1  5260 157 PROGRESSIVE OSSEOUS HETEROPLASIA, AS AN ISOLATED ENTITY OR OVERLAPPING WITH ALBRIGHT HEREDITARY OSTEODYSTROPHY. INTRODUCTION: PROGRESSIVE OSSEOUS HETEROPLASIA (POH) IS A CONDITION OF INVASIVE HETEROTOPIC OSSIFICATION. REPORTS OF PATIENTS WITH MILD POH WITH ALBRIGHT HEREDITARY OSTEODYSTROPHY (AHO), SPECIFICALLY PSEUDOHYPOPARATHYROIDISM TYPE IA (PHP IA) WITH HORMONAL RESISTANCE, SUGGEST THE POSSIBILITY OF A COMMON MOLECULAR BASIS. GNAS HAS BEEN IMPLICATED TO ACCOUNT FOR OVERLAPPING FEATURES OF POH AND PHP IA. CASE 1: A 4-YEAR-OLD BOY WITH OBESITY, SPEECH DELAY, AND EXPANDING SUBCUTANEOUS MASSES ON BUTTOCK/FOREARM. PHYSICAL EXAM REVEALED ROUND FACIES AND BRACHYDACTYLY. BLOOD TESTS SHOWED NORMAL CA, P, MG, 25-OH VITAMIN D LEVELS BUT ELEVATED PARATHYROID HORMONE (PTH) AND THYROID-STIMULATING HORMONE (TSH). ABDOMINAL COMPUTED TOMOGRAPHY (CT) SHOWED AREAS WITH CALCIFICATIONS IN THE SUBCUTANEOUS TISSUE, FAT, AND MUSCLE. PATHOLOGY OF EXCISED TISSUE REVEALED OSSIFICATIONS. GENOMIC STUDY REVEALED NO GNAS MUTATION. HE HAD POH AND PHP IA. CASE 2: A 3-YEAR-OLD BOY WITH PAINFUL OSSIFICATIONS IN THE LEFT LOWER EXTREMITY. LAB TESTS WERE NOTABLE FOR ELEVATED PTH AND HIGH-NORMAL TSH. THE CT-SCAN SHOWED SUBCUTANEOUS/INTRAMUSCULAR CALCIFICATIONS. GENETIC TESTING SHOWED GNAS MUTATION IN EXON 12 [C.1024C>T (R342X)]. PATIENT HAD POH AND PHP IA. CASE 3: A 9-YEAR-OLD BOY WITH KNEE PAIN AND SUBCUTANEOUS OSSIFICATIONS IN BACK AND UPPER/LOWER EXTREMITY, CAUSING SIGNIFICANTLY LIMITED JOINT MOBILITY. LAB TESTS WERE NORMAL. THE CT-SCAN SHOWED AREAS CORRESPONDING TO SUBCUTANEOUS/INTRAMUSCULAR OSSIFICATIONS THROUGHOUT TORSO AND EXTREMITIES, CONSISTENT WITH POH. THERE WAS NO GNAS MUTATION. CONCLUSIONS: PATIENTS WITH HETEROTOPIC OSSIFICATIONS PRESENT WITH A WIDE SPECTRUM OF DISEASE. ALTHOUGH GNAS-BASED MUTATIONS HAVE BEEN POSTULATED TO ACCOUNT FOR OVERLAPPING FEATURES OF AHO AND POH, NORMAL DNA STUDIES IN CERTAIN PATIENTS WITH POH/AHO SUGGEST THAT THERE MAY EXIST OTHER MOLECULAR/EPIGENETIC MECHANISMS EXPLAINING THEIR OVERLAPPING FEATURES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2  4331  19 MICRORNAS: EMERGING BIOMARKERS AND THERAPEUTIC TARGETS OF BONE FRAGILITY IN CHRONIC KIDNEY DISEASE. BONE FRAGILITY IS HIGHLY PREVALENT, YET UNDERDIAGNOSED IN PATIENTS WITH CHRONIC KIDNEY DISEASE. INCOMPLETE UNDERSTANDING OF THE PATHOPHYSIOLOGY AND LIMITATIONS OF CURRENT DIAGNOSTICS CONTRIBUTE TO THERAPEUTIC HESITATION, IF NOT NIHILISM. THIS NARRATIVE REVIEW ADDRESSES THE QUESTION OF WHETHER MICRORNAS (MIRNAS) MAY IMPROVE THERAPEUTIC DECISION MAKING IN OSTEOPOROSIS AND RENAL OSTEODYSTROPHY. MIRNAS ARE KEY EPIGENETIC REGULATORS OF BONE HOMEOSTASIS AND SHOW PROMISE AS BOTH THERAPEUTIC TARGETS AND AS BIOMARKERS, PRIMARILY OF BONE TURNOVER. EXPERIMENTAL STUDIES SHOW THAT MIRNAS ARE INVOLVED IN SEVERAL OSTEOGENIC PATHWAYS. CLINICAL STUDIES EXPLORING THE USEFULNESS OF CIRCULATING MIRNAS FOR FRACTURE RISK STRATIFICATION AND FOR GUIDING AND MONITORING THERAPY ARE FEW AND, SO FAR, PROVIDE INCONCLUSIVE RESULTS. LIKELY, (PRE)ANALYTICAL HETEROGENEITY CONTRIBUTES TO THESE EQUIVOCAL RESULTS. IN CONCLUSION, MIRNAS ARE PROMISING IN METABOLIC BONE DISEASE, BOTH AS A DIAGNOSTIC TOOL AND AS THERAPEUTIC TARGETS, BUT NOT YET READY FOR CLINICAL PRIME TIME.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  4706  25 NMP4/CIZ CLOSES THE PARATHYROID HORMONE ANABOLIC WINDOW. CHRONIC DEGENERATIVE DISEASES ARE INCREASING WITH THE AGING U.S. POPULATION. ONE CONSEQUENCE OF THIS PHENOMENON IS THE NEED FOR LONG-TERM OSTEOPOROSIS THERAPIES. PARATHYROID HORMONE (PTH), THE ONLY FDA-APPROVED TREATMENT THAT ADDS BONE TO THE AGED SKELETON, LOSES ITS POTENCY WITHIN TWO YEARS OF INITIAL TREATMENT BUT THE MECHANISM REGULATING ITS LIMITED "ANABOLIC WINDOW" IS UNKNOWN. WE HAVE DISCOVERED THAT DISABLING THE NUCLEOCYTOPLASMIC SHUTTLING TRANSCRIPTION FACTOR NUCLEAR MATRIX PROTEIN 4/CAS INTERACTING ZINC FINGER PROTEIN (NMP4/CIZ) IN MICE EXTENDS THE PTH BONE-FORMING CAPACITY. NMP4 WAS DISCOVERED DURING OUR SEARCH FOR NUCLEAR MATRIX TRANSCRIPTION FACTORS THAT COUPLE THIS HORMONE'S IMPACT ON OSTEOBLAST CYTOSKELETAL AND NUCLEAR ORGANIZATION WITH ITS ANABOLIC CAPACITY. CIZ WAS INDEPENDENTLY DISCOVERED AS A PROTEIN THAT ASSOCIATES WITH THE FOCAL ADHESION-ASSOCIATED MECHANOSENSOR P130CAS. THE NMP4/CIZ-KNOCKOUT (KO) SKELETAL PHENOTYPE EXHIBITS A MODESTLY ENHANCED BONE MINERAL DENSITY BUT MANIFESTS AN EXAGGERATED RESPONSE TO BOTH PTH AND TO BMP2 AND IS RESISTANT TO DISUSE-INDUCED BONE LOSS. THE CELLULAR BASIS OF THE GLOBAL NMP4/CIZ-KO SKELETAL PHENOTYPE REMAINS TO BE ELUCIDATED BUT MAY INVOLVE AN EXPANSION OF THE BONE MARROW OSTEOPROGENITOR POPULATION ALONG WITH MODESTLY ENHANCED OSTEOBLAST AND OSTEOCLAST ACTIVITIES SUPPORTING ANABOLIC BONE TURNOVER. AS A SHUTTLING CYS(2)HIS(2) ZINC FINGER PROTEIN, NMP4/CIZ ACTS AS A REPRESSIVE TRANSCRIPTION FACTOR PERHAPS ASSOCIATED WITH EPIGENETIC REMODELING COMPLEXES, BUT THE FUNCTIONAL SIGNIFICANCE OF ITS INTERACTION WITH P130CAS IS NOT KNOWN. DESPITE NUMEROUS REMAINING QUESTIONS, NMP4/CIZ PROVIDES INSIGHTS INTO HOW THE ANABOLIC WINDOW IS REGULATED, AND ITSELF MAY PROVIDE AN ADJUVANT THERAPY TARGET FOR THE TREATMENT OF OSTEOPOROSIS BY EXTENDING PTH ANABOLIC EFFICACY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  3850  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  2960  21 GENETIC AND EPIGENETIC MARKERS IN THE EVALUATION OF PANCREATIC MASSES. BACKGROUND: METHYLATION MARKERS HAVE SHOWN PROMISE IN THE EARLY DIAGNOSIS OF PANCREATIC CARCINOMA. THE AIM OF THIS STUDY WAS TO ASSESS THE DIAGNOSTIC UTILITY OF HYPERMETHYLATION STATUS OF CANDIDATE GENES IN COMBINATION WITH KRAS MUTATION DETECTION IN THE EVALUATION OF PANCREATIC MASSES. EXPERIMENTAL DESIGN: SIXTY-ONE FINE NEEDLE ASPIRATES OF PANCREATIC MASSES (43 PANCREATIC ADENOCARCINOMAS AND 18 CHRONIC PANCREATITIS) WERE STUDIED. METHYLATION STATUS OF HRH2, EN1, SPARC, CDH13 AND APC WERE ANALYSED USING MELTING CURVE ANALYSIS AFTER DNA BISULFITE TREATMENT. KRAS MUTATIONS WERE ALSO ANALYSED. RESULTS: THE METHYLATION PANEL HAD A SENSITIVITY OF 73% (27 OF 37, CI 95% 56 TO 86%) AND A SPECIFICITY OF 100% WHENEVER TWO OR MORE PROMOTERS WERE FOUND HYPERMETHYLATED. KRAS MUTATIONS SHOWED A SENSITIVITY OF 77% (33 OF 43, CI 95% 62 TO 88%) AND A SPECIFICITY OF 100%. BOTH MOLECULAR ANALYSES ADDED USEFUL INFORMATION TO CYTOLOGY BY INCREASING THE NUMBER OF INFORMATIVE CASES. WHEN GENETIC AND EPIGENETIC ANALYSES WERE COMBINED SENSITIVITY WAS 84% (36 OF 43 CI 95% 69 TO 93%) MAINTAINING A 100% SPECIFICITY. CONCLUSIONS: ANALYSIS OF HYPERMETHYLATION STATUS OF A PANEL OF GENES AND KRAS MUTATION DETECTION OFFER A SIMILAR DIAGNOSTIC YIELD IN THE EVALUATION OF PANCREATIC MASSES. THE COMBINED MOLECULAR ANALYSIS INCREASES THE NUMBER OF INFORMATIVE CASES WITHOUT DIMINISHING SPECIFICITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  4522  27 MULTIDIMENSIONAL EVALUATION OF THE PAIN PROFILE AS PROGNOSTIC FACTOR IN INDIVIDUALS WITH HIP OR KNEE OSTEOARTHRITIS RECEIVING TOTAL JOINT REPLACEMENT: PROTOCOL OF A 2-YEAR LONGITUDINAL PROGNOSTIC COHORT STUDY. INTRODUCTION: KNEE AND HIP OSTEOARTHRITIS ARE TWO HIGHLY PREVALENT MUSCULOSKELETAL PAIN CONDITIONS. UNSUCCESSFUL RATES AFTER HIP/KNEE REPLACEMENT RANGE FROM 10% TO 20%. SUBJECTS WITH SENSITISATION MANIFESTATIONS ARE VULNERABLE TO WORSE CLINICAL OUTCOMES. MOST STUDIES HAVE ANALYSED OUTCOMES UP TO 1 YEAR AFTER SURGERY. THE AIM OF THIS 2-YEAR LONGITUDINAL STUDY WILL BE TO EVALUATE SENSORY-RELATED, PSYCHOLOGICAL AND PSYCHOPHYSICAL PAIN SENSITISATION MANIFESTATIONS AND A POTENTIAL EPIGENETIC BIOMARKER AS PROGNOSTIC CLINICAL OUTCOMES FOR THE DEVELOPMENT OF CHRONIC POSTOPERATIVE PAIN AFTER KNEE OR HIP REPLACEMENT. METHODS AND ANALYSIS: A PROSPECTIVE LONGITUDINAL STUDY WITH A 2-YEAR FOLLOW-UP PERIOD WILL BE CONDUCTED. THE PROGNOSTIC VARIABLES WILL INCLUDE PAIN, FUNCTION, RELATED-DISABILITY, ANXIETY, DEPRESSION, QUALITY OF LIFE, SENSITISATION-ASSOCIATED SYMPTOMS, KINESIOPHOBIA, NEUROPATHIC PAIN AND CATASTROPHISING, AND EXPECTATIVE OF THE INTERVENTION WILL BE ASSESSED BEFORE SURGERY. WE WILL ALSO EVALUATE THE PRESENCE OF THE VAL158MET POLYMORPHISM AS A POSSIBLE EPIGENETIC MARKER. CLINICAL OUTCOMES INCLUDING PAIN, RELATED-DISABILITY AND SELF-PERCEIVED SATISFACTION, SENSITISATION-ASSOCIATED SYMPTOMS AND NEUROPATHIC PAIN WILL BE ASSESSED 3, 6, 12, 18 AND 24 MONTHS AFTER SURGERY. THESE VARIABLES WILL BE USED TO CONSTRUCT THREE PREDICTION MODELS: (1) PAIN AND FUNCTION, (2) SENSITISATION-ASSOCIATED SYMPTOMATOLOGY AND (3) NEUROPATHIC PAIN FEATURES CLASSIFYING THOSE PATIENTS IN RESPONDERS AND NON-RESPONDERS. DATA FROM KNEE OR HIP OSTEOARTHRITIS WILL BE ANALYSED SEPARATELY. STATISTICAL ANALYSES WILL BE CONDUCTED WITH LOGISTIC REGRESSIONS. ETHICS AND DISSEMINATION: THE STUDY HAS BEEN APPROVED BY THE ETHICS COMMITTEE OF BOTH INSTITUTIONS INVOLVED (HOSPITAL UNIVERSITARIO FUNDACION ALCORCON (HUFA) 19-141 AND UNIVERSIDAD REY JUAN CARLOS (URJC) 0312201917319). PARTICIPANTS WILL SIGN THE WRITTEN INFORMED CONSENT BEFORE THEIR INCLUSION. STUDY RESULTS WILL BE DISSEMINATED THROUGH PEER-REVIEWED PUBLICATIONS AND PRESENTATIONS AT SCIENTIFIC MEETINGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  1343  28 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  5005  25 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  4612  21 NEONATAL PAIN AND COMT VAL158MET GENOTYPE IN RELATION TO SEROTONIN TRANSPORTER (SLC6A4) PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT SCHOOL AGE. CHILDREN BORN VERY PRETERM ARE EXPOSED TO REPEATED NEONATAL PROCEDURES THAT INDUCE PAIN AND STRESS DURING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU). THE COMT VAL158MET GENOTYPE IS INVOLVED WITH PAIN SENSITIVITY, AND EARLY LIFE STRESS IS IMPLICATED IN ALTERED EXPRESSION OF METHYLATION OF THE SEROTONIN TRANSPORTER. WE EXAMINED: (1) WHETHER METHYLATION OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) PROMOTER DIFFERS BETWEEN VERY PRETERM CHILDREN AND FULL-TERM CONTROLS AT SCHOOL AGE, (2) RELATIONSHIPS WITH CHILD BEHAVIOR PROBLEMS, AND (3) WHETHER THE EXTENT OF NEONATAL PAIN EXPOSURE INTERACTS WITH THE COMT VAL158MET GENOTYPE TO PREDICT SLC6A4 METHYLATION AT 7 YEARS IN THE VERY PRETERM CHILDREN. WE EXAMINED THE ASSOCIATIONS BETWEEN THE COMT GENOTYPES, NEONATAL PAIN EXPOSURE (ADJUSTED FOR NEONATAL CLINICAL CONFOUNDERS), SLC6A4 METHYLATION AND BEHAVIOR PROBLEMS. VERY PRETERM CHILDREN HAD SIGNIFICANTLY HIGHER METHYLATION AT 7/10 CPG SITES IN THE SLC6A4 PROMOTER COMPARED TO FULL-TERM CONTROLS AT 7 YEARS. NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) WAS SIGNIFICANTLY ASSOCIATED WITH TOTAL CHILD BEHAVIOR PROBLEMS ON THE CHILD BEHAVIOR CHECKLIST (CBCL) QUESTIONNAIRE (ADJUSTED FOR CONCURRENT STRESSORS AND 5HTTLPR GENOTYPE) (P = 0.035). CBCL TOTAL PROBLEMS WAS SIGNIFICANTLY ASSOCIATED WITH GREATER SLC6A4 METHYLATION IN VERY PRETERM CHILDREN (P = 0.01). NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) AND COMT MET/MET GENOTYPE WERE ASSOCIATED WITH SLC6A4 PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT 7 YEARS (P = 0.001). THESE FINDINGS PROVIDE EVIDENCE THAT BOTH GENETIC PREDISPOSITION AND EARLY ENVIRONMENT NEED TO BE CONSIDERED IN UNDERSTANDING SUSCEPTIBILITY FOR DEVELOPING BEHAVIORAL PROBLEMS IN THIS VULNERABLE POPULATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  5652  25 SEX DIMORPHIC CHANGES IN TRH GENE METHYLATION AND THYROID-AXIS RESPONSE TO ENERGY DEMANDS IN MATERNALLY SEPARATED RATS. THE HYPOTHALAMUS-PITUITARY-THYROID (HPT) AXIS REGULATES ENERGY BALANCE THROUGH THE PLEIOTROPIC ACTION OF THYROID HORMONES. HPT BASAL ACTIVITY AND STIMULATION BY COLD OR VOLUNTARY EXERCISE ARE REPRESSED BY PREVIOUS CHRONIC STRESS IN ADULTS. MATERNAL SEPARATION (MS) MODIFIES HPT BASAL ACTIVITY; WE THUS STUDIED THE RESPONSE OF THE AXIS TO ENERGY DEMANDS AND ANALYZED POSSIBLE EPIGENETIC CHANGES ON TRH PROMOTER. NONHANDLED (NH) OR MS MALE WISTAR RATS WERE COLD EXPOSED 1 H AT ADULTHOOD; TRH EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN) AND SERUM THYROTROPIN (TSH) CONCENTRATION WERE INCREASED ONLY IN NH RATS. TWO WEEKS OF VOLUNTARY EXERCISE DECREASED FAT MASS AND INCREASED TRH EXPRESSION, AND THYROID HORMONES CONCENTRATION CHANGED PROPORTIONALLY TO RUNNING DISTANCE IN NH MALE RATS AND MS MALE RATS. ALTHOUGH NH FEMALES RAN MORE THAN MS AND MUCH MORE THAN MALES, EXERCISE DECREASED BODY WEIGHT AND FAT MASS ONLY IN NH RATS WITH NO CHANGE ON ANY PARAMETER OF THE HPT AXIS BUT INCREASED POMC EXPRESSION IN ARCUATE-NUCLEUS OF NH AND NPY IN MS FEMALES. OVERALL, THE METHYLATION PATTERN OF PVN TRH GENE PROMOTER WAS SIMILAR IN NH MALES AND FEMALES; MS MODIFIED METHYLATION OF SPECIFIC CPG SITES, A THYROID HORMONE RECEPTOR (THR)-BINDING SITE PRESENT AFTER THE INITIATION SITE WAS HYPOMETHYLATED IN MS MALES; IN MS FEMALES, THE THR BINDING SITE OF THE PROXIMAL PROMOTER (SITE 4) AND 2 SITES IN THE FIRST INTRON WERE HYPERMETHYLATED. OUR STUDIES SHOWED THAT, IN A SEX-DIMORPHIC MANNER, MS BLUNTED THE RESPONSES OF HPT AXIS TO ENERGY DEMANDS IN ADULT ANIMALS AND CAUSED METHYLATION CHANGES ON TRH PROMOTER THAT COULD ALTER T3 FEEDBACK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  1663  28 DOWNREGULATION OF DNA METHYLTRANSFERASE-3A AMELIORATES THE OSTEOGENIC DIFFERENTIATION ABILITY OF ADIPOSE-DERIVED STEM CELLS IN DIABETIC OSTEOPOROSIS VIA WNT/BETA-CATENIN SIGNALING PATHWAY. BACKGROUND: DIABETES-RELATED OSTEOPOROSIS (DOP) IS A CHRONIC DISEASE CAUSED BY THE HIGH GLUCOSE ENVIRONMENT THAT INDUCES A METABOLIC DISORDER OF OSTEOCYTES AND OSTEOBLAST-ASSOCIATED MESENCHYMAL STEM CELLS. THE PROCESSES OF BONE DEFECT REPAIR AND REGENERATION BECOME EXTREMELY DIFFICULT WITH DOP. ADIPOSE-DERIVED STEM CELLS (ASCS), AS SEED CELLS IN BONE TISSUE ENGINEERING TECHNOLOGY, PROVIDE A PROMISING THERAPEUTIC APPROACH FOR BONE REGENERATION IN DOP PATIENTS. THE OSTEOGENIC ABILITY OF ASCS IS LOWER IN A DOP MODEL THAN THAT OF CONTROL ASCS. DNA METHYLATION, AS A MECHANISM OF EPIGENETIC REGULATION, MAY BE INVOLVED IN DNA METHYLATION OF VARIOUS GENES, THEREBY PARTICIPATING IN BIOLOGICAL BEHAVIORS OF VARIOUS CELLS. EMERGING EVIDENCE SUGGESTS THAT INCREASED DNA METHYLATION LEVELS ARE ASSOCIATED WITH ACTIVATION OF WNT/BETA-CATENIN SIGNALING PATHWAY. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INFLUENCE OF THE DIABETIC ENVIRONMENT ON THE OSTEOGENIC POTENTIAL OF ASCS, TO EXPLORE THE ROLE OF DNA METHYLATION ON OSTEOGENIC DIFFERENTIATION OF DOP-ASCS VIA WNT/BETA-CATENIN SIGNALING PATHWAY, AND TO IMPROVE THE OSTEOGENIC DIFFERENTIATION ABILITY OF ASCS WITH DOP. METHODS: DOP-ASCS AND CONTROL ASCS WERE ISOLATED FROM DOP C57BL/6 AND CONTROL MICE, RESPECTIVELY. THE MULTIPOTENCY OF DOP-ASCS WAS CONFIRMED BY ALIZARIN RED-S, OIL RED-O, AND ALCIAN BLUE STAINING. REAL-TIME POLYMERASE CHAIN REACTION (RT-PCR), IMMUNOFLUORESCENCE, AND WESTERN BLOTTING WERE USED TO ANALYZE CHANGES IN MARKERS OF OSTEOGENIC DIFFERENTIATION, DNA METHYLATION, AND WNT/BETA-CATENIN SIGNALING. ALIZARIN RED-S STAINING WAS ALSO USED TO CONFIRM CHANGES IN THE OSTEOGENIC ABILITY. DNMT SMALL INTERFERING RNA (SIRNA), SHRNA-DNMT3A, AND LVRNA-DNMT3A WERE USED TO ASSESS THE ROLE OF DNMT3A IN OSTEOGENIC DIFFERENTIATION OF CONTROL ASCS AND DOP-ASCS. MICRO-COMPUTED TOMOGRAPHY, HEMATOXYLIN AND EOSIN STAINING, AND MASSON STAINING WERE USED TO ANALYZE CHANGES IN THE OSTEOGENIC CAPABILITY WHILE DOWNREGULATING DNMT3A WITH LENTIVIRUS IN DOP MICE IN VIVO. RESULTS: THE PROLIFERATIVE ABILITY OF DOP-ASCS WAS LOWER THAN THAT OF CONTROL ASCS. DOP-ASCS SHOWED A DECREASE IN OSTEOGENIC DIFFERENTIATION CAPACITY, LOWER WNT/BETA-CATENIN SIGNALING PATHWAY ACTIVITY, AND A HIGHER LEVEL OF DNMT3A THAN CONTROL ASCS. WHEN DNMT3A WAS DOWNREGULATED BY SIRNA AND SHRNA, OSTEOGENIC-RELATED FACTORS RUNT-RELATED TRANSCRIPTION FACTOR 2 AND OSTEOPONTIN, AND ACTIVITY OF WNT/BETA-CATENIN SIGNALING PATHWAY WERE INCREASED, WHICH RESCUED THE POOR OSTEOGENIC POTENTIAL OF DOP-ASCS. WHEN DNMT3A WAS UPREGULATED BY LVRNA-DNMT3A, THE OSTEOGENIC ABILITY WAS INHIBITED. THE SAME RESULTS WERE OBTAINED IN VIVO. CONCLUSIONS: DNMT3A SILENCING RESCUES THE NEGATIVE EFFECTS OF DOP ON ASCS AND PROVIDES A POSSIBLE APPROACH FOR BONE TISSUE REGENERATION IN PATIENTS WITH DIABETIC OSTEOPOROSIS.	2022	

12    93  29 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  4913  29 PAIN MODULATION IN WAG/RIJ EPILEPTIC RATS (A GENETIC MODEL OF ABSENCE EPILEPSY): EFFECTS OF BIOLOGICAL AND PHARMACOLOGICAL HISTONE DEACETYLASE INHIBITORS. EPIGENETIC MECHANISMS ARE INVOLVED IN EPILEPSY AND CHRONIC PAIN DEVELOPMENT. ABOUT THAT, WE STUDIED THE EFFECTS OF THE NATURAL HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE (BUT) IN COMPARISON WITH VALPROIC ACID (VPA) IN A VALIDATED GENETIC MODEL OF GENERALIZED ABSENCE EPILEPSY AND EPILEPTOGENESIS. WAG/RIJ RATS WERE TREATED WITH BUT (30 MG/KG), VPA (300 MG/KG), AND THEIR COMBINATION (BUT + VPA) DAILY PER OS FOR 6 MONTHS. RATS WERE SUBJECTED AT RANDALL-SELITTO, VON FREY, HOT PLATE, AND TAIL FLICK TESTS AFTER 1, 3, AND 6 MONTHS OF TREATMENT TO EVALUATE HYPERSENSITIVITY TO NOXIOUS AND NON-NOXIUOUS STIMULI. MOREOVER, PPAR-GAMMA (G3335 1 MG/KG), GABA-B (CGP35348 80 MG/KG), AND OPIOID (NALOXONE 1 MG/KG) RECEPTOR ANTAGONISTS WERE ADMINISTRATED TO INVESTIGATE THE POSSIBLE MECHANISMS INVOLVED IN ANALGESIC ACTIVITY. THE EXPRESSION OF NFKB, GLUTATHIONE REDUCTASE, AND PROTEIN OXIDATION (CARBONYLATION) WAS ALSO EVALUATED BY WESTERN BLOT ANALYSIS. WAG/RIJ RATS SHOWED AN ALTERED PAIN THRESHOLD THROUGHOUT THE STUDY (P < 0.001). BUT AND BUT + VPA TREATMENT REDUCED HYPERSENSITIVITY (P < 0.01). VPA WAS SIGNIFICANTLY EFFECTIVE ONLY AFTER 1 MONTH (P < 0.01). ALL THE THREE RECEPTORS ARE INVOLVED IN BUT + VPA EFFECTS (P < 0.001). BUT AND BUT + VPA DECREASED THE EXPRESSION OF NFKB AND ENHANCED GLUTATHIONE REDUCTASE (P < 0.01); PROTEIN OXIDATION (CARBONYLATION) WAS REDUCED (P < 0.01). NO EFFECT WAS REPORTED WITH VPA. IN CONCLUSION BUT, ALONE OR IN COADMINISTRATION WITH VPA, IS A VALUABLE CANDIDATE FOR MANAGING THE EPILEPSY-RELATED PERSISTENT PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  1964  25 EPIGENETIC AGING, KNEE PAIN AND PHYSICAL PERFORMANCE IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. KNEE PAIN IS A LEADING CAUSE OF DISABILITY IN THE AGING POPULATION AND MAY INDIRECTLY ACCELERATE BIOLOGICAL AGING PROCESSES. CHRONOLOGICAL AGING INCREASES THE RISK OF DEVELOPING OF KNEE PAIN AND KNEE PAIN REDUCES PHYSICAL FUNCTION; HOWEVER, LIMITED DATA EXIST ON HOW EPIGENETIC AGING, A KNOWN HALLMARK OF BIOLOGICAL AGING SHOWN TO PREDICT HEALTH SPAN AND MORTALITY, MAY INFLUENCE THIS RELATIONSHIP. THE PURPOSE OF THIS STUDY WAS TO EXAMINE WHETHER DECREASED PHYSICAL PERFORMANCE ASSOCIATED WITH KNEE PAIN IS MEDIATED BY MARKERS OF EPIGENETIC AGING. PARTICIPANTS (57.91 +/- 8.04 YEARS) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53) AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW AND A SHORT PHYSICAL PERFORMANCE BATTERY (SPPB) THAT INCLUDED BALANCE, WALKING, AND SIT TO STAND TASKS. WE EMPLOYED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN AND SHOWN TO PREDICT OVERALL MORTALITY RISK (DNAMGRIMAGE). BOOTSTRAPPED-MEDIATION ANALYSES WERE USED TO DETERMINE ASSOCIATIONS OF DNAMGRIMAGE AND SPPB BETWEEN PAIN GROUPS. THOSE WITH HIGH IMPACT AND LOW IMPACT PAIN HAD A BIOLOGICALLY OLDER EPIGENETIC AGE (5.14Y +/- 5.66 AND 1.32Y +/- 5.41, RESPECTIVELY). HOWEVER, WHILE THERE WERE DIRECT EFFECTS OF PAIN ON OVERALL PHYSICAL PERFORMANCE, THESE WERE NOT EXPLAINED BY EPIGENETIC AGING. EPIGENETIC AGING ONLY MEDIATED THE EFFECT OF PAIN ON BALANCE PERFORMANCE. FUTURE WORK IS NEEDED TO EXAMINE PAIN'S IMPACT ON BIOLOGICAL AGING PROCESSES INCLUDING EPIGENETIC AGING AND ITS ULTIMATE EFFECT ON PHYSICAL FUNCTION MEASURES KNOWN TO PREDICT HEALTH SPAN AND MORTALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  3258  24 HEPATITIS C AND INTERFERON INDUCED THYROIDITIS. AUTOIMMUNE THYROID DISEASES (AITDS) ARE COMPLEX DISEASES THAT DEVELOP AS A RESULT OF INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. SIGNIFICANT PROGRESS HAS BEEN MADE IN OUR UNDERSTANDING OF THE GENETIC AND ENVIRONMENTAL TRIGGERS CONTRIBUTING TO AITD. THE MAJOR ENVIRONMENTAL TRIGGERS OF AITD INCLUDE IODINE, SMOKING, MEDICATIONS, PREGNANCY, AND POSSIBLY STRESS. IN THIS REVIEW WE WILL FOCUS ON TWO WELL-DOCUMENTED ENVIRONMENTAL TRIGGERS OF AITD, HEPATITIS C VIRUS (HCV) INFECTION AND INTERFERON ALPHA (IFNA) THERAPY. CHRONIC HCV INFECTION HAS BEEN SHOWN TO BE ASSOCIATED WITH INCREASED INCIDENCE OF CLINICAL AND SUBCLINICAL AUTOIMMUNE THYROIDITIS (I.E. THE PRESENCE OF THYROID ANTIBODIES IN EUTHYROID SUBJECTS). MOREOVER, IFNA THERAPY OF CHRONIC HCV INFECTION IS ASSOCIATED WITH SUBCLINICAL OR CLINICAL THYROIDITIS IN UP TO 40% OF CASES WHICH CAN BE AUTOIMMUNE, OR NON-AUTOIMMUNE THYROIDITIS. IN SOME CASES INTERFERON INDUCED THYROIDITIS (IIT) IN CHRONIC HCV PATIENTS MAY RESULT IN SEVERE SYMPTOMATOLOGY NECESSITATING DISCONTINUATION OF THERAPY. WHILE THE EPIDEMIOLOGY AND CLINICAL PRESENTATION OF HCV AND INTERFERON INDUCED THYROIDITIS HAVE BEEN WELL CHARACTERIZED, THE MECHANISMS CAUSING THESE CONDITIONS ARE STILL POORLY UNDERSTOOD.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16    33  26 A CASE STUDY OF CHIROPRACTIC MANAGEMENT OF PREGNANCY-RELATED HEARTBURN WITH POSTULATED FETAL EPIGENOME IMPLICATIONS. OBJECTIVE: THIS CASE STUDY REPORTS ON CHIROPRACTIC CARE FOR PREGNANCY-RELATED HEARTBURN. THE PURPOSE OF THIS ARTICLE IS TO RELATE THE BENEFIT OF CHIROPRACTIC TREATMENT FOR ONE INDIVIDUAL, TO CONTRAST CHIROPRACTIC MANAGEMENT WITH THE BIOMEDICAL STANDARD OF CARE FOR PREGNANCY-RELATED HEARTBURN, AND TO POINT TO POTENTIAL EPIGENETIC IMPLICATIONS OF THE STANDARD OF CARE. CLINICAL FEATURES: A 32-YEAR-OLD WOMAN WHO WAS 24 WEEKS PREGNANT PRESENTED WITH PERSISTENT HEARTBURN THAT SHE WAS TREATING WITH RANITIDINE (ZANTAC(R)) AND CALCIUM CARBONATE (TUMS(R)) DAILY AT THE INITIATION OF CHIROPRACTIC CARE. INTERVENTION AND OUTCOME: FINDINGS OF THE INITIAL EXAMINATION WERE THORACIC INTERSEGMENTAL DYSFUNCTION AND PAIN UPON PALPATION OF THE DIAPHRAGM, WITH HYPERTONICITY NOTED. THERAPY LOCALIZATION WAS POSITIVE FOR REFLEXES ASSOCIATED WITH THE ESOPHAGUS AND LOWER ESOPHAGEAL SPHINCTER, SUGGESTING SPASMS. EMOTIONAL COMPONENTS ALSO WERE IDENTIFIED IN ASSOCIATION WITH THE SYMPTOMS BY THE USE OF A MIND-BODY THERAPY CALLED NEUROEMOTIONAL TECHNIQUE. THE PATIENT WAS TREATED BY ADJUSTING THE THORACIC SPINE, MANUALLY RELEASING THE DIAPHRAGM SPASMS, AND RELEASING THE ESOPHAGEAL SPASM WITH AN ACTIVATOR (A SMALL HAND-HELD INSTRUMENT THAT CREATES A PERCUSSIVE FORCE). THE PATIENT WAS SYMPTOM-FREE AND DID NOT USE MEDICATION AFTER THE FIFTH TREATMENT. SHE WAS FOLLOWED THROUGHOUT THE REMAINDER OF HER PREGNANCY AND WAS ASYMPTOMATIC AND REQUIRED NO FURTHER TREATMENT. CONCLUSIONS: A LARGER STUDY SHOULD INVESTIGATE THE EFFECTIVENESS OF CHIROPRACTIC CARE FOR THE TREATMENT OF PREGNANCY-RELATED HEARTBURN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   517  23 ASSOCIATION STUDY OF FOXO3A SINGLE-NUCLEOTIDE POLYMORPHISM AND BRONCHIAL ASTHMA IN EGYPTIAN CHILDREN. ASTHMA IS THE MOST COMMON CHRONIC ILLNESS IN CHILDREN AND IS A LEADING CAUSE OF CHILDHOOD HOSPITALIZATION AND SCHOOL ABSENTEEISM. ASTHMA PRESENTS WITH DIFFERENT PHENOTYPES DEPENDING ON AGE, GENDER, GENETIC BACKGROUND, ENVIRONMENTAL EXPOSURES AND EPIGENETIC FACTORS. FORKHEAD BOX O3 (FOXO3) IS A TRANSCRIPTION FACTOR INVOLVED IN THE PATHOGENESIS OF A NUMBER OF INFLAMMATORY AND RESPIRATORY DISEASES. THE STUDY AIMS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SNP RS13217795 IN FOXO3 GENE AND PEDIATRIC ONSET ASTHMA IN THE EGYPTIAN POPULATION. NINETY ASTHMATICS AND 160 HEALTHY CONTROLS WERE SUBJECTED TO GENOTYPING OF FOXO3 SNP (RS13217795) USING THE PCR-RFLP METHOD. THE PROPORTION OF HOMOZYGOUS (CC) AND HETEROZYGOUS (CT) GENOTYPES WAS LOWER IN THE ASTHMATIC GROUP COMPARED TO THE CONTROL GROUP BUT STATISTICALLY INSIGNIFICANT; P > 0.05. ON THE OTHER HAND THE PROPORTION OF THE MUTANT HOMOZYGOUS (TT) GENOTYPE IN ASTHMATIC GROUP WAS HIGHER; 30 (33.3%) THAN THE CONTROL GROUP; 28(17.5%), THE DIFFERENCE WAS SIGNIFICANT IN RECESSIVE MODEL OF DISEASE PENETRANCE WITH ODDS RATIO OR (95% CI) OF 2.4(1 - 5.49) AND P=0.039. THIS ASSOCIATION WAS MORE PRONOUNCED IN MALE GENDER; OR AND 95% CI OF 5.3 (1.4- 19.3) AND P=0.01. IN CONCLUSIONS, EGYPTIAN CHILDREN CARRYING THE MUTANT (TT) GENOTYPE WERE AT HIGHER RISK TO DEVELOP ASTHMA WITH A HIGHER RISK IN MALE GENDER.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  5658  20 SEX-DIMORPHIC PATHWAYS IN THE ASSOCIATIONS BETWEEN MATERNAL TRAIT ANXIETY, INFANT BDNF METHYLATION, AND NEGATIVE EMOTIONALITY. MATERNAL ANTENATAL ANXIETY IS AN EMERGING RISK FACTOR FOR CHILD EMOTIONAL DEVELOPMENT. BOTH SEX AND EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, MAY CONTRIBUTE TO THE EMBEDDING OF MATERNAL DISTRESS INTO EMOTIONAL OUTCOMES. HERE, WE INVESTIGATED SEX-DEPENDENT PATTERNS IN THE ASSOCIATION BETWEEN ANTENATAL MATERNAL TRAIT ANXIETY, METHYLATION OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF DNAM), AND INFANT NEGATIVE EMOTIONALITY (NE). MOTHER-INFANT DYADS (N = 276) WERE RECRUITED AT DELIVERY. MATERNAL TRAIT ANXIETY, AS A MARKER OF ANTENATAL CHRONIC STRESS EXPOSURE, WAS ASSESSED SOON AFTER DELIVERY USING THE STAIT-TRAIT ANXIETY INVENTORY (STAI-Y). INFANTS' BDNF DNAM AT BIRTH WAS ASSESSED IN 11 CPG SITES IN BUCCAL CELLS WHEREAS INFANTS' NE WAS ASSESSED AT 3 (N = 225) AND 6 MONTHS (N = 189) USING THE INFANT BEHAVIOR QUESTIONNAIRE-REVISED (IBQ-R). HIERARCHICAL LINEAR ANALYSES SHOWED THAT HIGHER MATERNAL ANTENATAL ANXIETY WAS ASSOCIATED WITH GREATER 6-MONTH-OLDS' NE. FURTHERMORE, MATERNAL ANTENATAL ANXIETY PREDICTED GREATER INFANTS' BDNF DNAM IN FIVE CPG SITES IN MALES BUT NOT IN FEMALES. HIGHER METHYLATION AT THESE SITES WAS ASSOCIATED WITH GREATER 3-TO-6-MONTH NE INCREASE, INDEPENDENTLY OF INFANTS' SEX. MATERNAL ANTENATAL ANXIETY EMERGED AS A RISK FACTOR FOR INFANT'S NE. BDNF DNAM MIGHT MEDIATE THIS EFFECT IN MALES. THESE RESULTS MAY INFORM THE DEVELOPMENT OF STRATEGIES TO PROMOTE MOTHERS AND INFANTS' EMOTIONAL WELL-BEING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19    67  29 A LONGITUDINAL STUDY OF THE ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION WITH POSTSTROKE ANXIETY. BACKGROUND: ALTHOUGH THE PRECISE ETIOLOGY OF POSTSTROKE ANXIETY (PSA) HAS YET TO BE FULLY ELUCIDATED, IT IS KNOWN THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS IMPORTANT FOR NEURAL PLASTICITY AND LONG-TERM POTENTIATION, ASSOCIATED WITH THE PATHOPHYSIOLOGY OF ANXIETY. THE EXPRESSION OF BDNF IS REGULATED BY EPIGENETIC AND GENETIC PROFILES. THUS, WE INVESTIGATED THE ASSOCIATION BETWEEN BDNF METHYLATION STATUS AND PSA AT 2 WEEKS AND 1 YEAR AFTER STROKE WHILE ACCOUNTING FOR INTERACTIONS WITH THE BDNF VAL66MET POLYMORPHISM. METHODS: THE BASELINE SAMPLE COMPRISED 286 PATIENTS WHO WERE ASSESSED AT 2 WEEKS AFTER STROKE; OF THESE PATIENTS, 222 (78%) WERE FOLLOWED UP WITH AT 1 YEAR AFTER STROKE. THE PRESENCE OF PSA WAS DETERMINED USING THE ANXIETY SUBSCALE OF THE HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS), AND THE EFFECTS OF BDNF METHYLATION STATUS AND POLYMORPHISMS ON PSA STATUS WERE ASSESSED WITH MULTIVARIATE LOGISTIC REGRESSION MODELS. RESULTS: THE PREVALENCE OF PSA WAS SLIGHTLY LOWER (27 [9.4%]) AT BASELINE, AND 35 (15.8%) PATIENTS WERE IDENTIFIED AS HAVING PSA AT THE 1-YEAR FOLLOW-UP. STROKE PATIENTS WITH A HIGHER AVERAGE METHYLATION STATUS WERE MORE LIKELY TO HAVE PSA AT 1 YEAR. THE BDNF VAL66MET POLYMORPHISM WAS NOT INDEPENDENTLY ASSOCIATED WITH PSA DURING EITHER THE ACUTE OR CHRONIC PHASE AFTER STROKE, BUT THERE WAS A SIGNIFICANT INTERACTIVE EFFECT BETWEEN BDNF METHYLATION AND GENOTYPE ON PSA AT 2 WEEKS. CONCLUSIONS: IN THIS STUDY, BDNF METHYLATION IN COMBINATION WITH THE MET/MET BDNF POLYMORPHISM (VAL66MET POLYMORPHISM) WAS ASSOCIATED WITH PSA. THESE FINDINGS MAY HELP IDENTIFY PATIENTS AT HIGHER RISK FOR PSA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20   404  33 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS.	2020