1 3934 260 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 2 1931 44 ENVIRONMENTAL EXPOSURES, THE EPIGENOME, AND AFRICAN AMERICAN WOMEN'S HEALTH. STRESS IS A COMMON FEATURE OF MODERN LIFE, BUT BOTH THE EXTENT OF EXPOSURE TO STRESSORS AND THE DOWNSTREAM EFFECTS OF THESE STRESS EXPOSURES CAN VARY CONSIDERABLY AMONG INDIVIDUALS, COMMUNITIES, AND POPULATIONS. WHEN INDIVIDUALS ARE EXPOSED TO REPEATED OR CHRONIC STRESS, WEAR AND TEAR ON THE BODY CAN ACCUMULATE AND MANIFEST IN MANY WAYS. THE TERM "ALLOSTATIC LOAD" REPRESENTS THE PHYSIOLOGICAL CONSEQUENCES OF REPEATED OR CHRONIC EXPOSURE TO ENVIRONMENTAL STRESSORS AND IS LINKED TO FLUCTUATING AND/OR HEIGHTENED NEURAL OR NEUROENDOCRINE RESPONSES. AFRICAN AMERICAN WOMEN ARE ONE POPULATION SUBGROUP THAT HAS BEEN IDENTIFIED AS POTENTIALLY HAVING BOTH AN ELEVATED ALLOSTATIC LOAD AND AN ENHANCED RESILIENCE TO EXTERNAL FACTORS. ONE MECHANISM BY WHICH ENVIRONMENTAL STRESSORS MAY IMPACT HUMAN HEALTH IS VIA EPIGENETIC REMODELING OF THE GENOME. THIS REVIEW WILL FOCUS ON WHAT IS KNOWN ABOUT HOW DIFFERENT TYPES OF ENVIRONMENTAL STRESSORS MAY AFFECT THE EPIGENOME AND EXPLORE LINKS BETWEEN EPIGENETIC REPROGRAMMING AND ALTERED ALLOSTATIC LOAD AND RESILIENCE AS IT PERTAINS TO AFRICAN AMERICAN WOMEN'S HEALTH. 2019 3 5644 27 SEX AND THE MIGRAINE BRAIN. THE BRAIN RESPONDS DIFFERENTLY TO ENVIRONMENTAL AND INTERNAL SIGNALS THAT RELATE TO THE STAGE OF DEVELOPMENT OF NEURAL SYSTEMS. WHILE GENETIC AND EPIGENETIC FACTORS CONTRIBUTE TO A PREMORBID STATE, HORMONAL FLUCTUATIONS IN WOMEN MAY ALTER THE SET POINT OF MIGRAINE. THE CYCLIC SURGES OF GONADAL HORMONES MAY DIRECTLY ALTER NEURONAL, GLIAL AND ASTROCYTE FUNCTION THROUGHOUT THE BRAIN. ESTROGEN IS MAINLY EXCITATORY AND PROGESTERONE INHIBITORY ON BRAIN NEURONAL SYSTEMS. THESE CHANGES CONTRIBUTE TO THE ALLOSTATIC LOAD OF THE MIGRAINE CONDITION THAT MOST NOTABLY STARTS AT PUBERTY IN GIRLS. 2014 4 6157 38 THE GENETICS AND EPIGENETICS OF ALTERED PROLIFERATIVE HOMEOSTASIS IN AGEING AND CANCER. AGEING MAMMALS ARE SUBJECT TO AN AMAZING ARRAY OF ABERRATIONS IN PROLIFERATIVE HOMEOSTASIS. THESE ARE OF TWO BASIC TYPES: THE POST-MATURATIONAL FAILURE TO ADEQUATELY REPLACE EFFETE SOMATIC CELLS (ATROPHIES) AND EXCESSIVE PROLIFERATIONS OF SOMATIC CELLS (HYPERPLASIAS). TO A SURPRISING DEGREE, THESE OCCUR SIDE BY SIDE WITHIN THE SAME TISSUES AND ARE FEATURES OF NUMEROUS MAMMALIAN GERIATRIC DISORDERS. ATROPHY IS THE LIKELY USUAL INITIAL EVENT, THE PROLIFERATIVE RESPONSE PERHAPS DEVELOPING AS A SECONDARY, COMPENSATORY, INITIALLY ADAPTIVE REACTION. WE HAVE LITTLE UNDERSTANDING OF WHY THIS PUTATIVE COMPENSATORY REACTION SO OFTEN FAILS TO BE APPROPRIATELY REGULATED IN AGEING MAMMALS, LEADING TO SUCH PATHOLOGIES AS CHRONIC INFLAMMATION, FIBROSIS, METAPLASIA AND NEOPLASIA. ADVANCES IN FORMAL GENETIC ANALYSIS, MUTAGENESIS, STEM CELL BIOLOGY AND EPIGENETICS ARE LIKELY TO PROVIDE MAJOR NEW UNDERSTANDING. STOCHASTIC EPIGENETIC SHIFTS IN GENE EXPRESSION ARE OF GROWING INTEREST, PARTICULARLY IN EXPLAINING INTRA-SPECIFIC VARIATIONS ON RATES AND PATTERNS OF AGEING. NATURE MAY WELL HAVE EVOLVED SUCH RANDOM FLUCTUATIONS IN GENE EXPRESSION AS A TYPE OF GROUP-SELECTIONIST ADAPTIVE STRATEGY TO COPE WITH DIVERSE STOCHASTIC ENVIRONMENTAL CHALLENGES. ALTERNATIVELY, SUCH BACKGROUND "NOISE" IN TRANSCRIPTION AND TRANSLATION MAY SIMPLY REFLECT A TYPE OF INFORMATIONAL ENTROPY. 2007 5 5520 53 RISK FACTORS OF POSTPARTUM DEPRESSION. POSTPARTUM DEPRESSION (PPD) IS A WIDESPREAD MENTAL HEALTH PROBLEM AND ONE OF THE PRIME CAUSES OF MATERNAL SUFFERING AND ILL HEALTH. ON A GLOBAL LEVEL, THE PREVALENCE OF THE DISORDER IS ABOUT 10 TO 15%. SYMPTOMS GENERALLY APPEAR WITHIN THE FIRST FOUR TO SIX WEEKS, WHICH IS THE HIGH-RISK PERIOD. HOWEVER, IT MAY DEVELOP UP TO ONE YEAR POST-DELIVERY. PPD PRESENTS WITH SYMPTOMS OF CLASSICAL DEPRESSION, INCLUDING MOOD FLUCTUATIONS, BOUTS OF CRYING, LACK OF INTEREST IN THE CHILD, AND EVEN THOUGHTS OF SUICIDE. PPD NOT ONLY HAS ADVERSE EFFECTS ON THE MOTHER'S HEALTH BUT ALSO HAMPERS THE GROWTH AND DEVELOPMENT OF THE CHILD. IT HAMPERS THE FORMATION OF A HEALTHY MOTHER-CHILD BOND, WHICH IN TURN MAY IMPACT FEEDING PRACTICES. THE SOCIAL ENVIRONMENT OF THE INFANT DURING THE FIRST FEW MONTHS IS PRIMARILY PROVIDED BY THE MOTHER, AND PPD MAY THUS IMPACT THE CHILD'S DEVELOPMENT. IT ALSO INCREASES THE CHILD'S SUSCEPTIBILITY TO MALNUTRITION. RESEARCH ON POSTPARTUM DEPRESSION HAS GARNERED MOMENTUM WITHIN THE LAST FEW YEARS. HOWEVER, THE MASSES ARE STILL LARGELY UNAWARE OF THE DISORDER AND ITS IMPLICATIONS. THERE IS ALSO AN INADEQUACY OF AWARENESS OF THE RISK FACTORS OF PPD. THE CROSS-CULTURAL DIFFERENCES IN MANIFESTATIONS AND APPROPRIATE PREVENTIVE MEASURES HAVE NOT BEEN EXTENSIVELY STUDIED. SOME RISK FACTORS FOR PPD ARE SIMILAR TO THOSE FOR CLASSIC DEPRESSION; HOWEVER, OBSTETRICAL AND PEDIATRIC FACTORS ARE ALSO INVOLVED. THIS LITERATURE REVIEW AIMS TO ASSESS THE CURRENTLY KNOWN RISK FACTORS FOR PPD, THEIR STRENGTH OF ASSOCIATION, AND PROBABLE MECHANISMS TO HELP IDENTIFY THE HIGH-RISK GROUP AND ENABLE THE IMPLEMENTATION OF PREVENTIVE MEASURES OR FACILITATE EARLY DIAGNOSIS. THE FACTORS IDENTIFIED SPANNED SOCIODEMOGRAPHIC, BIOLOGICAL, PSYCHOLOGICAL, AND OBSTETRIC DOMAINS. THESE INCLUDED SOCIOECONOMIC STANDING, MARITAL RELATIONSHIP, HISTORY OF PSYCHIATRIC ILLNESS, SOCIAL SUPPORT, GESTATIONAL DIABETES, VITAMIN D DEFICIENCY, IMMIGRATION STATUS, DELIVERY METHOD, VIOLENCE AND ABUSE, BIRTH EXPERIENCE, AND BIOLOGICAL AND EPIGENETIC MARKERS. THE RISK FACTORS FOR POSTPARTUM DEPRESSION ARE NUMEROUS AND MAY HAVE STRONG TO WEAK ASSOCIATIONS WITH THE DEVELOPMENT OF PPD. A PREVIOUS HISTORY OF DEPRESSION OR PSYCHIATRIC ILLNESS, DEPRESSIVE SYMPTOMS DURING PREGNANCY, GESTATIONAL DIABETES, AND A LACK OF SPOUSAL AND SOCIAL SUPPORT WERE THE MOST POWERFUL RISK FACTORS. OTHER SIGNIFICANT FACTORS INCLUDE COMPLICATIONS DURING PREGNANCY, LOW SOCIOECONOMIC STATUS, AND STRESSFUL LIFE EVENTS. STUDIES ON MATERNAL AGE AND CHRONIC ILLNESS AS RISK FACTORS WERE INCONCLUSIVE. THE ROLES OF GENETIC AND EPIGENETIC MARKERS, CULTURAL FACTORS, AND VITAMIN D INSUFFICIENCY REQUIRE FURTHER INVESTIGATION. 2022 6 4166 56 MEDICAL, ETHICAL, AND LEGAL ASPECTS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CROHN'S DISEASE IN BRAZIL. CROHN'S DISEASE (CD) IS A CHRONIC INFLAMMATORY BOWEL DISEASE THAT CAN AFFECT ANY PART OF THE GASTROINTESTINAL TRACT. THE ETIOLOGY OF CD IS UNKNOWN; HOWEVER, GENETIC, EPIGENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS COULD PLAY AN ESSENTIAL ROLE IN THE ONSET AND ESTABLISHMENT OF THE DISEASE. CD RESULTS FROM IMMUNE DYSREGULATION DUE TO LOSS OF THE HEALTHY SYMBIOTIC RELATIONSHIP BETWEEN HOST AND INTESTINAL FLORA AND OR ITS ANTIGENS. IT AFFECTS BOTH SEXES EQUALLY WITH A MALE TO FEMALE RATIO OF 1.0, AND ITS ONSET CAN OCCUR AT ANY AGE, BUT THE DIAGNOSIS IS MOST COMMONLY OBSERVED IN THE RANGE OF 20 TO 40 YEARS OF AGE. CD DIMINISHES QUALITY OF LIFE, INTERFERES WITH SOCIAL ACTIVITIES, TRAUMATIZES DUE TO THE STIGMA OF INCONTINENCE, FISTULAE, STRICTURES, AND COLOSTOMIES, AND IN SEVERE CASES, AFFECTS SURVIVAL WHEN COMPARED TO THE GENERAL POPULATION. SYMPTOMS FLUCTUATE BETWEEN PERIODS OF REMISSION AND ACTIVITY IN WHICH COMPLICATIONS SUCH AS FISTULAS, STRICTURES, AND THE NEED FOR BOWEL RESECTION, SURGERY, AND COLOSTOMY IMPLANTATION MAKE UP THE MOST SEVERE ASPECTS OF THE DISEASE. CD CAN BE PROGRESSIVE AND THE COMPLICATIONS RECURRENT DESPITE TREATMENT WITH ANTI-INFLAMMATORY DRUGS, CORTICOSTEROIDS, IMMUNOSUPPRESSANTS, AND BIOLOGICAL AGENTS. HOWEVER, OVER TIME MANY PATIENTS BECOME REFRACTORY WITHOUT TREATMENT ALTERNATIVES, AND IN THIS SCENARIO, HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) HAS EMERGED AS A POTENTIAL TREATMENT OPTION. THE RATIONALE FOR THE USE OF HSCT FOR CD IS ANCHORED IN ANIMAL STUDIES AND HUMAN CLINICAL TRIALS WHERE HSCT COULD RESET A PATIENT'S IMMUNE SYSTEM BY ELIMINATING DISEASE-CAUSING EFFECTOR CELLS AND UPON IMMUNE RECOVERY INCREASE REGULATORY AND SUPPRESSIVE IMMUNE CELLS. AUTOLOGOUS HSCT USING A NON-MYELOABLATIVE REGIMEN OF CYCLOPHOSPHAMIDE AND ANTI-THYMOCYTE GLOBULIN WITHOUT CD34+ SELECTION HAS BEEN TO DATE THE MOST COMMON TRANSPLANT CONDITIONING REGIMEN ADOPTED. IN THIS REVIEW WE WILL ADDRESS THE CURRENT SITUATION REGARDING CD TREATMENT WITH HSCT AND EMPHASIZE THE MEDICAL, ETHICAL, AND LEGAL ASPECTS THAT PERMEATE THE PROCEDURE IN BRAZIL. 2020 7 6044 44 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022 8 2976 47 GENETIC AND MOLECULAR BASIS OF DIABETIC FOOT ULCERS: CLINICAL REVIEW. DIABETIC FOOT ULCERS (DFUS) ARE MAJOR COMPLICATIONS ASSOCIATED WITH DIABETES AND OFTEN CORRELATE WITH PERIPHERAL NEUROPATHY, TRAUMA AND PERIPHERAL VASCULAR DISEASE. IT IS NECESSARY TO UNDERSTAND THE MOLECULAR AND GENETIC BASIS OF DIABETIC FOOT ULCERS IN ORDER TO TAILOR PATIENT CENTRED CARE TOWARDS PARTICULAR PATIENT GROUPS. THIS REVIEW AIMED TO EVALUATE WHETHER CURRENT LITERATURE WAS INDICATIVE OF AN UNDERLYING MOLECULAR AND GENETIC BASIS FOR DFUS AND TO DISCUSS CLINICAL APPLICATIONS. FROM A MOLECULAR PERSPECTIVE, WOUND HEALING IS A PROCESS THAT TRANSPIRES FOLLOWING BREACH OF THE SKIN BARRIER AND IS USUALLY MEDIATED BY GROWTH FACTORS AND CYTOKINES RELEASED BY SPECIALISED CELLS ACTIVATED BY THE IMMUNE RESPONSE, INCLUDING FIBROBLASTS, ENDOTHELIAL CELLS, PHAGOCYTES, PLATELETS AND KERATINOCYTES. GROWTH FACTORS AND CYTOKINES ARE FUNDAMENTAL IN THE ORGANISATION OF THE MOLECULAR PROCESSES INVOLVED IN MAKING CUTANEOUS WOUND HEALING POSSIBLE. THERE IS A SIGNIFICANT ROLE FOR SINGLE NUCLEOTIDE POLYMORPHISM (SNPS) IN THE FLUCTUATION OF THESE GROWTH FACTORS AND CYTOKINES IN DFUS. FURTHERMORE, RECENT EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION FROM LONG STANDING HYPERGLYCEMIA AND NON-CODING RNAS IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. GENETIC FACTORS AND ETHNICITY CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF DIABETIC NEUROPATHY LEADING TO DFUS. CLINICALLY, INTERVENTIONS WHICH HAVE IMPROVED OUTCOMES FOR PEOPLE WITH DFUS OR THOSE AT RISK OF DFUS INCLUDE SOME SYSTEMIC THERAPEUTIC DRUG INTERVENTIONS WHICH IMPROVE MICROVASCULAR BLOOD FLOW, SURGICAL INTERVENTIONS, HUMAN GROWTH FACTORS, AND HYPERBARIC OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, SKIN REPLACEMENT OR SHOCKWAVE THERAPY AND THE USE OF TOPICAL TREATMENTS. FUTURE TREATMENT MODALITIES INCLUDING STEM CELL AND GENE THERAPIES ARE PROMISING IN THE THERAPEUTIC APPROACH TO PREVENT THE PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. 2016 9 1451 33 DISALLOWED AND ALLOWED GENE EXPRESSION: TWO FACES OF MATURE ISLET BETA CELLS. GLUCOSE HOMEOSTASIS GREATLY DEPENDS ON THE MATCH BETWEEN FLUCTUATING INSULIN DEMANDS AND ADJUSTED RATES OF INSULIN SECRETION, WHICH IS THE FUNCTION OF PANCREATIC BETA CELLS. EMERGING EVIDENCE SUGGESTS THAT WHEN NEONATAL BETA CELLS MATURE, THEY ACQUIRE TWO FACES OF DIFFERENTIATED FUNCTION: AN EXPECTED "VISIBLE FACE" THAT DEPENDS ON SPECIFIC BETA CELL PROTEINS NEEDED FOR REGULATED INSULIN RELEASE, BUT ALSO A "HIDDEN FACE" THAT REPRESSES UBIQUITOUS PROTEINS TO PREVENT INAPPROPRIATE BETA CELL FUNCTION SUCH AS ELEVATED BASAL HORMONE SECRETION OR INSULIN RELEASE TRIGGERED BY EXERCISE. THIS REVIEW HIGHLIGHTS THIS NOVEL CONCEPT, AND WE FIRST PROPOSE THAT HIDDEN FACES MAY ALSO BE RELEVANT FOR OTHER SPECIALIZED TISSUE FUNCTIONS, SUCH AS KETOGENESIS IN THE LIVER. NEXT, WE DISCUSS THREE SCENARIOS IN WHICH ABERRANT GENE EXPRESSION CAUSES ABNORMAL GLUCOSE-INDUCED INSULIN RELEASE AND THE EPIGENETIC REGULATION OF THE HIDDEN FACE IN BETA CELLS. WE CONCLUDE WITH PERSPECTIVES FOR NEW RESEARCH, INCLUDING BETA CELL REPLACEMENT TO CURE DIABETES. 2016 10 1361 41 DEVELOPMENTAL CONSEQUENCES OF TRACE MINERAL DEFICIENCIES IN RODENTS: ACUTE AND LONG-TERM EFFECTS. APPROXIMATELY 3% OF INFANTS BORN HAVE AT LEAST ONE SERIOUS CONGENITAL MALFORMATION. IN THE U.S., AN AVERAGE OF 10 INFANTS PER THOUSAND DIE BEFORE 1 Y OF LIFE; ABOUT HALF OF THESE DEATHS CAN BE ATTRIBUTED TO BIRTH DEFECTS, LOW BIRTH WEIGHT OR PREMATURITY. ALTHOUGH THE CAUSES OF DEVELOPMENTAL ABNORMALITIES ARE CLEARLY MULTIFACTORIAL IN NATURE, WE SUGGEST THAT A COMMON FACTOR CONTRIBUTING TO THE OCCURRENCE OF DEVELOPMENTAL ABNORMALITIES IS SUBOPTIMAL MINERAL NUTRITION DURING EMBRYONIC AND FETAL DEVELOPMENT. USING ZINC AND COPPER AS EXAMPLES, EVIDENCE IS PRESENTED THAT NUTRITIONAL DEFICIENCIES CAN RAPIDLY AFFECT THE DEVELOPING CONCEPTUS AND RESULT IN GROSS STRUCTURAL ABNORMALITIES. DEFICITS OF ZINC OR COPPER CAN RESULT IN RAPID CHANGES IN CELLULAR REDOX BALANCE, TISSUE OXIDATIVE STRESS, INAPPROPRIATE PATTERNS OF CELL DEATH, ALTERATIONS IN THE MIGRATION OF NEURAL CREST CELLS AND CHANGES IN THE EXPRESSION OF KEY PATTERNING GENES. IN ADDITION TO WELL-RECOGNIZED MALFORMATIONS, MINERAL DEFICIENCIES DURING PERINATAL DEVELOPMENT CAN RESULT IN BEHAVIORAL, IMMUNOLOGICAL AND BIOCHEMICAL ABNORMALITIES THAT PERSIST INTO ADULTHOOD. ALTHOUGH THESE PERSISTENT DEFECTS CAN IN PART BE ATTRIBUTED TO SUBTLE MORPHOLOGICAL ABNORMALITIES, IN OTHER CASES THEY MAY BE SECONDARY TO EPIGENETIC OR DEVELOPMENTAL CHANGES IN DNA METHYLATION PATTERNS. EPIGENETIC DEFECTS COMBINED WITH SUBTLE MORPHOLOGICAL ABNORMALITIES CAN INFLUENCE AN INDIVIDUAL'S RISK FOR CERTAIN CHRONIC DISEASES AND THUS INFLUENCE HIS OR HER RISK FOR MORBIDITY AND MORTALITY LATER IN LIFE. 2003 11 3463 46 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 12 1407 47 DIETARY INFLUENCES ON MUTAGENESIS--WHERE IS THIS FIELD GOING? EARLY STUDIES ON DIETARY MUTAGENESIS WERE MOSTLY OBSERVATIONAL, WITH LARGE NUMBERS OF POTENTIAL DIETARY MUTAGENS BEING IDENTIFIED FROM EVERY CONCEIVABLE DIETARY SOURCE. THESE INCLUDED KNOWN DIETARY CARCINOGENS SUCH AS AFLATOXIN B1 AND BENZO[A]PYRENE, AND HITHERTO UNRECOGNIZED DIETARY MUTAGENS, SUCH AS THE PYROLYSIS PRODUCTS FORMED DURING THE HEATING OF PROTEINACEOUS MATERIALS (HETEROCYCLIC AMINES). THE 1993 EVALUATION OF 2-AMINO-3-METHYL-3H-IMIDAZO(4,5-J)QUINOLINE AS A PROBABLE HUMAN CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER WAS A LANDMARK, AS THIS WAS DONE IN THE ABSENCE OF SPECIFIC HUMAN CARCINOGENICITY DATA, AND STRONGLY INFLUENCED BY MUTAGENICITY TEST DATA. IN THE 21ST CENTURY, THE FIELD HAS MOVED FROM THE IDENTIFICATION OF MORE AND MORE MUTAGENS, TO MOLECULAR EPIDEMIOLOGIC APPROACHES THAT NOT ONLY SHOW A MUTAGENIC EFFECT BUT ALSO SEEK TO LINK IT TO A DIETARY (OR ENVIRONMENTAL) CAUSE. EFFECTS OF DIET IN STIMULATING CHRONIC INFLAMMATION MAY LEAD TO REACTIVE SPECIES AND THEREBY MUTATION AS A SECONDARY CONSEQUENCE, WHILE DIETARY DEFICIENCIES AND NUTRIENT IMBALANCES MAY BE STRONG SOURCES OF MUTAGENESIS. RECOGNITION OF THE ROLES OF NUTRIENTS IN CELL SIGNALING PROCESSES AND CONTROL OF MICRORNAS SUGGEST MAJOR INFLUENCES ON GENE EXPRESSION, IN THE ABSENCE OF PERMANENT DNA CHANGES. GENOME-WIDE ASSOCIATION STUDIES HAVE HIGHLIGHTED NEW PATHWAYS SUCH AS JAK/STAT SIGNALING THAT PROFOUNDLY INFLUENCE GENOMIC INSTABILITY AND RESPONSES TO DIETARY MUTAGENS. WITH IMPROVED METHODOLOGIES FOR DNA SEQUENCING AND EPIGENETIC CHANGES, IT IS TIME TO APPLY MORE SOPHISTICATED APPROACHES TO RECOGNIZING AND PROVING THE ROLE OF DIET AS A PRIMARY MODULATOR OF MUTAGENESIS IN HUMANS. 2010 13 30 58 A BRIEF LOOK AT HASHIMOTO'S DISEASE, ADRENAL INCIDENTALOMAS, OBESITY AND INSULIN RESISTANCE-COULD ENDOCRINE DISRUPTORS BE THE OTHER SIDE OF THE SAME COIN? HASHIMOTO'S DISEASE (HD) IS THE MOST COMMON CAUSE OF HYPOTHYROIDISM IN DEVELOPED COUNTRIES. THE EXACT PATHOMECHANISM BEHIND IT HAS NOT BEEN CLEARLY ESTABLISHED; HOWEVER, AN INTERPLAY OF GENETIC SUSCEPTIBILITY, ENVIRONMENTAL TRIGGERS (INCLUDING DIET) AND EPIGENETIC FACTORS SEEMS TO BE INVOLVED. AMONG THE LATTER, INCREASINGLY MORE ATTENTION HAS BEEN PAID TO SOME HORMONALLY ACTIVE SUBSTANCES, KNOWN AS ENDOCRINE DISRUPTORS, WHICH ARE COMMONLY USED WORLDWIDE. HD HAS BECOME A CONDITION WIDELY REPORTED IN THE MEDIA, ACTING AS A CULPRIT FOR INEXPLICABLE WEIGHT GAIN, CHRONIC FATIGUE OR WEAKNESS. NEVERTHELESS, THE RECOGNITION OF HD IS UNDENIABLY INCREASING AND REPRESENTS A MAJOR PUBLIC HEALTH BURDEN. AT THE SAME TIME, IMPROVING ACCESS TO IMAGING TESTS HAS INCREASED THE NUMBER OF INCIDENTALLY DIAGNOSED ADRENAL TUMORS. ABOVE ALL, THE WIDESPREAD USE OF CHEST COMPUTED TOMOGRAPHY (CT) DUE TO THE COVID-19 PANDEMIC HAS CONTRIBUTED TO FREQUENT INCIDENTAL DETECTION OF ADRENAL LESIONS. FORTUNATELY, A VAST MAJORITY OF THESE FINDINGS ARE ASYMPTOMATIC BENIGN TUMORS WITH NO EXCESSIVE HORMONAL ACTIVITY, AND THEREFORE, THEY ARE DEFINED AS ADRENAL INCIDENTALOMAS (AIS). INTERESTINGLY, RECENT STUDIES HAVE INDICATED THAT PATIENTS WITH AIS ARE MORE PRONE TO OBESITY AND INSULIN RESISTANCE. ALTHOUGH MUTUAL RELATIONSHIPS BETWEEN THE THYROID AND THE ADRENAL GLANDS HAVE BEEN STUDIED WIDELY, STILL, LITTLE IS KNOWN ABOUT THE POSSIBLE PATHOPHYSIOLOGICAL ASSOCIATIONS BETWEEN THYROID AUTOIMMUNITY AND THE OCCURRENCE OF ADRENAL INCIDENTALOMAS. THIS ARTICLE PRESENTS A BRIEF REVIEW OF THE COMMON ENDOCRINE DISORDERS WITH A SPECIAL FOCUS ON THE FREQUENTLY COEXISTING INSULIN RESISTANCE AND/OR OBESITY. FURTHERMORE, IN RESPONSE TO THE RECENT GROWING INTEREST IN ENDOCRINE DISRUPTORS, WITH THEIR TRANSGENERATIONAL EPIGENETIC EFFECTS THAT INFLUENCE HORMONAL SYSTEM FUNCTION, A CONCISE OVERVIEW OF THE TOPIC HAS ALSO BEEN INCLUDED. 2023 14 1911 44 ENVIRONMENT IN CHILDREN'S HEALTH: A NEW CHALLENGE FOR RISK ASSESSMENT. IN THE LAST FEW YEARS, MANY STUDIES HAVE FOCUSED ON THE EFFECTS OF ENVIRONMENTAL CONTAMINANT EXPOSURE DURING THE PRENATAL PERIOD OR INFANCY AS PREDICTORS OF HEALTH OUTCOMES IN THE FUTURE. IN THESE TIME WINDOWS, DUE TO THEIR RAPID GROWTH, AND PHYSIOLOGIC AND METABOLIC DEVELOPMENT, WE CAN OBSERVE A HIGHER VULNERABILITY TO THE EFFECTS OF ENVIRONMENT, WITH RESPECT TO ADULTHOOD. THE EVIDENCE OF POSSIBLE INFLUENCES, PARTLY MEDIATED BY EPIGENETIC MECHANISMS, INVOLVE NEUROBEHAVIORAL RESPONSES AND IMMUNE, ENDOCRINE, AND RESPIRATORY SYSTEMS, ACTING DIRECTLY ON THE CHILD OR INDIRECTLY WHEN MEDIATED BY PLACENTAL TRANSFER OR BREAST FEEDING. IN PARTICULAR, DUE TO A GREATER INTAKE OF AIR, FOOD, AND FLUIDS RELATIVE TO BODY WEIGHT, CRAWLING BEHAVIORS AND SHORT STATURE, THE RISK OF EXCESSIVE EXPOSURE IS GREATER IN CHILDREN. HOWEVER, DATA ON THE LONG-TERM IMPLICATIONS OF EARLY EXPOSURES ARE SCARCE. ADDITIONALLY, SO THAT PHYSICIANS AND INSTITUTIONS FOR CHILD CARE AND ASSISTANCE OF PREGNANT WOMEN CAN TAKE ACTIONS TO COUNTERACT THE EFFECTS OF CHEMICAL POLLUTION (I.E., BY EDUCATIONAL OPPORTUNITIES), A RISK ASSESSMENT PERSPECTIVE THAT RESPONDS TO THE BIOCOMPLEXITY OF THE HUMAN BEING IS NEEDED. THE PRESENT PAPER PROVIDES AN OVERVIEW OF PHYSIOLOGIC AND BEHAVIORAL CHARACTERISTICS DURING THE PERINATAL PERIOD AND IN CHILDHOOD, SUGGESTING IN A MORE INTEGRATED WAY, THE NEED OF A NEW RISK-ASSESSMENT APPROACH TO MANAGING CHRONIC DISEASE IN PEDIATRIC PATIENTS. 2021 15 835 56 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 16 3763 44 INTEGRATION OF NUTRIGENOMICS, MELATONIN, SEROTONIN AND INFLAMMATORY CYTOKINES IN THE PATHOPHYSIOLOGY OF PREGNANCY-SPECIFIC URINARY INCONTINENCE IN WOMEN WITH GESTATIONAL DIABETES MELLITUS. GESTATIONAL DIABETES MELLITUS IS AN IMPORTANT PUBLIC HEALTH PROBLEM AND HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF PREGNANCY-SPECIFIC URINARY INCONTINENCE. THE INTERACTION IS RELATED TO HYPERGLYCEMIA, AND INFLAMMATORY AND HORMONAL PATTERNS, WHICH FAVOR FUNCTIONAL ALTERATIONS IN DIFFERENT ORGANS AND SYSTEMS. SEVERAL GENES ASSOCIATED WITH HUMAN DISEASES HAVE BEEN IDENTIFIED AND PARTIALLY CHARACTERIZED. MOST OF THESE GENES ARE KNOWN TO CAUSE MONOGENIC DISEASES. HOWEVER, ABOUT 3 % OF DISEASES DO NOT FIT THE MONOGENIC THEORY DUE TO THE COMPLEX INTERACTIONS BETWEEN MULTIPLE GENES AND ENVIRONMENTAL FACTORS, AS IN CHRONIC METABOLIC DISEASES SUCH AS DIABETES. THE NUTRITIONAL, IMMUNOLOGICAL, AND HORMONAL PATTERNS ASSOCIATED WITH CHANGES IN MATERNAL METABOLISM MAY INFLUENCE AND CONTRIBUTE TO GREATER SUSCEPTIBILITY TO URINARY TRACT DISORDERS. HOWEVER, EARLY SYSTEMATIC REVIEWS HAVE NOT YIELDED CONSISTENT FINDINGS FOR THESE ASSOCIATIONS. THIS LITERATURE REVIEW SUMMARIZES IMPORTANT NEW FINDINGS FROM INTEGRATING NUTRIGENOMICS, HORMONES, AND CYTOKINES IN WOMEN WITH GESTATIONAL DIABETES MELLITUS AND PREGNANCY-SPECIFIC URINARY INCONTINENCE. CHANGES IN MATERNAL METABOLISM DUE TO HYPERGLYCEMIA CAN GENERATE AN INFLAMMATORY ENVIRONMENT WITH INCREASED INFLAMMATORY CYTOKINES. THIS ENVIRONMENT MODULATED BY INFLAMMATION CAN ALTER TRYPTOPHAN UPTAKE THROUGH FOOD AND THUS INFLUENCE THE PRODUCTION OF SEROTONIN AND MELATONIN. AS THESE HORMONES SEEM TO HAVE PROTECTIVE EFFECTS AGAINST SMOOTH MUSCLE DYSFUNCTION AND TO RESTORE THE IMPAIRED CONTRACTILITY OF THE DETRUSOR MUSCLE, IT IS ASSUMED THAT THESE CHANGES MAY FAVOR THE ONSET OF URINARY INCONTINENCE SPECIFIC TO PREGNANCY. 2023 17 4805 43 OBESITY AND METABOLIC COMORBIDITIES: ENVIRONMENTAL DISEASES? OBESITY AND METABOLIC COMORBIDITIES REPRESENT INCREASING HEALTH PROBLEMS. ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ARE EXOGENOUS AGENTS THAT CHANGE ENDOCRINE FUNCTION AND CAUSE ADVERSE HEALTH EFFECTS. MOST EDCS ARE SYNTHETIC CHEMICALS; SOME ARE NATURAL FOOD COMPONENTS AS PHYTOESTROGENS. PEOPLE ARE EXPOSED TO COMPLEX MIXTURES OF CHEMICALS THROUGHOUT THEIR LIVES. EDCS IMPACT HORMONE-DEPENDENT METABOLIC SYSTEMS AND BRAIN FUNCTION. LABORATORY AND HUMAN STUDIES PROVIDE COMPELLING EVIDENCE THAT HUMAN CHEMICAL CONTAMINATION CAN PLAY A ROLE IN OBESITY EPIDEMIC. CHEMICAL EXPOSURES MAY INCREASE THE RISK OF OBESITY BY ALTERING THE DIFFERENTIATION OF ADIPOCYTES. EDCS CAN ALTER METHYLATION PATTERNS AND NORMAL EPIGENETIC PROGRAMMING IN CELLS. OXIDATIVE STRESS MAY BE INDUCED BY MANY OF THESE CHEMICALS, AND ACCUMULATING EVIDENCE INDICATES THAT IT PLAYS IMPORTANT ROLES IN THE ETIOLOGY OF CHRONIC DISEASES. THE INDIVIDUAL SENSITIVITY TO CHEMICALS IS VARIABLE, DEPENDING ON ENVIRONMENT AND ABILITY TO METABOLIZE HAZARDOUS CHEMICALS. A NUMBER OF GENES, ESPECIALLY THOSE REPRESENTING ANTIOXIDANT AND DETOXIFICATION PATHWAYS, HAVE POTENTIAL APPLICATION AS BIOMARKERS OF RISK ASSESSMENT. THE POTENTIAL HEALTH EFFECTS OF COMBINED EXPOSURES MAKE THE RISK ASSESSMENT PROCESS MORE COMPLEX COMPARED TO THE ASSESSMENT OF SINGLE CHEMICALS. TECHNIQUES AND METHODS NEED TO BE FURTHER DEVELOPED TO FILL DATA GAPS AND INCREASE THE KNOWLEDGE ON HARMFUL EXPOSURE COMBINATIONS. 2013 18 4786 45 NUTRITION AND HEALTH DURING MID-LIFE: SEARCHING FOR SOLUTIONS AND MEETING CHALLENGES FOR THE AGING POPULATION. INTERACTIONS BETWEEN GENETIC (GENOME) AND ENVIRONMENTAL FACTORS (EPIGENOME) OPERATE DURING A PERSON'S ENTIRE LIFESPAN. THE AGING PROCESS IS ASSOCIATED WITH SEVERAL CELLULAR AND ORGANIC FUNCTIONAL ALTERATIONS THAT, AT THE END, CAUSE MULTI-ORGANIC CELL FAILURE. EPIGENETIC MECHANISMS OF AGING ARE MODIFIABLE BY APPROPRIATE PREVENTIVE ACTIONS MEDIATED BY SIRTUINS, CALORIC INPUT, DIET COMPONENTS, ADIPOSE TISSUE-RELATED INFLAMMATORY REACTIONS, AND PHYSICAL ACTIVITY. THE MEDITERRANEAN LIFESTYLE HAS BEEN FOR MANY MILLENNIA A DAILY HABIT FOR PEOPLE IN WESTERN CIVILIZATIONS LIVING AROUND THE MEDITERRANEAN SEA WHO WORKED INTENSIVELY AND SURVIVED WITH VERY FEW SEASONAL FOODS. A HIGH ADHERENCE TO THE TRADITIONAL MEDITERRANEAN DIET IS ASSOCIATED WITH LOW MORTALITY (HIGHER LONGEVITY) AND REDUCED RISK OF DEVELOPING CHRONIC DISEASES, INCLUDING CANCER, THE METABOLIC SYNDROME, DEPRESSION AND CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. REPORTS INDICATE THAT SOME DIETARY COMPONENTS, SUCH AS OLIVE OIL, ANTIOXIDANTS, OMEGA-3 AND -6 POLYUNSATURATED ACIDS, POLYPHENOLS AND FLAVONOIDS, MEDIATE BENEFICIAL ANTI-AGING EFFECTS (ANTI-CHRONIC DISEASES AND INCREASED LONGEVITY). EQUALLY, PHYSICAL ACTIVITY DISPLAYS A POSITIVE EFFECT, PRODUCING CALORIC CONSUMPTION AND REGULATION OF ADIPOSE AND PANCREATIC FUNCTION. THE PREDICTIVE STRENGTH OF SOME FOOD PATTERNS MAY BE A WAY OF DEVELOPING RECOMMENDATIONS FOR FOOD AND HEALTH POLICIES. THIS PAPER WILL DISCUSS SEVERAL WAYS OF IMPROVING HEALTH DURING MID-LIFE, FOCUSING ON CERTAIN GROUPS OF FUNCTIONAL FOODS AND HEALTHY HABITS WHICH MAY REDUCE OR PREVENT AGE-RELATED CHRONIC DISEASES. 2013 19 734 47 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 20 380 39 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