THE SAME MAY BE TRUE OF PERSISTENT PARVOVIRUS B12 AND MYCOPLASMA INFECTION. A HISTORY OF CHRONIC MOLD EXPOSURE IS A FEASIBLE EXPLANATION FOR SUCH SYMPTOMS, AS IS THE PRESENCE OF B. BURGDORFERI. THE COMPLEX TROPISM, LIFE CYCLES, GENETIC VARIABILITY, AND LOW TITER OF MANY OF THESE PATHOGENS MAKES THEIR DETECTION IN BLOOD A CHALLENGE. EXAMINATION OF LYMPHOID TISSUE OR CSF IN SUCH CIRCUMSTANCES MAY BE WARRANTED. 2016 2 6159 42 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 3 1736 32 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 4 3676 37 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 5 6791 33 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON. 2007 6 2901 32 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 7 2816 45 FIBROMYALGIA: PATHOGENESIS, MECHANISMS, DIAGNOSIS AND TREATMENT OPTIONS UPDATE. FIBROMYALGIA IS A SYNDROME CHARACTERIZED BY CHRONIC AND WIDESPREAD MUSCULOSKELETAL PAIN, OFTEN ACCOMPANIED BY OTHER SYMPTOMS, SUCH AS FATIGUE, INTESTINAL DISORDERS AND ALTERATIONS IN SLEEP AND MOOD. IT IS ESTIMATED THAT TWO TO EIGHT PERCENT OF THE WORLD POPULATION IS AFFECTED BY FIBROMYALGIA. FROM A MEDICAL POINT OF VIEW, THIS PATHOLOGY STILL PRESENTS INEXPLICABLE ASPECTS. IT IS KNOWN THAT FIBROMYALGIA IS CAUSED BY A CENTRAL SENSITIZATION PHENOMENON CHARACTERIZED BY THE DYSFUNCTION OF NEURO-CIRCUITS, WHICH INVOLVES THE PERCEPTION, TRANSMISSION AND PROCESSING OF AFFERENT NOCICEPTIVE STIMULI, WITH THE PREVALENT MANIFESTATION OF PAIN AT THE LEVEL OF THE LOCOMOTOR SYSTEM. IN RECENT YEARS, THE PATHOGENESIS OF FIBROMYALGIA HAS ALSO BEEN LINKED TO OTHER FACTORS, SUCH AS INFLAMMATORY, IMMUNE, ENDOCRINE, GENETIC AND PSYCHOSOCIAL FACTORS. A RHEUMATOLOGIST TYPICALLY MAKES A DIAGNOSIS OF FIBROMYALGIA WHEN THE PATIENT DESCRIBES A HISTORY OF PAIN SPREADING IN ALL QUADRANTS OF THE BODY FOR AT LEAST THREE MONTHS AND WHEN PAIN IS CAUSED BY DIGITAL PRESSURE IN AT LEAST 11 OUT OF 18 ALLOGENIC POINTS, CALLED TENDER POINTS. FIBROMYALGIA DOES NOT INVOLVE ORGANIC DAMAGE, AND SEVERAL DIAGNOSTIC APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS, INCLUDING THE ANALYSIS OF GENETIC, EPIGENETIC AND SEROLOGICAL BIOMARKERS. SYMPTOMS OFTEN BEGIN AFTER PHYSICAL OR EMOTIONAL TRAUMA, BUT IN MANY CASES, THERE APPEARS TO BE NO OBVIOUS TRIGGER. WOMEN ARE MORE PRONE TO DEVELOPING THE DISEASE THAN MEN. UNFORTUNATELY, THE CONVENTIONAL MEDICAL THERAPIES THAT TARGET THIS PATHOLOGY PRODUCE LIMITED BENEFITS. THEY REMAIN LARGELY PHARMACOLOGICAL IN NATURE AND TEND TO TREAT THE SYMPTOMATIC ASPECTS OF VARIOUS DISORDERS REPORTED BY THE PATIENT. THE STATISTICS, HOWEVER, HIGHLIGHT THE FACT THAT 90% OF PEOPLE WITH FIBROMYALGIA ALSO TURN TO COMPLEMENTARY MEDICINE TO MANAGE THEIR SYMPTOMS. 2021 8 5038 22 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 9 5133 36 POTENTIAL EPIGENETIC MECHANISM(S) ASSOCIATED WITH THE PERSISTENCE OF PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN RECEIVING CHEMOTHERAPY FOR BREAST CANCER: A HYPOTHESIS. DUE TO RECENT TREATMENT ADVANCES, THERE HAVE BEEN IMPROVEMENTS IN THE PROPORTION OF WOMEN SURVIVING A DIAGNOSIS OF BREAST CANCER (BC). HOWEVER, MANY OF THESE SURVIVORS REPORT PERSISTENT ADVERSE SIDE EFFECTS FOLLOWING TREATMENT, SUCH AS COGNITIVE DYSFUNCTION, DEPRESSIVE SYMPTOMS, ANXIETY, FATIGUE, SLEEP DISTURBANCES, AND PAIN. INVESTIGATORS HAVE EXAMINED CIRCULATING LEVELS OF INFLAMMATORY MARKERS, PARTICULARLY SERUM CYTOKINES, FOR A POTENTIAL CAUSAL RELATIONSHIP TO THE DEVELOPMENT/PERSISTENCE OF THESE PSYCHONEUROLOGICAL SYMPTOMS (PNS). WHILE INFLAMMATORY ACTIVATION, RESULTING FROM PERCEIVED STRESS OR OTHER FACTORS, MAY DIRECTLY CONTRIBUTE TO THE DEVELOPMENT OF PNS, WE OFFER AN ALTERNATIVE HYPOTHESIS, SUGGESTING THAT THESE SYMPTOMS ARE AN EARLY STEP IN A CASCADE OF BIOLOGICAL CHANGES LEADING TO EPIGENETIC ALTERATIONS AT THE LEVEL OF DEOXYRIBONUCLEIC ACID (DNA) METHYLATION, HISTONE MODIFICATIONS, AND/OR CHROMATIN STRUCTURE/CHROMOSOMAL INSTABILITY. GIVEN THAT EPIGENETIC PATTERNS HAVE PLASTICITY, IF THIS CONJECTURED RELATIONSHIP BETWEEN EPIGENOMIC/ACQUIRED GENOMIC ALTERATIONS AND THE DEVELOPMENT/PERSISTENCE OF PNS IS CONFIRMED, IT COULD PROVIDE FOUNDATIONAL KNOWLEDGE FOR FUTURE RESEARCH LEADING TO THE RECOGNITION OF PREDICTIVE MARKERS AND/OR TREATMENTS TO ALLEVIATE PNS IN WOMEN WITH BC. IN THIS ARTICLE, WE DISCUSS AN EVOLVING THEORY OF THE BIOLOGICAL BASIS OF PNS, INTEGRATING KNOWLEDGE RELATED TO INFLAMMATION AND DNA REPAIR IN THE CONTEXT OF GENETIC AND EPIGENETIC SCIENCE TO EXPAND THE PARADIGM FOR UNDERSTANDING SYMPTOM ACQUISITION/PERSISTENCE FOLLOWING CHEMOTHERAPY. 2014 10 1340 30 DESIGNING SAFER DRUGS: (Q)SAR-BASED IDENTIFICATION OF MUTAGENS AND CARCINOGENS. MUTAGENICITY AND CARCINOGENICITY ARE CHRONIC EFFECTS OF PRIMARY CONCERN FOR HUMAN HEALTH. A UNIFYING APPROACH TO THEIR MECHANISTIC UNDERSTANDING IS THE RECOGNITION THAT MANY CHEMICALS PROVOKE BOTH EFFECTS BY ELECTROPHILIC ATTACK TO THE BIOLOGICAL MACROMOLECULES, AS SUCH OR AFTER METABOLISM (GENOTOXIC CARCINOGENICITY). QSARS OF INDIVIDUAL CLASSES OF GENOTOXIC CARCINOGENS HAVE CONTRIBUTED TO THE ELUCIDATION OF THE CHEMICAL DETERMINANTS OF THIS ACTIVITY. LITTLE WORK HAS BEEN DONE ON THE EPIGENETIC CARCINOGENS, ACTING THROUGH NON-GENOTOXIC, VERY SPECIFIC MECHANISMS. HOWEVER, THE EXISTING QSARS FOR INDIVIDUAL CHEMICAL CLASSES ARE TOO FEW TO BE OF REAL USEFULNESS IN THE SCREENING OF MASSES OF CANDIDATE DRUGS. MODELS FOR PREDICTING THE CARCINOGENICITY OF "ANY TYPE" OF CHEMICALS HAVE BEEN PROPOSED: PROSPECTIVE PREDICTION EXERCISES POINTED TO THE SERIOUS LIMITATIONS OF MOST OF THESE APPROACHES. THE BEST ALTERNATIVE IS PROVIDED BY PANELS OF HUMAN EXPERTS. THE ABOVE PREDICTION EXERCISES CONSIDERED SAMPLES OF GENERAL CHEMICALS, THUS WE SPECIFICALLY ADDRESSED IN THIS PAPER THE ISSUE OF PHARMACEUTICAL DRUGS. WE APPLIED OUR EXPERT KNOWLEDGE TO A DATABASE OF DRUGS WHOSE CARCINOGENICITY/NONCARCINOGENICITY STATUS WAS KNOWN. WHEREAS MOST OF THE NONCARCINOGENS WERE CORRECTLY IDENTIFIED, OUR PREDICTION OF CARCINOGENS WAS LESS SUCCESSFUL THAN WITH THE GENERAL CHEMICALS. SEVERAL CARCINOGENIC DRUGS DID NOT SHOW RECOGNIZED STRUCTURAL ALERTS, AND SUPPOSEDLY ACTED BY EPIGENETIC MECHANISMS. WHEREAS THE CONTRIBUTION OF HUMAN EXPERTS IS HIGHLY VALUABLE IN THIS PHASE (E.G. PRIORITY SETTING), MORE WORK IS NECESSARY ON: A) EPIGENETIC CARCINOGENS; B) EFFICIENT COMPUTERIZED MODELS. 2003 11 4651 37 NEUROPROGRESSION IN SCHIZOPHRENIA: PATHWAYS UNDERPINNING CLINICAL STAGING AND THERAPEUTIC COROLLARIES. OBJECTIVE: WHILST DOPAMINERGIC DYSFUNCTION REMAINS A NECESSARY COMPONENT INVOLVED IN THE PATHOGENESIS OF SCHIZOPHRENIA, OUR CURRENT PHARMACOLOGICAL ARMOURY OF DOPAMINE ANTAGONISTS DOES LITTLE TO CONTROL THE NEGATIVE SYMPTOMS OF SCHIZOPHRENIA. THIS SUGGESTS OTHER PATHOLOGICAL PROCESSES MUST BE IMPLICATED. THIS PAPER AIMS TO ELABORATE ON SUCH THEORIES. METHODS: DATA FOR THIS REVIEW WERE SOURCED FROM THE ELECTRONIC DATABASE PUBMED, AND WAS NOT LIMITED BY LANGUAGE OR DATE OF PUBLICATION. RESULTS: IT HAS BEEN SUGGESTED THAT MULTIPLE 'HITS' MAY BE REQUIRED TO UNVEIL THE CLINICAL SYNDROME IN SUSCEPTIBLE INDIVIDUALS. SUCH HITS POTENTIALLY FIRST OCCUR IN UTERO, LEADING TO NEURONAL DISRUPTION, EPIGENETIC CHANGES AND THE ESTABLISHMENT OF AN ABNORMAL INFLAMMATORY RESPONSE. THE DEVELOPMENT OF SCHIZOPHRENIA MAY THEREFORE POTENTIALLY BE VIEWED AS A NEUROPROGRESSIVE RESPONSE TO THESE EARLY STRESSORS, DRIVEN ON BY CHANGES IN TRYPTOPHAN CATABOLITE (TRYCAT) METABOLISM, REACTIVE OXYGEN SPECIES HANDLING AND N-METHYL D-ASPARTATE (NMDA) CIRCUITRY. GIVEN THE POTENTIAL FOR SUCH PROGRESSION OVER TIME, IT IS PRUDENT TO EXPLORE THE NEW TREATMENT STRATEGIES WHICH MAY BE IMPLEMENTED BEFORE SUCH CHANGES BECOME ESTABLISHED. CONCLUSIONS: OUTSIDE OF THE DOPAMINERGIC MODEL, THE POTENTIAL PATHOGENESIS OF SCHIZOPHRENIA HAS YET TO BE FULLY ELUCIDATED, BUT COMMON THEMES INCLUDE NEUROPIL SHRINKAGE, THE DEVELOPMENT OF ABNORMAL NEURONAL CIRCUITRY, AND A CHRONIC INFLAMMATORY STATE WHICH FURTHER DISRUPTS NEURONAL FUNCTION. WHILST SOME EARLY NON-DOPAMINERGIC TREATMENTS SHOW PROMISE, NONE HAVE YET TO BE FULLY STUDIED IN APPROPRIATELY STRUCTURED RANDOMIZED CONTROLLED TRIALS AND THEY REMAIN LITTLE MORE THAN POTENTIAL ATTRACTIVE TARGETS. 2014 12 3511 35 IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI): FROM MOLECULAR EPIDEMIOLOGY TO MOLECULAR MEDICINE. INHERITED OR ACQUIRED IMPAIRMENT OF XENOBIOTICS METABOLISM IS A POSTULATED MECHANISM UNDERLYING ENVIRONMENT-ASSOCIATED PATHOLOGIES SUCH AS MULTIPLE CHEMICAL SENSITIVITY, FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, DENTAL AMALGAM DISEASE, AND OTHERS, ALSO COLLECTIVELY NAMED IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI). IN VIEW OF THE POOR CURRENT KNOWLEDGE OF THEIR ETIOLOGY AND PATHOGENESIS, AND THE ABSENCE OF RECOGNISED GENETIC AND METABOLIC MARKERS OF THE DISEASES. THEY ARE OFTEN CONSIDERED "MEDICALLY UNEXPLAINED SYNDROMES",. THESE DISABLING CONDITIONS SHARE THE FEATURES OF POLYSYMPTOMATIC MULTI-ORGAN SYNDROMES, CONSIDERED BY PART OF THE MEDICAL COMMUNITY TO BE ABERRANT RESPONSES TRIGGERED BY EXPOSURE TO LOW-DOSE ORGANIC AND INORGANIC CHEMICALS AND METALS, IN CONCENTRATIONS FAR BELOW AVERAGE REFERENCE LEVELS ADMITTED FOR ENVIRONMENTAL TOXICANTS. A GENETIC PREDISPOSITION TO ALTERED BIOTRANSFORMATION OF ENVIRONMENTAL CHEMICALS, DRUGS, AND METALS, AND OF ENDOGENOUS LOW-MOLECULAR WEIGHT METABOLITES, CAUSED BY POLYMORPHISMS OF GENES CODING FOR XENOBIOTIC METABOLIZING ENZYMES, THEIR RECEPTORS AND TRANSCRIPTION FACTORS APPEARS TO BE INVOLVED IN THE SUSCEPTIBILITY TO THESE ENVIRONMENT-ASSOCIATED PATHOLOGIES, ALONG WITH EPIGENETIC FACTORS. FREE RADICAL/ANTIOXIDANT HOMEOSTASIS MAY ALSO BE HEAVILY IMPLICATED, INDIRECTLY BY AFFECTING THE REGULATION OF XENOBIOTIC METABOLIZING ENZYMES, AND DIRECTLY BY CAUSING INCREASED LEVELS OF OXIDATIVE PRODUCTS, IMPLICATED IN THE CHRONIC DAMAGE OF CELLS AND TISSUES, WHICH IS IN PART CORRELATED WITH CLINICAL SYMPTOMS. MORE SYSTEMATIC STUDIES OF MOLECULAR EPIDEMIOLOGY, TOXICO- AND PHARMACO-GENOMICS, ELUCIDATING THE MECHANISMS OF REGULATION, EXPRESSION, INDUCTION, AND ACTIVITY OF ANTIOXIDANT/DETOXIFYING ENZYMES, AND THE POSSIBLE ROLE OF INFLAMMATORY MEDIATORS, PROMISE A BETTER UNDERSTANDING OF THIS PATHOLOGICALLY INCREASED SENSITIVITY TO LOW-LEVEL CHEMICAL STIMULI, AND A SOLID BASIS FOR EFFECTIVE INDIVIDUALIZED ANTIOXIDANT- AND/OR CHELATOR-BASED TREATMENTS. 2010 13 5318 31 PSYCHONEUROENDOCRINE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE: A REVIEW. THERE IS EVIDENCE SUGGESTING THAT IMMUNOSENESCENCE CAN BE ACCELERATED BY EXTERNAL FACTORS SUCH AS CHRONIC STRESS. HERE WE REVIEW POTENTIAL PSYCHONEUROENDOCRINE DETERMINANTS OF PREMATURE AGING OF THE IMMUNE SYSTEM AND DISCUSS AVAILABLE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE. CHRONIC STRESS MAY ACCELERATE VARIOUS FEATURES OF IMMUNOSENESCENCE BY ACTIVATING KEY ALLOSTATIC SYSTEMS, NOTABLY THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THE IMMUNOLOGICAL IMPACT OF SUCH NEUROENDOCRINE DYSREGULATION MAY BE FURTHER AMPLIFIED BY A DRAMATIC DECLINE IN DEHYDROEPIANDROSTERONE (DHEA) LEVELS, ACTING IN PART AS AN ENDOGENOUS GLUCOCORTICOID ANTAGONIST. STRESS-BUFFERING STRATEGIES SHOW BENEFICIAL EFFECTS ON VARIOUS BIOMARKERS IN ELDERLY POPULATIONS. LIKEWISE, SUPPLEMENTATION OF DHEA, MELATONIN OR GROWTH HORMONE HAS YIELDED SIGNIFICANT BENEFICIAL EFFECTS IN A NUMBER OF STUDIES, INCLUDING: INCREASED WELL-BEING, MEMORY PERFORMANCE, BONE MINERAL DENSITY AND IMPROVED IMMUNOCOMPETENCE AS EVIDENCED BY RESULTS OF IN VITRO (T CELL PROLIFERATION, CYTOTOXICITY, CYTOKINE PRODUCTION), AND IN VIVO IMMUNE CHALLENGES. HOWEVER, THE SIDE-EFFECTS OF HORMONAL SUPPLEMENTATION ARE ALSO DISCUSSED. FINALLY, MODERATE EXERCISE VIA THE PROMOTION OF CORTISOL/DHEA BALANCE OR EPIGENETIC MODIFICATIONS, IS ASSOCIATED WITH LOWER SERUM PRO-INFLAMMATORY CYTOKINES, GREATER LYMPHOPROLIFERATIVE RESPONSES AND LOWER COUNTS OF SENESCENT T CELLS. TAKEN TOGETHER, THESE DATA SUGGEST THAT IMMUNE SYSTEM IS PLASTIC AND IMMUNOSENESCENCE CAN BE ATTENUATED PSYCHONEUROENDOCRINE INTERVENTIONS. 2013 14 2412 39 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009 15 728 35 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 16 3472 28 IDENTIFICATION AND MANAGEMENT OF PAIN MEDICATION ABUSE AND MISUSE: CURRENT STATE AND FUTURE DIRECTIONS. LONG-TERM OPIOID THERAPY POSES A RISK FOR ABUSE AND MISUSE IN SOME PATIENTS. IDENTIFYING WHICH PATIENTS MAY POTENTIALLY BE AT RISK PRIOR TO INITIATION OF THERAPY, AND IDENTIFYING PATIENTS IN WHOM THESE PROBLEMS DEVELOP DURING THERAPY, ARE SIGNIFICANT CHALLENGES. OUTCOME PREDICTION IS IMPEDED BY THE COMPLEXITY OF THE PROBLEM, WHERE CONSIDERABLE HETEROGENEITY RESULTS FROM PSYCHOLOGICAL AND SOCIOECONOMIC FACTORS, AS WELL AS INTERINDIVIDUAL VARIATION IN BIOLOGICAL PATHWAYS DUE TO GENETIC AND EPIGENETIC FACTORS. SCREENING TOOLS DESIGNED TO DETECT OPIOID MISUSE AND URINE DRUG TESTING ARE BOTH USED CLINICALLY; SCANT EVIDENCE CURRENTLY EXISTS TO ALLOW THE FORMULATION OF AN ALGORITHM FOR JUDICIOUS USE OF THESE TOOLS. MOREOVER, THESE TOOLS MAY NOT BE ADDRESSING THE UNDERLYING ALTERATIONS IN BIOLOGICAL PATHWAYS THAT OCCUR OWING TO THE DEVELOPMENT OF CHRONIC PAIN OR IN RESPONSE TO CHRONIC OPIOID ADMINISTRATION. AN EVIDENCE-BASED ALGORITHMIC APPROACH TO RISK MITIGATION THAT CAN BE APPLIED IN A COST-EFFECTIVE MANNER TO GUIDE THERAPY IS URGENTLY NEEDED. 2012 17 6459 23 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 18 5643 29 SEX AND AUTOIMMUNITY: PROPOSED MECHANISMS OF DISEASE ONSET AND SEVERITY. CHRONIC AUTOIMMUNE DISEASES AFFECT 5-10% OF THE POPULATION WORLDWIDE AND ARE LARGELY PREDOMINANT IN WOMEN. SEX HORMONE CHANGES HAVE BEEN WIDELY INVESTIGATED BASED ON CHANGES IN THE CLINICAL PHENOTYPES OBSERVED DURING PREGNANCY AND MENOPAUSE. IT IS KNOWN THAT FEMALES WITH AUTOIMMUNE DISEASES MANIFEST A HIGHER RATE OF CIRCULATING LEUKOCYTES WITH A SINGLE X CHROMOSOME, AND THERE HAVE BEEN SEVERAL REPORTS ON THE ROLE OF X CHROMOSOME GENE DOSAGE THROUGH INACTIVATION OR DUPLICATION IN AUTOIMMUNITY. HOWEVER, IT IS ALSO IMPORTANT NOT TO OVERLOOK MEN WITH AUTOIMMUNE DISEASES, WHO MIGHT MANIFEST A MORE FREQUENT LOSS OF THE Y CHROMOSOME IN CIRCULATING LEUKOCYTES. AREAS COVERED: IN THE PRESENT REVIEW, WE WILL DISCUSS THE CURRENT EVIDENCE SUPPORTING THE MECHANISMS OF FEMALE PREDOMINANCE IN RHEUMATIC DISEASES, BY DISCUSSING THE ROLE OF REPRODUCTIVE HISTORY, SEX HORMONES AND ABNORMALITIES RELATED TO THEM, CLINICAL DIFFERENCES BETWEEN MALE AND FEMALE PATIENTS, AND EPIGENETIC CHANGES THAT HAVE BEEN EVALUATED THROUGH TWIN STUDIES ON GENETIC AND ENVIRONMENTAL CHANGES IN RHEUMATIC PATIENTS. EXPERT OPINION: THE INFLUENCE OF SEX HORMONES AND CHROMOSOMES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS NEEDS TO BE CLARIFIED, TO BETTER UNDERSTAND THE RISK OF AUTOIMMUNE DISEASES, EARLY DIAGNOSTIC TOOLS, AND THERAPEUTIC RESPONSE. 2019 19 1314 33 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 20 4536 28 MULTIPLE SCLEROSIS - RISK FACTORS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNOLOGICAL CONDITION OF THE CENTRAL NERVOUS SYSTEM (CNS) AFFECTING MAINLY YOUNG ADULT INDIVIDUALS. THE PREVALENCE RANGES APPROXIMATELY BETWEEN 50 AND 300 PER 100000 INDIVIDUALS. IT IS CHARACTERIZED BY AN INFLAMMATORY PROCESS, DEMYELINATION AND AXONAL LOSS. IMMUNOLOGICAL MECHANISMS RESULTING IN THE DAMAGE TO THE MYELIN SHEATH EFFECTING THEN IN IMPAIRED NERVE IMPULSE CONDUCTION HAVE THE KEY ROLE IN MS PATHOGENESIS. THE ROLE OF INFLAMMATORY FACTORS HAS ALSO BEEN PROVED. HOWEVER, IT HAS NOT BEEN EXPLICITLY SHOWN WHETHER SUCH AN INFLAMMATORY PROCESS IS THE TRIGGERING FACTOR OR SECONDARY TO A YET UNKNOWN INFECTIOUS FACTOR OR A DEGENERATIVE PROCESS OF THE CNS. THEREFORE, RECOGNITION OF THE EPIGENETIC RISK FACTORS, SUCH AS: GEOGRAPHICAL LATITUDE, VITAMIN D LEVEL, HYGIENE HYPOTHESIS, EPSTEIN-BARR VIRUS (EBV) INFECTION AND OTHERS MAY CONTRIBUTE TO BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING MULTIPLE SCLEROSIS. ADDITIONALLY, THEY MAY PROVIDE GUIDELINES FOR MORE EFFICIENT THERAPIES AND BETTER PREVENTION OF THE DISEASE. AIM OF THIS REVIEW IS TO PRESENT MOST CURRENT DATA ON MULTIPLE SCLEROSIS RISK FACTORS, CONSIDERING THOSE LESS KNOWN. 2020