1 361 158 AMBIENT AIR POLLUTION AND THROMBOSIS. AIR POLLUTION IS A GROWING PUBLIC HEALTH CONCERN OF GLOBAL SIGNIFICANCE. ACUTE AND CHRONIC EXPOSURE IS KNOWN TO IMPAIR CARDIOVASCULAR FUNCTION, EXACERBATE DISEASE AND INCREASE CARDIOVASCULAR MORTALITY. SEVERAL PLAUSIBLE BIOLOGICAL MECHANISMS HAVE BEEN PROPOSED FOR THESE ASSOCIATIONS, HOWEVER, AT PRESENT, THE PATHWAYS ARE INCOMPLETE. A SEMINAL REVIEW BY THE AMERICAN HEART ASSOCIATION (2010) CONCLUDED THAT THE THROMBOTIC EFFECTS OF PARTICULATE AIR POLLUTION LIKELY CONTRIBUTED TO THEIR EFFECTS ON CARDIOVASCULAR MORTALITY AND MORBIDITY. THE AIM OF THE CURRENT REVIEW IS TO APPRAISE THE NEWLY ACCUMULATED SCIENTIFIC EVIDENCE (2009-2016) ON CONTRIBUTION OF HAEMOSTASIS AND THROMBOSIS TOWARDS CARDIOVASCULAR DISEASE INDUCED BY EXPOSURE TO BOTH PARTICULATE AND GASEOUS POLLUTANTS.SEVENTY FOUR PUBLICATIONS WERE REVIEWED IN-DEPTH. THE WEIGHT OF EVIDENCE SUGGESTS THAT ACUTE EXPOSURE TO FINE PARTICULATE MATTER (PM(2.5)) INDUCES A SHIFT IN THE HAEMOSTATIC BALANCE TOWARDS A PRO-THROMBOTIC/PRO-COAGULATIVE STATE. INSUFFICIENT DATA WAS AVAILABLE TO ASCERTAIN IF A SIMILAR RELATIONSHIP EXISTS FOR GASEOUS POLLUTANTS, AND VERY FEW STUDIES HAVE ADDRESSED LONG-TERM EXPOSURE TO AMBIENT AIR POLLUTION. PLATELET ACTIVATION, OXIDATIVE STRESS, INTERPLAY BETWEEN INTERLEUKIN-6 AND TISSUE FACTOR, ALL APPEAR TO BE POTENTIALLY IMPORTANT MECHANISMS IN POLLUTION-MEDIATED THROMBOSIS, TOGETHER WITH AN EMERGING ROLE FOR CIRCULATING MICROVESICLES AND EPIGENETIC CHANGES.OVERALL, THE RECENT LITERATURE SUPPORTS, AND ARGUABLY STRENGTHENS, THE CONTENTION THAT AIR POLLUTION CONTRIBUTES TO CARDIOVASCULAR MORBIDITY BY PROMOTING HAEMOSTASIS. THE VOLUME AND DIVERSITY OF THE EVIDENCE HIGHLIGHTS THE COMPLEXITY OF THE PATHOPHYSIOLOGIC MECHANISMS BY WHICH AIR POLLUTION PROMOTES THROMBOSIS; MULTIPLE PATHWAYS ARE PLAUSIBLE AND IT IS MOST LIKELY THEY ACT IN CONCERT. FUTURE RESEARCH SHOULD ADDRESS THE ROLE GASEOUS POLLUTANTS PLAY IN THE CARDIOVASCULAR EFFECTS OF AIR POLLUTION MIXTURE AND DIRECT COMPARISON OF POTENTIALLY SUSCEPTIBLE GROUPS TO HEALTHY INDIVIDUALS. 2018 2 6438 26 THERAPEUTIC AND PREVENTIVE INTERVENTIONS FOR POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE FATIGUE-RELATED DISORDERS. MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING THE RELATIVELY NOVEL GROUP OF VASOACTIVE (VASODILATORY) NEUROPEPTIDES (VNS) IN HUMANS. VNS COMPRISE A NOVEL BUT EXPANDING GROUP OF SUBSTANCES HAVING IMMUNOREGULATION, INFLAMMATION MODULATION, NEUROTRANSMITTER, NEUROTROPHIC, HORMONAL AND METABOLIC FUNCTIONS. THESE SUBSTANCES MAY CONTROL GENE EXPRESSION FOR MRNA FOR THEMSELVES AND THEIR RECEPTORS. THEY HAVE COMPLEX RELATIONSHIPS WITH GASEOUS AND OTHER NEUROTRANSMITTERS AND XENOBIOTIC SUBSTANCES. THEORETICAL ARGUMENTS HAVE IMPLICATED THESE SUBSTANCES IN AUTOIMMUNE PHENOMENA RESULTING IN FATIGUE-RELATED CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME (CFS), SUDDEN INFANT DEATH SYNDROME (SIDS), FIBROMYALGIA (FM) AND GULF WAR SYNDROME (GWS) BUT REMAIN UNPROVEN. AS WELL AS POSSIBLY SPONTANEOUS ONSET, THE PRECIPITATING CAUSES OF VN AUTOIMMUNE DYSFUNCTION ARE LIKELY TO BE A COMBINATION OF GENETIC PREDISPOSITION, INFECTION AND XENOBIOTIC SUBSTANCES. THERAPEUTIC AND PREVENTIVE POSSIBILITIES FOR POSTULATED VN AUTOIMMUNE CONDITIONS WILL BE INFLUENCED BY THE COMPLEX PATHOLOPHYSIOLOGY UNDERPINNING THEM. SOME SPECULATIVE POSSIBILITIES ARE VN SUBSTITUTION/REPLACEMENT, PRESERVATION OF BIOLOGICAL EFFECT, EPIGENETIC DNA MODIFICATIONS, PLASMA EXCHANGE, ANTI-CHOLINESTERASES, E.G., PYRIDOSTIGMINE, CORTICOSTEROIDS AND OTHER DRUG TREATMENTS, THYMECTOMY, INTRAVENOUS IMMUNOGLOBULIN AND ANTI-IDIOTYPE ANTIBODIES, AND CPG/DNA VACCINES. PREVENTION AND TREATMENT OF POSSIBLE VN AUTOIMMUNE FATIGUE-RELATED DISORDERS MAY PROVE TO BE IMPORTANT AREAS FOR FUTURE RESEARCH AND DEVELOPMENT. 2005 3 6742 40 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 4 298 48 AIR POLLUTION AND AIRWAY DISEASE. EPIDEMIOLOGICAL AND TOXICOLOGICAL RESEARCH CONTINUES TO SUPPORT A LINK BETWEEN URBAN AIR POLLUTION AND AN INCREASED INCIDENCE AND/OR SEVERITY OF AIRWAY DISEASE. DETRIMENTAL EFFECTS OF OZONE (O(3)), NITROGEN DIOXIDE (NO(2)) AND PARTICULATE MATTER (PM), AS WELL AS TRAFFIC-RELATED POLLUTION AS A WHOLE, ON RESPIRATORY SYMPTOMS AND FUNCTION ARE WELL DOCUMENTED. NOT ONLY DO WE HAVE STRONG EPIDEMIOLOGICAL EVIDENCE OF A RELATIONSHIP BETWEEN AIR POLLUTION AND EXACERBATION OF ASTHMA AND RESPIRATORY MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT RECENT STUDIES, PARTICULARLY IN URBAN AREAS, HAVE SUGGESTED A ROLE FOR POLLUTANTS IN THE DEVELOPMENT OF BOTH ASTHMA AND COPD. SIMILARLY, WHILE PREVALENCE AND SEVERITY OF ATOPIC CONDITIONS APPEAR TO BE MORE COMMON IN URBAN COMPARED WITH RURAL COMMUNITIES, EVIDENCE IS EMERGING THAT TRAFFIC-RELATED POLLUTANTS MAY CONTRIBUTE TO THE DEVELOPMENT OF ALLERGY. FURTHERMORE, NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST AN ASSOCIATION BETWEEN EXPOSURE TO NO(2) , O(3) , PM AND COMBUSTION PRODUCTS OF BIOMASS FUELS AND AN INCREASED SUSCEPTIBILITY TO AND MORBIDITY FROM RESPIRATORY INFECTION. GIVEN THE CONSIDERABLE CONTRIBUTION THAT TRAFFIC EMISSIONS MAKE TO URBAN AIR POLLUTION RESEARCHERS HAVE SOUGHT TO CHARACTERIZE THE RELATIVE TOXICITY OF TRAFFIC-RELATED PM POLLUTANTS. RECENT ADVANCES IN MECHANISMS IMPLICATED IN THE ASSOCIATION OF AIR POLLUTANTS AND AIRWAY DISEASE INCLUDE EPIGENETIC ALTERATION OF GENES BY COMBUSTION-RELATED POLLUTANTS AND HOW POLYMORPHISMS IN GENES INVOLVED IN ANTIOXIDANT PATHWAYS AND AIRWAY INFLAMMATION CAN MODIFY RESPONSES TO AIR POLLUTION EXPOSURES. OTHER INTERESTING EPIDEMIOLOGICAL OBSERVATIONS RELATED TO INCREASED HOST SUSCEPTIBILITY INCLUDE A POSSIBLE LINK BETWEEN CHRONIC PM EXPOSURE DURING CHILDHOOD AND VULNERABILITY TO COPD IN ADULTHOOD, AND THAT INFANTS SUBJECTED TO HIGHER PRENATAL LEVELS OF AIR POLLUTION MAY BE AT GREATER RISK OF DEVELOPING RESPIRATORY CONDITIONS. WHILE THE CHARACTERIZATION OF POLLUTANT COMPONENTS AND SOURCES PROMISE TO GUIDE POLLUTION CONTROL STRATEGIES, THE IDENTIFICATION OF SUSCEPTIBLE SUBPOPULATIONS WILL BE NECESSARY IF TARGETED THERAPY/PREVENTION OF POLLUTION-INDUCED RESPIRATORY DISEASES IS TO BE DEVELOPED. 2011 5 6743 42 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2013 6 3432 38 HYDROGEN SULFIDE BIOSYNTHESIS IS IMPAIRED IN THE OSTEOARTHRITIC JOINT. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF ARTHRITIS AND IT IS A LEADING CAUSE OF DISABILITY IN THE ELDERLY. ITS COMPLETE ETIOLOGY IS NOT KNOWN ALTHOUGH THERE ARE SEVERAL METABOLIC, GENETIC, EPIGENETIC, AND LOCAL CONTRIBUTING FACTORS INVOLVED. AT THE MOMENT, THERE IS NO CURE FOR THIS PATHOLOGY AND TREATMENT ALTERNATIVES TO RETARD OR STOP ITS PROGRESSION ARE INTENSIVELY BEING SOUGHT. HYDROGEN SULFIDE (H(2)S) IS A SMALL GASEOUS MOLECULE AND IS PRESENT IN SULFUROUS MINERAL WATERS AS ITS ACTIVE COMPONENT. DATA FROM RECENT CLINICAL TRIALS SHOWS THAT BALNEOTHERAPY (IMMERSION IN MINERAL AND/OR THERMAL WATERS FROM NATURAL SPRINGS) IN SULFUROUS WATERS CAN IMPROVE OA SYMPTOMS, IN PARTICULAR, PAIN AND FUNCTION. YET, THE UNDERLYING MECHANISMS ARE POORLY KNOWN. HYDROGEN SULFIDE IS ALSO CONSIDERED, WITH NO AND CO, AN ENDOGENOUS SIGNALING GASOTRANSMITTER. IT IS SYNTHESIZED ENDOGENOUSLY WITH THE HELP OF THREE ENZYMES, CYSTATHIONINE GAMMA-LYASE (CTH), CYSTATHIONINE BETA-SYNTHASE (CBS), AND 3-MERCAPTOPYRUVATE SULFURTRANSFERASE (3-MPST). HERE, THE EXPRESSION OF THESE THREE ENZYMES WAS DEMONSTRATED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) AND THEIR PROTEIN ABUNDANCE [BY IMMUNOHISTOCHEMISTRY AND WESTERN BLOT (WB)] IN HUMAN ARTICULAR CARTILAGE. NO SIGNIFICANT DIFFERENCES WERE FOUND IN CBS OR CTH EXPRESSION OR ABUNDANCE, BUT MRNA AND PROTEIN LEVELS OF 3-MPST WERE SIGNIFICANTLY REDUCED IN CARTILAGE FORM OA DONORS. ALSO, THE BIOSYNTHESIS OF H(2)S FROM OA CARTILAGE, MEASURED WITH A SPECIFIC MICROELECTRODE, WAS SIGNIFICANTLY LOWER THAN IN OA-FREE TISSUE. YET, NO DIFFERENCES WERE FOUND IN H(2)S CONCENTRATION IN SERUM FROM OA PATIENTS AND OA-FREE DONORS. THE CURRENT RESULTS SUGGEST THAT REDUCED LEVELS OF THE MITOCHONDRIAL ENZYME 3-MPST IN OA CARTILAGE MIGHT BE, AT LEAST IN PART, RESPONSIBLE FOR A REDUCTION IN H(2)S BIOSYNTHESIS IN THIS TISSUE AND THAT IMPAIRED H(2)S BIOSYNTHESIS IN THE JOINT MIGHT BE A CONTRIBUTING FACTOR TO OA. THIS COULD CONTRIBUTE TO EXPLAIN WHY EXOGENOUS SUPPLEMENTATION OF H(2)S, FOR INSTANCE WITH SULFUROUS THERMAL WATER, HAS POSITIVE EFFECTS IN OA PATIENTS. 2020 7 1637 33 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 8 3630 43 INCLUSION OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH TO ADVANCE UNDERSTANDING OF THEIR INFLUENCE ON THE BIOLOGY OF CHRONIC DISEASE. SOCIAL DETERMINANTS OF HEALTH (SDOH) CONSIDER SOCIAL, POLITICAL, AND ECONOMIC FACTORS THAT CONTRIBUTE TO HEALTH DISPARITIES IN PATIENTS AND POPULATIONS. THE MOST COMMON HEALTH-RELATED SDOH EXPOSURES ARE FOOD AND HOUSING INSECURITY, FINANCIAL INSTABILITY, TRANSPORTATION NEEDS, LOW LEVELS OF EDUCATION, AND PSYCHOSOCIAL STRESS. THESE DOMAINS DESCRIBE RISKS THAT CAN IMPACT HEALTH OUTCOMES MORE THAN HEALTH CARE. EPIDEMIOLOGIC AND TRANSLATIONAL RESEARCH DEMONSTRATES THAT SDOH FACTORS REPRESENT EXPOSURES THAT PREDICT HARM AND IMPACT THE HEALTH OF INDIVIDUALS. INTERNATIONAL AND NATIONAL GUIDELINES URGE HEALTH PROFESSIONALS TO ADDRESS SDOH IN CLINICAL PRACTICE AND PUBLIC HEALTH. THE FURTHER IMPLEMENTATION OF THESE RECOMMENDATIONS INTO BASIC AND TRANSLATIONAL RESEARCH, HOWEVER, IS LAGGING. HEREIN, WE CONSIDER A PRECISION HEALTH FRAMEWORK TO DESCRIBE HOW SDOH CONTRIBUTES TO THE EXPOSOME AND EXACERBATES PHYSIOLOGIC PATHWAYS THAT LEAD TO CHRONIC DISEASE. SDOH FACTORS ARE ASSOCIATED WITH VARIOUS FORMS OF STRESSORS THAT IMPACT PHYSIOLOGICAL PROCESSES THROUGH EPIGENETIC, INFLAMMATORY, AND REDOX REGULATION. MANY SDOH EXPOSURES MAY ADD TO OR POTENTIATE THE PATHOLOGIC EFFECTS OF ADDITIONAL ENVIRONMENTAL EXPOSURES. THIS OVERVIEW AIMS TO INFORM BASIC LIFE SCIENCE AND TRANSLATIONAL RESEARCHERS ABOUT SDOH EXPOSURES THAT CAN CONFOUND ASSOCIATIONS BETWEEN CLASSIC BIOMEDICAL DETERMINANTS OF DISEASE AND HEALTH OUTCOMES. TO ADVANCE THE STUDY OF TOXICOLOGY THROUGH EITHER QUALITATIVE OR QUANTITATIVE ASSESSMENT OF EXPOSURES TO CHEMICAL AND BIOLOGICAL SUBSTANCES, A MORE COMPLETE ENVIRONMENTAL EVALUATION SHOULD INCLUDE SDOH EXPOSURES. WE DISCUSS COMMON APPROACHES TO MEASURE SDOH FACTORS AT INDIVIDUAL AND POPULATION LEVELS AND REVIEW THE ASSOCIATIONS BETWEEN SDOH RISK FACTORS AND PHYSIOLOGIC MECHANISMS THAT INFLUENCE CHRONIC DISEASE. WE PROVIDE CLINICAL AND POLICY-BASED MOTIVATION TO ENCOURAGE RESEARCHERS TO CONSIDER THE IMPACT OF SDOH EXPOSURES ON STUDY RESULTS AND DATA INTERPRETATION. WITH VALID MEASURES OF SDOH FACTORS INCORPORATED INTO STUDY DESIGN AND ANALYSES, FUTURE TOXICOLOGICAL RESEARCH MAY CONTRIBUTE TO AN EVIDENCE BASE THAT CAN BETTER INFORM PREVENTION AND TREATMENT OPTIONS, TO IMPROVE EQUITABLE CLINICAL CARE AND POPULATION HEALTH. (C) 2022 WILEY PERIODICALS LLC. 2022 9 3712 35 INHALED POLLUTANTS: THE MOLECULAR SCENE BEHIND RESPIRATORY AND SYSTEMIC DISEASES ASSOCIATED WITH ULTRAFINE PARTICULATE MATTER. AIR POLLUTION OF ANTHROPOGENIC ORIGIN IS LARGELY FROM THE COMBUSTION OF BIOMASS (E.G., WOOD), FOSSIL FUELS (E.G., CARS AND TRUCKS), INCINERATORS, LANDFILLS, AGRICULTURAL ACTIVITIES AND TOBACCO SMOKE. AIR POLLUTION IS A COMPLEX MIXTURE THAT VARIES IN SPACE AND TIME, AND CONTAINS HUNDREDS OF COMPOUNDS INCLUDING VOLATILE ORGANIC COMPOUNDS (E.G., BENZENE), METALS, SULPHUR AND NITROGEN OXIDES, OZONE AND PARTICULATE MATTER (PM). PM(0.1) (ULTRAFINE PARTICLES (UFP)), THOSE PARTICLES WITH A DIAMETER LESS THAN 100 NM (INCLUDES NANOPARTICLES (NP)) ARE CONSIDERED ESPECIALLY DANGEROUS TO HUMAN HEALTH AND MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF NUMEROUS RESPIRATORY AND CARDIOVASCULAR DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ATHEROSCLEROSIS. SOME OF THE PATHOGENIC MECHANISMS THROUGH WHICH PM(0.1) MAY CONTRIBUTE TO CHRONIC DISEASE IS THEIR ABILITY TO INDUCE INFLAMMATION, OXIDATIVE STRESS AND CELL DEATH BY MOLECULAR MECHANISMS THAT INCLUDE TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR KAPPAB (NF-KAPPAB) AND NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NRF2). EPIGENETIC MECHANISMS INCLUDING NON-CODING RNA (NCRNA) MAY ALSO CONTRIBUTE TOWARDS THE DEVELOPMENT OF CHRONIC DISEASE ASSOCIATED WITH EXPOSURE TO PM(0.1). THIS PAPER HIGHLIGHTS EMERGING MOLECULAR CONCEPTS ASSOCIATED WITH INHALATIONAL EXPOSURE TO PM(0.1) AND THEIR ABILITY TO CONTRIBUTE TO CHRONIC RESPIRATORY AND SYSTEMIC DISEASE. 2017 10 363 40 AMBIENT AIR POLLUTION: HEALTH HAZARDS TO CHILDREN. AMBIENT AIR POLLUTION IS PRODUCED BY SOURCES INCLUDING VEHICULAR TRAFFIC, COAL-FIRED POWER PLANTS, HYDRAULIC FRACTURING, AGRICULTURAL PRODUCTION, AND FOREST FIRES. IT CONSISTS OF PRIMARY POLLUTANTS GENERATED BY COMBUSTION AND SECONDARY POLLUTANTS FORMED IN THE ATMOSPHERE FROM PRECURSOR GASES. AIR POLLUTION CAUSES AND EXACERBATES CLIMATE CHANGE, AND CLIMATE CHANGE WORSENS HEALTH EFFECTS OF AIR POLLUTION. INFANTS AND CHILDREN ARE UNIQUELY SENSITIVE TO AIR POLLUTION, BECAUSE THEIR ORGANS ARE DEVELOPING AND THEY HAVE HIGHER AIR PER BODY WEIGHT INTAKE. HEALTH EFFECTS LINKED TO AIR POLLUTION INCLUDE NOT ONLY EXACERBATIONS OF RESPIRATORY DISEASES BUT ALSO REDUCED LUNG FUNCTION DEVELOPMENT AND INCREASED ASTHMA INCIDENCE. ADDITIONAL OUTCOMES OF CONCERN INCLUDE PRETERM BIRTH, LOW BIRTH WEIGHT, NEURODEVELOPMENTAL DISORDERS, IQ LOSS, PEDIATRIC CANCERS, AND INCREASED RISKS FOR ADULT CHRONIC DISEASES. THESE EFFECTS ARE MEDIATED BY OXIDATIVE STRESS, CHRONIC INFLAMMATION, ENDOCRINE DISRUPTION, AND GENETIC AND EPIGENETIC MECHANISMS ACROSS THE LIFE SPAN. NATURAL EXPERIMENTS DEMONSTRATE THAT WITH INITIATIVES SUCH AS INCREASED USE OF PUBLIC TRANSPORTATION, BOTH AIR QUALITY AND COMMUNITY HEALTH IMPROVE. SIMILARLY, THE CLEAN AIR ACT HAS IMPROVED AIR QUALITY, ALTHOUGH EXPOSURE INEQUITIES PERSIST. OTHER EFFECTIVE STRATEGIES FOR REDUCING AIR POLLUTION INCLUDE ENDING RELIANCE ON COAL, OIL, AND GAS; REGULATING INDUSTRIAL EMISSIONS; REDUCING EXPOSURE WITH ATTENTION TO PROXIMITY OF RESIDENCES, SCHOOLS, AND CHILD CARE FACILITIES TO TRAFFIC; AND A GREATER AWARENESS OF THE AIR QUALITY INDEX. THIS POLICY REVIEWS BOTH SHORT- AND LONG-TERM HEALTH CONSEQUENCES OF AMBIENT AIR POLLUTION, ESPECIALLY IN RELATION TO DEVELOPMENTAL EXPOSURES. IT EXAMINES INDIVIDUAL, COMMUNITY, AND LEGISLATIVE STRATEGIES TO MITIGATE AIR POLLUTION. 2021 11 244 41 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS. 2011 12 1066 36 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 13 2940 44 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5). 2017 14 108 29 A REVIEW OF THE PROTECTIVE EFFECT OF MELATONIN IN PESTICIDE-INDUCED TOXICITY. PESTICIDES ARE AMONG THE MOST IMPORTANT CHEMICALS USED IN AGRICULTURE SECTOR. HOWEVER, THEIR EXTENSIVE USE HAS POLLUTED THE ENVIRONMENT AND INCREASED HUMAN VULNERABILITY TO VARIOUS CHRONIC DISEASES. PESTICIDE EXPOSURE CAUSES GENETIC AND EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS. AREAS COVERED: THIS REVIEW IS BASED ON THE LITERATURE STUDIES CURRENTLY REPORTED ON PESTICIDE-INDUCED TOXICITY AND THE PROTECTIVE ROLE OF MELATONIN. SCIENTIFIC DATABASES SUCH AS PUBMED, SCOPUS AND WEB OF SCIENCE WERE SEARCHED USING KEYWORDS 'PESTICIDE' AND 'MELATONIN' UP TO JANUARY 2016. FULL LENGTH ARTICLES RELATED TO ANIMAL AND HUMAN EXPOSURE WERE RETRIEVED. A TOTAL NUMBER OF 181 RECORDS WERE OBTAINED, AND AFTER EXCLUDING THE DUPLICATES, 97 PAPERS WERE FURTHER SCREENED ON THE BASIS OF RELEVANCE TO THE TOPIC. EXPERT OPINION: MELATONIN AS A BROAD-SPECTRUM ANTIOXIDANT IS ABLE TO PENETRATE CELLULAR COMPARTMENTS SPECIFICALLY THE MITOCHONDRIA. IT IS A POTENT FREE RADICAL SCAVENGER WITH LOW TOXICITY AND DESIRABLE SOLUBILITY IN ORGANIC AND AQUEOUS PHASES. WE ARE OF THE OPINION THAT MELATONIN IS A PROMISING AGENT IN MINIMIZING ORGAN INJURIES INDUCED BY PESTICIDES. 2017 15 107 38 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 16 642 50 BIOMARKERS OF PARTICULATE MATTER EXPOSURE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A SYSTEMATIC REVIEW. BACKGROUND: IN RECENT YEARS, AMBIENT PARTICULATE MATTER (PM) EXPOSURE HAS BEEN STRONGLY LINKED WITH HEALTH EFFECTS. ELEVATED LEVELS OF PM IN POLLUTED AIR HAVE BEEN CORRELATED WITH THE ONSET AND DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS SYSTEMATIC REVIEW WAS CONDUCTED TO EVALUATE BIOMARKERS THAT COULD REFLECT THE EFFECTS OF PM EXPOSURE IN PATIENTS WITH COPD. METHODS: WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES PUBLISHED ON BIOMARKERS ASSOCIATED WITH PM EXPOSURE IN PATIENTS WITH COPD BETWEEN JANUARY 01, 2012 AND JUNE 30, 2022 IN PUBMED/MEDLINE, EMBASE, AND COCHRANE DATABASES. STUDIES THAT INCLUDED DATA ON BIOMARKERS WITH COPD EXPOSED PM WERE ELIGIBLE FOR INCLUSION. BIOMARKERS WERE CLASSIFIED INTO 4 GROUPS ACCORDING TO THEIR MECHANISMS. RESULTS: OF THE 105 STUDIES IDENTIFIED, 22 WERE INCLUDED IN THIS STUDY. NEARLY 50 BIOMARKERS HAVE BEEN PROPOSED IN THE STUDIES INCLUDED IN THIS REVIEW, AND THE MOST STUDIED IN RELATION TO PM ARE SEVERAL INTERLEUKINS. VARIOUS MECHANISMS HAVE BEEN REPORTED BY WHICH PM INDUCES AND AGGRAVATES COPD. SIX STUDIES RELATED TO OXIDATIVE STRESS, ONE RELATED TO DIRECT EFFECT OF INNATE AND ADAPTIVE IMMUNE SYSTEMS, 16 ASSOCIATED WITH GENETIC REGULATION OF INFLAMMATION, AND TWO RELATED TO EPIGENETIC REGULATION OF PHYSIOLOGY AND SUSCEPTIBILITY WERE FOUND. BIOMARKERS RELATED TO THESE MECHANISMS WERE DETECTED IN SERUM, SPUTUM, URINE, EXHALED BREATH CONCENTRATION (EBC), AND SHOWED VARIOUS CORRELATIONS WITH PM IN COPD. CONCLUSIONS: VARIOUS BIOMARKERS HAVE SHOWN POTENTIAL IN PREDICTING THE EXTENT OF PM EXPOSURE IN COPD PATIENTS. FUTURE STUDIES ARE NEEDED TO ESTABLISH RECOMMENDATIONS FOR REGULATION TO REDUCE AIRBORNE PM, WHICH COULD BE USED TO DEVELOP STRATEGIES FOR PREVENTION AND MANAGEMENT OF ENVIRONMENTAL RESPIRATORY DISEASES. 2023 17 5450 41 REPRODUCTIVE TOXICITY OF COMBINED EFFECTS OF ENDOCRINE DISRUPTORS ON HUMAN REPRODUCTION. CONFLUENCE OF ENVIRONMENTAL, GENETIC, AND LIFESTYLE VARIABLES IS RESPONSIBLE FOR DETERIORATION OF HUMAN FECUNDITY. ENDOCRINE DISRUPTORS OR ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY BE FOUND IN A VARIETY OF FOODS, WATER, AIR, BEVERAGES, AND TOBACCO SMOKE. IT HAS BEEN DEMONSTRATED IN EXPERIMENTAL INVESTIGATIONS THAT A WIDE RANGE OF ENDOCRINE DISRUPTING CHEMICALS HAVE NEGATIVE EFFECTS ON HUMAN REPRODUCTIVE FUNCTION. HOWEVER, EVIDENCE ON THE REPRODUCTIVE CONSEQUENCES OF HUMAN EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS IS SPARSE AND/OR CONFLICTING IN THE SCIENTIFIC LITERATURE. THE COMBINED TOXICOLOGICAL ASSESSMENT IS A PRACTICAL METHOD FOR ASSESSING THE HAZARDS OF COCKTAILS OF CHEMICALS, CO-EXISTING IN THE ENVIRONMENT. THE CURRENT REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF STUDIES EMPHASIZING THE COMBINED TOXICITY OF ENDOCRINE DISRUPTING CHEMICALS ON HUMAN REPRODUCTION. ENDOCRINE DISRUPTING CHEMICALS INTERACT WITH EACH OTHER TO DISRUPT THE DIFFERENT ENDOCRINE AXES, RESULTING IN SEVERE GONADAL DYSFUNCTIONS. TRANSGENERATIONAL EPIGENETIC EFFECTS HAVE ALSO BEEN INDUCED IN GERM CELLS, MOSTLY THROUGH DNA METHYLATION AND EPIMUTATIONS. SIMILARLY, AFTER ACUTE OR CHRONIC EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS COMBINATIONS, INCREASED OXIDATIVE STRESS (OS), ELEVATED ANTIOXIDANT ENZYMATIC ACTIVITY, DISRUPTED REPRODUCTIVE CYCLE, AND REDUCED STEROIDOGENESIS ARE OFTEN REPORTED CONSEQUENCES. THE ARTICLE ALSO DISCUSSES THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) PREDICTION MODELS, WHICH REVEAL THE IMPORTANCE OF VARIOUS SYNERGISTIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS MIXTURES. MORE CRUCIALLY, THIS EVIDENCE-BASED STUDY ADDRESSES THE RESEARCH LIMITATIONS AND INFORMATION GAPS, AS WELL AS PARTICULARLY PRESENTS THE FUTURE RESEARCH VIEWS ON COMBINED ENDOCRINE DISRUPTING CHEMICALS TOXICITY ON HUMAN REPRODUCTION. 2023 18 360 29 AMBIENT AIR POLLUTION AND BIOMARKERS OF HEALTH EFFECT. RECENTLY, THE AIR POLLUTION SITUATION OF OUR COUNTRY IS VERY SERIOUS ALONG WITH THE DEVELOPMENT OF URBANIZATION AND INDUSTRIALIZATION. STUDIES INDICATE THAT THE EXPOSURE OF AIR POLLUTION CAN CAUSE A RISE OF INCIDENCE AND MORTALITY OF MANY DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, MYOCARDIAL INFARCTION, AND SO ON. HOWEVER, THERE IS NOW GROWING EVIDENCE SHOWING THAT SIGNIFICANT AIR POLLUTION EXPOSURES ARE ASSOCIATED WITH EARLY BIOMARKERS IN VARIOUS SYSTEMS OF THE BODY. IN ORDER TO BETTER PREVENT AND CONTROL THE DAMAGE EFFECT OF AIR POLLUTION, THIS ARTICLE SUMMARIZES COMPREHENSIVELY EPIDEMIOLOGICAL STUDIES ABOUT THE BAD EFFECTS ON THE BIOMARKERS OF RESPIRATORY SYSTEM, CARDIOVASCULAR SYSTEM, AND GENETIC AND EPIGENETIC SYSTEM EXPOSURE TO AMBIENT AIR POLLUTION. 2017 19 3901 43 LEAD (PB) AND NEURODEVELOPMENT: A REVIEW ON EXPOSURE AND BIOMARKERS OF EFFECT (BDNF, HDL) AND SUSCEPTIBILITY. LEAD (PB) IS A UBIQUITOUS ENVIRONMENTAL POLLUTANT AND A POTENT TOXIC COMPOUND. HUMANS ARE EXPOSED TO PB THROUGH INHALATION, INGESTION, AND SKIN CONTACT VIA FOOD, WATER, TOBACCO SMOKE, AIR, DUST, AND SOIL. PB ACCUMULATES IN BONES, BRAIN, LIVER AND KIDNEY. FETAL EXPOSURE OCCURS VIA TRANSPLACENTAL TRANSMISSION. THE MOST CRITICAL HEALTH EFFECTS ARE DEVELOPMENTAL NEUROTOXICITY IN INFANTS AND CARDIOVASCULAR EFFECTS AND NEPHROTOXICITY IN ADULTS. PB EXPOSURE HAS BEEN STEADILY DECREASING OVER THE PAST DECADES, BUT THERE ARE FEW RECENT EXPOSURE DATA FROM THE GENERAL EUROPEAN POPULATION; MOREOVER, NO SAFE PB LIMIT HAS BEEN SET. SENSITIVE BIOMARKERS OF EXPOSURE, EFFECT AND SUSCEPTIBILITY, THAT RELIABLY AND TIMELY INDICATE PB-ASSOCIATED TOXICITY ARE REQUIRED TO ASSESS HUMAN EXPOSURE-HEALTH RELATIONSHIPS IN A SITUATION OF LOW TO MODERATE EXPOSURE. THEREFORE, A SYSTEMATIC LITERATURE REVIEW BASED ON PUBMED ENTRIES PUBLISHED BEFORE JULY 2019 THAT ADDRESSED PB EXPOSURE AND BIOMARKERS OF EFFECT AND SUSCEPTIBILITY, NEURODEVELOPMENTAL TOXICITY, EPIGENETIC MODIFICATIONS, AND TRANSCRIPTOMICS WAS CONDUCTED. FINALLY INCLUDED WERE 58 ORIGINAL PAPERS ON PB EXPOSURE AND 17 STUDIES ON BIOMARKERS. THE BIOMARKERS THAT ARE LINKED TO PB EXPOSURE AND NEURODEVELOPMENT WERE GROUPED INTO EFFECT BIOMARKERS (SERUM BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND SERUM/SALIVA CORTISOL), SUSCEPTIBILITY MARKERS (EPIGENETIC MARKERS AND GENE SEQUENCE VARIANTS) AND OTHER BIOMARKERS (SERUM HIGH-DENSITY LIPOPROTEIN (HDL), MATERNAL IRON (FE) AND CALCIUM (CA) STATUS). SERUM BDNF AND PLASMA HDL ARE POTENTIAL CANDIDATES TO BE FURTHER VALIDATED AS EFFECT MARKERS FOR ROUTINE USE IN HBM STUDIES OF PB, COMPLEMENTED BY MARKERS OF FE AND CA STATUS TO ALSO ADDRESS NUTRITIONAL INTERACTIONS RELATED TO NEURODEVELOPMENTAL DISORDERS. FOR SEVERAL MARKERS, A CAUSAL RELATIONSHIP WITH PB-INDUCED NEURODEVELOPMENTAL TOXICITY IS LIKELY. RESULTS ON BDNF ARE DISCUSSED IN RELATION TO ADVERSE OUTCOME PATHWAY (AOP) 13 ("CHRONIC BINDING OF ANTAGONIST TO N-METHYL-D-ASPARTATE RECEPTORS (NMDARS) DURING BRAIN DEVELOPMENT INDUCES IMPAIRMENT OF LEARNING AND MEMORY ABILITIES") OF THE AOP-WIKI. FURTHER STUDIES ARE NEEDED TO VALIDATE SENSITIVE, RELIABLE, AND TIMELY EFFECT BIOMARKERS, ESPECIALLY FOR LOW TO MODERATE PB EXPOSURE SCENARIOS. 2021 20 1737 32 EARLY DETECTION OF ACCELERATED AGING AND CELLULAR DECLINE (AACD): A CONSENSUS STATEMENT. THE CELLULAR HALLMARKS OF ACCELERATED AGING AND THEIR CLINICAL EXPRESSION MAY BE GROUPED USING THE TERMS 'ACCELERATED AGING AND CELLULAR DECLINE' (AACD) AND/OR 'AGE-ASSOCIATED CELLULAR DECLINE'. THIS CONSTRUCT IS DESIGNED TO CAPTURE THE BIOLOGICAL BACKGROUND PREDISPOSING THE DEVELOPMENT OF AGE-RELATED CONDITIONS. BY CLASSIFYING RISK FACTORS, EARLY INDICATORS, AND CLINICAL DIFFERENTIATORS OF AACD THROUGH EXPERT CONSENSUS, THIS STUDY AIMED TO IDENTIFY THE SIGNS, SYMPTOMS, AND MARKERS INDICATIVE OF AACD. IN DOING SO, THIS WORK PAVES THE WAY FOR FUTURE IMPLEMENTATION OF THE AACD CONCEPT IN THE CLINICAL AND RESEARCH SETTINGS. AN INTERDISCIPLINARY PANEL OF EXPERTS WITH CLINICAL AND RESEARCH EXPERTISE WAS SELECTED TO PARTICIPATE IN A VIRTUAL WORKSHOP TO DISCUSS AACD. A MODIFIED NOMINAL GROUP TECHNIQUE WAS USED TO ESTABLISH CONSENSUS AMONG THE GROUP. AN EXTENDED GROUP OF INTERNATIONAL EXPERTS CRITICALLY REVIEWED AN EARLY DRAFT OF THE MANUSCRIPT, AND THEIR FEEDBACK WAS THEN INCORPORATED INTO THE MODEL. EXPERTS IDENTIFIED 13 FACTORS PREDISPOSING TO OR CLINICALLY MANIFESTING AACD. AMONG THESE, CHRONIC DISEASES, OBESITY, AND UNFAVORABLE GENETIC BACKGROUND WERE CONSIDERED AS THE MOST IMPORTANT. THERE WAS A CONSENSUS THAT A GRADUAL AND NONSPECIFIC DEVELOPMENT OFTEN CHARACTERIZES AACD, MAKING ITS CLINICAL DETECTION POTENTIALLY CHALLENGING. IN ADDITION, SIGNS AND SYMPTOMS MIGHT HAVE MULTIFACTORIAL CAUSES AND OVERLAPPING ORIGINS, SUCH AS GENETIC AND EPIGENETIC PREDISPOSITIONS. AS A RESULT, AN INITIAL CHECKLIST WAS OUTLINED, LISTING CLINICAL FACTORS OF SPECIAL RELEVANCE (E.G., FATIGUE, LOW QUALITY OF SLEEP, AND LOW MOOD) TO REPRESENT EARLY MANIFESTATIONS OF THE ORGANISM'S EXHAUSTION, WHICH ARE ALSO FREQUENTLY NEGLECTED IN THE CLINICAL SETTING. DIFFERENTIATING AACD FROM OTHER CONDITIONS IS ESSENTIAL. THE USE OF A COMBINATION OF BIOMARKERS WAS PROPOSED AS A VIABLE METHOD IN A TWO-STEP PROCESS OF DIFFERENTIATION: 1) IDENTIFICATION OF EARLY AACD CLINICAL INDICATORS, FOLLOWED BY 2) SYMPTOM AND BIOMARKER CONFIRMATION WITH A FOCUS ON SYSTEM DOMAINS (TO BE POTENTIALLY TARGETED BY FUTURE SPECIFIC INTERVENTIONS). ALTHOUGH THE AACD CONSTRUCT IS NOT YET READY FOR ROUTINE USE IN CLINICAL PRACTICE, ITS OPERATIONALIZATION MAY SUPPORT THE EARLY IDENTIFICATION OF AGE-RELATED CONDITIONS (WHEN THIS MIGHT STILL BE AMENABLE TO REVERSION) AND ALSO ENCOURAGE PREVENTATIVE INTERVENTIONS. FURTHER INVESTIGATION IS NEEDED TO ESTABLISH SPECIFIC BIOMARKERS THAT CONFIRM INDEPENDENT RISK FACTORS FOR AACD AND PROVIDE A MORE DEFINITIVE STRUCTURE TO THE CONCEPT OF AACD (AND AGE-ASSOCIATED CELLULAR DECLINE). 2021