1 5107 127 POLYCYSTIC OVARY SYNDROME: A BRAIN DISORDER CHARACTERIZED BY EATING PROBLEMS ORIGINATING DURING PUBERTY AND ADOLESCENCE. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE CONDITION ASSOCIATED WITH REPRODUCTIVE AND PSYCHIATRIC DISORDERS, AND WITH OBESITY. EATING DISORDERS, SUCH AS BULIMIA AND RECURRENT DIETING, ARE ALSO LINKED TO PCOS. THEY CAN LEAD TO THE EPIGENETIC DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS, THEREBY IMPACTING ON OVARIAN FOLLICULOGENESIS. WE POSTULATE THAT PCOS IS INDUCED BY PSYCHOLOGICAL DISTRESS AND EPISODES OF OVEREATING AND/OR DIETING DURING PUBERTY AND ADOLESCENCE, WHEN BODY DISSATISFACTION AND EMOTIONAL DISTRESS ARE OFTEN PRESENT. WE PROPOSE THAT UPREGULATED ACTIVATION OF THE CENTRAL HPG AXIS DURING THIS PERIOD CAN BE EPIGENETICALLY ALTERED BY PSYCHOLOGICAL STRESSORS AND BY BULIMIA/RECURRENT DIETING, WHICH ARE COMMON DURING ADOLESCENCE AND WHICH CAN LEAD TO PCOS. THIS HYPOTHESIS IS BASED ON EVENTS THAT OCCUR DURING A LARGELY NEGLECTED STAGE OF FEMALE REPRODUCTIVE DEVELOPMENT. TO DATE, MOST RESEARCH INTO THE ORIGINS OF PCOS HAS FOCUSED ON THE PRENATAL INDUCTION OF THIS DISORDER, PARTICULARLY IN UTERO ANDROGENIZATION AND THE ROLE OF ANTI-MULLERIAN HORMONE. ESTABLISHING CAUSALITY IN OUR PERIPUBERTAL MODEL REQUIRES PROSPECTIVE COHORT STUDIES FROM INFANCY. MECHANISTIC STUDIES SHOULD CONSIDER THE ROLE OF THE GUT MICROBIOTA IN ADDITION TO THE EPIGENETIC REGULATION OF (NEURO) HORMONES. FINALLY, CLINICIANS SHOULD CONSIDER THE IMPORTANCE OF UNDERLYING CHRONIC PSYCHOLOGICAL DISTRESS AND EATING DISORDERS IN PCOS. 2020 2 2034 22 EPIGENETIC CHANGES IN THE ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. PREVIOUSLY ACUTE KIDNEY INJURY (AKI) HAD BEEN BELIEVED TO BE A TRANSIENT EVENT, AND RECOVERY FROM AKI HAD BEEN THOUGHT TO LEAD TO NO CONSEQUENCES. HOWEVER, RECENT EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT EVEN IF THERE IS COMPLETE RECOVERY OF THE KIDNEY FUNCTION, AKI CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD) AND EVENTUALLY IN END-STAGE KIDNEY DISEASE IN THE LONG TERM. TRANSITION OF AKI TO CKD IS MEDIATED BY MULTIPLE MECHANISMS, INCLUDING ABERRANT CELL CYCLE ARREST AND HYPOXIA. HYPOXIA OF THE KIDNEY IS INDUCED BY RAREFACTION OF THE PERITUBULAR CAPILLARIES AFTER AKI EPISODES, AND INDUCES INFLAMMATION AND FIBROSIS. IT SHOULD ALSO BE NOTED THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO HYPOXIA, AND EPIGENETIC CHANGES INDUCED BY HYPOXIA, CALLED "HYPOXIC MEMORY" CAN EXPLAIN THE AKI-TO-CKD TRANSITION IN THE LONG TERM AFTER COMPLETE RECOVERY FROM THE INITIAL AKI EPISODE. TARGETING HYPOXIA AND SUBSEQUENT EPIGENETIC CHANGES ARE PROMISING STRATEGIES TO BLOCK THE TRANSITION FROM AKI TO CKD. 2017 3 3466 24 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 4 5171 24 PREDATOR-BASED PSYCHOSOCIAL STRESS ANIMAL MODEL OF PTSD: PRECLINICAL ASSESSMENT OF TRAUMATIC STRESS AT COGNITIVE, HORMONAL, PHARMACOLOGICAL, CARDIOVASCULAR AND EPIGENETIC LEVELS OF ANALYSIS. RESEARCH ON POST-TRAUMATIC STRESS DISORDER (PTSD) IS FACED WITH THE CHALLENGE OF UNDERSTANDING HOW A TRAUMATIC EXPERIENCE PRODUCES LONG-LASTING DETRIMENTAL EFFECTS ON BEHAVIOR AND BRAIN FUNCTIONING, AND MORE GLOBALLY, HOW STRESS EXACERBATES SOMATIC DISORDERS, INCLUDING CARDIOVASCULAR DISEASE. MOREOVER, THE DESIGN OF TRANSLATIONAL RESEARCH NEEDS TO LINK ANIMAL MODELS OF PTSD TO CLINICALLY RELEVANT RISK FACTORS WHICH ADDRESS WHY ONLY A SUBSET OF TRAUMATIZED INDIVIDUALS DEVELOP PERSISTENT PSYCHOPATHOLOGY. IN THIS REVIEW, WE HAVE SUMMARIZED OUR PSYCHOSOCIAL STRESS RODENT MODEL OF PTSD WHICH IS BASED ON WELL-DESCRIBED PTSD-INDUCING RISK FACTORS, INCLUDING A LIFE-THREATENING EXPERIENCE, A SENSE OF HORROR AND UNCONTROLLABILITY, AND INSUFFICIENT SOCIAL SUPPORT. SPECIFICALLY, OUR ANIMAL MODEL OF PTSD INTEGRATES ACUTE EPISODES OF INESCAPABLE EXPOSURE OF IMMOBILIZED RATS TO A PREDATOR WITH CHRONIC DAILY SOCIAL INSTABILITY. THIS STRESS REGIMEN PRODUCES PTSD-LIKE EFFECTS IN RATS AT BEHAVIORAL, COGNITIVE, PHYSIOLOGICAL, PHARMACOLOGICAL AND EPIGENETIC LEVELS OF ANALYSIS. WE HAVE DISCUSSED A RECENT EXTENSION OF OUR ANIMAL MODEL OF PTSD IN WHICH STRESS EXACERBATED CORONARY PATHOLOGY FOLLOWING AN ISCHEMIC EVENT, ASSESSED IN VITRO. IN ADDITION, WE HAVE REVIEWED OUR RESEARCH INVESTIGATING PHARMACOLOGICAL AND NON-PHARMACOLOGICAL THERAPEUTIC STRATEGIES WHICH MAY HAVE VALUE IN CLINICAL APPROACHES TOWARD THE TREATMENT OF TRAUMATIZED PEOPLE. OVERALL, OUR TRANSLATIONAL APPROACH BRIDGES THE GAP BETWEEN HUMAN AND ANIMAL PTSD RESEARCH TO CREATE A FRAMEWORK WITH WHICH TO ENHANCE OUR UNDERSTANDING OF THE BIOLOGICAL BASIS OF TRAUMA-INDUCED PATHOLOGY AND TO ASSESS THERAPEUTIC APPROACHES IN THE TREATMENT OF PSYCHOPATHOLOGY. 2016 5 6329 34 THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. THIS REVIEW WILL DISCUSS THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. RELEVANT STUDIES WERE IDENTIFIED VIA MEDLINE (PUBMED) AND PSYCINFO DATABASES PUBLISHED UP TO AND INCLUDING JULY 2015. THIS REVIEW CONTRIBUTES TO A NEW UNDERSTANDING OF THE NEGATIVE CONSEQUENCES OF EARLY LIFE STRESS, AS WELL AS SETTING CHILDHOOD TRAUMA IN A BIOLOGICAL CONTEXT OF SUSCEPTIBILITY AND DISCUSSING NOVEL LONG-TERM PATHOPHYSIOLOGICAL CONSEQUENCES IN BIPOLAR DISORDERS. CHILDHOOD TRAUMATIC EVENTS ARE RISK FACTORS FOR DEVELOPING BIPOLAR DISORDERS, IN ADDITION TO A MORE SEVERE CLINICAL PRESENTATION OVER TIME (PRIMARILY AN EARLIER AGE AT ONSET AND AN INCREASED RISK OF SUICIDE ATTEMPT AND SUBSTANCE MISUSE). CHILDHOOD TRAUMA LEADS TO ALTERATIONS OF AFFECT REGULATION, IMPULSE CONTROL, AND COGNITIVE FUNCTIONING THAT MIGHT DECREASE THE ABILITY TO COPE WITH LATER STRESSORS. CHILDHOOD TRAUMA INTERACTS WITH SEVERAL GENES BELONGING TO SEVERAL DIFFERENT BIOLOGICAL PATHWAYS [HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, SEROTONERGIC TRANSMISSION, NEUROPLASTICITY, IMMUNITY, CALCIUM SIGNALING, AND CIRCADIAN RHYTHMS] TO DECREASE THE AGE AT THE ONSET OF THE DISORDER OR INCREASE THE RISK OF SUICIDE. EPIGENETIC FACTORS MAY ALSO BE INVOLVED IN THE NEUROBIOLOGICAL CONSEQUENCES OF CHILDHOOD TRAUMA IN BIPOLAR DISORDER. BIOLOGICAL SEQUELAE SUCH AS CHRONIC INFLAMMATION, SLEEP DISTURBANCE, OR TELOMERE SHORTENING ARE POTENTIAL MEDIATORS OF THE NEGATIVE EFFECTS OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS, IN PARTICULAR WITH REGARD TO PHYSICAL HEALTH. THE MAIN CLINICAL IMPLICATION IS TO SYSTEMATICALLY ASSESS CHILDHOOD TRAUMA IN PATIENTS WITH BIPOLAR DISORDERS, OR AT LEAST IN THOSE WITH A SEVERE OR INSTABLE COURSE. THE CHALLENGE FOR THE NEXT YEARS WILL BE TO FILL THE GAP BETWEEN CLINICAL AND FUNDAMENTAL RESEARCH AND ROUTINE PRACTICE, SINCE RECOMMENDATIONS FOR MANAGING THIS SPECIFIC POPULATION ARE LACKING. IN PARTICULAR, LITTLE IS KNOWN ON WHICH PSYCHOTHERAPIES SHOULD BE PROVIDED OR WHICH TARGETS THERAPISTS SHOULD FOCUS ON, AS WELL AS HOW CHILDHOOD TRAUMA COULD EXPLAIN THE RESISTANCE TO MOOD STABILIZERS. 2016 6 3463 42 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 7 29 31 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 8 5387 33 REDOX MECHANISMS IN MIGRAINE: NOVEL THERAPEUTICS AND DIETARY INTERVENTIONS. SIGNIFICANCE: MIGRAINE REPRESENTS THE THIRD MOST PREVALENT AND THE SEVENTH MOST DISABLING HUMAN DISORDER. APPROXIMATELY 30% OF MIGRAINE PATIENTS EXPERIENCE TRANSIENT, FULLY REVERSIBLE, FOCAL NEUROLOGICAL SYMPTOMS (AURA) PRECEDING THE ATTACK. RECENT ADVANCES: AWARENESS OF THE HYPOTHESIS THAT MIGRAINE ACTUALLY EMBODIES A SPECTRUM OF ILLNESSES-RANGING FROM EPISODIC TO CHRONIC FORMS-IS PROGRESSIVELY INCREASING AND POSES NOVEL CHALLENGES FOR CLARIFYING THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF MIGRAINE AS WELL AS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTIONS. SEVERAL THEORIES HAVE EVOLVED TO THE CURRENT CONCEPT THAT A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY PLAY A ROLE IN MIGRAINE PATHOGENESIS, ALTHOUGH THEIR RELATIVE IMPORTANCE IS STILL BEING DEBATED. CRITICAL ISSUES: ONE CRITICAL ISSUE THAT DESERVES A PARTICULAR ATTENTION IS THE ROLE OF OXIDATIVE STRESS IN MIGRAINE. INDEED, POTENTIALLY HARMFUL OXIDATIVE EVENTS OCCUR DURING THE MIGRAINE ATTACK AND LONG-LASTING OR FREQUENT MIGRAINE EPISODES MAY INCREASE BRAIN EXPOSURE TO OXIDATIVE EVENTS THAT CAN LEAD TO CHRONIC TRANSFORMATION. MOREOVER, A WIDE VARIETY OF DIETARY, ENVIRONMENTAL, PHYSIOLOGICAL, BEHAVIORAL, AND PHARMACOLOGICAL MIGRAINE TRIGGERS MAY ACT THROUGH OXIDATIVE STRESS, WITH CLEAR IMPLICATIONS FOR MIGRAINE TREATMENT AND PROPHYLAXIS. INTERESTINGLY, ALMOST ALL CURRENT PROPHYLACTIC MIGRAINE AGENTS EXERT ANTIOXIDANT EFFECTS. FUTURE DIRECTIONS: INCREASING AWARENESS OF THE ROLE OF OXIDATIVE STRESS AND/OR DECREASED ANTIOXIDANT DEFENSES IN MIGRAINE PATHOGENESIS AND PROGRESSION TO A CHRONIC CONDITION LAYS THE FOUNDATIONS FOR THE DESIGN OF NOVEL PROPHYLACTIC APPROACHES, WHICH, BY REDUCING BRAIN OXIDATIVE PHENOMENA, COULD FAVORABLY MODIFY THE CLINICAL COURSE OF MIGRAINE. ANTIOXID. REDOX SIGNAL. 28, 1144-1183. 2018 9 380 31 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 10 4623 26 NEUROBIOLOGY OF BIPOLAR DISORDERS: A REVIEW OF GENETIC COMPONENTS, SIGNALING PATHWAYS, BIOCHEMICAL CHANGES, AND NEUROIMAGING FINDINGS. BIPOLAR DISORDER (BD) IS A CHRONIC MENTAL ILLNESS CHARACTERIZED BY CHANGES IN MOOD THAT ALTERNATE BETWEEN MANIA AND HYPOMANIA OR BETWEEN DEPRESSION AND MIXED STATES, OFTEN ASSOCIATED WITH FUNCTIONAL IMPAIRMENT. ALTHOUGH EFFECTIVE PHARMACOLOGICAL AND NON-PHARMACOLOGICAL TREATMENTS ARE AVAILABLE, SEVERAL PATIENTS WITH BD REMAIN SYMPTOMATIC. THE ADVANCE IN THE UNDERSTANDING OF THE NEUROBIOLOGY UNDERLYING BD COULD HELP IN THE IDENTIFICATION OF NEW THERAPEUTIC TARGETS AS WELL AS BIOMARKERS FOR EARLY DETECTION, PROGNOSIS, AND RESPONSE TO TREATMENT IN BD. IN THIS REVIEW, WE DISCUSS GENETIC, EPIGENETIC, MOLECULAR, PHYSIOLOGICAL AND NEUROIMAGING FINDINGS ASSOCIATED WITH THE NEUROBIOLOGY OF BD. DESPITE THE ADVANCES IN THE PATHOPHYSIOLOGICAL KNOWLEDGE OF BD, THE DIAGNOSIS AND MANAGEMENT OF THE DISEASE ARE STILL ESSENTIALLY CLINICAL. GIVEN THE COMPLEXITY OF THE BRAIN AND THE CLOSE RELATIONSHIP BETWEEN ENVIRONMENTAL EXPOSURE AND BRAIN FUNCTION, INITIATIVES THAT INCORPORATE GENETIC, EPIGENETIC, MOLECULAR, PHYSIOLOGICAL, CLINICAL, ENVIRONMENTAL DATA, AND BRAIN IMAGING ARE NECESSARY TO PRODUCE INFORMATION THAT CAN BE TRANSLATED INTO PREVENTION AND BETTER OUTCOMES FOR PATIENTS WITH BD. 2020 11 6626 27 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 12 2917 24 GENE-ENVIRONMENT INTERACTIONS IN COMMON MENTAL DISORDERS: AN UPDATE AND STRATEGY FOR A GENOME-WIDE SEARCH. A DECADE OF RESEARCH HAS DEMONSTRATED THE EXPLANATORY POTENTIAL OF INTERPLAY BETWEEN GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF COMMON MENTAL DISORDERS. INITIAL FINDINGS HAVE UNDERGONE TESTS OF REPLICABILITY AND SPECIFICITY. SOME GENE-ENVIRONMENT INTERACTIONS HAVE BEEN CONFIRMED, SOME HAVE NOT REPLICATED AND YET OTHER TURNED OUT TO BE MORE SPECIFIC THAN INITIALLY THOUGHT. SPECIFIC AND COMPLEMENTARY ROLES OF GENETIC FACTORS HAVE BEEN DELINEATED: A COMMON FUNCTIONAL LENGTH POLYMORPHISM IN THE SEROTONIN TRANSPORTER GENE (5-HTTLPR) MODERATED THE EFFECT OF CHILDHOOD MALTREATMENT ON CHRONIC DEPRESSION IN ADULTHOOD, BUT DID NOT SUBSTANTIALLY INFLUENCE THE EFFECTS OF ADULT STRESSFUL LIFE EVENTS ON THE ONSET OF NEW DEPRESSIVE EPISODES; IN CONTRAST, A COMMON FUNCTIONAL POLYMORPHISM IN THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF) MODERATED THE EFFECT OF STRESSFUL LIFE EVENTS IN ADULTHOOD IN TRIGGERING NEW DEPRESSIVE EPISODES, BUT DID NOT INFLUENCE THE EFFECTS OF CHILDHOOD MALTREATMENT. MOLECULAR MECHANISMS UNDERLYING GENE-ENVIRONMENT INTERACTIONS ARE BEING UNCOVERED, INCLUDING DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS. NEW GENE-ENVIRONMENT INTERACTIONS CONTINUE TO BE REPORTED, STILL LARGELY FROM HYPOTHESIS-DRIVEN RESEARCH. STATISTICAL AND BIOLOGICAL PRIORITIZATION STRATEGIES ARE PROPOSED TO FACILITATE A SYSTEMATIC DISCOVERY OF NOVEL GENE-ENVIRONMENT INTERACTIONS IN GENOME-WIDE ANALYSES. 2014 13 5439 27 RENAL CONSEQUENCES OF PRETERM BIRTH. BACKGROUND: THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE CONCEPT IDENTIFIES THE BRAIN, CARDIOVASCULAR, LIVER, AND KIDNEY SYSTEMS AS TARGETS OF FETAL ADVERSE PROGRAMMING WITH ADULT CONSEQUENCES. AS THE LIMITS OF VIABILITY IN PREMATURE INFANTS HAVE BEEN PUSHED TO LOWER GESTATIONAL AGES, THE LONG-TERM IMPACT OF PREMATURITY ON KIDNEYS STILL REMAINS A SIGNIFICANT BURDEN DURING HOSPITAL STAY AND BEYOND. OBJECTIVES: THE PURPOSE OF THIS STUDY IS TO SUMMARIZE AVAILABLE EVIDENCE, MECHANISMS, AND SHORT- AND LONG-TERM RENAL CONSEQUENCES OF PREMATURITY AND IDENTIFY NEPHROPROTECTIVE STRATEGIES AND AREAS OF UNCERTAINTY. RESULTS: KIDNEY SIZE AND NEPHRON NUMBER ARE KNOWN TO BE REDUCED IN SURVIVING PREMATURE INFANTS DUE TO DISRUPTION OF ORGANOGENESIS AT A CRUCIAL DEVELOPMENTAL TIME POINT. INFLAMMATION, HYPEROXIA, AND ANTIANGIOGENIC FACTORS PLAY A ROLE IN EPIGENETIC CONDITIONING WITH POTENTIAL LIFE-LONG CONSEQUENCES. ADDITIONAL KIDNEY INJURY FROM HYPOPERFUSION AND NEPHROTOXICITY RESULTS IN STRUCTURAL AND FUNCTIONAL CHANGES OVER TIME WHICH ARE OFTEN UNNOTICED. NEPHROPATHY OF PREMATURITY AND ACUTE KIDNEY INJURY CONFOUND GLOMERULAR AND TUBULAR MATURATION OF PRETERM KIDNEYS. KIDNEY PROTECTIVE STRATEGIES MAY AMELIORATE GROWTH FAILURE AND SUBOPTIMAL NEURODEVELOPMENTAL OUTCOMES IN THE SHORT TERM. IN LATER LIFE, SUBCLINICAL CHRONIC RENAL DISEASE MAY PROGRESS, EVEN IN ASYMPTOMATIC SURVIVORS. CONCLUSION: AWARENESS OF RENAL IMPLICATIONS OF THERAPEUTIC INTERVENTIONS AND RENAL CONSERVATION EFFORTS MAY LEAD TO A VARIETY OF SHORT AND LONG-TERM BENEFITS. ADEQUATE MONITORING AND SUPPLEMENTATION OF MICROELEMENT LOSSES, GATHERING IMPROVED DATA ON RENAL HANDLING, AND EXPLORATION OF NEW AVENUES SUCH AS RELIABLE MARKERS OF INJURY AND NEW THERAPEUTIC STRATEGIES IN CONTEMPORARY POPULATIONS, AS WELL AS LONG-TERM FOLLOW-UP OF RENAL FUNCTION, IS WARRANTED. 2017 14 3884 42 KIDNEY DISEASE IN DIABETES. PERSONS WITH DIABETES MAKE UP THE FASTEST GROWING GROUP OF KIDNEY DIALYSIS AND TRANSPLANT RECIPIENTS IN THE UNITED STATES. IN 1985, WHEN THE FIRST EDITION OF DIABETES IN AMERICA WAS PUBLISHED, 20,961 PERSONS WITH DIABETES WERE RECEIVING RENAL REPLACEMENT THERAPY, REPRESENTING 29% OF ALL NEW CASES OF END-STAGE RENAL DISEASE (ESRD). BY 2012, 239,837 PERSONS WITH DIABETES WERE ON RENAL REPLACEMENT THERAPY, ACCOUNTING FOR 44% OF ALL NEW ESRD CASES. THE INCREASED COUNT REFLECTS GROWTH IN DIABETES PREVALENCE AND INCREASED ACCESS TO DIALYSIS AND TRANSPLANTATION. THOSE WITH A PRIMARY DIAGNOSIS OF DIABETES HAVE LOWER SURVIVAL RELATIVE TO OTHER CAUSES OF ESRD, PRIMARILY BECAUSE OF THE COEXISTENT MORBIDITY ASSOCIATED WITH DIABETES, PARTICULARLY CARDIOVASCULAR DISEASES (CVD). WHILE SURVIVAL ON DIALYSIS HAS SLOWLY IMPROVED ACROSS MODALITIES SINCE THE 1990S, IT REMAINS REDUCED IN PERSONS WITH DIABETES, HALF OF WHOM DIE WITHIN 3 YEARS OF BEGINNING DIALYSIS IN THE UNITED STATES. SIMILAR TO PERSONS WITH ESRD IN GENERAL, THE LEADING CAUSES OF DEATH AMONG ADULTS WITH DIABETES WHO STARTED DIALYSIS IN 1995-2009 WERE CVD (58% OF THE DEATHS) AND INFECTIONS (13% OF THE DEATHS). KIDNEY TRANSPLANT RECIPIENTS WITH DIABETES HAVE MUCH BETTER SURVIVAL THAN THOSE ON DIALYSIS, INDICATING A SIGNIFICANT IMPACT OF THE TYPE OF RENAL REPLACEMENT THERAPY (TRANSPLANT VERSUS DIALYSIS) ON LONG-TERM SURVIVAL. KIDNEY FAILURE AFFECTS ABOUT 1% OF PERSONS WITH DIABETES IN THE UNITED STATES. A CONSIDERABLY HIGHER PROPORTION, ABOUT 40%, HAVE LESS SEVERE KIDNEY DISEASE. SINCE THE SECOND EDITION OF DIABETES IN AMERICA WAS PUBLISHED IN 1995, A WEALTH OF NEW INFORMATION HAS CONTRIBUTED SUBSTANTIALLY TO THE UNDERSTANDING OF KIDNEY DISEASE ASSOCIATED WITH DIABETES. IN 2002, THE NATIONAL KIDNEY FOUNDATION'S KIDNEY DISEASE OUTCOME QUALITY INITIATIVE PUBLISHED A UNIFORM DEFINITION OF CHRONIC KIDNEY DISEASE (CKD) AND CLASSIFICATION OF ITS STAGES IRRESPECTIVE OF UNDERLYING CAUSE, THUS PROVIDING A COMMON LANGUAGE FOR DEFINING BOTH THE SEVERITY AND PROGNOSIS OF KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CKD WERE SUBSEQUENTLY UPDATED AND REFINED BY THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES IN 2012. ACCORDINGLY, CKD IS CLASSIFIED BASED ON BOTH ALBUMINURIA AND GLOMERULAR FILTRATION RATE (GFR) CATEGORIES, AND TOGETHER WITH KIDNEY FAILURE, THESE CONDITIONS ARE COLLECTIVELY REFERRED TO AS CKD, REGARDLESS OF ETIOLOGY. IN ADDITION, THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES RECOMMENDS USING EQUATIONS TO ESTIMATE GFR (EGFR), WHICH INCLUDE THE ROUTINELY OBTAINED VARIABLES SERUM CREATININE, AGE, SEX, AND RACE/ETHNICITY. THE USE OF SERUM CYSTATIN C, AN ENDOGENOUS FILTRATION MARKER LESS INFLUENCED THAN SERUM CREATININE BY VARIATIONS IN MUSCLE MASS, DIET, AND TUBULAR SECRETION, HAS EMERGED AS AN ALTERNATIVE OR AN ADJUNCT TO SERUM CREATININE-BASED EQUATIONS, PARTICULARLY IN PERSONS WITH DIABETES, IN WHOM EARLY KIDNEY DISEASE IS OFTEN CHARACTERIZED BY ELEVATED GFR. SINCE THE LATE 1990S, NEW MOLECULAR MECHANISMS HAVE BEEN DEFINED THAT ARE HELPING TO EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETIC KIDNEY DISEASE. GLOMERULAR STRUCTURAL LESIONS WERE FOUND TO EXPLAIN 95% OF THE VARIABILITY IN ALBUMIN EXCRETION AND 78% OF GFR VARIABILITY. THE LATTER PERCENTAGE INCREASED TO 92% BY ADDING INDICES OF GLOMERULAR-TUBULAR JUNCTION ABNORMALITIES AND INTERSTITIAL EXPANSION TO THE REGRESSION MODELS. PODOCYTE INJURY APPEARS TO PLAY AN ESSENTIAL ROLE IN THE PROGRESSION OF DIABETIC NEPHROPATHY. IN PERSONS WITH EITHER TYPE 1 OR TYPE 2 DIABETES, PODOCYTE CHANGES MAY OCCUR EVEN BEFORE THE INCREASE IN ALBUMINURIA, SUGGESTING THAT DIABETES ITSELF MAY INDUCE PODOCYTE ALTERATIONS. MUCH HAS ALSO BEEN WRITTEN ABOUT THE PROGNOSTIC IMPLICATIONS OF CKD. ELEVATED ALBUMINURIA AND LOW GFR ARE ASSOCIATED WITH ESRD, FATAL AND NONFATAL CVD, AND ALL-CAUSE MORTALITY. A META-ANALYSIS OF 1,024,977 PARTICIPANTS (NEARLY 13% WITH DIABETES) FROM 30 GENERAL POPULATION AND HIGH-RISK CARDIOVASCULAR COHORTS AND 13 CKD COHORTS INDICATED THAT WHILE THE ABSOLUTE RISKS FOR ALL-CAUSE AND CVD MORTALITY ARE HIGHER IN THE PRESENCE OF DIABETES, THE RELATIVE RISKS OF ESRD OR DEATH BY EGFR AND ALBUMINURIA ARE SIMILAR WITH OR WITHOUT DIABETES. THESE FINDINGS UNDERSCORE THE IMPORTANCE OF KIDNEY DISEASE PER SE AS A PREDICTOR OF IMPORTANT CLINICAL OUTCOMES, REGARDLESS OF THE UNDERLYING CAUSE OF KIDNEY DISEASE. NEW BIOMARKERS OF DIABETIC KIDNEY DISEASE APPEAR TO HAVE ADDITIONAL PROGNOSTIC INFORMATION BEYOND THAT PROVIDED BY ALBUMINURIA. THESE MARKERS INCLUDE KIDNEY INJURY MOLECULE 1, LIVER FATTY ACID-BINDING PROTEIN, N-ACETYL-BETA-D-GLUCOSAMINIDASE, NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN, BETA-TRACE PROTEIN, BETA(2)-MICROGLOBULIN, AND TUMOR NECROSIS FACTOR RECEPTORS 1 AND 2. MANY CONCEPTS ABOUT RISK FACTORS FOR CKD ILLUSTRATED IN THIS CHAPTER HAVE NOT CHANGED SINCE 1995, AND WHERE THEY HAVE, THOSE CHANGES ARE DISCUSSED. IN PARTICULAR, MAJOR ADVANCES HAVE BEEN MADE IN ELUCIDATING THE GENETIC AND EPIGENETIC COMPLEXITY OF CKD, WHICH CONTRIBUTED TO DEFINING CELLULAR METABOLIC MEMORY AND THE UNDERSTANDING OF THE LONGLASTING EFFECTS OF STRICT GLYCEMIC CONTROL OBSERVED IN PERSONS WITH TYPE 1 DIABETES OR TYPE 2 DIABETES. IMPROVEMENTS IN THE MANAGEMENT OF PERSONS WITH DIABETES AND CKD HAVE EXTENDED THE TIME COURSE FROM ONSET OF SEVERE ALBUMINURIA TO ESRD AND REDUCED THE OCCURRENCE OF CVD. IN TYPE 1 DIABETES, THE COMBINED DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) AND ITS LONG-TERM FOLLOW-UP, THE EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC) OBSERVATIONAL STUDY, INDICATED THAT INTENSIVE EARLY METABOLIC CONTROL REDUCED THE RISK OF IMPAIRED GFR BY 50% AND OF CVD OUTCOMES BY 42%, WITH A SPECIFIC 57% DECREASE IN MYOCARDIAL INFARCTION, STROKE, OR DEATH FROM CVD, EFFECTS THAT WERE PARTLY MEDIATED BY THE REDUCED INCIDENCE OF DIABETIC KIDNEY DISEASE. AMONG PERSONS WITH TYPE 2 DIABETES, A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS INDICATED THAT MORE INTENSIVE GLYCEMIC CONTROL (GLYCOSYLATED HEMOGLOBIN [A1C] <7%) WAS ASSOCIATED WITH A SIGNIFICANT 10% REDUCTION IN ALBUMINURIA BUT HAD NO EFFECTS ON MORTALITY, KIDNEY FAILURE, OR OTHER VASCULAR OUTCOMES. THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD) TRIAL, TARGETING AN A1C LEVEL <6.0% IN THE INTENSIVE INTERVENTION ARM, REPORTED AN INCREASED RISK OF CVD DEATH FOR INTENSIVE VERSUS CONVENTIONAL GLYCEMIC CONTROL, ALTHOUGH IT REMAINS UNCLEAR WHETHER THIS EFFECT WAS RELATED TO MORE HYPOGLYCEMIC EPISODES, THE USE OF ADDITIONAL HYPOGLYCEMIC MEDICINES, OR TO THE TARGET GLYCEMIC LEVEL ITSELF. LIKEWISE, THE MODEST GAINS IN INTERMEDIATE OUTCOMES IN THE INTENSIVE TREATMENT ARMS OF THE ACTION IN DIABETES AND VASCULAR DISEASE: PRETERAX AND DIAMICRON MODIFIED RELEASE CONTROLLED EVALUATION (ADVANCE) AND THE VETERANS AFFAIRS DIABETES (VADT) TRIAL WERE COUNTERBALANCED BY A TWOFOLD TO THREEFOLD HIGHER RISK OF SEVERE HYPOGLYCEMIA. TOGETHER, THESE TRIALS INDICATE THAT GLYCEMIC CONTROL IS EXTREMELY USEFUL UP TO A POINT, BUT MORE AGGRESSIVE GLYCEMIC CONTROL MAY BE HARMFUL. SIMILARLY, FOR BLOOD PRESSURE CONTROL, 2014-2015 RECOMMENDATIONS BY THE GUIDELINE-WRITING GROUPS ENDORSE LESS INTENSIVE AND MORE INDIVIDUALIZED BLOOD PRESSURE TARGETS FOR DIABETES AND CKD THAN IN THE PAST. PERSONS WITH DIABETES AND CKD REQUIRE MULTIDISCIPLINARY MANAGEMENT INVOLVING A COMBINATION OF TREATMENTS AND BEHAVIORAL ADJUSTMENTS TO DELAY PROGRESSION OF CKD AND TO PREVENT THE ASSOCIATED COMPLICATIONS. THE STENO-2 STUDY, A LANDMARK PROSPECTIVE, RANDOMIZED TRIAL IN DENMARK, DEMONSTRATED THAT COMPARED WITH CONVENTIONAL TREATMENT, INTENSIVE MULTIFACTORIAL INTERVENTION LED TO 46% LOWER DEATH RATE, 56% LESS SEVERE ALBUMINURIA, 43% LOWER INCIDENCE OF DIABETIC RETINOPATHY, AND 47% LOWER INCIDENCE OF AUTONOMIC NEUROPATHY DURING THE 13.3-YEAR STUDY PERIOD. 2018 15 4381 28 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 16 6451 23 THERAPIES TARGETING EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. ACUTE KIDNEY INJURY (AKI) WAS PREVIOUSLY THOUGHT TO BE A MERELY TRANSIENT EVENT; HOWEVER, RECENT EPIDEMIOLOGICAL EVIDENCE SUPPORTS THE EXISTENCE OF A CAUSAL RELATIONSHIP BETWEEN AKI EPISODES AND SUBSEQUENT PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION IS NOT FULLY UNDERSTOOD, IT IS MEDIATED BY THE INTERPLAY AMONG MULTIPLE COMPONENTS OF THE KIDNEY INCLUDING TUBULAR EPITHELIAL CELLS, ENDOTHELIAL CELLS, PERICYTES, INFLAMMATORY CELLS, AND MYOFIBROBLASTS. EPIGENETIC ALTERATIONS INCLUDING HISTONE MODIFICATION, DNA METHYLATION, NON-CODING RNAS, AND CHROMATIN CONFORMATIONAL CHANGES, ARE ALSO EXPECTED TO BE LARGELY INVOLVED IN THE PATHOPHYSIOLOGY AS A "MEMORY" OF THE INITIAL INJURY THAT CAN PERSIST AND PREDISPOSE TO CHRONIC PROGRESSION OF FIBROSIS. EACH EPIGENETIC MODIFICATION HAS A GREAT POTENTIAL AS A THERAPEUTIC TARGET OF AKI-TO-CKD TRANSITION; TIMELY AND TARGET-SPECIFIC EPIGENETIC INTERVENTIONS TO THE VARIOUS TEMPORAL STAGES OF AKI-TO-CKD TRANSITION WILL BE THE KEY TO FUTURE THERAPEUTIC APPLICATIONS IN CLINICAL PRACTICE. THIS REVIEW ELABORATES ON THE LATEST KNOWLEDGE OF EACH MECHANISM AND THE CURRENTLY AVAILABLE THERAPEUTIC AGENTS THAT TARGET EPIGENETIC MODIFICATION IN THE CONTEXT OF AKI-TO-CKD TRANSITION. FURTHER STUDIES WILL ELUCIDATE MORE DETAILED MECHANISMS AND NOVEL THERAPEUTIC TARGETS OF AKI-TO-CKD TRANSITION. 2022 17 4622 24 NEUROBIOLOGICAL DEVELOPMENT IN THE CONTEXT OF CHILDHOOD TRAUMA. NEUROBIOLOGICAL SYSTEMS MAY BE PARTICULARLY SUSCEPTIBLE TO DELETERIOUS IMPACT OF CHILDHOOD TRAUMA, AND THE IMPACT OF CHILDHOOD TRAUMA ON DEVELOPMENT AND SUBSEQUENT FUNCTIONAL OUTCOMES ACROSS THE LIFESPAN HAS BEEN WELL-DOCUMENTED. THE CURRENT REVIEW ADDRESSES THE NEUROBIOLOGICAL IMPACT OF EXPOSURE TO INTERPERSONAL TRAUMA IN CHILDHOOD IN THE CONTEXT OF EXECUTIVE FUNCTION, EMOTION REGULATION, AND DISSOCIATION/INTEROCEPTIVE AWARENESS. SUBSEQUENT RISK FOR PTSD AND DEPRESSION IS ALSO DISCUSSED. THE PATHWAY OF RISK FROM CHILDHOOD TRAUMA TO THESE COGNITIVE, EMOTIONAL, AND PSYCHIATRIC OUTCOMES IS ADDRESSED IN TERMS OF POTENTIAL STRUCTURAL AND FUNCTIONAL ALTERATIONS WITHIN THE HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA RESULTING FROM CHRONIC OR REPEATED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ITS INTERACTION WITH AND INFLUENCE ON GENETIC AND EPIGENETIC PROCESSES DURING SENSITIVE PERIODS OF DEVELOPMENT. IMPLICATIONS FOR PRACTICE ARE DISCUSSED. 2017 18 734 29 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 19 4344 20 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 20 103 24 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