1 367 127 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 2 4344 26 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 3 6406 28 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 4 1887 34 ENDOMETRIAL RECEPTIVITY IN WOMEN OF ADVANCED AGE: AN UNDERRATED FACTOR IN INFERTILITY. BACKGROUND: MODERN LIFESTYLE HAS LED TO AN INCREASE IN THE AGE AT CONCEPTION. ADVANCED AGE IS ONE OF THE CRITICAL RISK FACTORS FOR FEMALE-RELATED INFERTILITY. IT IS WELL KNOWN THAT MATERNAL AGE POSITIVELY CORRELATES WITH THE DETERIORATION OF OOCYTE QUALITY AND CHROMOSOMAL ABNORMALITIES IN OOCYTES AND EMBRYOS. THE EFFECT OF AGE ON ENDOMETRIAL FUNCTION MAY BE AN EQUALLY IMPORTANT FACTOR INFLUENCING IMPLANTATION RATE, PREGNANCY RATE, AND OVERALL FEMALE FERTILITY. HOWEVER, THERE ARE ONLY A FEW PUBLISHED STUDIES ON THIS TOPIC, SUGGESTING THAT THIS AREA HAS BEEN UNDER-EXPLORED. IMPROVING OUR KNOWLEDGE OF ENDOMETRIAL AGING FROM THE BIOLOGICAL (CELLULAR, MOLECULAR, HISTOLOGICAL) AND CLINICAL PERSPECTIVES WOULD BROADEN OUR UNDERSTANDING OF THE RISKS OF AGE-RELATED FEMALE INFERTILITY. OBJECTIVE AND RATIONALE: THE OBJECTIVE OF THIS NARRATIVE REVIEW IS TO CRITICALLY EVALUATE THE EXISTING LITERATURE ON ENDOMETRIAL AGING WITH A FOCUS ON SYNTHESIZING THE EVIDENCE FOR THE IMPACT OF ENDOMETRIAL AGING ON CONCEPTION AND PREGNANCY SUCCESS. THIS WOULD PROVIDE INSIGHTS INTO EXISTING GAPS IN THE CLINICAL APPLICATION OF RESEARCH FINDINGS AND PROMOTE THE DEVELOPMENT OF TREATMENT OPTIONS IN THIS FIELD. SEARCH METHODS: THE REVIEW WAS PREPARED USING PUBMED (MEDLINE) UNTIL FEBRUARY 2023 WITH THE KEYWORDS SUCH AS 'ENDOMETRIAL AGING', 'RECEPTIVITY', 'DECIDUALIZATION', 'HORMONE', 'SENESCENCE', 'CELLULAR', 'MOLECULAR', 'METHYLATION', 'BIOLOGICAL AGE', 'EPIGENETIC', 'OOCYTE RECIPIENT', 'OOCYTE DONATION', 'EMBRYO TRANSFER', AND 'PREGNANCY RATE'. ARTICLES IN A LANGUAGE OTHER THAN ENGLISH WERE EXCLUDED. OUTCOMES: IN THE AGING ENDOMETRIUM, ALTERATIONS OCCUR AT THE MOLECULAR, CELLULAR, AND HISTOLOGICAL LEVELS SUGGESTING THAT AGING HAS A NEGATIVE EFFECT ON ENDOMETRIAL BIOLOGY AND MAY IMPAIR ENDOMETRIAL RECEPTIVITY. ADDITIONALLY, ADVANCED AGE INFLUENCES CELLULAR SENESCENCE, WHICH PLAYS AN IMPORTANT ROLE DURING THE INITIAL PHASE OF IMPLANTATION AND IS A MAJOR OBSTACLE IN THE DEVELOPMENT OF SUITABLE SENOLYTIC AGENTS FOR ENDOMETRIAL AGING. AGING IS ALSO ACCOUNTABLE FOR CHRONIC CONDITIONS ASSOCIATED WITH INFLAMMAGING, WHICH EVENTUALLY CAN LEAD TO INCREASED PRO-INFLAMMATION AND TISSUE FIBROSIS. FURTHERMORE, ADVANCED AGE INFLUENCES EPIGENETIC REGULATION IN THE ENDOMETRIUM, THUS ALTERING THE RELATION BETWEEN ITS EPIGENETIC AND CHRONOLOGICAL AGE. THE STUDIES IN OOCYTE DONATION CYCLES TO DETERMINE THE EFFECT OF AGE ON ENDOMETRIAL RECEPTIVITY WITH RESPECT TO THE RATES OF IMPLANTATION, CLINICAL PREGNANCY, MISCARRIAGE, AND LIVE BIRTH HAVE REVEALED CONTRADICTORY INFERENCES INDICATING THE NEED FOR FUTURE RESEARCH ON THE MECHANISMS AND CORRESPONDING CAUSAL EFFECTS OF WOMEN'S AGE ON ENDOMETRIAL RECEPTIVITY. WIDER IMPLICATIONS: INCREASING AGE CAN BE ACCOUNTABLE FOR FEMALE INFERTILITY AND IVF FAILURES. BASED ON THE COMPLIED OBSERVATIONS AND SYNTHESIZED CONCLUSIONS IN THIS REVIEW, ADVANCED AGE HAS BEEN SHOWN TO HAVE A NEGATIVE IMPACT ON ENDOMETRIAL FUNCTIONING. THIS INFORMATION CAN PROVIDE RECOMMENDATIONS FOR FUTURE RESEARCH FOCUSING ON MOLECULAR MECHANISMS OF AGE-RELATED CELLULAR SENESCENCE, CELLULAR COMPOSITION, AND TRANSCRIPTOMIC CHANGES IN RELATION TO ENDOMETRIAL AGING. ADDITIONALLY, FURTHER PROSPECTIVE RESEARCH IS NEEDED TO EXPLORE NEWLY EMERGING THERAPEUTIC OPTIONS, SUCH AS THE SENOLYTIC AGENTS THAT CAN TARGET ENDOMETRIAL AGING WITHOUT AFFECTING DECIDUALIZATION. MOREOVER, CLINICAL TRIAL PROTOCOLS, FOCUSING ON OOCYTE DONATION CYCLES, WOULD BE BENEFICIAL IN UNDERSTANDING THE DIRECT CLINICAL IMPLICATIONS OF ENDOMETRIAL AGING ON PREGNANCY OUTCOMES. 2023 5 5025 32 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 6 4796 32 NUTRITIONAL INTERVENTION AS AN ESSENTIAL PART OF MULTIPLE SCLEROSIS TREATMENT? MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE GENETIC, EPIGENETIC AND IMMUNOLOGICAL COMPONENTS, VARIOUS OTHER FACTORS, E.G. UNHEALTHY DIETARY HABITS, PLAY A ROLE IN THE MS PATHOGENESIS. DIETARY INTERVENTION IS A HIGHLY APPEALING APPROACH, AS IT PRESENTS A SIMPLE AND RELATIVELY LOW RISK METHOD TO POTENTIALLY IMPROVE OUTCOMES IN PATIENTS WITH BRAIN DISORDERS IN ORDER TO ACHIEVE REMISSION AND IMPROVEMENT OF CLINICAL STATUS, WELL-BEING AND LIFE EXPECTANCY OF PATIENTS WITH MS. THE IMPORTANCE OF SATURATED FAT INTAKE RESTRICTION FOR THE CLINICAL STATUS IMPROVEMENT OF MS PATIENTS WAS POINTED FOR THE FIRST TIME IN 1950S. RECENTLY, DECREASED RISK OF FIRST CLINICAL DIAGNOSIS OF CNS DEMYELINATION ASSOCIATED WITH HIGHER INTAKE OF OMEGA-3 POLYUNSATURATED FATTY ACIDS PARTICULARLY ORIGINATING FROM FISH WAS REPORTED. ONLY FEW CLINICAL TRIALS HAVE BEEN PERFORMED TO ADDRESS THE QUESTION OF THE ROLE OF DIETARY INTERVENTION, SUCH IS E.G. LOW SATURATED FAT DIET IN MS TREATMENT. THIS REVIEW SUMMARIZES CURRENT KNOWLEDGE ABOUT THE EFFECT OF DIFFERENT DIETARY APPROACHES (DIETS LOW IN SATURATED FAT AND DIETARY SUPPLEMENTS SUCH AS FISH OIL, LIPOIC ACID, OMEGA-3 POLYUNSATURATED FATTY ACIDS, SEEDS OILS, HIGH FIBER DIET, VITAMIN D, ETC.) ON NEUROLOGICAL SIGNS, PATIENT'S WELL-BEING, PHYSICAL AND INFLAMMATORY STATUS. SO FAR THE RESULTS ARE NOT CONCLUSIVE, THEREFORE MUCH MORE RESEARCH IS NEEDED TO CONFIRM AND TO UNDERSTAND THE EFFECTIVENESS OF THESE DIETARY INTERVENTIONS IN THE LONG TERM AND WELL DEFINED STUDIES. 2018 7 4515 30 MULTI-OMICS APPROACHES FOR PRECISION OBESITY MANAGEMENT : POTENTIALS AND LIMITATIONS OF OMICS IN PRECISION PREVENTION, TREATMENT AND RISK REDUCTION OF OBESITY. INTRODUCTION: OBESITY IS A MULTIFACTORIAL CHRONIC DISEASE THAT CANNOT BE ADDRESSED BY SIMPLY PROMOTING BETTER DIETS AND MORE PHYSICAL ACTIVITY. TO DATE, NOT A SINGLE COUNTRY HAS SUCCESSFULLY BEEN ABLE TO CURB THE ACCUMULATING BURDEN OF OBESITY. ONE EXPLANATION FOR THE LACK OF PROGRESS IS THAT LIFESTYLE INTERVENTION PROGRAMS ARE TRADITIONALLY IMPLEMENTED WITHOUT A COMPREHENSIVE EVALUATION OF AN INDIVIDUAL'S DIAGNOSTIC BIOMARKERS. EVIDENCE FROM GENOME-WIDE ASSOCIATION STUDIES HIGHLIGHT THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IN THE DEVELOPMENT OF OBESITY AND HOW THEY IN TURN AFFECT THE TRANSCRIPTOME, METABOLITES, MICROBIOMES, AND PROTEOMES. OBJECTIVE: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE DIFFERENT TYPES OF OMICS DATA: GENOMICS, EPIGENOMICS, TRANSCRIPTOMICS, PROTEOMICS, METABOLOMICS AND ILLUSTRATE HOW A MULTI-OMICS APPROACH CAN BE FUNDAMENTAL FOR THE IMPLEMENTATION OF PRECISION OBESITY MANAGEMENT. RESULTS: THE DIFFERENT TYPES OF OMICS DESIGNS ARE GROUPED INTO TWO CATEGORIES, THE GENOTYPE APPROACH AND THE PHENOTYPE APPROACH. WHEN APPLIED TO OBESITY PREVENTION AND MANAGEMENT, EACH OMICS TYPE COULD POTENTIALLY HELP TO DETECT SPECIFIC BIOMARKERS IN PEOPLE WITH RISK PROFILES AND GUIDE HEALTHCARE PROFESSIONALS AND DECISION MAKERS IN DEVELOPING INDIVIDUALIZED TREATMENT PLANS ACCORDING TO THE NEEDS OF THE INDIVIDUAL BEFORE THE ONSET OF OBESITY. CONCLUSION: INTEGRATING MULTI-OMICS APPROACHES WILL ENABLE A PARADIGM SHIFT FROM THE ONE SIZE FITS ALL APPROACH TOWARDS PRECISION OBESITY MANAGEMENT, I.E. (1) PRECISION PREVENTION OF THE ONSET OF OBESITY, (2) PRECISION MEDICINE AND TAILORED TREATMENT OF OBESITY, AND (3) PRECISION RISK REDUCTION AND PREVENTION OF SECONDARY DISEASES RELATED TO OBESITY. 2023 8 103 40 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 9 6169 28 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING. 2018 10 2881 25 FUTURE PERSPECTIVES OF PERSONALIZED WEIGHT LOSS INTERVENTIONS BASED ON NUTRIGENETIC, EPIGENETIC, AND METAGENOMIC DATA. AS OBESITY HAS BECOME A MAJOR GLOBAL PUBLIC HEALTH CHALLENGE, A LARGE NUMBER OF STUDIES HAVE ANALYZED DIFFERENT STRATEGIES AIMED AT INDUCING A NEGATIVE ENERGY BALANCE AND, CONSEQUENTLY, BODY WEIGHT LOSS. HOWEVER, MOST EXISTING WEIGHT LOSS PROGRAMS ARE GENERALLY UNSUCCESSFUL, SO SEVERAL INTERVENTIONS HAVE BEEN CARRIED OUT TO IDENTIFY PHYSIOLOGIC AND BEHAVIORAL FACTORS CONCERNING THIS VARIABILITY IN ORDER TO IMPLEMENT MORE PERSONALIZED TREATMENT. NOWADAYS, AN INDIVIDUALIZED APPROACH IS BEING PROPOSED THROUGH SO-CALLED PERSONALIZED NUTRITION, WHEREBY NOT ONLY THE PHENOTYPE BUT ALSO THE GENOTYPE IS USED FOR CUSTOMIZED NUTRITION TREATMENT. REGARDING BODY WEIGHT REGULATION, APPROXIMATELY 70 POLYMORPHISMS HAVE BEEN IDENTIFIED IN OR NEAR GENES RELATED TO ENERGY EXPENDITURE, APPETITE, ADIPOGENESIS, INSULIN RESISTANCE, AND LIPID METABOLISM. ALTHOUGH PERSONALIZED NUTRITION REFERS MAINLY TO GENETIC MAKEUP, RECENT ADVANCES IN THE INVESTIGATION OF THE EPIGENOME AND THE MICROBIOME OPEN THE DOOR TO IMPLEMENT MORE PERSONALIZED RECOMMENDATIONS FOR BODY WEIGHT MANAGEMENT. IN THIS CONTEXT, RECENT STUDIES HAVE DEMONSTRATED THE EXISTENCE OF SEVERAL EPIGENETIC MARKERS THAT MAY MODIFY GENE EXPRESSION AND COULD BE INVOLVED IN THE OUTCOME OF WEIGHT LOSS INTERVENTIONS. MOREOVER, DIFFERENT STUDIES HAVE SHOWN THAT DIETARY INTERVENTIONS COULD AFFECT THE COMPOSITION OF GUT MICROBIOTA AND HAVE AN IMPACT ON BODY WEIGHT. THE INTEGRATION OF NUTRIGENETIC, EPIGENETIC, AND METAGENOMIC DATA MAY LEAD TO THE DESIGN OF MORE PERSONALIZED DIETARY TREATMENTS TO PREVENT CHRONIC DISEASES AND TO OPTIMIZE THE INDIVIDUAL'S RESPONSE TO DIETARY INTERVENTIONS. 2015 11 3773 25 INTERACTION OF CERVICAL MICROBIOME WITH EPIGENOME OF EPITHELIAL CELLS: SIGNIFICANCE OF INFLAMMATION TO PRIMARY HEALTHCARE. ONE PILLAR OF THE PREDICTIVE, PREVENTIVE, AND PERSONALIZED MEDICINE FRAMEWORK STRATEGIES IS THE FEMALE HEALTH. THE EVALUATION OF WOMEN'S LIFESTYLE AND DIETARY HABITS IN CONTEXT WITH GENETIC AND MODIFIABLE RISK FACTORS MAY REFLECT THE PREVENTION OF CERVICAL CANCER BEFORE THE OCCURRENCE OF CLINICAL SYMPTOMS AND PREDICTION OF CERVICAL LESION BEHAVIOR. THE MAIN AIM OF THIS REVIEW IS TO ANALYZE PUBLICATIONS IN THE FIELD OF PRECISION MEDICINE THAT ALLOW THE USE OF RESEARCH KNOWLEDGE OF CERVICAL MICROBIOME, EPIGENETIC MODIFICATIONS, AND INFLAMMATION IN POTENTIAL APPLICATION IN CLINICAL PRACTICE. PERSONALIZED APPROACH IN EVALUATING PATIENT'S RISK OF FUTURE DEVELOPMENT OF CERVICAL ABNORMALITY SHOULD CONSIDER THE BIOMARKERS OF THE LOCAL MICROENVIRONMENT CHARACTERIZED BY THE MICROBIAL COMPOSITION, EPIGENETIC PATTERN OF CERVICAL EPITHELIUM, AND PRESENCE OF CHRONIC INFLAMMATION. NOVEL SEQUENCING TECHNIQUES ENABLE A MORE DETAILED CHARACTERIZATION OF ACTUAL STATE IN CERVICAL EPITHELIUM. BETTER UNDERSTANDING OF ALL CHANGES IN MULTIOMICS LEVEL ENABLES A BETTER ASSESSMENT OF DISEASE PROGNOSIS AND SELECTS THE ELIGIBLE TARGETED THERAPY IN PERSONALIZED MEDICINE. RESTORING OF HEALTHY VAGINAL MICROFLORA AND REVERSING THE OUTBREAK OF CERVICAL ABNORMALITY CAN BE ALSO ACHIEVED BY DIETARY HABITS AS WELL AS UPTAKE OF PREBIOTICS, PROBIOTICS, SYNBIOTICS, MICROBIAL TRANSPLANTATION, AND OTHERS. 2022 12 30 36 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 13 734 37 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 14 4663 36 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 15 1066 32 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 16 1253 24 CURRENT PROBLEMS AND FUTURE DIRECTIONS OF TRANSFUSION-INDUCED ALLOIMMUNIZATION: SUMMARY OF AN NHLBI WORKING GROUP. IN APRIL 2010, A WORKING GROUP SPONSORED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WAS ASSEMBLED TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE OUR UNDERSTANDING OF ALLOIMMUNIZATION CAUSED BY THE TRANSFUSION OF ALLOGENEIC BLOOD COMPONENTS AND TO EVALUATE POTENTIAL APPROACHES TO BOTH REDUCE ITS OCCURRENCE AND MANAGE ITS EFFECTS. SIGNIFICANT SEQUELAE OF ALLOIMMUNIZATION WERE DISCUSSED AND IDENTIFIED, INCLUDING DIFFICULTIES IN MAINTAINING CHRONIC TRANSFUSION OF RED BLOOD CELLS AND PLATELETS, HEMOLYTIC DISEASE OF THE NEWBORN, NEONATAL ALLOIMMUNE THROMBOCYTOPENIA, AND REJECTION OF TRANSPLANTED CELLS AND TISSUES. THE DISCUSSIONS RESULTED IN A CONSENSUS THAT IDENTIFIED KEY AREAS OF FUTURE RESEARCH AND DEVELOPMENTAL AREAS, INCLUDING GENETIC AND EPIGENETIC RECIPIENT FACTORS THAT REGULATE ALLOIMMUNIZATION, BIOCHEMICAL SPECIFICS OF TRANSFUSED PRODUCTS THAT AFFECT ALLOIMMUNIZATION, AND NOVEL TECHNOLOGIES FOR HIGH-THROUGHPUT GENOTYPING TO FACILITATE EXTENSIVE AND EFFICIENT ANTIGEN MATCHING BETWEEN DONOR AND RECIPIENT. ADDITIONAL AREAS OF IMPORTANCE INCLUDED ANALYSIS OF UNAPPRECIATED MEDICAL SEQUELAE OF ALLOIMMUNIZATION, SUCH AS CELLULAR IMMUNITY AND ITS EFFECT UPON TRANSPLANT AND AUTOIMMUNITY. IN ADDITION, SUPPORT FOR RESEARCH INFRASTRUCTURE WAS DISCUSSED, WITH AN EMPHASIS ON ENCOURAGING COLLABORATION AND SYNERGY OF ANIMAL MODELS BIOLOGY AND HUMAN CLINICAL RESEARCH. FINALLY, TRAINING FUTURE INVESTIGATORS WAS IDENTIFIED AS AN AREA OF IMPORTANCE. IN AGGREGATE, THIS COMMUNICATION PROVIDES A SYNOPSIS OF THE OPINIONS OF THE WORKING GROUP ON THE ABOVE ISSUES AND PRESENTS BOTH A LIST OF SUGGESTED PRIORITIES AND THE RATIONALE FOR THE TOPICS OF FOCUS. THE AREAS OF RESEARCH IDENTIFIED IN THIS REPORT REPRESENT POTENTIAL FERTILE GROUND FOR THE MEDICAL ADVANCEMENT OF PREVENTING AND MANAGING ALLOIMMUNIZATION IN ITS DIFFERENT FORMS AND MITIGATING THE CLINICAL PROBLEMS IT PRESENTS TO MULTIPLE PATIENT POPULATIONS. 2011 17 4803 22 OBESITY AND MALE INFERTILITY. THE WORLDWIDE PREVALENCE OF OBESITY IS INCREASING AMONG BOTH SEXES, WITH ASSOCIATED IMPACTS ON CHRONIC HEALTH AND MEDICAL COMORBIDITIES. SIMILARLY, THE EFFECTS OF OBESITY ON REPRODUCTIVE HEALTH ARE INCREASINGLY BEING RECOGNIZED. ADIPOSITY IS ASSOCIATED WITH REDUCED FERTILITY IN MEN, WITH A COMPLEX AND MULTIFACTORIAL ETIOLOGY. THE REPORTED EFFECTS OF OBESITY ON SEMEN PARAMETERS AND IMPAIRED FERTILITY ARE CONTRASTING, WITH SOME STUDIES SHOWING A CLEAR REDUCTION IN REPRODUCTIVE OUTCOMES ASSOCIATED WITH INCREASED BODY MASS INDEX, WHILE OTHERS DO NOT SHOW SUCH IMPACTS. THESE CONTROVERSIES MAY BE DUE TO THE COMPLEX PATHOPHYSIOLOGY AND INTERPLAY BETWEEN GONADOTROPINS AND END ORGANS, AS WELL AS GENETIC AND EPIGENETIC CHANGES AND OXIDATIVE STRESS ON MALE FERTILITY AND FUNCTION. THESE DIFFERENT ASPECTS HAVE LED TO HETEROGENEOUS PARTICIPANTS IN STUDIES AND VARYING IMPLICATIONS FOR ASSISTED REPRODUCTIVE OUTCOMES AS WELL AS OFFSPRING HEALTH. TREATMENT MODALITIES TO MANAGE OBESITY INCLUDE LIFESTYLE, MEDICAL, AND SURGICAL OPTIONS, WITH EMERGING AND EFFECTIVE MEDICAL TREATMENTS SHOWING PROMISE IN REPRODUCTIVE OUTCOMES. 2023 18 3934 36 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 19 6891 27 [SIGNAL RECEPTORS OF CONGENITAL IMMUNITY: A NEW MOLECULAR TARGET FOR DIAGNOSTICS AND TREATMENT OF INFLAMMATORY DISEASES]. THE DISCOVERY OF SIGNAL RECEPTORS OF CONGENITAL IMMUNITY (SIGNAL PRR) NOT ONLY PROVIDED A NOVEL VIEW OF BASIC ASPECTS OF PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BUT ALSO CREATED A BASIS FOR THE DEVELOPMENT OF ADDITIONAL DIAGNOSTIC CRITERIA FOR THESE PATHOLOGIES AND NEW PHARMACEUTICALS FOR THEIR TREATMENT. REDUCED EXPRESSION AND FUNCTION OF PRR DUE TO MUTATIONS/POLYMORPHISMS OR EPIGENETIC DISTURBANCES OF REGULATION CAN BE REGARDED AS IMMUNODEFICIENT CONDITIONS MANIFEST AS SEVERE INFECTIOUS INFLAMMATORY DISEASES. IN CONTRAST, EXCESSIVE EXPRESSION AND ACTIVATION OF PRR AS A RULE LEADS TO CHRONIC AUTOINFLAMMATORY, AUTOIMMUNE, AND ATOPIC DISEASES INVOLVING ADAPTIVE IMMUNITY AND AGGRESSION AGAINST OWN TISSUES AND CELLS. ASSESSMENT OF CERTAIN MUTATIONS IN PRR GENES, THEIR EXPRESSION AND ACTIVATION PROVIDES A POWERFUL TOOL FOR IN-DEPTH DIAGNOSTICS OF INFLAMMATORY DISEASES. SIMULTANEOUSLY, NEW LINES OF IMMUNOSTIMULATING AND ANTI-INFLAMMATORY THERAPY ARE DEVELOPED BASED ON THE KNOWLEDGE OF MOLECULAR PHYSIOLOGY OF PRR WITH THE USE OF SYNTHETIC AGONISTS AND ANTAGONISTS OF SIGNAL PRR. 2011 20 2900 30 GENDER BIAS IN THERAPEUTIC EFFORT: FROM RESEARCH TO HEALTH CARE. THERE ARE RELEVANT DIMENSIONS FROM A GENDER PERSPECTIVE RELATED TO THERAPEUTIC EFFORT. TO ILLUSTRATE AND DISCUSS POSSIBLE GENDER BIAS RELATED TO MEDICINES, THROUGH THE CONSUMPTION ANALYSIS IN WOMEN, THE PRESCRIPTION OF BIOLOGICAL DRUGS ACCORDING TO SEX, THE POTENTIAL GENDER INEQUALITY IN ADVERSE DRUG REACTIONS, AND RESEARCH WITH CLINICAL TRIALS, AS WELL AS THE DECISIONS OF INTERNATIONAL INSTITUTIONS IN THE MARKETING OF MEDICINAL PRODUCTS. THERE IS GREATER TENDENCY TO PRESCRIBE PAIN RELIEVERS, REGARDLESS OF PAIN, AND DRUGS FOR LOW INTENSITY DEPRESSIVE SYMPTOMS IN WOMEN THAN IN MEN. THE OPPOSITE OCCURS IN THE PRESCRIPTION OF STATINS AND ADEQUATE DOSES, AND WITH THE GREATER PROBABILITY OF PRESCRIBING ANTI-TUMOR NECROSIS FACTOR IN MEN THAN IN WOMEN WITH ANKYLOSING SPONDYLITIS, DESPITE A SIMILAR DISEASE BURDEN. ADVERSE DRUG REACTIONS ARE OBSERVED MORE FREQUENTLY IN WOMEN THAN IN MEN, WHERE DETERMINANTS SUCH AS BODY WEIGHT ARE HAVING LITTLE INFLUENCE ON THE DOSAGE. IT IS CURRENTLY SCARCELY CONSIDERED IN THE PRESCRIPTION THAT WOMEN HAVE DIFFERENCES IN THE ACTIVITY OF CYTOCHROME CYPP450 ENZYMES, WHICH CAN AFFECT THE LIVER'S METABOLISM RATE. THERE ARE EVEN IMMUNOLOGICAL, GENETIC AND EPIGENETIC EFFECTS (DUE TO HEREDITY AND UNEVEN GENE DOSING LOCATED IN THE X AND Y CHROMOSOMES) THAT CAN INFLUENCE THESE DIFFERENCES BY SEX. FINALLY, THROUGH CASES OF HORMONAL THERAPY CLINICAL TRIALS, A DRUG FOR WOMEN'S INHIBITED SEXUAL DESIRE AND A CONTRACEPTIVE FOR MEN, GENDER BIAS AND STEREOTYPES ARE SHOWN TO INFLUENCE A POTENTIAL GENERATION OF INEQUALITIES, ESPECIALLY IN ADVERSE DRUG REACTIONS TO THE DETRIMENT OF WOMEN. IN CONCLUSION, HEALTH PROFESSIONALS FREQUENTLY ATTRIBUTE PHYSICAL SYMPTOMS TO WOMEN'S EMOTIONALITY, INFLUENCING THEIR GREATER PRESCRIPTION OF SYMPTOMATIC DRUGS. WHETHER THE SAME REASON INFLUENCES THE LOWER PRESCRIPTION OF THERAPEUTIC DRUGS IN WOMEN THAN IN MEN SHOULD BE ANALYZED. THERE ARE BIOLOGICAL DETERMINANTS TO CONSIDER DUE TO THEIR INFLUENCE ON A GREATER PHARMACOLOGICAL TOXICITY IN WOMEN. CLINICAL TRIALS SHOULD IMPROVE ACCORDING TO THE GENDER RECOMMENDATIONS BY THE FOOD AND DRUGS ADMINISTRATION. 2020