1 3201 169 HDAC2 IN PRIMARY SENSORY NEURONS CONSTITUTIVELY RESTRAINS CHRONIC PAIN BY REPRESSING ALPHA2DELTA-1 EXPRESSION AND ASSOCIATED NMDA RECEPTOR ACTIVITY. ALPHA2DELTA-1 (ENCODED BY THE CACNA2D1 GENE) IS A NEWLY DISCOVERED NMDA RECEPTOR-INTERACTING PROTEIN AND IS THE THERAPEUTIC TARGET OF GABAPENTINOIDS (E.G., GABAPENTIN AND PREGABALIN) FREQUENTLY USED FOR TREATING PATIENTS WITH NEUROPATHIC PAIN. NERVE INJURY CAUSES SUSTAINED ALPHA2DELTA-1 UPREGULATION IN THE DORSAL ROOT GANGLION (DRG), WHICH PROMOTES NMDA RECEPTOR SYNAPTIC TRAFFICKING AND ACTIVATION IN THE SPINAL DORSAL HORN, A HALLMARK OF CHRONIC NEUROPATHIC PAIN. HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY INITIATES AND MAINTAINS THE HIGH EXPRESSION LEVEL OF ALPHA2DELTA-1 TO SUSTAIN CHRONIC PAIN. HERE, WE SHOW THAT NERVE INJURY CAUSED HISTONE HYPERACETYLATION AND DIMINISHED ENRICHMENT OF HISTONE DEACETYLASE-2 (HDAC2), BUT NOT HDAC3, AT THE CACNA2D1 PROMOTER IN THE DRG. STRIKINGLY, HDAC2 KNOCKDOWN OR CONDITIONAL KNOCKOUT IN DRG NEURONS IN MALE AND FEMALE MICE CONSISTENTLY INDUCED LONG-LASTING MECHANICAL PAIN HYPERSENSITIVITY, WHICH WAS READILY REVERSED BY BLOCKING NMDA RECEPTORS, INHIBITING ALPHA2DELTA-1 WITH GABAPENTIN OR DISRUPTING THE ALPHA2DELTA-1-NMDA RECEPTOR INTERACTION AT THE SPINAL CORD LEVEL. HDAC2 DELETION IN DRG NEURONS INCREASED HISTONE ACETYLATION LEVELS AT THE CACNA2D1 PROMOTER, UPREGULATED ALPHA2DELTA-1 IN THE DRG, AND POTENTIATED ALPHA2DELTA-1-DEPENDENT NMDA RECEPTOR ACTIVITY AT PRIMARY AFFERENT CENTRAL TERMINALS IN THE SPINAL DORSAL HORN. CORRESPONDINGLY, HDAC2 KNOCKDOWN-INDUCED PAIN HYPERSENSITIVITY WAS BLUNTED IN CACNA2D1 KNOCKOUT MICE. THUS, OUR FINDINGS REVEAL THAT HDAC2 FUNCTIONS AS A PIVOTAL TRANSCRIPTIONAL REPRESSOR OF NEUROPATHIC PAIN VIA CONSTITUTIVELY SUPPRESSING ALPHA2DELTA-1 EXPRESSION AND ENSUING PRESYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD. HDAC2 ENRICHMENT LEVELS AT THE CACNA2D1 PROMOTER IN DRG NEURONS CONSTITUTE A UNIQUE EPIGENETIC MECHANISM THAT GOVERNS ACUTE-TO-CHRONIC PAIN TRANSITION.SIGNIFICANCE STATEMENT EXCESS ALPHA2DELTA-1 PROTEINS PRODUCED AFTER NERVE INJURY DIRECTLY INTERACT WITH GLUTAMATE NMDA RECEPTORS TO POTENTIATE SYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD, A PROMINENT MECHANISM OF NERVE PAIN. BECAUSE ALPHA2DELTA-1 UPREGULATION AFTER NERVE INJURY IS LONG LASTING, GABAPENTINOIDS RELIEVE PAIN SYMPTOMS ONLY TEMPORARILY. OUR STUDY DEMONSTRATES FOR THE FIRST TIME THE UNEXPECTED ROLE OF INTRINSIC HDAC2 ACTIVITY AT THE ALPHA2DELTA-1 GENE PROMOTER IN LIMITING ALPHA2DELTA-1 GENE TRANSCRIPTION, NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY, AND CHRONIC PAIN DEVELOPMENT AFTER NERVE INJURY. THESE FINDINGS CHALLENGE THE PREVAILING VIEW ABOUT THE ROLE OF GENERAL HDAC ACTIVITY IN PROMOTING CHRONIC PAIN. RESTORING THE REPRESSIVE HDAC2 FUNCTION AND/OR REDUCING HISTONE ACETYLATION AT THE ALPHA2DELTA-1 GENE PROMOTER IN PRIMARY SENSORY NEURONS COULD LEAD TO LONG-LASTING RELIEF OF NERVE PAIN. 2022 2 114 27 A SOCIO-BIOLOGICAL EXPLANATION FOR SOCIAL DISPARITIES IN NON-COMMUNICABLE CHRONIC DISEASES: THE PRODUCT OF HISTORY? THIS STUDY PLACES SOCIAL DISPARITIES IN THE MAJOR NON-COMMUNICABLE CHRONIC DISEASES WITHIN THEIR GLOBAL ECONOMIC AND HISTORICAL CONTEXTS. RAPID ECONOMIC TRANSITION OUTSIDE THE DEVELOPED WORLD PROVIDES A UNIQUE OPPORTUNITY TO RE-EXAMINE THE ORIGINS OF, AND BIOLOGICAL MECHANISMS DRIVING, SOCIAL DISPARITIES. GAPS IN PREVAILING THEORIES FOCUSING ON MATERIAL RESOURCES, CIVIC INFRASTRUCTURE AND SOCIAL STRUCTURE ARE IDENTIFIED. USING LONGSTANDING EXPERIMENTAL EVIDENCE AND EPIGENETIC THEORIES, IT IS SUGGESTED THAT EXPOSURE TO ECONOMIC DEVELOPMENT OVER GENERATIONS (IE, IMPROVED LIVING CONDITIONS OVER HISTORICAL TIME) COULD BY ACTING ON DIFFERENT BIOLOGICAL AXES (SOMATOTROPHIC AND GONADOTROPHIC) GENERATE SPECIFIC PATTERNS OF SOCIAL DISPARITIES. MOREOVER, THESE SAME PROCESSES COULD INITIALLY GENERATE A TRANSIENT EPIDEMIC OF DIABETES AS WELL AS A PERMANENT INCREASE IN MALE RISK OF PREMATURE ISCHAEMIC HEART DISEASE. AS SUCH, THIS STUDY DEMONSTRATES THE IMPORTANCE OF CONTEXT, AND IMPLIES THAT CURRENT EVIDENCE FROM THE DEVELOPED WORLD MAY BE LARGELY UNINFORMATIVE FOR PREVENTING OR MITIGATING SOCIAL DISPARITIES IN NON-COMMUNICABLE CHRONIC DISEASES ELSEWHERE, SUGGESTING RESEARCH EFFORTS SHOULD BE FOCUSED ON DEVELOPING COUNTRIES. 2010 3 1281 19 DECIPHERING NEURODEGENERATIVE DISEASES USING LONG-READ SEQUENCING. NEURODEGENERATIVE DISEASES EXHIBIT CHRONIC PROGRESSIVE LESIONS IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS WITH UNCLEAR CAUSES. THE SEARCH FOR PATHOGENIC MUTATIONS IN HUMAN NEURODEGENERATIVE DISEASES HAS BENEFITED FROM MASSIVELY PARALLEL SHORT-READ SEQUENCERS. HOWEVER, GENOMIC REGIONS, INCLUDING REPETITIVE ELEMENTS, ESPECIALLY WITH HIGH/LOW GC CONTENT, ARE FAR BEYOND THE CAPABILITY OF CONVENTIONAL APPROACHES. RECENTLY, LONG-READ SINGLE-MOLECULE DNA SEQUENCING TECHNOLOGIES HAVE EMERGED AND ENABLED RESEARCHERS TO STUDY GENOMES, TRANSCRIPTOMES, AND METAGENOMES AT UNPRECEDENTED RESOLUTIONS. THE IDENTIFICATION OF NOVEL MUTATIONS IN UNRESOLVED NEURODEGENERATIVE DISORDERS, THE CHARACTERIZATION OF CAUSATIVE REPEAT EXPANSIONS, AND THE DIRECT DETECTION OF EPIGENETIC MODIFICATIONS ON NAIVE DNA BY VIRTUE OF LONG-READ SEQUENCERS WILL FURTHER EXPAND OUR UNDERSTANDING OF NEURODEGENERATIVE DISEASES. IN THIS ARTICLE, WE REVIEW AND COMPARE 2 PREVAILING LONG-READ SEQUENCING TECHNOLOGIES, PACIFIC BIOSCIENCES AND OXFORD NANOPORE TECHNOLOGIES, AND DISCUSS THEIR APPLICATIONS IN NEURODEGENERATIVE DISEASES. 2021 4 3606 24 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 5 103 29 A REHABILOMICS FRAMEWORK FOR PERSONALIZED AND TRANSLATIONAL REHABILITATION RESEARCH AND CARE FOR INDIVIDUALS WITH DISABILITIES: PERSPECTIVES AND CONSIDERATIONS FOR SPINAL CORD INJURY. DESPITE MANY PEOPLE HAVING SIMILAR CLINICAL PRESENTATION, DEMOGRAPHIC FACTORS, AND CLINICAL CARE, OUTCOME CAN DIFFER FOR THOSE SUSTAINING SIGNIFICANT INJURY SUCH AS SPINAL CORD INJURY (SCI) AND TRAUMATIC BRAIN INJURY (TBI). IN ADDITION TO TRADITIONAL DEMOGRAPHIC, SOCIAL, AND CLINICAL FACTORS, VARIABILITY ALSO MAY BE ATTRIBUTABLE TO INNATE (INCLUDING GENETIC, TRANSCRIPTOMIC PROTEOMIC, EPIGENETIC) BIOLOGICAL VARIATION THAT INDIVIDUALS BRING TO RECOVERY AND THEIR UNIQUE RESPONSE TO THEIR CARE AND ENVIRONMENT. TECHNOLOGIES COLLECTIVELY CALLED "-OMICS" ENABLE SIMULTANEOUS MEASUREMENT OF AN ENORMOUS NUMBER OF BIOMOLECULES THAT CAN CAPTURE MANY POTENTIAL BIOLOGICAL CONTRIBUTORS TO HETEROGENEITY OF INJURY/DISEASE COURSE AND OUTCOME. DUE TO THE NATURE OF INJURY AND COMPLEX DISEASE, AND ITS ASSOCIATIONS WITH IMPAIRMENT, DISABILITY, AND RECOVERY, REHABILITATION DOES NOT LEND ITSELF TO A SINGULAR "PROTOCOLIZED" PLAN OF THERAPY. YET, BY NATURE AND BY NECESSITY, REHABILITATION MEDICINE OPERATES AS A FUNCTIONAL MODEL OF "PERSONALIZED CARE". THUS, THE CHALLENGE FOR SUCCESSFUL PROGRAMS OF TRANSLATIONAL REHABILITATION CARE AND RESEARCH IS TO IDENTIFY VIABLE APPROACHES TO EXAMINE BROAD POPULATIONS, WITH VARIED IMPAIRMENTS AND FUNCTIONAL LIMITATIONS, AND TO IDENTIFY EFFECTIVE TREATMENT RESPONSES THAT INCORPORATE PERSONALIZED PROTOCOLS TO OPTIMIZE FUNCTIONAL RECOVERY. THE REHABILOMICS FRAMEWORK IS A TRANSLATIONAL MODEL THAT PROVIDES AN "-OMICS" OVERLAY TO THE SCIENTIFIC STUDY OF REHABILITATION PROCESSES AND MULTIDIMENSIONAL OUTCOMES. REHABILOMICS RESEARCH PROVIDES NOVEL OPPORTUNITIES TO EVALUATE THE NEUROBIOLOGY OF COMPLEX INJURY OR CHRONIC DISEASE AND CAN BE USED TO EXAMINE METHODS AND TREATMENTS FOR PERSON-CENTERED CARE AMONG POPULATIONS WITH DISABILITIES. EXEMPLARS FOR APPLICATION IN SCI AND OTHER NEUROREHABILITATION POPULATIONS ARE DISCUSSED. 2014 6 4344 22 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 7 3425 38 HUMAN SYMPATHETIC NERVE BIOLOGY: PARALLEL INFLUENCES OF STRESS AND EPIGENETICS IN ESSENTIAL HYPERTENSION AND PANIC DISORDER. PATIENTS WITH PANIC DISORDER PROVIDE A CLINICAL MODEL OF STRESS. ON A "GOOD DAY," FREE FROM A PANIC ATTACK, THEY SHOW PERSISTENT STRESS-RELATED CHANGES IN SYMPATHETIC NERVE BIOLOGY, INCLUDING ABNORMAL SYMPATHETIC NERVE SINGLE-FIBER FIRING ("SALVOS" OF MULTIPLE FIRING WITHIN A CARDIAC CYCLE) AND RELEASE OF EPINEPHRINE AS A COTRANSMITTER. THE CORELEASED EPINEPHRINE PERHAPS ORIGINATES FROM IN SITU SYNTHESIS BY PHENYLETHANOLAMINE N-METHYLTRANSFERASE (PNMT). IN SEARCHING FOR BIOLOGICAL EVIDENCE THAT ESSENTIAL HYPERTENSION IS CAUSED BY MENTAL STRESS--A DISPUTED PROPOSITION--WE NOTE PARALLELS WITH PANIC DISORDER, WHICH PROVIDES AN EXPLICIT CLINICAL MODEL OF STRESS: (1) THERE IS CLINICAL COMORBIDITY; PANIC DISORDER PREVALENCE IS INCREASED THREEFOLD IN ESSENTIAL HYPERTENSION. (2) FOR BOTH, EPINEPHRINE COTRANSMISSION IS PRESENT IN SYMPATHETIC NERVES. (3) IN PANIC DISORDER AND ESSENTIAL HYPERTENSION, BUT NOT IN HEALTH, SINGLE-FIBER SYMPATHETIC NERVE FIRING SALVOS OCCUR. (4) TISSUE NERVE GROWTH FACTOR IS INCREASED IN BOTH CONDITIONS (NERVE GROWTH FACTOR IS A STRESS REACTANT). (5) THERE IS INDUCTION OF PNMT IN SYMPATHETIC NERVES. ESSENTIAL HYPERTENSION EXHIBITS A FURTHER MANIFESTATION OF MENTAL STRESS: THERE IS ACTIVATION OF NORADRENERGIC BRAIN STEM NEURONS PROJECTING TO THE HYPOTHALAMUS AND AMYGDALA. THESE PATHOPHYSIOLOGICAL FINDINGS STRONGLY SUPPORT THE VIEW THAT CHRONIC MENTAL STRESS IS IMPORTANT IN THE PATHOGENESIS OF ESSENTIAL HYPERTENSION. A HYPOTHESIS NOW UNDER TEST IS WHETHER IN BOTH DISORDERS, UNDER PREVAILING CONDITIONS OF ONGOING STRESS, PNMT INDUCED IN SYMPATHETIC NERVES ACTS AS A DNA METHYLASE, CAUSING THE NOREPINEPHRINE TRANSPORTER (NET) GENE SILENCING THAT IS PRESENT IN BOTH CONDITIONS. PNMT CAN HAVE AN INTRANUCLEAR DISTRIBUTION, BINDING TO DNA. WE HAVE DEMONSTRATED THAT THE REDUCED NEURONAL NORADRENALINE REUPTAKE PRESENT IN BOTH DISORDERS DOES HAVE AN EPIGENETIC MECHANISM, WITH DEMONSTRABLE REDUCTION IN THE ABUNDANCE OF THE TRANSPORTER PROTEIN, THE NET GENE SILENCING BEING ASSOCIATED WITH DNA BINDING BY THE METHYLATION-RELATED INHIBITORY TRANSCRIPTION FACTOR MECP2. 2008 8 29 19 A BIOPSYCHOSOCIAL OVERVIEW OF THE OPIOID CRISIS: CONSIDERING NUTRITION AND GASTROINTESTINAL HEALTH. THE OPIOID CRISIS HAS REACHED EPIDEMIC PROPORTIONS IN THE UNITED STATES WITH RISING OVERDOSE DEATH RATES. IDENTIFYING THE UNDERLYING FACTORS THAT CONTRIBUTE TO ADDICTION VULNERABILITY MAY LEAD TO MORE EFFECTIVE PREVENTION STRATEGIES. SUPPLY SIDE ENVIRONMENTAL FACTORS ARE A MAJOR CONTRIBUTING COMPONENT. PSYCHOSOCIAL FACTORS SUCH AS STRESS, TRAUMA, AND ADVERSE CHILDHOOD EXPERIENCES HAVE BEEN LINKED TO EMOTIONAL PAIN LEADING TO SELF-MEDICATION. GENETIC AND EPIGENETIC FACTORS ASSOCIATED WITH BRAIN REWARD PATHWAYS AND IMPULSIVITY ARE KNOWN PREDICTORS OF ADDICTION VULNERABILITY. THIS REVIEW ATTEMPTS TO PRESENT A BIOPSYCHOSOCIAL APPROACH THAT CONNECTS VARIOUS SOCIAL AND BIOLOGICAL THEORIES RELATED TO THE ADDICTION CRISIS. THE EMERGING ROLE OF NUTRITION THERAPY WITH AN EMPHASIS ON GASTROINTESTINAL HEALTH IN THE TREATMENT OF OPIOID USE DISORDER IS PRESENTED. THE BIOPSYCHOSOCIAL MODEL INTEGRATES CONCEPTS FROM SEVERAL DISCIPLINES, EMPHASIZING MULTICAUSALITY RATHER THAN A REDUCTIONIST APPROACH. POTENTIAL SOLUTIONS AT MULTIPLE LEVELS ARE PRESENTED, CONSIDERING INDIVIDUAL AS WELL AS POPULATION HEALTH. THIS SINGLE COHESIVE FRAMEWORK IS BASED ON THE INTERDEPENDENCY OF THE ENTIRE SYSTEM, IDENTIFYING RISK AND PROTECTIVE FACTORS THAT MAY INFLUENCE SUBSTANCE-SEEKING BEHAVIOR. NUTRITION SHOULD BE INCLUDED AS ONE FACET OF A MULTIDISCIPLINARY APPROACH TOWARD IMPROVED RECOVERY OUTCOMES. CROSS-DISCIPLINARY COLLABORATIVE EFFORTS, NEW IDEAS, AND FISCAL RESOURCES WILL BE CRITICAL TO ADDRESS THE EPIDEMIC. 2019 9 6744 26 WHO CARES ABOUT OLIGOZOOSPERMIA WHEN WE HAVE ICSI. THE VALUE OF ASSESSING SUBFERTILE MALES WITH OLIGOZOOSPERMIA IS CONTROVERSIAL DUE TO PREVAILING NOTIONS THAT THERAPIES ARE LIMITED AND ICSI MAY PROVIDE THE COUPLE WITH A BABY WITHOUT THE NEED TO EXPLAIN THE NATURE OR CAUSE OF UNDERLYING MALE INFERTILITY. THIS ARTICLE HIGHLIGHTS THAT INDISCRIMINATELY OFFERING ICSI TO OLIGOZOOSPERMIC MEN IS NOT FREE OF POTENTIAL ADVERSE EFFECTS AND DOES NOT GRANT SUBFERTILE MEN THE BEST FERTILITY PATHWAY. RECENT DATA SUPPORT ASSOCIATIONS BETWEEN OLIGOZOOSPERMIA AND POOR MALE REPRODUCTIVE HEALTH, DNA AND EPIGENETIC DAMAGE IN SPERMATOZOA, AND POSSIBLE ADVERSE HEALTH CONSEQUENCES TO OFFSPRING. MANY CONDITIONS AFFECTING THE TESTICLES ARE CAPABLE OF CAUSING OLIGOZOOSPERMIA (VARICOCELE, GENITAL INFECTIONS, CONGENITAL AND GENETIC DEFECTS TESTICULAR TORSION/TRAUMA, CHRONIC DISEASES, INADEQUATE LIFESTYLE, OCCUPATIONAL/ENVIRONMENTAL EXPOSURE TO TOXICANTS, DRUGS, CANCER AND RELATED TREATMENTS, ACUTE FEBRILE ILLNESS, ENDOCRINE DISORDERS, AND IATROGENIC DAMAGE TO THE GENITOURINARY SYSTEM). IF OLIGOZOOSPERMIA IS DETECTED, THERAPEUTIC INTERVENTIONS CAN IMPROVE SPERM QUANTITY/QUALITY AND THE OVERALL MALE HEALTH, ULTIMATELY RESULTING IN BETTER PREGNANCY OUTCOMES EVEN WHEN ICSI IS USED. FERTILITY CLINICS ARE URGED TO ENGAGE MALE INFERTILITY SPECIALISTS IN DIAGNOSING AND TREATING OLIGOZOOSPERMIA AS A MATTER OF BEST CLINICAL PRACTICE. A WELL-CONDUCTED MALE INFERTILITY EVALUATION REPRESENTS A UNIQUE OPPORTUNITY TO IDENTIFY RELEVANT MEDICAL AND INFERTILITY CONDITIONS, MANY OF WHICH MAY BE TREATED OR ALLEVIATED. THE ANDROLOGICAL ASSESSMENT MAY ALSO HELP GUIDE THE OPTIMAL APPLICATION OF ICSI. THE FINAL GOALS ARE TO POSITIVELY IMPACT THE OVERALL PATIENT HEALTH, THE COUPLE'S PREGNANCY PROSPECTS, AND THE OFFSPRING'S WELL-BEING. 2022 10 734 20 CANCER HEALTHCARE DISPARITIES AMONG AFRICAN AMERICANS IN THE UNITED STATES. A NEED EXISTS TO EXAMINE RACIAL DISPARITIES IN THE HEALTHCARE ARENA AND THE IMPACT ON PATIENTS WITH CANCER. DESPITE ONGOING EFFORTS TO INCREASE EQUITY IN PRIMARY HEALTHCARE ACCESS, RACIAL AND SOCIOECONOMIC DISPARITIES PERSIST, THUS CONTRIBUTING TO DISPROPORTIONATE TREATMENT OUTCOMES AND SURVIVORSHIP AMONG MINORITY AND LOW-INCOME PATIENTS. SUCH DISPARITIES HAVE BEEN REVEALED IN TREATMENT COHORTS OF PATIENTS WITH MULTIPLE FORMS OF CANCER, INCLUDING BREAST, CERVICAL, OVARIAN, ENDOMETRIAL, PROSTATE, LUNG, COLORECTAL, GASTROINTESTINAL, AND HEPATOCELLULAR, AND HAVE BEEN ATTRIBUTED TO A RANGE OF CO-OCCURRING BEHAVIORAL, SOCIAL DETERMINANTS OF HEALTH, UNDERLYING GENETIC FACTORS, AS WELL AS ACCESS TO EDUCATIONAL OPPORTUNITIES THAT LIMIT THE QUALITY OF INFORMED HEALTHCARE. THESE VARIOUS INTERRELATED FACTORS WIDEN CANCER HEALTHCARE DISPARITIES SYNERGISTICALLY THROUGHOUT UNDERSERVED COMMUNITIES, AND THEIR INFLUENCE HAS BEEN AMPLIFIED BY THE CORONAVIRUS DISEASE 2019 (COVID-19) PANDEMIC. FUNDAMENTALLY, A LACK OF BASIC AND CLINICAL RESEARCH EXISTS THAT FAILS TO ADEQUATELY REFLECT DIVERSITY AND MINORITY INVOLVEMENT IN DRUG DEVELOPMENT. ALTHOUGH OVERCOMING THE OBSTACLES RESPONSIBLE FOR CHRONIC TREATMENT DISPARITIES IS A FORMIDABLE TASK, PROMISING MEANS OF ACHIEVING MORE UNIFORM QUALITY HEALTHCARE ARE BECOMING MORE CLEARLY ELUCIDATED. TO REDUCE DISEASE PROGRESSION, INCREASE OVERALL SURVIVAL, AND IMPROVE THE HEALTH OF VULNERABLE POPULATIONS, IT IS NECESSARY TO IDENTIFY AND FULLY DISCLOSE ENVIRONMENTAL, BIOLOGICAL, AND ANCESTRAL FACTORS THAT IMPACT THE RISK FOR CANCER; HEAL HISTORICAL FRACTURES WITHIN COMMUNITIES; AND INCREASE PARTICIPATION OF RACIAL AND ETHNIC MINORITIES IN SCREENING EFFORTS AND RESEARCH STUDIES. THIS REQUIRES DEVELOPING A SYSTEM OF JUSTICE AND TRUST BASED ON SPECIFIC, SOLUTION-ORIENTED GRASSROOTS COMMUNITY EFFORTS WORKING IN TANDEM WITH MEDICAL AND PHARMACEUTICAL LEADERS. BY FULLY EXPLORING AND PINPOINTING THE UNDERLYING CAUSES OF HEALTHCARE DISPARITIES, IT SHOULD BE POSSIBLE TO DEFINE STRATEGIES AND INTERVENTIONS MOST LIKELY TO TRANSFORM CANCER CARE. THE ULTIMATE GOAL IS UNDERSTANDING INDIVIDUAL, CULTURAL, AND BIOLOGICAL VULNERABILITIES, INCLUDING ENVIRONMENTAL AND EPIGENETIC LIABILITIES, TO OPTIMIZE CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022 11 6406 30 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 12 4006 23 LOST AMONG THE TREES? THE AUTONOMIC NERVOUS SYSTEM AND PAEDIATRICS. THE AUTONOMIC NERVOUS SYSTEM (ANS) HAS BEEN STRIKINGLY NEGLECTED IN WESTERN MEDICINE. DESPITE ITS PROFOUND IMPORTANCE FOR REGULATION, ADJUSTMENT AND COORDINATION OF BODY SYSTEMS, IT LACKS PRIORITY IN TRAINING AND PRACTICE AND RECEIVES SCANT ATTENTION IN NUMEROUS MAJOR TEXTBOOKS. THE ANS IS INTEGRAL TO MANIFESTATIONS OF ILLNESS, UNDERLYING FAMILIAR PHYSICAL AND PSYCHOLOGICAL SYMPTOMS. WHEN ANS ACTIVITY IS ITSELF DYSFUNCTIONAL, USUAL INDICATORS OF ACUTE ILLNESS MAY PROVE DECEPTIVE. RECOGNISING THE RELEVANCE OF THE ANS CAN INVOLVE SEEING THE FAMILIAR THROUGH FRESH EYES, CHALLENGING ASSUMPTIONS IN CLINICAL ASSESSMENT AND IN APPROACHES TO PRACTICE. ITS IMPORTANCE EXTENDS FROM PHYSICAL AND PSYCHOLOGICAL WELL-BEING TO PARENTING AND SAFEGUARDING, PUBLIC SERVICES AND THE FUNCTIONING OF SOCIETY. EXPLORATION OF ITS ROLE IN CONDITIONS RANGING FROM NEUROLOGICAL, GASTROINTESTINAL AND CONNECTIVE TISSUE DISORDERS, DIABETES AND CHRONIC FATIGUE SYNDROME, TO AUTISM, BEHAVIOURAL AND MENTAL HEALTH DIFFICULTIES MAY OPEN THERAPEUTIC AVENUES. THE ANS OFFERS A MECHANISM FOR SO-CALLED FUNCTIONAL ILLNESSES AND ILLUSTRATES THE IMPORTANCE OF RECOGNISING THAT 'STRESS' TAKES MANY FORMS, PHYSICAL, PSYCHOLOGICAL AND ENVIRONMENTAL, DESIRABLE AND OTHERWISE. EVIDENCE OF INTRAUTERINE AND POST-NATAL PROGRAMMING OF ANS REACTIVITY SUGGESTS THAT NEONATAL CARE AND SAFEGUARDING PRACTICE MAY OFFER PREVENTIVE OPPORTUNITY, AS MAY GREATER UNDERSTANDING OF EPIGENETIC CHANGE OF ANS ACTIVITY THROUGH, FOR EXAMPLE, ACCIDENTAL OR PSYCHOLOGICAL TRAUMA OR INFECTION. THE AIM OF THIS ARTICLE IS TO ACCELERATE RECOGNITION OF THE IMPORTANCE OF THE ANS THROUGHOUT PAEDIATRICS, AND OF THE POTENTIAL PHYSICAL AND PSYCHOLOGICAL COST OF NEGLECTING IT. 2014 13 265 36 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE. 2021 14 367 24 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM. 2014 15 380 25 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 16 1160 16 CONTINUING WAR ON PAIN: A PERSONALIZED APPROACH TO THE THERAPY WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS. SUCCESSFUL PAIN MANAGEMENT REQUIRES THE DELIVERY OF ANALGESIA WITH MINIMAL RISK OF ADVERSE DRUG REACTIONS. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS REMAIN THE MAINSTAY OF TREATMENT FOR THE MAJORITY OF PATIENTS. UNFORTUNATELY, ALMOST 50% OF ALL PATIENTS EXPERIENCE INADEQUATE PAIN RELIEF AND SERIOUS SIDE EFFECTS. ALLELIC VARIANTS IN GENES CODING FOR TARGET PROTEINS, TRANSPORTERS AND ENZYMES, WHICH GOVERN ANALGESIC DRUGS ACTION AND THEIR FATE IN THE ORGANISM, MIGHT EXPLAIN INTER-INDIVIDUAL VARIABILITY IN PAIN SEVERITY AND IN DRUG-INDUCED PAIN RELIEF AND TOXICITIES. ADDITIONALLY, IT SEEMS THAT EPIGENETIC CHANGES CONTRIBUTE TO THE HIGHLY VARIABLE RESPONSE TO PAIN TREATMENT. THEREFORE, PHARMACOGENOMIC TESTING MIGHT BE A VALUABLE TOOL FOR PERSONALIZATION OF PAIN TREATMENT, WITH A MULTIDISCIPLINARY TEAM APPROACH INVOLVED. 2019 17 1688 30 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 18 5280 25 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 19 6025 21 THE BIOLOGY OF CHRONIC PAIN AND ITS IMPLICATIONS FOR PAIN NEUROSCIENCE EDUCATION: STATE OF THE ART. PAIN IS AN INDIVIDUALIZED EXPERIENCE FOR THE PERSON SUFFERING FROM CHRONIC PAIN. SIGNIFICANT STRIDES HAVE BEEN MADE IN THE LAST FEW DECADES IN UNDERSTANDING VARIOUS BIOLOGICAL CHANGES THAT COINCIDE WITH CHRONIC PAIN. THIS STATE-OF-THE-ART OVERVIEW LOOKS AT THE CURRENT EVIDENCE RELATED TO THE BIOLOGY OF CHRONIC PAIN AND THE IMPLICATIONS THESE FINDINGS HAVE ON THE DELIVERY OF PAIN NEUROSCIENCE EDUCATION (PNE). THE PAPER SUMMARIZES THE VARIOUS (EPI)GENETIC, NEURAL, ENDOCRINE, AND IMMUNE FACTORS DISCOVERED AND EXPLORED IN THE SCIENTIFIC LITERATURE CONCERNING CHRONIC PAIN. EACH OF THESE BIOLOGICAL FACTORS HAS VARIOUS IMPLICATIONS FOR THE CONTENT AND DELIVERY OF PNE. WE DISCUSS THE FUTURE DIRECTIONS THESE BIOLOGICAL FACTORS HAVE FOR THE CLINICAL IMPLEMENTATION OF PNE BY LINKING THE IMPORTANCE OF BEHAVIOR CHANGE, OPTIMIZING THE LEARNING ENVIRONMENT, AND USING AN INDIVIDUALIZED MULTIMODAL TREATMENT APPROACH WITH PNE. IN ADDITION, FUTURE DIRECTIONS FOR RESEARCH OF PNE BASED ON THESE BIOLOGICAL FACTORS ARE PROVIDED WITH IMPORTANCE PLACED ON INDIVIDUALIZED PATIENT-CENTERED CARE AND HOW PNE CAN BE USED WITH TRADITIONAL MODES OF CARE AND GROWING TRENDS WITH OTHER CARE METHODS. PNE WAS ORIGINALLY AND CONTINUES TO BE ROOTED IN UNDERSTANDING CHRONIC PAIN BIOLOGY AND HOW THAT UNDERSTANDING CAN IMPROVE PATIENT CARE AND OUTCOMES. 2023 20 843 36 CHEMOSENSORY ABILITY AND SENSITIVITY IN HEALTH AND DISEASE: EPIGENETIC REGULATION AND COVID-19. THROUGHOUT THE ANIMAL KINGDOM, OUR TWO CHEMICAL SENSES, OLFACTION AND GUSTATION, ARE DEFINED BY TWO PRIMARY FACTORS: GENOMIC ARCHITECTURE OF THE ORGANISMS AND THEIR LIVING ENVIRONMENT. DURING THE PAST THREE YEARS OF THE GLOBAL COVID-19 PANDEMIC, THESE TWO SENSORY MODALITIES HAVE DRAWN MUCH ATTENTION AT THE BASIC SCIENCE AND CLINICAL LEVELS BECAUSE OF THE STRONG ASSOCIATION OF OLFACTORY AND GUSTATORY DYSFUNCTION WITH VIRAL INFECTION. LOSS OF OUR SENSE OF SMELL ALONE, OR TOGETHER WITH A LOSS OF TASTE, HAS EMERGED AS A RELIABLE INDICATOR OF COVID-19 INFECTION. PREVIOUSLY, SIMILAR DYSFUNCTIONS HAVE BEEN DETECTED IN A LARGE COHORT OF PATIENTS WITH CHRONIC CONDITIONS. THE RESEARCH FOCUS REMAINS ON UNDERSTANDING THE PERSISTENCE OF OLFACTORY AND GUSTATORY DISTURBANCES IN THE POST-INFECTION PHASE, ESPECIALLY IN CASES WITH LONG-TERM EFFECT OF INFECTION (LONG COVID). ALSO, BOTH SENSORY MODALITIES SHOW CONSISTENT AGE-RELATED DECLINE IN STUDIES AIMED TO UNDERSTAND THE PATHOLOGY OF NEURODEGENERATIVE CONDITIONS. SOME STUDIES USING CLASSICAL MODEL ORGANISMS SHOW AN IMPACT ON NEURAL STRUCTURE AND BEHAVIOR IN OFFSPRING AS AN OUTCOME OF PARENTAL OLFACTORY EXPERIENCE. THE METHYLATION STATUS OF SPECIFIC ODORANT RECEPTORS, ACTIVATED IN PARENTS, IS PASSED ON TO THE OFFSPRING. FURTHERMORE, EXPERIMENTAL EVIDENCE INDICATES AN INVERSE CORRELATION OF GUSTATORY AND OLFACTORY ABILITIES WITH OBESITY. SUCH DIVERSE LINES OF EVIDENCE EMERGING FROM BASIC AND CLINICAL RESEARCH STUDIES INDICATE A COMPLEX INTERPLAY OF GENETIC FACTORS, EVOLUTIONARY FORCES, AND EPIGENETIC ALTERATIONS. ENVIRONMENTAL FACTORS THAT REGULATE GUSTATION AND OLFACTION COULD INDUCE EPIGENETIC MODULATION. HOWEVER, IN TURN, SUCH MODULATION LEADS TO VARIABLE EFFECTS DEPENDING ON GENETIC MAKEUP AND PHYSIOLOGICAL STATUS. THEREFORE, A LAYERED REGULATORY HIERARCHY REMAINS ACTIVE AND IS PASSED ON TO MULTIPLE GENERATIONS. IN THE PRESENT REVIEW, WE ATTEMPT TO UNDERSTAND THE EXPERIMENTAL EVIDENCE THAT INDICATES VARIABLE REGULATORY MECHANISMS THROUGH MULTILAYERED AND CROSS-REACTING PATHWAYS. OUR ANALYTICAL APPROACH WILL ADD TO ENHANCEMENT OF PREVAILING THERAPEUTIC INTERVENTIONS AND BRING TO THE FOREFRONT THE SIGNIFICANCE OF CHEMOSENSORY MODALITIES FOR THE EVALUATION AND MAINTENANCE OF LONG-TERM HEALTH. 2023