1 5260 157 PROGRESSIVE OSSEOUS HETEROPLASIA, AS AN ISOLATED ENTITY OR OVERLAPPING WITH ALBRIGHT HEREDITARY OSTEODYSTROPHY. INTRODUCTION: PROGRESSIVE OSSEOUS HETEROPLASIA (POH) IS A CONDITION OF INVASIVE HETEROTOPIC OSSIFICATION. REPORTS OF PATIENTS WITH MILD POH WITH ALBRIGHT HEREDITARY OSTEODYSTROPHY (AHO), SPECIFICALLY PSEUDOHYPOPARATHYROIDISM TYPE IA (PHP IA) WITH HORMONAL RESISTANCE, SUGGEST THE POSSIBILITY OF A COMMON MOLECULAR BASIS. GNAS HAS BEEN IMPLICATED TO ACCOUNT FOR OVERLAPPING FEATURES OF POH AND PHP IA. CASE 1: A 4-YEAR-OLD BOY WITH OBESITY, SPEECH DELAY, AND EXPANDING SUBCUTANEOUS MASSES ON BUTTOCK/FOREARM. PHYSICAL EXAM REVEALED ROUND FACIES AND BRACHYDACTYLY. BLOOD TESTS SHOWED NORMAL CA, P, MG, 25-OH VITAMIN D LEVELS BUT ELEVATED PARATHYROID HORMONE (PTH) AND THYROID-STIMULATING HORMONE (TSH). ABDOMINAL COMPUTED TOMOGRAPHY (CT) SHOWED AREAS WITH CALCIFICATIONS IN THE SUBCUTANEOUS TISSUE, FAT, AND MUSCLE. PATHOLOGY OF EXCISED TISSUE REVEALED OSSIFICATIONS. GENOMIC STUDY REVEALED NO GNAS MUTATION. HE HAD POH AND PHP IA. CASE 2: A 3-YEAR-OLD BOY WITH PAINFUL OSSIFICATIONS IN THE LEFT LOWER EXTREMITY. LAB TESTS WERE NOTABLE FOR ELEVATED PTH AND HIGH-NORMAL TSH. THE CT-SCAN SHOWED SUBCUTANEOUS/INTRAMUSCULAR CALCIFICATIONS. GENETIC TESTING SHOWED GNAS MUTATION IN EXON 12 [C.1024C>T (R342X)]. PATIENT HAD POH AND PHP IA. CASE 3: A 9-YEAR-OLD BOY WITH KNEE PAIN AND SUBCUTANEOUS OSSIFICATIONS IN BACK AND UPPER/LOWER EXTREMITY, CAUSING SIGNIFICANTLY LIMITED JOINT MOBILITY. LAB TESTS WERE NORMAL. THE CT-SCAN SHOWED AREAS CORRESPONDING TO SUBCUTANEOUS/INTRAMUSCULAR OSSIFICATIONS THROUGHOUT TORSO AND EXTREMITIES, CONSISTENT WITH POH. THERE WAS NO GNAS MUTATION. CONCLUSIONS: PATIENTS WITH HETEROTOPIC OSSIFICATIONS PRESENT WITH A WIDE SPECTRUM OF DISEASE. ALTHOUGH GNAS-BASED MUTATIONS HAVE BEEN POSTULATED TO ACCOUNT FOR OVERLAPPING FEATURES OF AHO AND POH, NORMAL DNA STUDIES IN CERTAIN PATIENTS WITH POH/AHO SUGGEST THAT THERE MAY EXIST OTHER MOLECULAR/EPIGENETIC MECHANISMS EXPLAINING THEIR OVERLAPPING FEATURES. 2015 2 4706 25 NMP4/CIZ CLOSES THE PARATHYROID HORMONE ANABOLIC WINDOW. CHRONIC DEGENERATIVE DISEASES ARE INCREASING WITH THE AGING U.S. POPULATION. ONE CONSEQUENCE OF THIS PHENOMENON IS THE NEED FOR LONG-TERM OSTEOPOROSIS THERAPIES. PARATHYROID HORMONE (PTH), THE ONLY FDA-APPROVED TREATMENT THAT ADDS BONE TO THE AGED SKELETON, LOSES ITS POTENCY WITHIN TWO YEARS OF INITIAL TREATMENT BUT THE MECHANISM REGULATING ITS LIMITED "ANABOLIC WINDOW" IS UNKNOWN. WE HAVE DISCOVERED THAT DISABLING THE NUCLEOCYTOPLASMIC SHUTTLING TRANSCRIPTION FACTOR NUCLEAR MATRIX PROTEIN 4/CAS INTERACTING ZINC FINGER PROTEIN (NMP4/CIZ) IN MICE EXTENDS THE PTH BONE-FORMING CAPACITY. NMP4 WAS DISCOVERED DURING OUR SEARCH FOR NUCLEAR MATRIX TRANSCRIPTION FACTORS THAT COUPLE THIS HORMONE'S IMPACT ON OSTEOBLAST CYTOSKELETAL AND NUCLEAR ORGANIZATION WITH ITS ANABOLIC CAPACITY. CIZ WAS INDEPENDENTLY DISCOVERED AS A PROTEIN THAT ASSOCIATES WITH THE FOCAL ADHESION-ASSOCIATED MECHANOSENSOR P130CAS. THE NMP4/CIZ-KNOCKOUT (KO) SKELETAL PHENOTYPE EXHIBITS A MODESTLY ENHANCED BONE MINERAL DENSITY BUT MANIFESTS AN EXAGGERATED RESPONSE TO BOTH PTH AND TO BMP2 AND IS RESISTANT TO DISUSE-INDUCED BONE LOSS. THE CELLULAR BASIS OF THE GLOBAL NMP4/CIZ-KO SKELETAL PHENOTYPE REMAINS TO BE ELUCIDATED BUT MAY INVOLVE AN EXPANSION OF THE BONE MARROW OSTEOPROGENITOR POPULATION ALONG WITH MODESTLY ENHANCED OSTEOBLAST AND OSTEOCLAST ACTIVITIES SUPPORTING ANABOLIC BONE TURNOVER. AS A SHUTTLING CYS(2)HIS(2) ZINC FINGER PROTEIN, NMP4/CIZ ACTS AS A REPRESSIVE TRANSCRIPTION FACTOR PERHAPS ASSOCIATED WITH EPIGENETIC REMODELING COMPLEXES, BUT THE FUNCTIONAL SIGNIFICANCE OF ITS INTERACTION WITH P130CAS IS NOT KNOWN. DESPITE NUMEROUS REMAINING QUESTIONS, NMP4/CIZ PROVIDES INSIGHTS INTO HOW THE ANABOLIC WINDOW IS REGULATED, AND ITSELF MAY PROVIDE AN ADJUVANT THERAPY TARGET FOR THE TREATMENT OF OSTEOPOROSIS BY EXTENDING PTH ANABOLIC EFFICACY. 2012 3 4295 26 MICRORNA RESPONSE OF INHALATION EXPOSURE TO HEXANAL IN LUNG TISSUES FROM FISCHER 344 RATS. IN PREVIOUS STUDIES, WE HAVE INVESTIGATED THE RELATIONSHIPS BETWEEN ENVIRONMENTAL CHEMICALS AND HEALTH RISK BASED ON OMICS ANALYSIS AND IDENTIFIED SIGNIFICANT BIOMARKERS. OUR CURRENT FINDINGS INDICATE THAT HEXANAL MAY BE AN IMPORTANT TOXICANT OF THE PULMONARY SYSTEM IN EPIGENETIC INSIGHTS. MICRORNA (MIRNA) IS AN IMPORTANT INDICATOR OF BIOMEDICAL RISK ASSESSMENT AND TARGET IDENTIFICATION. HEXANAL IS HIGHLY DETECTABLE IN THE EXHALED BREATH OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND CHRONIC INFLAMMATORY LUNG DISEASE. IN THIS STUDY, WE AIMED TO IDENTIFY HEXANAL-CHARACTERIZED MIRNA-MRNA CORRELATIONS INVOLVED IN LUNG TOXICITY. MICROARRAY ANALYSIS IDENTIFIED 56 MIRNAS THAT COMMONLY CHANGED THEIR EXPRESSION MORE THAN 1.3-FOLD IN THREE DOSES (600, 1000, AND 1500 PPM) WITHIN HEXANAL-EXPOSED FISCHER 344 RATS BY INHALATION, AND 226 GENES WERE PREDICTED TO BE TARGET GENES OF MIRNAS THROUGH TARGETSCAN ANALYSIS. BY INTEGRATING ANALYSES OF MIRNA AND MRNA EXPRESSION PROFILES, WE IDENTIFIED ONE ANTI-CORRELATED TARGET GENE (CHGA; CHROMOGRANIN A; PARATHYROID SECRETORY PROTEIN 1). COMPARATIVE TOXICOGENOMICS DATABASE (CTD) ANALYSIS OF THIS GENE SHOWED THAT CHGA IS INVOLVED WITH SEVERAL DISEASE CATEGORIES SUCH AS CANCER, RESPIRATORY TRACT DISEASE, NERVOUS SYSTEM DISEASE, AND CARDIOVASCULAR DISEASE. FURTHER RESEARCH IS NECESSARY TO ELUCIDATE THE MECHANISMS OF HEXANAL-RESPONSIVE TOXICOLOGIC PATHWAYS AT THE MOLECULAR LEVEL. THIS STUDY CONCLUDES THAT OUR INTEGRATED APPROACH TO MIRNA AND MRNA ENABLES US TO IDENTIFY MOLECULAR EVENTS IN DISEASE DEVELOPMENT INDUCED BY HEXANAL IN AN IN VIVO RAT MODEL. (C) 2015 WILEY PERIODICALS, INC. ENVIRON TOXICOL 31: 1909-1921, 2016. 2016 4 4158 25 MECHANOTRANSDUCTION DETERMINES THE STRUCTURE AND FUNCTION OF LUNG AND BONE: A THEORETICAL MODEL FOR THE PATHOPHYSIOLOGY OF CHRONIC DISEASE. MULTICELLULAR ORGANISMS HAVE EVOLVED IN ADAPTATION TO THE EARTH'S GRAVITATIONAL AND OXYGEN ENVIRONMENT. THIS EPIGENETIC PROCESS IS DEPENDENT ON THE CAPACITY OF MESODERMAL CELLS TO ACT AS MECHANOSENSORS THAT CAN CONFORM, DEFORM, AND REFORM IN ADAPTATION TO THE ORGANISM'S PHYSICAL ENVIRONMENT. MECHANICAL FORCES, SUCH AS HYDROSTATIC PRESSURE AND GRAVITY, PLAY IMPORTANT ROLES IN THE EMBRYONIC DEVELOPMENT, HOMEOSTASIS, AND REPAIR OF LUNG AND BONE. WE DISCUSS THE ROLE OF PARATHYROID HORMONE-RELATED PROTEIN (PTHRP) AS A MECHANOTRANSDUCER FOR STRETCH IN THESE ORGANS DURING NORMAL DEVELOPMENT, PARTICULARLY AS IT LENDS ITSELF TO HOMEOSTASIS; WE FURTHER DEMONSTRATE THAT "UNCOUPLING" OF SUCH MECHANISMS MAY PLAY A CENTRAL ROLE IN INJURY REPAIR, PARTICULARLY AS IT RELATES TO CHRONIC DISEASES OF LUNG AND BONE. ENDOTHERMAL PTHRP SIGNALING THROUGH ITS G-PROTEIN COUPLED RECEPTOR PROMOTES NORMAL CELL-CELL SIGNALING THAT MAINTAINS THE HOMEOSTATIC PHENOTYPES OF LUNG AND BONE. MOLECULAR DISRUPTION OF THE PTHRP/PTHRP RECEPTOR PATHWAY FROM ENDODERM TO MESODERM, BECAUSE OF SUCH FACTORS AS VOLUTRAUMA, HYPEROXIA, INFLAMMATION, AND MICROGRAVITY, ALTERS INTRACELLULAR SIGNALING, CAUSING MALADAPTIVE CELLULAR CHANGES, RESULTING IN MYOFIBROBLAST PROLIFERATION AND GRANULATION. EXAMPLES OF SUCH PATHOLOGIC CHANGES SPECIFICALLY RELATED TO THIS CELLULAR/MOLECULAR MECHANISM OF MALADAPTATION ARE CHRONIC LUNG DISEASE AND OSTEOPOROSIS. WE SUGGEST A NEW PARADIGM THAT MAY HELP IN THE FUTURE CREATION OF DIAGNOSTIC AND THERAPEUTIC MODALITIES FOR A WIDE RANGE OF DEVELOPMENTAL AND CHRONIC DISEASES RANGING FROM BRONCHOPULMONARY DYSPLASIA IN NEWBORNS TO IDIOPATHIC PULMONARY FIBROSIS AND OSTEOPOROSIS AS A RESULT OF AGING OR MICROGRAVITY. 2003 5 5136 17 POTENTIAL MECHANISMS LINKING PSYCHOLOGICAL STRESS TO BONE HEALTH. CHRONIC PSYCHOLOGICAL STRESS AFFECTS MANY BODY SYSTEMS, INCLUDING THE SKELETON, THROUGH VARIOUS MECHANISMS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF THE FACTORS MEDIATING THE RELATIONSHIP BETWEEN PSYCHOLOGICAL STRESS AND BONE HEALTH. THESE FACTORS CAN BE DIVIDED INTO PHYSIOLOGICAL AND BEHAVIOURAL CHANGES INDUCED BY PSYCHOLOGICAL STRESS. THE PHYSIOLOGICAL FACTORS INVOLVE ENDOCRINOLOGICAL CHANGES, SUCH AS INCREASED GLUCOCORTICOIDS, PROLACTIN, LEPTIN AND PARATHYROID HORMONE LEVELS AND REDUCED GONADAL HORMONES. LOW-GRADE INFLAMMATION AND HYPERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM DURING PSYCHOLOGICAL STRESS ARE ALSO PHYSIOLOGICAL CHANGES DETRIMENTAL TO BONE HEALTH. THE BEHAVIOURAL CHANGES DURING MENTAL STRESS, SUCH AS ALTERED DIETARY PATTERN, CIGARETTE SMOKING, ALCOHOLISM AND PHYSICAL INACTIVITY, ALSO THREATEN THE SKELETAL SYSTEM. PSYCHOLOGICAL STRESS MAY BE PARTLY RESPONSIBLE FOR EPIGENETIC REGULATION OF SKELETAL DEVELOPMENT. IT MAY ALSO MEDIATE THE RELATIONSHIP BETWEEN SOCIOECONOMIC STATUS AND BONE HEALTH. HOWEVER, MORE DIRECT EVIDENCE IS REQUIRED TO PROVE THESE HYPOTHESES. IN CONCLUSION, CHRONIC PSYCHOLOGICAL STRESS SHOULD BE RECOGNISED AS A RISK FACTOR OF OSTEOPOROSIS AND STRESS-COPING METHODS SHOULD BE INCORPORATED AS PART OF THE COMPREHENSIVE OSTEOPOROSIS-PREVENTING STRATEGY. 2021 6 6815 16 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES. 2011 7 2361 14 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 8 5255 17 PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF BPD USING THE BABOON AND SHEEP MODELS. BRONCHOPULMONARY DYSPLASIA (BPD) IS AMONG THE MOST COMMON CHRONIC LUNG DISEASES IN INFANTS IN THE US. IMPROVED SURVIVAL OF PRETERM INFANTS WHO DEVELOPED BPD IS BECOMING INCREASINGLY IMPORTANT BECAUSE OF THE HIGH RISK FOR PERSISTENT PULMONARY MORBIDITIES SUCH AS POOR RESPIRATORY GAS EXCHANGE, PULMONARY HYPERTENSION, AND EXCESS AIRWAY EXPIRATORY RESISTANCE LATER IN LIFE. THIS REVIEW FOCUSES ON UNIQUE INSIGHTS PROVIDED BY THE TWO LARGE-ANIMAL, PHYSIOLOGICAL MODELS OF NEONATAL CHRONIC LUNG DISEASE: PRETERM BABOONS AND PRETERM LAMBS. THE MODELS' ARE VALUABLE BECAUSE THEY CONTRIBUTE TO BETTER UNDERSTANDING OF THE UNDERLYING MOLECULAR PATHOGENIC MECHANISMS. AN EPIGENETIC HYPOTHESIS IS PROPOSED AS A PATHOGENIC MECHANISM FOR BPD AND ITS PERSISTENT PULMONARY MORBIDITIES. 2013 9 1392 25 DIAGNOSTIC APPROACH TO PULMONARY HYPERTENSION IN PREMATURE NEONATES. BRONCHOPULMONARY DYSPLASIA (BPD) IS A FORM OF CHRONIC LUNG DISEASE IN PREMATURE INFANTS FOLLOWING RESPIRATORY DISTRESS AT BIRTH. WITH INCREASING SURVIVAL OF EXTREMELY LOW BIRTH WEIGHT INFANTS, ALVEOLAR SIMPLIFICATION IS THE DEFINING LUNG CHARACTERISTIC OF INFANTS WITH BPD, AND ALONG WITH PULMONARY HYPERTENSION, INCREASINGLY CONTRIBUTES TO BOTH RESPIRATORY MORBIDITY AND MORTALITY IN THESE INFANTS. GROWTH RESTRICTED INFANTS, INFANTS BORN TO MOTHERS WITH OLIGOHYDRAMNIOS OR FOLLOWING PROLONGED PRETERM RUPTURE OF MEMBRANES ARE AT PARTICULAR RISK FOR EARLY ONSET PULMONARY HYPERTENSION. ALTERED VASCULAR AND ALVEOLAR GROWTH PARTICULARLY IN CANALICULAR AND EARLY SACCULAR STAGES OF LUNG DEVELOPMENT FOLLOWING MECHANICAL VENTILATION AND OXYGEN THERAPY, RESULTS IN DEVELOPMENTAL LUNG ARREST LEADING TO BPD WITH PULMONARY HYPERTENSION (PH). EARLY RECOGNITION OF PH IN INFANTS WITH RISK FACTORS IS IMPORTANT FOR OPTIMAL MANAGEMENT OF THESE INFANTS. SCREENING TOOLS FOR EARLY DIAGNOSIS OF PH ARE EVOLVING; HOWEVER, ECHOCARDIOGRAPHY IS THE MAINSTAY FOR NON-INVASIVE DIAGNOSIS OF PH IN INFANTS. CARDIAC COMPUTED TOMOGRAPHY (CT) AND MAGNETIC RESONANCE ARE BEING USED AS IMAGING MODALITIES, HOWEVER THEIR ROLE IN IMPROVING OUTCOMES IN THESE PATIENTS IS UNCERTAIN. FOLLOW-UP OF INFANTS AT RISK FOR PH WILL HELP NOT ONLY IN EARLY DIAGNOSIS, BUT ALSO IN APPROPRIATE MANAGEMENT OF THESE INFANTS. AGGRESSIVE MANAGEMENT OF LUNG DISEASE, AVOIDANCE OF HYPOXEMIC EPISODES, AND OPTIMAL NUTRITION DETERMINE THE PROGRESSION OF PH, AS EPIGENETIC FACTORS MAY HAVE SIGNIFICANT EFFECTS, PARTICULARLY IN GROWTH-RESTRICTED INFANTS. INFANTS WITH DIAGNOSIS OF PH ARE MANAGED WITH PULMONARY VASODILATORS AND THOSE RESISTANT TO THERAPY NEED TO BE WORKED UP FOR THE PRESENCE OF CARDIO-VASCULAR ANOMALIES. THE MANAGEMENT OF INFANTS AND TODDLERS WITH PH, ESPECIALLY FOLLOWING PREMATURE BIRTH IS AN EMERGING FIELD. NONETHELESS, COMBINATION THERAPIES IN A MULTI-DISCIPLINARY SETTING IMPROVES OUTCOMES FOR THESE INFANTS. 2017 10 1177 20 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 11 2646 22 EPIGENOMIC LINKS BETWEEN SOCIAL DETERMINANTS OF HEALTH AND SYMPTOMS: A SCOPING REVIEW. SOCIAL DETERMINANTS OF HEALTH (SDOH) IMPACT HEALTH AND WELLNESS. THE LINK BETWEEN SDOH AND ADVERSE HEALTH OUTCOMES, INCLUDING SYMPTOM OCCURRENCE AND SEVERITY, MAY BE EXPLAINED BY AN INDIVIDUAL'S PHYSIOLOGIC RESPONSE TO ONE OR MORE SDOH. ONE POTENTIAL MECHANISM UNDERLYING THIS PHYSIOLOGIC RESPONSE LINKING SDOH AND SYMPTOMS IS THE DYNAMIC EPIGENOME. THE PURPOSE OF THIS SCOPING REVIEW OF THE LITERATURE WAS TO EXAMINE DIFFERENTIAL SUSCEPTIBILITY FOR SYMPTOMS BY IDENTIFYING AND SUMMARIZING RESEARCH LINKING SDOH AND SYMPTOMS THROUGH EPIGENOMIC MECHANISMS. PUBMED WAS SEARCHED TO IDENTIFY EMPIRICAL RESEARCH WHERE AT LEAST ONE SDOH WAS AN INDEPENDENT OR DEPENDENT VARIABLE, AT LEAST ONE SYMPTOM WAS INVESTIGATED, AND THE INVESTIGATION INCLUDED AN EPIGENOMIC MEASURE. OF THE 484 ARTICLES INITIALLY RETRIEVED, AFTER THOROUGH VETTING, 41 ARTICLES MET ELIGIBILITY. THE MOST STUDIED SYMPTOM WAS DEPRESSIVE SYMPTOMS FOLLOWED BY ANXIETY, COGNITIVE FUNCTION, SLEEP DYSFUNCTION, AND PAIN. THE MOST FREQUENTLY STUDIED SDOH WERE: 1) STRESS, PARTICULARLY EARLY LIFE STRESS AND ACCULTURATIVE STRESS; AND 2) TRAUMA, PREDOMINANTLY CHILDHOOD TRAUMA. DNA METHYLATION AND TELOMERE LENGTH WERE THE MOST STUDIED EPIGENOMIC MEASURES. FOUR GENES (SLC6A4, BDNF, NR3C1, OXTR) HAD EVIDENCE FROM MULTIPLE STUDIES AND ACROSS METHODOLOGICAL APPROACHES LINKING SDOH TO SYMPTOMS. THIS REVIEW SUPPORTS THE INCLUSION OF EPIGENOMIC APPROACHES TO BETTER UNDERSTAND THE LINK BETWEEN SDOH AND SYMPTOMS AND PROVIDES EVIDENCE THAT SDOH IMPACT TELOMERE LENGTH AND THE METHYLATION OF GENES INVOLVED IN NEUROTRANSMITTER SIGNALING, NEURONAL SURVIVAL, BEHAVIOR, INFLAMMATION AND STRESS RESPONSE. 2023 12 6827 20 [GILLES DE LA TOURETTE'S DISEASE. SYMPTOMS, ETIOPATHOGENESIS AND THERAPEUTIC APPROACHES]. THE GILLES DE LA TOURETTE SYNDROME IS A USUALLY CHRONIC NEUROPSYCHIATRIC DISORDER WITH AN EARLY CHILDHOOD ONSET FEATURING MAINLY MOTOR AND VOCAL TICS. IT SEEMS THAT STRONG GENETIC FACTORS MAKE A MAJOR CONTRIBUTION TO THE ETIOLOGY OF THIS DISORDER, BUT THERE ARE ALSO CLUES THAT EPIGENETIC FACTORS ARE INVOLVED IN THE PATHOGENESIS OF TOURETTE'S SYNDROME, SUCH AS MATERNAL STRESS DURING PREGNANCY, BIRTH COMPLICATIONS AND HORMONAL INFLUENCES. FIRST IN LINE FOR ADEQUATE TREATMENT ARE NEUROLEPTIC COMPOUNDS OF HIGH POTENCY, BESIDES, SEVERAL OTHER PSYCHOACTIVE DRUGS HAVE SHOWN SOME THERAPEUTIC EFFECTS. LESS EVIDENT IS THE EFFICACY OF NEUROSURGICAL AND PSYCHOTHERAPEUTIC INTERVENTIONS. 1997 13 3630 21 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 14 3846 22 IS ATHEROSCLEROSIS A NEUROGENIC PHENOMENON? IDENTIFIED RISK FACTORS FOR ATHEROSCLEROSIS INCLUDE DIET, AGE, GENDER, FAMILY HISTORY, STRESS, LIFESTYLE, SMOKING, DIABETES, DYSLIPIDEMIAS, HYPERTENSION, AND HIV. THE MECHANISTIC RATIONALE TO EXPLAIN THESE ASSOCIATIONS REMAINS POORLY UNDERSTOOD. WE BELIEVE THAT THESE SEEMINGLY UNRELATED ENTITIES MAY PROMOTE ATHEROSCLEROSIS THROUGH A COMMON PATHWAY BY INDUCING ADVENTITIAL AUTONOMIC DYSFUNCTION, SPECIFICALLY AS AN ADVENTITIAL STRESS DYSFUNCTION OF NEUROGENIC ORIGIN. ATHEROSCLEROSIS MAY REPRESENT A LOCAL VASCULAR MANIFESTATION OF THE GLOBAL AUTONOMIC DYSFUNCTION INDUCED BY AGE, SMOKING, HYPERTENSION, HIV, AND DIABETES. ATHEROSCLEROSIS MAY ALSO PARTICIPATE IN A FEED-FORWARD CYCLE AS AGING, DIABETES, DYSLIPIDEMIA, AND HYPERTENSION MAY ALSO REPRESENT INDEPENDENT DOWNSTREAM CONSEQUENCES OF GLOBAL SYMPATHETIC BIAS. CHRONIC PHYSIOLOGIC STRESS AND BEHAVIORAL STRESS CAN SHIFT THE AUTONOMIC BALANCE TOWARDS A STATE OF SYMPATHETIC PREDOMINANCE. THE HIGHLY COMMUNICABLE NATURE OF BEHAVIORAL STRESS MAY PARTIALLY IMPLICATE THE FAMILIAL ASSOCIATION OF ATHEROSCLEROSIS AS AN EPIGENETIC PHENOMENON, INDEPENDENT OF PUTATIVE GENETIC MECHANISMS. HOST STRESS, GLOBAL AUTONOMIC DYSFUNCTION, AND SYMPATHETIC BIAS MAY ALSO ARISE FROM CHRONIC MALADAPTIVE CONSUMPTION OF STRESSED FOODS, AS ORGANISMS DETECT AND ASSIMILATE THE STRESS PHENOTYPES OF THEIR DIETARY CONSTITUENTS THROUGH A PROCESS CALLED XENOHORMESIS. THE BENEFITS OF EXERCISE MAY OPERATE THROUGH REDUCTION OF CHRONIC PHYSIOLOGIC STRESS ASSOCIATED WITH GLOBAL SYMPATHETIC BIAS. THE NEUROGENIC ADVENTITIAL STRESS RESPONSE MAY EXPLAIN THE LOCAL TISSUE REMODELING SEEN IN ATHEROSCLEROSIS, INCLUDING ADVENTITIAL ADIPOSE DYSFUNCTION, INFLAMMATION, ADVENTITIAL ANGIOGENESIS, THROMBOSIS, AND ENDOTHELIAL DYSFUNCTION. WE BELIEVE THAT THE LOCATIONS OF ATHEROSCLEROTIC LESIONS CORRESPOND TO REGIONS OF NEUROGENIC ADVENTITIAL AUTONOMIC DYSFUNCTION, IN SIMILAR FASHION TO THE SEGMENTAL PATTERNS OF INVOLVEMENT FOUND IN INFLAMMATORY BOWEL DISEASE. THE DIFFUSE ATHEROSCLEROSIS EXHIBITED IN TRANSPLANTED HEARTS MAY REFLECT A DIFFUSE SYMPATHETIC BIAS OF THE DONOR HEART, SINCE TISSUES AND ORGANS EXHIBIT AN INTRINSIC SYMPATHETIC BIAS IN THE ABSENCE OF AN EXTRINSIC SOURCE OF AUTONOMIC HEGEMONY. ONCE WE REGARD ATHEROSCLEROSIS AS A NEUROGENIC PHENOMENON MANIFESTED IN ADVENTITIAL AUTONOMIC DYSFUNCTION, NOVEL DIAGNOSTIC AND THERAPEUTIC PARADIGMS BECOME EVIDENT. 2007 15 4954 15 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ENCOMPASSES A NUMBER OF INJURIOUS PROCESSES, INCLUDING AN ABNORMAL INFLAMMATORY RESPONSE IN THE LUNGS TO INHALED PARTICLES AND GASES. OTHER PROCESSES, SUCH AS FAILURE TO RESOLVE INFLAMMATION, ABNORMAL CELL REPAIR, APOPTOSIS, ABNORMAL CELLULAR MAINTENANCE PROGRAMS, EXTRACELLULAR MATRIX DESTRUCTION (PROTEASE/ANTIPROTEASE IMBALANCE), AND OXIDATIVE STRESS (OXIDANT/ANTIOXIDANT IMBALANCE) ALSO HAVE A ROLE. THE INFLAMMATORY RESPONSES TO THE INHALATION OF ACTIVE AND PASSIVE TOBACCO SMOKE AND URBAN AND RURAL AIR POLLUTION ARE MODIFIED BY GENETIC AND EPIGENETIC FACTORS. THE SUBSEQUENT CHRONIC INFLAMMATORY RESPONSES LEAD TO MUCUS HYPERSECRETION, AIRWAY REMODELING, AND ALVEOLAR DESTRUCTION. THIS ARTICLE PROVIDES AN UPDATE ON THE CELLULAR AND MOLECULAR MECHANISMS OF THESE PROCESSES IN THE PATHOGENESIS OF COPD. 2007 16 4067 15 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 17 3428 18 HUMANS AT HIGH ALTITUDE: HYPOXIA AND FETAL GROWTH. HIGH-ALTITUDE STUDIES OFFER INSIGHT INTO THE EVOLUTIONARY PROCESSES AND PHYSIOLOGICAL MECHANISMS AFFECTING THE EARLY PHASES OF THE HUMAN LIFESPAN. CHRONIC HYPOXIA SLOWS FETAL GROWTH AND REDUCES THE PREGNANCY-ASSOCIATED RISE IN UTERINE ARTERY (UA) BLOOD FLOW. MULTIGENERATIONAL VS. SHORTER-TERM HIGH-ALTITUDE RESIDENTS ARE PROTECTED FROM THE ALTITUDE-ASSOCIATED REDUCTIONS IN UA FLOW AND FETAL GROWTH. PRESENTLY UNKNOWN IS WHETHER THIS FETAL-GROWTH PROTECTION IS DUE TO THE GREATER DELIVERY OR METABOLISM OF OXYGEN, GLUCOSE OR OTHER SUBSTRATES OR TO OTHER CONSIDERATIONS SUCH AS MECHANICAL FACTORS PROTECTING FRAGILE FETAL VILLI, THE CREATION OF A RESERVE PROTECTING AGAINST ISCHEMIA/REPERFUSION INJURY, OR IMPROVED PLACENTAL O(2) TRANSFER AS THE RESULT OF NARROWING THE A-V O(2) DIFFERENCE AND RAISING UTERINE P(V)O(2). PLACENTAL GROWTH AND DEVELOPMENT APPEAR TO BE NORMAL OR MODIFIED AT HIGH ALTITUDE IN WAYS LIKELY TO BENEFIT DIFFUSION. MUCH REMAINS TO BE LEARNED CONCERNING THE EFFECTS OF CHRONIC HYPOXIA ON EMBRYONIC DEVELOPMENT. FURTHER RESEARCH IS REQUIRED FOR IDENTIFYING THE FETOPLACENTAL AND MATERNAL MECHANISMS RESPONSIBLE FOR TRANSFORMING THE MATERNAL VASCULATURE AND REGULATING UA BLOOD FLOW AND FETAL GROWTH. GENOMIC AS WELL AS EPIGENETIC STUDIES ARE OPENING NEW AVENUES OF INVESTIGATION THAT CAN YIELD INSIGHTS INTO THE BASIC PATHWAYS AND EVOLUTIONARY PROCESSES INVOLVED. 2011 18 1946 30 EPIGENETIC ABNORMALITIES ASSOCIATED WITH A CHROMOSOME 18(Q21-Q22) INVERSION AND A GILLES DE LA TOURETTE SYNDROME PHENOTYPE. GILLES DE LA TOURETTE SYNDROME (GTS) IS A POTENTIALLY DEBILITATING NEUROPSYCHIATRIC DISORDER DEFINED BY THE PRESENCE OF BOTH VOCAL AND MOTOR TICS. DESPITE EVIDENCE THAT THIS AND A RELATED PHENOTYPIC SPECTRUM, INCLUDING CHRONIC TICS (CT) AND OBSESSIVE COMPULSIVE DISORDER (OCD), ARE GENETICALLY MEDIATED, NO GENE INVOLVED IN DISEASE ETIOLOGY HAS BEEN IDENTIFIED. CHROMOSOMAL ABNORMALITIES HAVE LONG BEEN PROPOSED TO PLAY A CAUSATIVE ROLE IN ISOLATED CASES OF GTS SPECTRUM PHENOMENA, BUT CONFIRMATION OF THIS HYPOTHESIS HAS YET TO BE FORTHCOMING. WE DESCRIBE AN I(18Q21.1-Q22.2) INVERSION IN A PATIENT WITH CT AND OCD. WE HAVE FINE MAPPED THE TELOMERIC ASPECT OF THE REARRANGEMENT TO WITHIN 1 MB OF A PREVIOUSLY REPORTED 18Q22 BREAKPOINT THAT COSEGREGATED IN A FAMILY WITH GTS AND RELATED PHENOTYPES. A COMPREHENSIVE CHARACTERIZATION OF THIS GENOMIC INTERVAL LED TO THE IDENTIFICATION OF TWO TRANSCRIPTS, NEITHER OF WHICH WAS FOUND TO BE STRUCTURALLY DISRUPTED. ANALYSIS OF THE EPIGENETIC CHARACTERISTICS OF THE REGION DEMONSTRATED A SIGNIFICANT INCREASE IN REPLICATION ASYNCHRONY IN THE PATIENT COMPARED TO CONTROLS, WITH THE INVERTED CHROMOSOME SHOWING DELAYED REPLICATION TIMING ACROSS AT LEAST A 500-KB INTERVAL. THESE FINDINGS ARE CONSISTENT WITH LONG-RANGE FUNCTIONAL DYSREGULATION OF ONE OR MORE GENES IN THE REGION. OUR DATA SUPPORT A LINK BETWEEN CHROMOSOMAL ABERRATIONS AND EPIGENETIC MECHANISMS IN GTS AND SUGGEST THAT THE STUDY OF THE FUNCTIONAL CONSEQUENCES OF BALANCED CHROMOSOMAL REARRANGEMENTS IS WARRANTED IN PATIENTS WITH PHENOTYPES OF INTEREST, IRRESPECTIVE OF THE FINDINGS REGARDING STRUCTURALLY DISRUPTED TRANSCRIPTS. 2003 19 3802 23 INTERSTITIAL LUNG DISEASE IN CONNECTIVE TISSUE DISEASE: A COMMON LESION WITH HETEROGENEOUS MECHANISMS AND TREATMENT CONSIDERATIONS. CONNECTIVE TISSUE DISEASE (CTD) RELATED INTERSTITIAL LUNG DISEASE (CTD-ILD) IS ONE OF THE LEADING CAUSES OF MORBIDITY AND MORTALITY OF CTD. CLINICALLY, CTD-ILD IS HIGHLY HETEROGENOUS AND INVOLVES RHEUMATIC IMMUNITY AND MULTIPLE MANIFESTATIONS OF RESPIRATORY COMPLICATIONS AFFECTING THE AIRWAYS, VESSELS, LUNG PARENCHYMA, PLEURA, AND RESPIRATORY MUSCLES. THE MAJOR PATHOLOGICAL FEATURES OF CTD ARE CHRONIC INFLAMMATION OF BLOOD VESSELS AND CONNECTIVE TISSUES, WHICH CAN AFFECT ANY ORGAN LEADING TO MULTI-SYSTEM DAMAGE. THE HUMAN LUNG IS PARTICULARLY VULNERABLE TO SUCH DAMAGE BECAUSE ANATOMICALLY IT IS ABUNDANT WITH COLLAGEN AND BLOOD VESSELS. THE COMPLEX ETIOLOGY OF CTD-ILD INCLUDES GENETIC RISKS, EPIGENETIC CHANGES, AND DYSREGULATED IMMUNITY, WHICH INTERACT LEADING TO DISEASE UNDER VARIOUS ILL-DEFINED ENVIRONMENTAL TRIGGERS. CTD-ILD EXHIBITS A BROAD SPECTRA OF CLINICAL MANIFESTATIONS: FROM ASYMPTOMATIC TO SEVERE DYSPNEA; FROM SINGLE-ORGAN RESPIRATORY SYSTEM INVOLVEMENT TO MULTI-ORGAN INVOLVEMENT. THE DISEASE COURSE IS ALSO FEATURED BY REMISSIONS AND RELAPSES. IT CAN RANGE FROM STABILITY OR SLOW PROGRESSION OVER SEVERAL YEARS TO RAPID DETERIORATION. IT CAN ALSO PRESENT CLINICALLY AS HIGHLY PROGRESSIVE FROM THE INITIAL ONSET OF DISEASE. CURRENTLY, THE DIAGNOSIS OF CTD-ILD IS PRIMARILY BASED ON DISTINCT PATHOLOGY SUBTYPE(S), IMAGING, AS WELL AS RELATED CTD AND AUTOANTIBODIES PROFILES. METICULOUS COMPREHENSIVE CLINICAL AND LABORATORY ASSESSMENT TO IMPROVE THE DIAGNOSTIC PROCESS AND MANAGEMENT STRATEGIES ARE MUCH NEEDED. IN THIS REVIEW, WE FOCUS ON EXAMINING THE PATHOGENESIS OF CTD-ILD WITH RESPECT TO GENETICS, ENVIRONMENTAL FACTORS, AND IMMUNOLOGICAL FACTORS. WE ALSO DISCUSS THE CURRENT STATE OF KNOWLEDGE AND ELABORATE ON THE CLINICAL CHARACTERISTICS OF CTD-ILD, DISTINCT PATHOHISTOLOGICAL SUBTYPES, IMAGING FEATURES, AND RELATED AUTOANTIBODIES. FURTHERMORE, WE COMMENT ON THE IDENTIFICATION OF HIGH-RISK PATIENTS AND ADDRESS HOW TO STRATIFY PATIENTS FOR PRECISION MEDICINE MANAGEMENT APPROACHES. 2021 20 6440 20 THERAPEUTIC APPROACHES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) EXACERBATIONS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE PULMONARY DISORDER UNDERPINNED BY POORLY REVERSIBLE AIRFLOW RESULTING FROM CHRONIC BRONCHITIS OR EMPHYSEMA. THE PREVALENCE AND MORTALITY OF COPD CONTINUE TO INCREASE. PHARMACOTHERAPY FOR PATIENTS WITH COPD HAS INCLUDED ANTIBIOTICS, BRONCHODILATORS, AND ANTI-INFLAMMATORY CORTICOSTEROIDS (BUT WITH LITTLE SUCCESS). ORAL DISEASES HAVE LONG BEEN ESTABLISHED AS CLINICAL RISK FACTORS FOR DEVELOPING RESPIRATORY DISEASES. THE ESTABLISHMENT OF A VERY SIMILAR MICROBIOME IN THE MOUTH AND THE LUNG CONFIRMS THE ORAL-LUNG CONNECTION. THE ASPIRATION OF PATHOGENIC MICROBES FROM THE ORAL CAVITY HAS BEEN IMPLICATED IN SEVERAL RESPIRATORY DISEASES, INCLUDING PNEUMONIA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS REVIEW FOCUSES ON CURRENT AND FUTURE PHARMACOTHERAPEUTIC APPROACHES FOR COPD EXACERBATION INCLUDING ANTIMICROBIALS, MUCOREGULATORS, THE USE OF BRONCHODILATORS AND ANTI-INFLAMMATORY DRUGS, MODIFYING EPIGENETIC MARKS, AND MODULATING DYSBIOSIS OF THE MICROBIOME. 2022