1 3884 456 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 2 4269 47 MICROBIAL DYSBIOSIS AND LACK OF SCFA PRODUCTION IN A SPANISH COHORT OF PATIENTS WITH MULTIPLE SCLEROSIS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, DEMYELINATING, AND IMMUNE-MEDIATED DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE INCIDENCE OF MS HAS INCREASED IN THE PAST SEVERAL DECADES, SUGGESTING CHANGES IN THE ENVIRONMENTAL RISK FACTORS. MUCH EFFORT HAS BEEN MADE IN THE DESCRIPTION OF THE GUT MICROBIOTA IN MS; HOWEVER, LITTLE IS KNOWN ABOUT THE DYSBIOSIS ON ITS FUNCTION. THE MICROBIOTA PRODUCES THOUSANDS OF BIOLOGICALLY ACTIVE SUBSTANCES AMONG WHICH ARE NOTABLE THE SHORT-CHAIN FATTY ACID (SCFA) EXCRETION. OBJECTIVES: ANALYZE THE INTERACTION BETWEEN MICROBIOTA, SCFAS, DIET, AND MS. METHODS: 16S, NUTRITIONAL QUESTIONNAIRES, AND SCFAS QUANTIFICATION HAVE BEEN RECOVERED FROM MS PATIENTS AND CONTROLS. RESULTS: OUR RESULTS REVEALED AN INCREMENT IN THE PHYLUM PROTEOBACTERIA, ESPECIALLY THE FAMILY ENTEROBACTERIACEAE, A LACK IN TOTAL SCFA EXCRETION, AND AN ALTERED PROFILE OF SCFAS IN A SPANISH COHORT OF MS PATIENTS. THESE ALTERATIONS ARE MORE EVIDENT IN PATIENTS WITH HIGHER DISABILITY. CONCLUSIONS: THE ABUNDANCE OF PROTEOBACTERIA AND ACETATE AND THE LOW EXCRETION OF TOTAL SCFAS, ESPECIALLY BUTYRATE, ARE COMMON CHARACTERISTICS OF MS PATIENTS, AND BESIDES, BOTH ARE ASSOCIATED WITH A WORSE PROGNOSIS OF THE DISEASE. 2022 3 1140 34 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT. 2020 4 518 55 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS. 2013 5 4066 48 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING. 2017 6 5385 59 REDOX BALANCE SIGNALLING IN OCCUPATIONAL STRESS: MODIFICATION BY NUTRACEUTICAL INTERVENTION. THERE IS INCREASING EVIDENCE THAT PSYCHOSOCIAL STRESS CAN BE VIEWED AS A SYSTEM-WIDE DERANGEMENT OF CELLULAR HOMEOSTASIS, WITH HEIGHTENED OXIDATIVE STRESS AND TRIGGERED PROINFLAMMATORY MECHANISMS. THE AIM OF THIS STUDY IS TWOFOLD: A) TO REPLICATE FINDINGS THAT PSYCHOLOGICAL STRESS INCREASES OXIDATIVE DAMAGE AND B) TO DETERMINE WHETHER A FERMENTED PAPAYA PREPARATION KNOWN TO EXERT SIGNIFICANT PROTECTIVE ANTIOXIDANT PROPERTIES COULD BUFFER SUCH INCREASES IN NUCLEAR DNA DAMAGE WHILE ALSO INDUCING EPIGENETIC PROTECTIVE MECHANISMS. TWENTY-EIGHT SEDENTARY MEN AND WOMEN (AGE RANGE: 28-52), WHO REPORTED LIVING A STRESSFUL LIFESTYLE BUT WITH AN OVERALL POSITIVE ATTITUDE, WERE RECRUITED FOR THIS STUDY. CHRONIC DISEASES AS WELL AS SEVERE BURNOUT AND USE OF DRUGS FOR ANXIETY CONSTITUTED EXCLUSION CRITERIA. SUBJECTS WERE SUPPLEMENTED FOR 1 MONTH WITH 9 G/DAY (4.5 G TWICE A DAY) OF A CERTIFIED FERMENTED PAPAYA PREPARATION. ALL SUBJECTS WERE GIVEN A STRESS AND SLEEP QUALITY QUESTIONNAIRE TOGETHER WITH A DIET AND LIFE STYLE ASSESSMENT. BLOOD WAS COLLECTED AT 2 AND 4 WEEK, ERYTHROCYTE AND LEUKOCYTE WERE SEPARATED TO ASSESS REDOX BALANCE AND HEME OXYGENASE-1 (HO-1) GENE EXPRESSION WHILE BILIRUBIN OXIDIZED METABOLITES (BOMS) WERE TESTED IN THE URINE. STRESSED INDIVIDUALS SHOWED A SIGNIFICANT ABNORMALITY OF REDOX STATUS WITH INCREASED MDA OF ERYTHROCYTE AND INCREASED LEVEL OF 8-0HDG IN LEUKOCYTE AND BOMS EXCRETION (P<0.05). NUTRACEUTICAL SUPPLEMENTATION BROUGHT ABOUT A NORMALIZATION OF SUCH VALUES ALREADY AT THE 2 WEEK OBSERVATION (P<0.05) TOGETHER WITH A SIGNIFICANT UPREGULATION OF HO-1 (P<0.01). TAKEN TOGETHER, THE RESULTS OF THIS STUDY CONFIRM THAT STRESSFUL OCCUPATIONAL LIFE PER SE, WITHOUT ANY OVERT PSYCHIATRIC ILLNESS, MAY BE ASSOCIATED TO INCREASED OXIDATIVE STRESS. SUPPLEMENTATION WITH FUNCTIONAL FOOD AFFECTING REDOX REGULATION MAY BE PART OF THE THERAPEUTIC ARMAMENTARIUM TO BE CONSIDERED IN THIS CLINICAL SETTING. 2011 7 933 97 CHRONIC KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD) HAVE EVOLVED OVER TIME, BUT CURRENT INTERNATIONAL GUIDELINES DEFINE THIS CONDITION AS DECREASED KIDNEY FUNCTION SHOWN BY GLOMERULAR FILTRATION RATE (GFR) OF LESS THAN 60 ML/MIN PER 1.73 M(2), OR MARKERS OF KIDNEY DAMAGE, OR BOTH, OF AT LEAST 3 MONTHS DURATION, REGARDLESS OF THE UNDERLYING CAUSE. DIABETES AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ALL HIGH-INCOME AND MIDDLE-INCOME COUNTRIES, AND ALSO IN MANY LOW-INCOME COUNTRIES. INCIDENCE, PREVALENCE, AND PROGRESSION OF CKD ALSO VARY WITHIN COUNTRIES BY ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH, POSSIBLY THROUGH EPIGENETIC INFLUENCE. MANY PEOPLE ARE ASYMPTOMATIC OR HAVE NON-SPECIFIC SYMPTOMS SUCH AS LETHARGY, ITCH, OR LOSS OF APPETITE. DIAGNOSIS IS COMMONLY MADE AFTER CHANCE FINDINGS FROM SCREENING TESTS (URINARY DIPSTICK OR BLOOD TESTS), OR WHEN SYMPTOMS BECOME SEVERE. THE BEST AVAILABLE INDICATOR OF OVERALL KIDNEY FUNCTION IS GFR, WHICH IS MEASURED EITHER VIA EXOGENOUS MARKERS (EG, DTPA, IOHEXOL), OR ESTIMATED USING EQUATIONS. PRESENCE OF PROTEINURIA IS ASSOCIATED WITH INCREASED RISK OF PROGRESSION OF CKD AND DEATH. KIDNEY BIOPSY SAMPLES CAN SHOW DEFINITIVE EVIDENCE OF CKD, THROUGH COMMON CHANGES SUCH AS GLOMERULAR SCLEROSIS, TUBULAR ATROPHY, AND INTERSTITIAL FIBROSIS. COMPLICATIONS INCLUDE ANAEMIA DUE TO REDUCED PRODUCTION OF ERYTHROPOIETIN BY THE KIDNEY; REDUCED RED BLOOD CELL SURVIVAL AND IRON DEFICIENCY; AND MINERAL BONE DISEASE CAUSED BY DISTURBED VITAMIN D, CALCIUM, AND PHOSPHATE METABOLISM. PEOPLE WITH CKD ARE FIVE TO TEN TIMES MORE LIKELY TO DIE PREMATURELY THAN THEY ARE TO PROGRESS TO END STAGE KIDNEY DISEASE. THIS INCREASED RISK OF DEATH RISES EXPONENTIALLY AS KIDNEY FUNCTION WORSENS AND IS LARGELY ATTRIBUTABLE TO DEATH FROM CARDIOVASCULAR DISEASE, ALTHOUGH CANCER INCIDENCE AND MORTALITY ARE ALSO INCREASED. HEALTH-RELATED QUALITY OF LIFE IS SUBSTANTIALLY LOWER FOR PEOPLE WITH CKD THAN FOR THE GENERAL POPULATION, AND FALLS AS GFR DECLINES. INTERVENTIONS TARGETING SPECIFIC SYMPTOMS, OR AIMED AT SUPPORTING EDUCATIONAL OR LIFESTYLE CONSIDERATIONS, MAKE A POSITIVE DIFFERENCE TO PEOPLE LIVING WITH CKD. INEQUITY IN ACCESS TO SERVICES FOR THIS DISEASE DISPROPORTIONALLY AFFECTS DISADVANTAGED POPULATIONS, AND HEALTH SERVICE PROVISION TO INCENTIVISE EARLY INTERVENTION OVER PROVISION OF CARE ONLY FOR ADVANCED CKD IS STILL EVOLVING IN MANY COUNTRIES. 2017 8 5221 46 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS. 2020 9 4752 53 NOVEL ROLE OF GESTATIONAL HYDRALAZINE IN LIMITING MATERNAL AND DIETARY OBESITY-RELATED CHRONIC KIDNEY DISEASE. BACKGROUND: MATERNAL OBESITY IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD) IN OFFSPRING, UNDERPINNING THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PROGRAMMING OF ADULT CHRONIC DISEASE BY MATERNAL OBESITY, THEREFORE, DNA DEMETHYLATING AGENTS MAY MITIGATE OFFSPRING RISK OF DISEASE. IN RODENT MODELS, LOW-DOSE HYDRALAZINE HAS PREVIOUSLY BEEN SHOWN TO REDUCE RENAL FIBROSIS VIA DNA DEMETHYLATION. WE USED MOUSE MODELS OF MATERNAL OBESITY AND OFFSPRING OBESITY TO DETERMINE WHETHER ADMINISTRATION OF LOW-DOSE HYDRALAZINE DURING GESTATION CAN PREVENT FETAL PROGRAMMING OF CKD IN OFFSPRING. METHODS: FEMALE C57BL/6 MICE RECEIVED HIGH FAT DIET (HFD) OR CHOW PRIOR TO MATING, DURING GESTATION AND LACTATION. DURING GESTATION, DAMS RECEIVED SUBCUTANEOUS HYDRALAZINE (5 MG/KG) OR SALINE THRICE-WEEKLY. MALE OFFSPRING WEANED TO HFD OR CHOW, WHICH CONTINUED UNTIL ENDPOINT AT 32 WEEKS. BIOMETRIC AND METABOLIC PARAMETERS, RENAL GLOBAL DNA METHYLATION, RENAL FUNCTIONAL AND STRUCTURAL CHANGES, AND RENAL MARKERS OF FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED AT ENDPOINT. RESULTS: OFFSPRING EXPOSED TO MATERNAL OBESITY OR DIET-INDUCED OBESITY HAD SIGNIFICANTLY INCREASED RENAL GLOBAL DNA METHYLATION, TOGETHER WITH OTHER ADVERSE RENAL EFFECTS INCLUDING ALBUMINURIA, GLOMERULOSCLEROSIS, RENAL FIBROSIS, AND OXIDATIVE STRESS. OFFSPRING EXPOSED TO GESTATIONAL HYDRALAZINE HAD SIGNIFICANTLY REDUCED RENAL GLOBAL DNA METHYLATION. IN OBESE OFFSPRING OF OBESE MOTHERS, GESTATIONAL HYDRALAZINE SIGNIFICANTLY DECREASED ALBUMINURIA, GLOMERULOSCLEROSIS, AND SERUM CREATININE. OBESE OFFSPRING OF HYDRALAZINE-TREATED LEAN MOTHERS DISPLAYED REDUCED MARKERS OF RENAL FIBROSIS AND OXIDATIVE STRESS. CONCLUSION: GESTATIONAL HYDRALAZINE DECREASED RENAL GLOBAL DNA METHYLATION AND EXERTED RENOPROTECTIVE EFFECTS IN OFFSPRING. THIS SUPPORTS A POTENTIAL THERAPEUTIC EFFECT OF HYDRALAZINE IN PREVENTING MATERNAL OBESITY OR DIETARY OBESITY-RELATED CKD, THROUGH AN EPIGENETIC MECHANISM. 2021 10 4069 43 MATERNAL CHRONIC FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET THROUGH METHYLATION ALTERATION OF BDNF AND GRIN2B IN OFFSPRING HIPPOCAMPUS. SCOPE: MATERNAL CONSUMPTION OF A HIGH-FAT DIET (HFD) DURING PREGNANCY INCREASES THE RISK OF BEHAVIORAL PROBLEMS. FOLATE PLAYS AN IMPORTANT ROLE IN NEUROPLASTICITY AND THE PRESERVATION OF NEURONAL INTEGRITY. THIS STUDY AIMS AT DETERMINING THE INFLUENCE OF DIETS SUPPLEMENTED WITH FOLATE ON OFFSPRING BEHAVIOR, AND THE MECHANISMS INVOLVED. METHODS AND RESULTS: FEMALE MICE WERE FED A CONTROL DIET, AN HFD, CONTROL DIET SUPPLEMENTED WITH FOLATE, OR AN HFD SUPPLEMENTED WITH FOLATE FOR 5 WEEKS BEFORE MATING. OPEN FIELD TASK AND ELEVATED PLUS MAZE ARE USED TO EVALUATE THE OFFSPRING BEHAVIORS. RESULTS SHOWED THAT OFFSPRING COGNITIVE PERFORMANCE AND ANXIETY-RELATED BEHAVIORS, INCLUDING THOSE RELATED TO OPEN FIELD EXPLORATION AND ELEVATED PLUS MAZE, WERE SIGNIFICANTLY IMPROVED WHEN DAMS WERE TREATED WITH FOLATE IN PREGNANCY. MOREOVER, THE MATERNAL FOLATE SUPPLEMENT DECREASED BDNF AND GRIN2B METHYLATION AND UPREGULATED THEIR EXPRESSIONS IN THE BRAIN OF OFFSPRING, WHICH WERE ASSOCIATED WITH DECREASING THE EXPRESSION OF DNA METHYLTRANSFERASES COMPARED WITH THOSE DAMS WERE TREATED ONLY HFD IN PREGNANCY. CONCLUSION: MATERNAL FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET. THE BENEFICIAL EFFECTS WERE ASSOCIATED WITH METHYLATION AND EXPRESSION ALTERATION OF BDNF AND GRIN2B GENES. 2017 11 307 66 ALBUMINURIA DOWNREGULATION OF THE ANTI-AGING FACTOR KLOTHO: THE MISSING LINK POTENTIALLY EXPLAINING THE ASSOCIATION OF PATHOLOGICAL ALBUMINURIA WITH PREMATURE DEATH. TEN PERCENT OF THE ADULT POPULATION HAS CHRONIC KIDNEY DISEASE (CKD), WHICH IS DIAGNOSED WHEN THE GLOMERULAR FILTRATION RATE (GFR) IS BELOW 60 ML/MIN PER 1.73 M(2) OR WHEN ALBUMINURIA IS ABOVE 30 MG/DAY. THE NUMERICAL THRESHOLDS WERE CHOSEN BECAUSE THEY ARE ASSOCIATED WITH AN INCREASED RISK OF CKD PROGRESSION OR PREMATURE DEATH WITHIN A WIDER SCENARIO OF ACCELERATED AGING. INDEED, CKD IS ONE OF THE FASTEST GROWING CAUSES OF DEATH WORLDWIDE. A DECREASED GFR IS ASSOCIATED WITH THE ACCUMULATION OF URAEMIC TOXINS THAT MAY PROMOTE TISSUE AND ORGAN DAMAGE. HOWEVER, CKD MAY BE DIAGNOSED WHEN THE GFR IS COMPLETELY NORMAL, AS LONG AS THERE IS PATHOLOGICAL ALBUMINURIA. A KEY UNANSWERED QUESTION TO STEM THE RISE OF CKD-ASSOCIATED DEATHS IS WHETHER THE ASSOCIATION BETWEEN ISOLATED ALBUMINURIA (WHEN THE GFR IS NORMAL) AND PREMATURE DEATH IS CAUSAL. THE RECENT DEMONSTRATION THAT ALBUMINURIA PER SE DIRECTLY SUPPRESSES THE PRODUCTION OF THE ANTI-AGING FACTOR KLOTHO BY KIDNEY TUBULAR CELLS MAY BE ONE OF THE FIRST STEPS TO ADDRESS THE CAUSALITY OF THE ALBUMINURIA-PREMATURE DEATH-ACCELERATED AGING ASSOCIATION. THIS HYPOTHESIS SHOULD BE TESTED IN INTERVENTIONAL STUDIES THAT SHOULD DRAW FROM TRANSLATIONAL SCIENCE ADVANCES. THUS, THE OBSERVATION THAT ALBUMINURIA DECREASES KLOTHO PRODUCTION THROUGH EPIGENETIC MECHANISMS IMPLIES THAT KLOTHO DOWNREGULATION MAY PERSIST AFTER THE CORRECTION OF ALBUMINURIA, AND INNOVATIVE THERAPEUTIC APPROACHES ARE NEEDED TO RESTORE KLOTHO PRODUCTION. ON THE BASIS OF RECENT LITERATURE, THESE MAY INCLUDE MANIPULATION OF NF-KAPPAB REGULATORS SUCH AS B CELL LYMPHOMA 3 PROTEIN (BCL-3), AND EPIGENETIC REGULATORS SUCH AS HISTONE DEACETYLASES, OR THE REPURPOSING OF DRUGS SUCH AS PENTOXIFYLLINE. 2020 12 4017 62 LOW-DOSE HYDRALAZINE REDUCES ALBUMINURIA AND GLOMERULOSCLEROSIS IN A MOUSE MODEL OF OBESITY-RELATED CHRONIC KIDNEY DISEASE. AIM: TO DETERMINE, USING A MOUSE MODEL OF OBESITY, WHETHER LOW-DOSE HYDRALAZINE PREVENTS OBESITY-RELATED CHRONIC KIDNEY DISEASE (CKD). METHODS: FROM 8 WEEKS OF AGE, MALE C57BL/6 MICE RECEIVED A HIGH-FAT DIET (HFD) OR CHOW, WITH OR WITHOUT LOW-DOSE HYDRALAZINE (25 MG/L) IN DRINKING WATER, FOR 24 WEEKS. BIOMETRIC AND METABOLIC VARIABLES, RENAL FUNCTION AND STRUCTURAL CHANGES, RENAL GLOBAL DNA METHYLATION, DNA METHYLATION PROFILE AND MARKERS OF RENAL FIBROSIS, INJURY, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED. RESULTS: THE HFD-FED MICE DEVELOPED OBESITY, WITH GLUCOSE INTOLERANCE, HYPERINSULINAEMIA AND DYSLIPIDAEMIA. OBESITY INCREASED ALBUMINURIA AND GLOMERULOSCLEROSIS, WHICH WERE SIGNIFICANTLY AMELIORATED BY LOW-DOSE HYDRALAZINE IN THE ABSENCE OF A BLOOD PRESSURE-LOWERING EFFECT. OBESITY INCREASED RENAL GLOBAL DNA METHYLATION AND THIS WAS ATTENUATED BY LOW-DOSE HYDRALAZINE. HFD-INDUCED CHANGES IN METHYLATION OF INDIVIDUAL LOCI WERE ALSO SIGNIFICANTLY REVERSED BY LOW-DOSE HYDRALAZINE. OBESE MICE DEMONSTRATED INCREASED MARKERS OF KIDNEY FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS, BUT THESE MARKERS WERE NOT SIGNIFICANTLY IMPROVED BY HYDRALAZINE. CONCLUSION: LOW-DOSE HYDRALAZINE AMELIORATED HFD-INDUCED ALBUMINURIA AND GLOMERULOSCLEROSIS, INDEPENDENT OF ALTERATIONS IN BIOMETRIC AND METABOLIC VARIABLES OR BLOOD PRESSURE REGULATION. ALTHOUGH THE PRECISE MECHANISM OF RENOPROTECTION IN OBESITY IS UNCLEAR, AN EPIGENETIC BASIS MAY BE IMPLICATED. THESE DATA SUPPORT REPURPOSING HYDRALAZINE AS A NOVEL THERAPY TO PREVENT CKD PROGRESSION IN OBESE PATIENTS. 2022 13 477 42 ARSENIC PROJECTS IN SE ASIA. EARLY LIFE EXPOSURE TO INORGANIC ARSENIC IS ASSOCIATED WITH A WIDE RANGE OF MALIGNANT AND CHRONIC DISEASE OUTCOMES IN HUMANS. PRENATAL ARSENIC EXPOSURE MAY GIVE RISE TO ADVERSE EFFECTS ON CHILD HEALTH AND DEVELOPMENT AS ARSENIC READILY PASSES THROUGH THE PLACENTA IN HUMAN BEINGS. THE IMPACT OF MATERNAL ARSENIC EXPOSURE ON FETAL GENE EXPRESSION WAS CONDUCTED IN PREGNANT WOMEN LIVING IN SOUTHERN THAILAND. ARSENIC EXPOSED NEWBORNS HAD SIGNIFICANTLY HIGHER LEVELS OF ARSENIC IN CORD BLOOD, AND A SET OF GENES ASSOCIATED WITH NUMEROUS BIOLOGICAL PATHWAYS, INCLUDING CELL SIGNALING, APOPTOSIS, INFLAMMATORY AND STRESS RESPONSE. A SLIGHT INCREASE IN PROMOTER METHYLATION OF P53 IN CORD BLOOD LYMPHOCYTES WHICH CORRELATED WITH ARSENIC ACCUMULATION IN NAILS WAS OBSERVED IN THESE EXPOSED NEWBORNS. A FOLLOW-UP STUDY ON THESE EXPOSED CHILDREN SHOWED A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE, MEASURED AS 8-HYDROXYDEOXYGUANOSINE (8-OHDG) IN SALIVA. IN ADDITION, LEVELS OF URINARY 8-OHDG EXCRETION AND SALIVARY HOGG1 EXPRESSION WERE SIGNIFICANTLY DECREASED IN EXPOSED CHILDREN SUGGESTING A DEFECT IN REPAIR OF 8-OHDG IN ARSENIC-EXPOSED CHILDREN. OUR STUDY INDICATES THAT PRENATAL ARSENIC AND CONTINUED EXPOSURE THROUGH EARLY CHILDHOOD CAN TRIGGER VARIOUS GENETIC AND EPIGENETIC ALTERATIONS THAT MAY LEAD TO DISEASE DEVELOPMENT LATER IN LIFE. 2016 14 3850 54 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME. 2022 15 4008 32 LOW DOSE OF URANIUM INDUCES MULTIGENERATIONAL EPIGENETIC EFFECTS IN RAT KIDNEY. PURPOSE: A PROTOCOL OF CHRONIC EXPOSURE TO LOW DOSE OF URANIUM WAS ESTABLISHED IN ORDER TO DISTINGUISH THE SEXUAL DIFFERENCES AND THE DEVELOPMENTAL PROCESS THAT ARE CRITICAL WINDOWS FOR EPIGENETIC EFFECTS OVER GENERATIONS. METHODS: BOTH MALE AND FEMALE RATS WERE CONTAMINATED THROUGH THEIR DRINKING WATER WITH A NON-TOXIC SOLUTION OF URANYL NITRATE FOR 9 MONTHS. THE EXPOSED GENERATION (F0) AND THE FOLLOWING TWO GENERATIONS (F1 AND F2) WERE EXAMINED. CLINICAL MONITORING, GLOBAL DNA METHYLATION PROFILE AND DNA METHYLTRANSFERASES (DNMTS) GENE EXPRESSION WERE ANALYZED IN KIDNEYS. RESULTS: WHILE THE BODY WEIGHT OF F1 MALES INCREASED, A SMALL DECREASE IN KIDNEY AND BODY WEIGHT WAS OBSERVED IN F2 MALES. IN ADDITION, GLOBAL DNA HYPERMETHYLATION PROFILE IN KIDNEY CELLS WAS OBSERVED IN F1 AND F2 MALES. QPCR RESULTS REVEAL A SIGNIFICANT INCREASE OF METHYLTRANSFERASE GENES EXPRESSION (DNMT1 AND DNMT3A) FOR F2 FEMALES. CONCLUSIONS: IN THE FIELD OF PUBLIC HEALTH POLICY AND TO RAISE ATTENTION TO GENERATIONAL EFFECTS FOR THE RISK ASSESSMENT OF THE ENVIRONMENTAL EXPOSURES, LOW DOSES OF URANIUM DO NOT IMPLY CLINICAL EFFECTS ON ADULT EXPOSED RATS. HOWEVER, OUR RESULTS CONFIRM THE IMPORTANCE OF THE DEVELOPMENTAL WINDOWS' SENSITIVITY IN ADDITION TO THE SEXUAL DIMORPHISMS OF THE OFFSPRING. 2018 16 4010 48 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS. 2017 17 2840 45 FRAMEWORK ANALYSIS FOR THE CARCINOGENIC MODE OF ACTION OF NITROBENZENE. NITROBENZENE (CASRN: 98-95-3) HAS BEEN SHOWN TO INDUCE CANCERS IN MANY TISSUES INCLUDING KIDNEY, LIVER, AND THYROID, FOLLOWING CHRONIC INHALATION IN ANIMALS. HOWEVER, WITH A FEW EXCEPTIONS, GENOTOXICITY ASSAYS USING NITROBENZENE HAVE GIVEN NEGATIVE RESULTS. SOME DNA BINDING/ADDUCT STUDIES HAVE BROUGHT FORTH QUESTIONABLE RESULTS AND, CONSIDERING THE AVAILABLE WEIGHT OF EVIDENCE, IT DOES NOT APPEAR THAT NITROBENZENE CAUSES CANCER VIA A GENOTOXIC MODE OF ACTION. NITROBENZENE PRODUCES A NUMBER OF FREE RADICALS DURING ITS REDUCTIVE METABOLISM, IN THE GUT AS WELL AS AT THE CELLULAR LEVEL, AND GENERATES SUPEROXIDE ANION AS A BY-PRODUCT DURING OXIDATIVE MELABOLISM. THE REACTIVE SPECIES GENERATED DURING NITROBENZENE METABOLISM ARE CONSIDERED CANDIDATES FOR CARCINOGENICITY. FURTHERMORE, SEVERAL LINES OF EVIDENCE SUGGEST THAT NITROBENZENE EXERTS ITS CARCINOGENICITY THROUGH A NON-DNA REACTIVE (EPIGENETIC) FASHION, SUCH AS A STRONG TEMPORAL RELATIONSHIP BETWEEN NON-, PRE-, AND NEOPLASTIC LESIONS LEADING TO CARCINOGENESIS. IN THIS REPORT, WE FIRST DESCRIBE THE ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION OF NITROBENZENE FOLLOWED BY A SUMMARY OF THE AVAILABLE GENOTOXICITY STUDIES AND THE ONLY AVAILABLE CANCER BIOASSAY. WE SUBSEQUENTLY REFER TO THE MODE OF ACTION FRAMEWORK OF THE U.S. ENVIRONMENTAL PROTECTION AGENCY'S 2005 GUIDELINES FOR CARCINOGEN RISK ASSESSMENT AS A BASIS FOR PRESENTING POSSIBLE MODES OF ACTION FOR NITROBENZENE-INDUCED CANCERS OF THE LIVER, THYROID, AND KIDNEY, AS SUPPORTED BY THE AVAILABLE EXPERIMENTAL DATA. THE RATIONALE(S) REGARDING HUMAN RELEVANCE OF EACH MODE OF ACTION IS ALSO PRESENTED. FINALLY, WE HYPOTHESIZE THAT THE CARCINOGENIC MODE OF ACTION FOR NITROBENZENE IS MULTIFACTORIAL IN NATURE AND REFLECTIVE OF FREE RADICALS, INFLAMMATION, AND/OR ALTERED METHYLATION. 2007 18 649 57 BIRTHWEIGHT, MATERNAL WEIGHT TRAJECTORIES AND GLOBAL DNA METHYLATION OF LINE-1 REPETITIVE ELEMENTS. LOW BIRTHWEIGHT, PREMATURE BIRTH, INTRAUTERINE GROWTH RETARDATION, AND MATERNAL MALNUTRITION HAVE BEEN RELATED TO AN INCREASED RISK OF CARDIOVASCULAR DISEASE, TYPE 2 DIABETES MELLITUS, OBESITY, AND NEUROPSYCHIATRIC DISORDERS LATER IN LIFE. CONVERSELY, HIGH BIRTHWEIGHT HAS BEEN LINKED TO FUTURE RISK OF CANCER. GLOBAL DNA METHYLATION ESTIMATED BY THE METHYLATION OF REPETITIVE SEQUENCES IN THE GENOME IS AN INDICATOR OF SUSCEPTIBILITY TO CHRONIC DISEASES. WE USED DATA AND BIOSPECIMENS FROM AN EPIGENETIC BIRTH COHORT TO EXPLORE THE ASSOCIATION BETWEEN TRAJECTORIES OF FETAL AND MATERNAL WEIGHT AND LINE-1 METHYLATION IN 319 MOTHER-CHILD DYADS. NEWBORNS WITH LOW OR HIGH BIRTHWEIGHT HAD SIGNIFICANTLY LOWER LINE-1 METHYLATION LEVELS IN THEIR CORD BLOOD COMPARED TO NORMAL WEIGHT INFANTS AFTER ADJUSTING FOR GESTATIONAL AGE, SEX OF THE CHILD, MATERNAL AGE AT DELIVERY, AND MATERNAL SMOKING DURING PREGNANCY (P = 0.007 AND P = 0.036, RESPECTIVELY), BUT THE MAGNITUDE OF THE DIFFERENCE WAS SMALL. INFANTS BORN PREMATURELY ALSO HAD LOWER LINE-1 METHYLATION LEVELS IN CORD BLOOD COMPARED TO TERM INFANTS, AND THIS DIFFERENCE, THOUGH SMALL, WAS STATISTICALLY SIGNIFICANT (P = 0.004). WE DID NOT FIND IMPORTANT ASSOCIATIONS BETWEEN MATERNAL PREPREGNANCY BMI OR GESTATIONAL WEIGHT GAIN AND GLOBAL METHYLATION OF THE CORD BLOOD OR FETAL PLACENTAL TISSUE. IN CONCLUSION, WE FOUND SIGNIFICANT DIFFERENCES IN CORD BLOOD LINE-1 METHYLATION AMONG NEWBORNS WITH LOW AND HIGH BIRTHWEIGHT AS WELL AS AMONG PREMATURELY BORN INFANTS. FUTURE STUDIES MAY ELUCIDATE WHETHER CHROMOSOMAL INSTABILITIES OR OTHER FUNCTIONAL CONSEQUENCES OF THESE CHANGES CONTRIBUTE TO THE INCREASED RISK OF CHRONIC DISEASES AMONG INDIVIDUALS WITH THESE CHARACTERISTICS. 2011 19 73 46 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE. 2014 20 1939 58 EPIDEMIOLOGY AND (PATHO)PHYSIOLOGY OF FOLIC ACID SUPPLEMENT USE IN OBESE WOMEN BEFORE AND DURING PREGNANCY. PRECONCEPTION FOLIC ACID SUPPLEMENT USE IS A WELL-KNOWN METHOD OF PRIMARY PREVENTION OF NEURAL TUBE DEFECTS (NTDS). OBESE WOMEN ARE AT A HIGHER RISK FOR HAVING A CHILD WITH A NTD. AS DIFFERENT INTERNATIONAL RECOMMENDATIONS ON FOLIC ACID SUPPLEMENT USE FOR OBESE WOMEN BEFORE AND DURING PREGNANCY EXIST, THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF EPIDEMIOLOGY OF FOLATE DEFICIENCY IN OBESE (PRE)PREGNANT WOMEN, ELABORATES ON POTENTIAL MECHANISMS UNDERLYING FOLATE DEFICIENCY, AND DISCUSSES CONSIDERATIONS FOR THE USAGE OF HIGHER DOSES OF FOLIC ACID SUPPLEMENTS. WOMEN WITH OBESITY MORE OFTEN SUFFER FROM AN ABSOLUTE FOLATE DEFICIENCY, AS THEY ARE LESS COMPLIANT TO PERICONCEPTIONAL FOLIC ACID SUPPLEMENT USE RECOMMENDATIONS. IN ADDITION, THEIR DIETARY FOLATE INTAKE IS LIMITED DUE TO AN UNBALANCED DIET (RELATIVE MALNUTRITION). THE ASSOCIATION OF OBESITY AND NTDS ALSO SEEMS TO BE INDEPENDENT OF FOLATE INTAKE, WITH STUDIES SUGGESTING AN INCREASED NEED OF FOLATE (RELATIVE DEFICIENCY) DUE TO DERANGEMENTS INVOLVED IN OTHER PATHWAYS. THE RELATIVE FOLATE DEFICIENCY, AS A RESULT OF AN INCREASED METABOLIC NEED FOR FOLATE IN OBESE WOMEN, CAN BE DUE TO: (1) LOW-GRADE CHRONIC INFLAMMATION (2) INSULIN RESISTANCE, (3) INOSITOL, AND (4) DYSBIOTIC GUT MICROBIOME, WHICH PLAYS A ROLE IN FOLATE PRODUCTION AND UPTAKE. IN ALL THESE PATHWAYS, THE FOLATE-DEPENDENT ONE-CARBON METABOLISM IS INVOLVED. IN CONCLUSION, SCIENTIFIC EVIDENCE OF THE INVOLVEMENT OF SEVERAL FOLATE-RELATED PATHWAYS IMPLIES TO INCREASE THE RECOMMENDED FOLIC ACID SUPPLEMENTATION IN OBESE WOMEN. HOWEVER, THE PHYSIOLOGICAL UPTAKE OF SYNTHETIC FOLIC ACID IS LIMITED AND SIDE-EFFECTS OF UNMETABOLIZED FOLIC ACID IN MOTHERS AND OFFSPRING, IN PARTICULAR VARIATIONS IN EPIGENETIC (RE)PROGRAMMING WITH LONG-TERM HEALTH EFFECTS, CANNOT BE EXCLUDED. THEREFORE, WE EMPHASIZE ON THE URGENT NEED FOR FURTHER RESEARCH AND PRECONCEPTION PERSONALIZED COUNSELING ON FOLATE STATUS, LIFESTYLE, AND MEDICAL CONDITIONS. 2021