1 4645 113 NEUROPATHIC PAIN: FROM MECHANISMS TO TREATMENT. NEUROPATHIC PAIN CAUSED BY A LESION OR DISEASE OF THE SOMATOSENSORY NERVOUS SYSTEM IS A COMMON CHRONIC PAIN CONDITION WITH MAJOR IMPACT ON QUALITY OF LIFE. EXAMPLES INCLUDE TRIGEMINAL NEURALGIA, PAINFUL POLYNEUROPATHY, POSTHERPETIC NEURALGIA, AND CENTRAL POSTSTROKE PAIN. MOST PATIENTS COMPLAIN OF AN ONGOING OR INTERMITTENT SPONTANEOUS PAIN OF, FOR EXAMPLE, BURNING, PRICKING, SQUEEZING QUALITY, WHICH MAY BE ACCOMPANIED BY EVOKED PAIN, PARTICULAR TO LIGHT TOUCH AND COLD. ECTOPIC ACTIVITY IN, FOR EXAMPLE, NERVE-END NEUROMA, COMPRESSED NERVES OR NERVE ROOTS, DORSAL ROOT GANGLIA, AND THE THALAMUS MAY IN DIFFERENT CONDITIONS UNDERLIE THE SPONTANEOUS PAIN. EVOKED PAIN MAY SPREAD TO NEIGHBORING AREAS, AND THE UNDERLYING PATHOPHYSIOLOGY INVOLVES PERIPHERAL AND CENTRAL SENSITIZATION. MALADAPTIVE STRUCTURAL CHANGES AND A NUMBER OF CELL-CELL INTERACTIONS AND MOLECULAR SIGNALING UNDERLIE THE SENSITIZATION OF NOCICEPTIVE PATHWAYS. THESE INCLUDE ALTERATION IN ION CHANNELS, ACTIVATION OF IMMUNE CELLS, GLIAL-DERIVED MEDIATORS, AND EPIGENETIC REGULATION. THE MAJOR CLASSES OF THERAPEUTICS INCLUDE DRUGS ACTING ON ALPHA(2)DELTA SUBUNITS OF CALCIUM CHANNELS, SODIUM CHANNELS, AND DESCENDING MODULATORY INHIBITORY PATHWAYS. 2021 2 820 23 CHARACTERIZATION OF A PORTUGUESE FAMILY WITH CHARCOT-MARIE-TOOTH DISEASE TYPE 1E DUE TO A NOVEL POINT MUTATION IN THE PMP22 GENE. INTRODUCTION: POINT MUTATIONS IN THE PERIPHERAL MYELIN PROTEIN 22 (PMP22) GENE COMPRISE LESS THAN 5% OF THE CHARCOT-MARIE-TOOTH (CMT) TYPE 1 CASES, AND INDIVIDUALIZE EITHER THE CMT 1E SUBTYPE, OR HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSY. THE PHENOTYPE OF CMT 1E PRESENTS WITH A SEVERE EARLY-ONSET POLYNEUROPATHY ASSOCIATED WITH DEAFNESS, ALTHOUGH THE CLINICAL SPECTRUM IS BROAD. CASE REPORT: WE DESCRIBE A NOVEL PMP22 GENE POINT MUTATION (C.84G>T;P.(TRP28CYS)) IN THREE PATIENTS OF A PORTUGUESE FAMILY WITH VARIABLE PHENOTYPES, RANGING FROM ASYMPTOMATIC TO MILD COMPLAINTS OF DISTAL LIMB NUMBNESS AND GAIT DIFFICULTIES, WITH THE AGE OF ONSET OF SYMPTOMS RANGING FROM MID-TWENTIES TO LATE-SIXTIES, AND NO ASSOCIATED DISABILITY. IN ALL AFFECTED PATIENTS, THERE WAS EVIDENCE OF DIFFUSE DEMYELINATING SENSORIMOTOR POLYNEUROPATHY. HEARING LOSS DOES NOT SEEM TO BE ASSOCIATED WITH THIS VARIANT, ALBEIT NEUROPATHIC PAIN WAS REPORTED. CONCLUSIONS: THESE FINDINGS SUGGEST THAT THIS PARTICULAR POINT MUTATION IN THE PMP22 GENE IS ASSOCIATED WITH A MILD PHENOTYPE, FURTHER EMPHASIZING THAT THERE ARE STILL UNKNOWN MECHANISMS (GENETIC AND/OR EPIGENETIC) THAT MAY PLAY A ROLE IN THE CLINICAL SPECTRUM OF CMT1E PATIENTS. NEXT GENERATION SEQUENCING PANELS INCLUDING COMMONLY MUTATED GENES IN CMT SHOULD BE CONSIDERED IN CMT1 CASES NEGATIVE FOR PMP22 GENE DUPLICATION. 2021 3 2685 27 EVIDENCE FOR EPIGENETIC REGULATION OF GENE EXPRESSION AND FUNCTION IN CHRONIC EXPERIMENTAL DIABETIC NEUROPATHY. DIABETIC POLYNEUROPATHY (DPN) IS A COMMON BUT IRREVERSIBLE NEURODEGENERATIVE COMPLICATION OF DIABETES MELLITUS. HERE WE SHOW THAT FEATURES OF SENSORY NEURON DAMAGE IN MICE WITH CHRONIC DPN MAY HAVE ALTERED EPIGENETIC MICRO RNA (MIRNA) TRANSCRIPTIONAL CONTROL. WE PROFILED SENSORY NEURON MESSENGER RNA AND MIRNA PROFILES IN MICE WITH TYPE I DIABETES MELLITUS AND FINDINGS OF DPN. DIABETIC SENSORY DORSAL ROOT GANGLIA NEURONS SHOWED A PATTERN OF ALTERED MESSENGER RNA PROFILES ASSOCIATED WITH UPREGULATED CYTOPLASMIC SITES OF MIRNA-MEDIATED MESSENGER RNA PROCESSING (GW/P BODIES). DORSAL ROOT GANGLIA MIRNA MICROARRAY IDENTIFIED SIGNIFICANT CHANGES IN EXPRESSION AMONG MICE WITH DIABETES, THE MOST PROMINENT OF WHICH WERE A 39% DOWNREGULATION OF MMU-LET-7I AND A 255% INCREASE IN MMU-MIR-341; BOTH WERE IDENTIFIED IN SENSORY NEURONS. TO COUNTERACT THESE ALTERATIONS, WE REPLENISHED LET-7I MIRNA BY INTRANASAL ADMINISTRATION; IN A SEPARATE EXPERIMENT, WE ADDED AN ANTI-MIR THAT ANTAGONIZED ELEVATED MMU-341 AFTER 5 MONTHS OF DIABETES. BOTH APPROACHES INDEPENDENTLY IMPROVED ELECTROPHYSIOLOGIC, STRUCTURAL, AND BEHAVIORAL ABNORMALITIES WITHOUT ALTERING HYPERGLYCEMIA; CONTROL SEQUENCES DID NOT HAVE THESE EFFECTS. DISSOCIATED ADULT SENSORY NEURONS EXPOSED TO AN EXOGENOUS MMU-LET-7I MIMIC DISPLAYED ENHANCED GROWTH AND BRANCHING, INDICATING A TROPHIC ACTION. THESE FINDINGS IDENTIFY ROLES FOR EPIGENETIC MIRNA ALTERATIONS AND ENHANCED GW/P EXPRESSION IN DIABETIC DORSAL ROOT GANGLIA THAT CONTRIBUTE TO THE COMPLEX DPN PHENOTYPE. 2015 4 2997 19 GENETIC VARIANTS IN DNMT1 AND THE RISK OF CARDIAC AUTONOMIC NEUROPATHY IN WOMEN WITH TYPE 1 DIABETES. AIMS/INTRODUCTION: EPIGENETICS PARTICIPATE IN THE PATHOGENESIS OF METABOLIC MEMORY, A SITUATION IN WHICH HYPERGLYCEMIA EXERTS PROLONGED DELETERIOUS EFFECTS EVEN AFTER ITS NORMALIZATION. WE TESTED THE HYPOTHESIS THAT GENETIC VARIANTS IN AN EPIGENETIC GENE COULD PREDISPOSE TO DIABETES COMPLICATIONS. MATERIAL AND METHODS: WE ASSESSED THE FREQUENCY OF FIVE SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE GENE ENCODING DEOXYRIBONUCLEIC ACID METHYTRANSFERASE 1 (DNMT1; RS8112895, RS7254567, RS11085721, RS17291414 AND RS10854076), AND THEIR ASSOCIATIONS WITH DIABETIC KIDNEY DISEASE, RETINOPATHY, DISTAL POLYNEUROPATHY AND AUTONOMIC CARDIOVASCULAR NEUROPATHY IN 359 INDIVIDUALS WITH LONG-TERM TYPE 1 DIABETES. RESULTS: NONE OF THE SINGLE-NUCLEOTIDE POLYMORPHISMS STUDIED WAS SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE OF CHRONIC COMPLICATIONS IN THE OVERALL POPULATION. HOWEVER, AFTER SEX STRATIFICATION, THE MINOR ALLELE C OF RS11085721 CONFERRED RISK FOR CARDIOVASCULAR NEUROPATHY IN WOMEN AFTER ADJUSTMENT FOR CONFOUNDING VARIABLES (ODDS RATIO 2.32; 95% CONFIDENCE INTERVAL 1.26-4.33; P = 0.006). CONCLUSIONS: THE FACT THAT HETEROZYGOUS MUTATIONS IN DNMT1 ARE ASSOCIATED WITH HEREDITARY SENSORY AUTONOMIC NEUROPATHY PROVIDES PLAUSIBILITY TO THE PRESENT FINDING. IF CONFIRMED IN INDEPENDENT SAMPLES, IT SUGGESTS THAT GENETIC VARIANTS IN EPIGENETIC GENES MIGHT PREDISPOSE TO MORE OR FEWER EPIGENETIC CHANGES IN THE FACE OF SIMILAR METABOLIC DERANGEMENTS TRIGGERED BY HYPERGLYCEMIA, CONSTITUTING THE "GENETICS OF EPIGENETICS" FOR MICROVASCULAR DIABETES COMPLICATIONS. 2019 5 6029 25 THE BURDEN OF DIABETES: EMERGING DATA. IN RECENT TIMES, THE GLOBAL PREVALENCE OF DIABETES HAS INCREASED SUBSTANTIALLY, REACHING 8.3% IN 2014, WHICH CORRESPONDS TO 387 MILLION PATIENTS. STUDIES IN EUROPE AND USA HAVE SHOWN INCREASED INCIDENCE OF TYPE 1 DIABETES (T1D) OVER TIME AT A RATE OF 3-5% PER YEAR. ANOTHER MOST WORRYING FEATURE OF THE RAPID INCREASE OF DIABETES IS THE EMERGENCE OF TYPE 2 DIABETES (T2D) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS. THE WELL-KNOWN BEHAVIORAL RISKS FACTORS AND EPIGENETIC MECHANISMS RECENTLY OBSERVED REQUIRE AN INTEGRATED APPROACH TO PREVENT T2D. DIABETES SIGNIFICANTLY INFLUENCES THE PATIENT' SURVIVAL, QUALITY OF LIFE, AND DEVELOPMENT OF ORGAN SYSTEM DEGENERATION. EPIDEMIOLOGICAL STUDIES HAVE SHOWN INCREASED MORTALITY IN DIABETIC PATIENTS, ESPECIALLY WOMEN, WHICH INCREASED APPROXIMATELY FIVEFOLD, WHEREAS CARDIOVASCULAR MORTALITY INCREASED 20- TO 30-FOLD WHEN COMPARED TO THE NORMAL POPULATION. DIABETES IS THE LEADING CAUSE OF END-STAGE RENAL DISEASE AND VISION LOSS IN DEVELOPED COUNTRIES. AROUND 40% OF T1D AND T2D START ON RENAL REPLACEMENT THERAPY. WHILE AFTER 40 YEARS OF DIABETES, THE CUMULATIVE PROPORTION OF PATIENTS WITH ANY RETINOPATHY AND ADVANCED RETINOPATHY WAS 84.1 AND 50.2%, RESPECTIVELY. HOWEVER, THE MOST PREVALENT CHRONIC COMPLICATION OF DIABETES IS NEUROPATHY. DISTAL SYMMETRIC POLYNEUROPATHY OCCURS IN AT LEAST 20% OF PEOPLE WITH T1D AFTER 20 YEARS AND IN 10-15% OF NEWLY DIAGNOSED T2D, INCREASING TO 50% AFTER 10 YEARS. CARDIOVASCULAR AUTONOMIC NEUROPATHY MAY BE PRESENT IN UP TO 60% OF PATIENTS AFTER 15 YEARS AND IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR MORTALITY. 2017 6 60 33 A GENOME-WIDE SCREEN REVEALS MICRORNAS IN PERIPHERAL SENSORY NEURONS DRIVING PAINFUL DIABETIC NEUROPATHY. DIABETES IS A LEADING CAUSE OF PERIPHERAL NEUROPATHY (DIABETIC PERIPHERAL NEUROPATHY, DPN), AND UNCONTROLLED LONG-LASTING HYPERGLYCEMIA LEADS TO SEVERE COMPLICATIONS. A MAJOR PROPORTION OF DIABETICS DEVELOP EXCRUCIATING PAIN WITH A VARIABLE COURSE. MECHANISMS LEADING TO PAINFUL DPN ARE NOT COMPLETELY UNDERSTOOD AND TREATMENT OPTIONS LIMITED. WE HYPOTHESIZED THAT EPIGENETIC MODULATION AT THE LEVEL OF MICRORNA (MIRNA) EXPRESSION TRIGGERED BY METABOLIC IMBALANCE AND NERVE DAMAGE REGULATES THE COURSE OF PAIN DEVELOPMENT. WE USED CLINICALLY RELEVANT PRECLINICAL MODELS, GENOME-WIDE SCREENING, IN SILICO ANALYSES, CELLULAR ASSAYS, MIRNA FLUORESCENT IN SITU HYBRIDIZATION, IN VIVO MOLECULAR MANIPULATIONS, AND BEHAVIORAL ANALYSES IN THE CURRENT STUDY. WE IDENTIFIED MIRNAS AND THEIR TARGETS THAT CRITICALLY IMPACT ON NOCICEPTIVE HYPERSENSITIVITY IN PAINFUL DPN. OUR ANALYSES IDENTIFY MIR-33 AND MIR-380 EXPRESSED IN NOCICEPTIVE NEURONS AS CRITICAL DENOMINATORS OF DIABETIC PAIN AND MIR-124-1 AS A MEDIATOR OF PHYSIOLOGICAL NOCICEPTION. OUR COMPREHENSIVE ANALYSES ON THE PUTATIVE MRNA TARGETS FOR MIR-33 OR MIR-124-1 IDENTIFIED A SET OF MRNAS THAT ARE REGULATED AFTER MIR-33 OR MIR-124-1 OVEREXPRESSION IN DORSAL ROOT GANGLIA IN VIVO. OUR RESULTS SHED LIGHT ON THE REGULATION OF DPN PATHOPHYSIOLOGY AND IMPLICATE SPECIFIC MIRNAS AS NOVEL THERAPEUTIC TARGETS FOR TREATING PAINFUL DPN. 2021 7 4708 26 NO ASSOCIATION OF POLYMORPHISMS IN NAV1.7 OR NERVE GROWTH FACTOR RECEPTOR GENES WITH TRIGEMINAL NEURALGIA. OBJECTIVE: TRIGEMINAL NEURALGIA IS DEFINED AS A SUDDEN SEVERE SHOCK-LIKE PAIN WITHIN THE DISTRIBUTION OF THE TRIGEMINAL NERVE. PAIN IS A SUBJECTIVE EXPERIENCE THAT IS INFLUENCED BY GENDER, CULTURE, ENVIRONMENT, PSYCHOLOGICAL TRAITS, AND GENES. SODIUM CHANNELS AND NERVE GROWTH FACTOR PLAY IMPORTANT ROLES IN THE TRANSMISSION OF NOCICEPTIVE SIGNALS AND PAIN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE OCCURRENCE OF NAV1.7 SODIUM CHANNEL AND NERVE GROWTH FACTOR RECEPTOR TRKA GENE POLYMORPHISMS (SCN9A/RS6746030 AND NTRK1/RS633, RESPECTIVELY) IN TRIGEMINAL NEURALGIA PATIENTS. METHODS: NINETY-SIX SUBJECTS FROM PAIN SPECIALTY CENTERS IN THE SOUTHEASTERN REGION OF BRAZIL WERE DIVIDED INTO 2 GROUPS: 48 WITH CLASSICAL TRIGEMINAL NEURALGIA DIAGNOSIS AND 48 CONTROLS. PAIN WAS EVALUATED USING THE VISUAL ANALOG SCALE AND MULTIDIMENSIONAL MCGILL PAIN QUESTIONNAIRE. GENOMIC DNA WAS OBTAINED FROM ORAL SWABS IN ALL INDIVIDUALS AND WAS ANALYZED BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NO ASSOCIATION WAS OBSERVED BETWEEN EVALUATED POLYMORPHISMS AND TRIGEMINAL NEURALGIA. FOR ALLELE ANALYSES, PATIENTS AND CONTROLS HAD SIMILAR FREQUENCIES FOR BOTH GENES. GENOTYPE DISTRIBUTION OR ALLELE FREQUENCIES OF POLYMORPHISMS ANALYZED HERE DID NOT CORRELATE TO PAIN SCORES. CONCLUSIONS: ALTHOUGH NO ASSOCIATION OF EVALUATED POLYMORPHISMS AND TRIGEMINAL NEURALGIA DIAGNOSIS OR PAIN SEVERITY WAS OBSERVED, OUR DATA DO NOT EXCLUDE THE POSSIBILITY THAT OTHER GENOTYPES AFFECTING THE EXPRESSION OF NAV1.7 OR TRKA ARE ASSOCIATED WITH THE DISEASE. FURTHER STUDIES SHOULD INVESTIGATE DISTINCT GENETIC POLYMORPHISMS AND EPIGENETIC FACTORS THAT MAY BE IMPORTANT IN EXPRESSION OF THESE MOLECULES. 2019 8 55 31 A GAIN-OF-FUNCTION SODIUM CHANNEL BETA2-SUBUNIT MUTATION IN PAINFUL DIABETIC NEUROPATHY. DIABETES MELLITUS IS A GLOBAL CHALLENGE WITH MANY DIVERSE HEALTH SEQUELAE, OF WHICH DIABETIC PERIPHERAL NEUROPATHY IS ONE OF THE MOST COMMON. A SUBSTANTIAL NUMBER OF PATIENTS WITH DIABETIC PERIPHERAL NEUROPATHY DEVELOP CHRONIC PAIN, BUT THE GENETIC AND EPIGENETIC FACTORS THAT PREDISPOSE DIABETIC PERIPHERAL NEUROPATHY PATIENTS TO DEVELOP NEUROPATHIC PAIN ARE POORLY UNDERSTOOD. RECENT TARGETED GENETIC STUDIES HAVE IDENTIFIED MUTATIONS IN ALPHA-SUBUNITS OF VOLTAGE-GATED SODIUM CHANNELS (NA(V)S) IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY. MUTATIONS IN PROTEINS THAT REGULATE TRAFFICKING OR FUNCTIONAL PROPERTIES OF NA(V)S COULD EXPAND THE SPECTRUM OF PATIENTS WITH NA(V)-RELATED PERIPHERAL NEUROPATHIES. THE AUXILIARY SODIUM CHANNEL BETA-SUBUNITS (BETA1-4) HAVE BEEN REPORTED TO INCREASE CURRENT DENSITY, ALTER INACTIVATION KINETICS, AND MODULATE SUBCELLULAR LOCALIZATION OF NA(V). MUTATIONS IN BETA-SUBUNITS HAVE BEEN ASSOCIATED WITH SEVERAL DISEASES, INCLUDING EPILEPSY, CANCER, AND DISEASES OF THE CARDIAC CONDUCTING SYSTEM. HOWEVER, MUTATIONS IN BETA-SUBUNITS HAVE NEVER BEEN SHOWN PREVIOUSLY TO CONTRIBUTE TO NEUROPATHIC PAIN. WE REPORT HERE A PATIENT WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY AND NEGATIVE GENETIC SCREENING FOR MUTATIONS IN SCN9A, SCN10A, AND SCN11A-GENES ENCODING SODIUM CHANNEL ALPHA-SUBUNIT THAT HAVE BEEN PREVIOUSLY LINKED TO THE DEVELOPMENT OF NEUROPATHIC PAIN. GENETIC ANALYSIS REVEALED AN ASPARTIC ACID TO ASPARAGINE MUTATION, D109N, IN THE BETA2-SUBUNIT. FUNCTIONAL ANALYSIS USING CURRENT-CLAMP REVEALED THAT THE BETA2-D109N RENDERED DORSAL ROOT GANGLION NEURONS HYPEREXCITABLE, ESPECIALLY IN RESPONSE TO REPETITIVE STIMULATION. UNDERLYING THE HYPEREXCITABILITY INDUCED BY THE BETA2-SUBUNIT MUTATION, AS EVIDENCED BY VOLTAGE-CLAMP ANALYSIS, WE FOUND A DEPOLARIZING SHIFT IN THE VOLTAGE DEPENDENCE OF NA(V)1.7 FAST INACTIVATION AND REDUCED USE-DEPENDENT INHIBITION OF THE NA(V)1.7 CHANNEL. 2019 9 5904 21 T677T METHYLENETETRAHYDROFOLATE REDUCTASE SINGLE NUCLEOTIDE POLYMORPHISMS INCREASED PREVALENCE IN A SUBGROUP OF INFERTILE PATIENTS WITH ENDOMETRIOSIS. BACKGROUND: APPROXIMATELY 10% (190 MILLION) OF WOMEN WORLDWIDE ARE AFFECTED BY ENDOMETRIOSIS, ECTOPIC DEPOSITS OF ENDOMETRIAL TISSUE THAT CREATE A MAJOR SOURCE OF PAIN THAT AFFECTS LIFESTYLE AND REPRODUCTIVE FUNCTION. THE PATHOGENESIS OF ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY PROCESS, INFLUENCED/CATALYZED BY OXIDATIVE STRESS AND CONSEQUENTLY DEFECTIVE METHYLATION, WITH BIOCHEMICAL FEATURES CENTERED AROUND THE FOLATE AND ONE-CARBON CYCLES. WE AIMED TO DETERMINE WHETHER A LINK COULD BE FOUND BETWEEN THE TWO MAJOR METHYLENETETRAHYDROFOLATE REDUCTASE SINGLE NUCLEOTIDE POLYMORPHISMS (MTHFR SNPS), C.677C>T AND C.1298A>C, INVOLVED IN METHYLATION PROCESS/EPIGENETIC MARKING FAILURES, AND ENDOMETRIOSIS. MATERIAL AND METHODS: WE STUDIED A POPULATION OF 158 PATIENTS IN A GROUP OF >1500 REFERRED FOR TREATMENT OF INFERTILITY. ALL THE PATIENTS HAD EXPERIENCED >2 FAILED ASSISTED REPRODUCTIVE TECHNOLOGY CYCLES AND/OR >2 MISCARRIAGES, A CLASSICAL COHORT FOR INVESTIGATION IN OUR GROUP. PATIENTS WITH ENDOMETRIOSIS HAD AT LEAST STAGE 2+ DISEASE CONFIRMED BY LAPAROSCOPY. RESULTS: THE PREVALENCE OF THE HOMOZYGOUS C.677C>T ISOFORM IS DOUBLED IN THE ENDOMETRIOSIS GROUP, 21.5% VERSUS 10.2% IN THE NON-ENDOMETRIOSIS GROUP (P > 0.01). SYMMETRICALLY, THE PERCENTAGE OF PATIENTS IN THE ENDOMETRIOSIS GROUP WITH THE WILD TYPE MTHFR SIGNIFICANTLY DECREASED BY ONE-HALF (8.2%-17.2%) IN THE NON-ENDOMETRIOSIS GROUP (P < 0.001). CONCLUSION: DETERMINATION OF MTHFR C.677C>T SHOULD NOT BE OVERLOOKED IN PATIENTS WITH HARMFUL ENDOMETRIOSIS AFFECTING THEIR FERTILITY. AS FOLATES METABOLISM IS IMPAIRED IN THESE MTHFR SNPS CARRIER PATIENTS, CO-TREATMENT WITH 5-METHYL FOLATE MAY CONSTITUTE A SUCCESSFUL (CO)-TREATMENT MODALITY. 2022 10 4522 26 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 11 1389 24 DIABETIC RETINOPATHY AND SYSTEMIC FACTORS. DIABETIC RETINOPATHY, AN OCULARDISEASE, IS GOVERNED BY SYSTEMIC AS WELL AS LOCAL OCULAR FACTORS. THESE INCLUDE PRIMARILY CHRONIC LEVELS OF BLOOD GLUCOSE. INDIVIDUALS WITH CHRONICALLY ELEVATED BLOOD GLUCOSE LEVELS HAVE SUBSTANTIALLY MORE, AND MORE SEVERE, RETINOPATHY THAN THOSE WITH LOWER BLOOD GLUCOSE LEVELS. THE RELATIONSHIP OF BLOOD GLUCOSE TO RETINOPATHY IS CONTINUOUS, WITH NO THRESHOLD ALTHOUGH INDIVIDUALS WITH HEMOGLOBIN A1C LEVELS (A MEASURE OF CHRONIC GLYCEMIA) <6.5%, GENERALLY DEVELOP LITTLE OR NO RETINOPATHY. BLOOD PRESSURE LEVELS HAVE BEEN CLAIMED TO INFLUENCE RETINOPATHY DEVELOPMENT AND PROGRESSION, BUT MULTIPLE CONTROLLED CLINICAL TRIALS OF ANTIHYPERTENSIVE AGENTS IN DIABETIC SUBJECTS HAVE PRODUCED ONLY WEAK EVIDENCE OF BENEFIT FROM BLOOD PRESSURE LOWERING ON THE INCIDENCE AND PROGRESSION OF DIABETIC RETINOPATHY. ELEVATED BLOOD LIPIDS SEEM TO PLAY A ROLE IN THE PROGRESSION OF RETINOPATHY, AND TWO TRIALS OF FENOFIBRATE, A LIPID-LOWERING AGENT THAT HAS NOT PROVED EFFECTIVE IN PREVENTING CARDIOVASCULAR DISEASE, HAVE SHOWN BENEFIT IN PREVENTING RETINOPATHY PROGRESSION. THE MECHANISM OF THIS EFFECT MAY NOT, HOWEVER, BE DIRECTLY RELATED TO THE REDUCTION IN BLOOD LIPIDS. FINALLY, THERE IS STRONG, BUT ONLY CIRCUMSTANTIAL, EVIDENCE FOR A GENETIC OR EPIGENETIC INFLUENCE ON THE PATHOGENESIS OF DIABETIC RETINOPATHY. DESPITE THE POWER OF LARGE-SCALE EPIDEMIOLOGIC STUDIES AND MODERN MOLECULAR BIOLOGICAL AND COMPUTATIONAL TECHNIQUES, THE GENE OR GENES, WHICH PREDISPOSE OR PROTECT AGAINST THE DEVELOPMENT AND PROGRESSION OF DIABETIC RETINOPATHY REMAIN ELUSIVE. 2015 12 6817 22 [FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY: REPORT OF SEVEN PATIENTS]. BACKGROUND: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY IS THE THIRD MOST COMMON MUSCULAR DYSTROPHY WITH AN ESTIMATED PREVALENCE OF 1 PER 20.000 AND A NORMAL LIFE EXPECTANCY IN THE MAJORITY OF PATIENTS. HOWEVER, APPROXIMATELY 15% OF PATIENTS BECOME WHEELCHAIR BOUND IN THE COURSE OF THEIR LIFE. IT IS A HEREDITARY AUTOSOMAL DOMINANT DISEASE WITH HIGH (95%) PENETRANCE BY THE AGE OF 20, BUT WITH VARIABLE DEGREE OF PHENOTYPIC EXPRESSION EVEN IN THE SAME FAMILY GROUP. SYMPTOMS FREQUENTLY START IN THE SECOND DECADE OF LIFE, WITH FACIAL AND SCAPULAR WEAKNESS. AIM: TO REPORT THE CLINICAL FEATURES OF SEVEN PATIENTS WITH THE DISEASE, SEEN AT A PUBLIC HOSPITAL. MATERIAL AND METHODS: ANALYSIS OF SEVEN PATIENTS WITH GENETIC STUDY SEEN IN A PUBLIC HOSPITAL IN SANTIAGO. RESULTS: THE AGE OF PATIENTS FLUCTUATED FROM 18 TO 61 YEARS AND FOUR WERE FEMALES. THE MEAN AGE AT ONSET OF SYMPTOMS WAS 29 YEARS AND FOUR HAD A FAMILY HISTORY OF THE DISEASE. THE USUAL PRESENTING COMPLAINT WAS ARM OR SHOULDER ASYMMETRIC WEAKNESS. FOUR PATIENTS HAD BONE PAIN. FACIAL INVOLVEMENT WAS PRESENT IN FOUR. A GENETIC STUDY WAS DONE IN FIVE PATIENTS, THE OTHER TWO PATIENTS WERE RELATIVES, CONFIRMING THE CONTRACTION OR LOWER NUMBER OF REPETITIONS IN D4Z4 REGION. AFTER 12 YEARS OF FOLLOW UP ONLY 2 PATIENTS OLDER THAN 60 YEARS CANNOT WORK AND ONE FEMALE PATIENTS IS IN A SEMI DEPENDENT STATE AT THE AGE OF 30. CONCLUSIONS: THE CLINICAL WORKUP IN THE DIAGNOSIS AND THE TIMELY INDICATION OF GENETIC STUDIES ARE HIGHLIGHTED, TO AVOID UNNECESSARY AND INVASIVE PROCEDURES. THE VARIABILITY IN THE PHENOTYPIC EXPRESSION IN A SIMILAR GENETIC DEFECT IS DISCUSSED AND THE GENETIC OR EPIGENETIC MECHANISMS OF THIS MUSCULAR DYSTROPHY ARE DESCRIBED. 2015 13 190 23 ACETYL-L-CARNITINE IN PAINFUL PERIPHERAL NEUROPATHY: A SYSTEMATIC REVIEW. ACETYL-L-CARNITINE (ALC) HAS SHOWN A NEUROPROTECTIVE EFFECT IN PATIENTS WITH PERIPHERAL NEUROPATHIES OF DIFFERENT ETIOLOGIES. PRECLINICAL STUDIES DEMONSTRATED A CENTRAL ANTI-NOCICEPTIVE ACTION, BOTH IN NEUROPATHIC AND NOCICEPTIVE PAIN MODELS. THE PRESENT REVIEW AIMS TO PROVIDE THE KNOWLEDGE ON THE EFFICACY OF ALC IN PATIENTS WITH PAINFUL PERIPHERAL NEUROPATHY, BASED ON THE EVIDENCE. CONSISTENT WITH THE PRISMA STATEMENT, AUTHORS SEARCHED PUBMED, EMBASE AND THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS FOR RELEVANT PAPERS, INCLUDING THOSE ISSUED BEFORE APRIL 2018. TWO AUTHORS INDEPENDENTLY SELECTED STUDIES FOR INCLUSION AND DATA EXTRACTION: ONLY TRIALS INCLUDING PATIENTS WITH A DIAGNOSIS OF PERIPHERAL NEUROPATHY AND INVOLVING AT LEAST 10 PATIENTS WERE CONSIDERED FOR THE PURPOSES OF THIS REVIEW. FOURTEEN CLINICAL TRIALS WERE REVISED, TO PROVIDE THE LEVEL OF EVIDENCE FOR NEUROPATHY. TO ASSESS THE GLOBAL EFFICACY OF ALC IN PAINFUL PERIPHERAL NEUROPATHY, A META-ANALYSIS OF FOUR RANDOMIZED CONTROLLED TRIALS WAS PERFORMED. MEAN DIFFERENCE IN PAIN REDUCTION AS MEASURED ON A 10-CM VAS, AND 95% CIS WERE USED FOR POOLING CONTINUOUS DATA FROM EACH TRIAL. FOUR RANDOMIZED CONTROLLED TRIALS TESTED ALC IN PATIENTS WITH NEUROPATHY SECONDARY TO DIABETES AND TO ANTIRETROVIRAL THERAPY FOR HIV. COMPARED TO PLACEBO, ALC PRODUCED A SIGNIFICANT PAIN REDUCTION EQUAL TO 20.2% (95% CI: 8.3%-32.1%, P<0.0001) WITH RESPECT TO BASELINE. CLINICAL TRIALS ALSO SHOWED BENEFICIAL EFFECTS ON NERVE CONDUCTION PARAMETERS AND NERVE FIBER REGENERATION, WITH A GOOD SAFETY PROFILE. THESE DATA INDICATE THAT ALC PROVIDES AN EFFECTIVE AND SAFE TREATMENT IN PATIENTS WITH PAINFUL PERIPHERAL NEUROPATHY. WE RECOMMEND FURTHER STUDIES TO ASSESS THE OPTIMAL DOSE AND DURATION OF THE THERAPEUTIC EFFECT (ALSO AFTER TREATMENT WITHDRAWAL). 2019 14 3052 23 GENOME-WIDE ASSOCIATION ANALYSIS OF PAIN SEVERITY IN DYSMENORRHEA IDENTIFIES ASSOCIATION AT CHROMOSOME 1P13.2, NEAR THE NERVE GROWTH FACTOR LOCUS. DYSMENORRHEA IS A COMMON CHRONIC PELVIC PAIN SYNDROME AFFECTING WOMEN OF CHILDBEARING POTENTIAL. FAMILY STUDIES SUGGEST THAT GENETIC BACKGROUND INFLUENCES THE SEVERITY OF DYSMENORRHEA, BUT GENETIC PREDISPOSITION AND MOLECULAR MECHANISMS UNDERLYING DYSMENORRHEA ARE NOT UNDERSTOOD. IN THIS STUDY, WE CONDUCT THE FIRST GENOME-WIDE ASSOCIATION STUDY TO IDENTIFY GENETIC FACTORS ASSOCIATED WITH DYSMENORRHEA PAIN SEVERITY. A COHORT OF FEMALES OF EUROPEAN DESCENT (N = 11,891) AGED 18 TO 45 YEARS RATED THEIR AVERAGE DYSMENORRHEA PAIN SEVERITY. WE USED A LINEAR REGRESSION MODEL ADJUSTING FOR AGE AND BODY MASS INDEX, IDENTIFYING ONE GENOME-WIDE SIGNIFICANT (P < 5 X 10) ASSOCIATION (RS7523086, P = 4.1 X 10, EFFECT SIZE 0.1 [95% CONFIDENCE INTERVAL, 0.074-0.126]). THIS SINGLE NUCLEOTIDE POLYMORPHISM IS COLOCALISING WITH NGF, ENCODING NERVE GROWTH FACTOR. THE PRESENCE OF ONE RISK ALLELE CORRESPONDS TO A PREDICTED 0.1-POINT INCREASE IN PAIN INTENSITY ON A 4-POINT ORDINAL PAIN SCALE. THE PUTATIVE EFFECTS ON NGF FUNCTION AND/OR EXPRESSION REMAIN UNKNOWN. HOWEVER, GENETIC VARIATION COLOCALISES WITH ACTIVE EPIGENETIC MARKS IN FAT AND OVARY TISSUES, AND EXPRESSION LEVELS IN AORTA TISSUE OF A NONCODING RNA FLANKING NGF CORRELATE. PARTICIPANTS REPORTING EXTREME DYSMENORRHEA PAIN WERE MORE LIKELY TO REPORT BEING POSITIVE FOR ENDOMETRIOSIS, POLYCYSTIC OVARIAN SYNDROME, DEPRESSION, AND OTHER PSYCHIATRIC DISORDERS. OUR RESULTS INDICATE THAT DYSMENORRHEA PAIN SEVERITY IS PARTLY GENETICALLY DETERMINED. NGF ALREADY HAS AN ESTABLISHED ROLE IN CHRONIC PAIN DISORDERS, AND OUR FINDINGS SUGGEST THAT NGF MAY BE AN IMPORTANT MEDIATOR FOR GYNAECOLOGICAL/PELVIC PAIN IN THE VISCERA. 2016 15 3968 28 LONG-LASTING ANALGESIA VIA TARGETED IN SITU REPRESSION OF NA(V)1.7 IN MICE. CURRENT TREATMENTS FOR CHRONIC PAIN RELY LARGELY ON OPIOIDS DESPITE THEIR SUBSTANTIAL SIDE EFFECTS AND RISK OF ADDICTION. GENETIC STUDIES HAVE IDENTIFIED IN HUMANS KEY TARGETS PIVOTAL TO NOCICEPTIVE PROCESSING. IN PARTICULAR, A HEREDITARY LOSS-OF-FUNCTION MUTATION IN NA(V)1.7, A SODIUM CHANNEL PROTEIN ASSOCIATED WITH SIGNALING IN NOCICEPTIVE SENSORY AFFERENTS, LEADS TO INSENSITIVITY TO PAIN WITHOUT OTHER NEURODEVELOPMENTAL ALTERATIONS. HOWEVER, THE HIGH SEQUENCE AND STRUCTURAL SIMILARITY BETWEEN NA(V) SUBTYPES HAS FRUSTRATED EFFORTS TO DEVELOP SELECTIVE INHIBITORS. HERE, WE INVESTIGATED TARGETED EPIGENETIC REPRESSION OF NA(V)1.7 IN PRIMARY AFFERENTS VIA EPIGENOME ENGINEERING APPROACHES BASED ON CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)-DCAS9 AND ZINC FINGER PROTEINS AT THE SPINAL LEVEL AS A POTENTIAL TREATMENT FOR CHRONIC PAIN. TOWARD THIS END, WE FIRST OPTIMIZED THE EFFICIENCY OF NA(V)1.7 REPRESSION IN VITRO IN NEURO2A CELLS AND THEN, BY THE LUMBAR INTRATHECAL ROUTE, DELIVERED BOTH EPIGENOME ENGINEERING PLATFORMS VIA ADENO-ASSOCIATED VIRUSES (AAVS) TO ASSESS THEIR EFFECTS IN THREE MOUSE MODELS OF PAIN: CARRAGEENAN-INDUCED INFLAMMATORY PAIN, PACLITAXEL-INDUCED NEUROPATHIC PAIN, AND BZATP-INDUCED PAIN. OUR RESULTS SHOW EFFECTIVE REPRESSION OF NA(V)1.7 IN LUMBAR DORSAL ROOT GANGLIA, REDUCED THERMAL HYPERALGESIA IN THE INFLAMMATORY STATE, DECREASED TACTILE ALLODYNIA IN THE NEUROPATHIC STATE, AND NO CHANGES IN NORMAL MOTOR FUNCTION IN MICE. WE ANTICIPATE THAT THIS LONG-LASTING ANALGESIA VIA TARGETED IN VIVO EPIGENETIC REPRESSION OF NA(V)1.7 METHODOLOGY WE DUB PAIN LATER, MIGHT HAVE THERAPEUTIC POTENTIAL IN MANAGEMENT OF PERSISTENT PAIN STATES. 2021 16 5260 22 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 17 4555 16 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES. 2011 18 4184 14 META-PREDICTION OF MTHFR GENE POLYMORPHISM-MUTATIONS, AIR POLLUTION, AND RISKS OF LEUKEMIA AMONG WORLD POPULATIONS. THE MAJOR OBJECTIVE OF THIS STUDY WAS TO EXAMINE THE ASSOCIATION BETWEEN METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) POLYMORPHISMS AND THE RISK OF VARIOUS TYPES OF LEUKEMIAS ACROSS THE LIFESPANS OF CHILDREN AND ADULTS BY USING THE META-PREDICTIVE TECHNIQUES. THE SECONDARY OBJECTIVE WAS TO EXAMINE THE INTERACTIONS AMONG EPIGENETIC RISK FACTORS (INCLUDING AIR POLLUTION), MTHFR POLYMORPHISMS, AND THE RISKS OF DEVELOPING LEUKEMIA. WE COMPLETED A COMPREHENSIVE SEARCH OF 6 DATABASES TO FIND 54 STUDIES (10,033 LEUKEMIA CASES AND 15,835 CONTROLS) FOR MTHFR 677, AND 43 STUDIES (8,868 CASES AND 14,301 CONTROLS) FOR MTHFR 1298, PUBLISHED FROM 1999 TO 2014. THE RESULTS REVEALED THAT, IN EUROPEAN POPULATIONS; CHILDHOOD POPULATIONS; CHILDREN FROM EUROPE, EAST ASIA, AND AMERICA; AND CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA (ALL), MTHFR 677 POLYMORPHISMS (BOTH TT AND CT TYPES TOGETHER AND INDIVIDUALLY) ARE PROTECTIVE, WHILE CC WILDTYPE WAS LEUKEMOGENIC. IN ADDITION, MTHFR 1298 POLYMORPHISMS WERE PROTECTIVE AGAINST ALL AND ACUTE MYELOID LEUKEMIA IN EUROPEAN CHILDREN, AND IN CHRONIC MYELOID LEUKEMIA IN ALL ADULTS WORLDWIDE AND AMERICAN ADULTS. AIR POLLUTION PLAYED A ROLE IN THE INCREASED POLYMORPHISMS OF MTHFR 677 GENOTYPES IN CHILDHOOD LEUKEMIA. 2017 19 5648 22 SEX DIFFERENCES IN OPIOID RESPONSE LINKED TO OPRM1 AND COMT GENES DNA METHYLATION/GENOTYPES CHANGES IN PATIENTS WITH CHRONIC PAIN. ANALGESIC-RESPONSE VARIABILITY IN CHRONIC NONCANCER PAIN (CNCP) HAS BEEN REPORTED DUE TO SEVERAL BIOLOGICAL AND ENVIRONMENTAL FACTORS. THIS STUDY WAS UNDERTAKEN TO EXPLORE SEX DIFFERENCES LINKED TO OPRM1 AND COMT DNA METHYLATION CHANGES AND GENETIC VARIANTS IN ANALGESIC RESPONSE. A RETROSPECTIVE STUDY WITH 250 REAL-WORLD CNCP OUTPATIENTS WAS PERFORMED IN WHICH DATA FROM DEMOGRAPHIC, CLINICAL, AND PHARMACOLOGICAL VARIABLES WERE COLLECTED. DNA METHYLATION LEVELS (CPG ISLAND) WERE EVALUATED BY PYROSEQUENCING, AND THEIR INTERACTION WITH THE OPRM1 (A118G) AND COMT (G472A) GENE POLYMORPHISMS WAS STUDIED. A PRIORI-PLANNED STATISTICAL ANALYSES WERE CONDUCTED TO COMPARE RESPONSES BETWEEN FEMALES AND MALES. SEX-DIFFERENTIAL OPRM1 DNA METHYLATION WAS OBSERVED TO BE LINKED TO LOWER OPIOID USE DISORDER (OUD) CASES FOR FEMALES (P = 0.006). PATIENTS WITH LOWER OPRM1 DNA METHYLATION AND THE PRESENCE OF THE MUTANT G-ALLELE REDUCED OPIOID DOSE REQUIREMENTS (P = 0.001), EQUAL FOR BOTH SEXES. MOREOVER, COMT DNA METHYLATION LEVELS WERE NEGATIVELY RELATED TO PAIN RELIEF (P = 0.020), QUALITY OF LIFE (P = 0.046), AND SOME ADVERSE EVENTS (PROBABILITY > 90%) SUCH AS CONSTIPATION, INSOMNIA, OR NERVOUSNESS. FEMALES WERE, SIGNIFICANTLY, 5 YEARS OLDER WITH HIGH ANXIETY LEVELS AND A DIFFERENT SIDE-EFFECTS DISTRIBUTION THAN MALES. THE ANALYSES DEMONSTRATED SIGNIFICANT DIFFERENCES BETWEEN FEMALES AND MALES RELATED TO OPRM1 SIGNALLING EFFICIENCY AND OUD, WITH A GENETIC-EPIGENETIC INTERACTION IN OPIOID REQUIREMENTS. THESE FINDINGS SUPPORT THE IMPORTANCE OF SEX AS A BIOLOGICAL VARIABLE TO BE FACTORED INTO CHRONIC PAIN-MANAGEMENT STUDIES. 2023 20 5701 21 SINGLE NUCLEOTIDE POLYMORPHISMS OF CAUDAL TYPE HOMEOBOX 1 AND 2 ARE ASSOCIATED WITH BARRETT'S ESOPHAGUS. BACKGROUND: BARRETT'S ESOPHAGUS (BE), THE PREMALIGNANT LESION OF ESOPHAGEAL ADENOCARCINOMA, IS BELIEVED TO DEVELOP AS A RESULT OF CHRONIC GASTROESOPHAGEAL REFLUX DISEASE (GERD). APPROXIMATELY 10 % OF SUBJECTS WITH GERD PROGRESS TO BE. GENETIC, EPIGENETIC AND OTHER RISK FACTORS MAY CONTRIBUTE TO THIS INTER-INDIVIDUAL VARIABILITY. CAUDAL TYPE HOMEOBOX 1 (CDX1) AND CAUDAL TYPE HOMEOBOX 2 (CDX2) PLAY IMPORTANT REGULATORY ROLES IN THE DEVELOPMENT OF HUMAN BE. AIMS: TO DETERMINE ASSOCIATIONS BETWEEN CDX1 AND CDX2 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND BE. METHODS: GENOMIC DNA WAS EXTRACTED FROM BLOOD SAMPLES COLLECTED FROM BE (N = 109) AND GERD (N = 223) PATIENTS FOR GENOTYPING OF 5 SNPS EACH OF CDX1 AND CDX2 USING TAQMAN ALLELIC DISCRIMINATION ASSAYS. ODDS RATIOS AND 95 % CONFIDENCE INTERVALS OF SNPS AND HAPLOTYPES WERE CALCULATED WITH A LOGISTIC REGRESSION MODEL ADJUSTED FOR FACTORS INCLUDING AGE, SEX AND HIATAL HERNIA. INTERACTIONS BETWEEN GENETIC VARIANTS AND THESE THREE RISK FACTORS WERE ALSO ANALYZED. RESULTS: OLDER AGE (>/=50 YEARS), MALE SEX AND HIATAL HERNIA WERE SIGNIFICANTLY ASSOCIATED WITH BE (P < 0.001). FIVE VARIANTS OF CDX1 SNPS (RS3776082, RS717746 AND RS3776083), ONE CDX1 HAPLOTYPE, AND THREE VARIANTS OF CDX2 SNPS (RS4769585 AND RS3812863) WERE ASSOCIATED WITH BE (P < 0.05). STATISTICALLY SIGNIFICANT INTERACTIONS WERE DETECTED BETWEEN MOST OF THESE SNPS AND THE THREE RISK FACTORS (P < 0.05). CONCLUSION: CERTAIN SNPS OF CDX1 AND CDX2 AND THEIR INTERACTIONS WITH OTHER RISK FACTORS ARE ASSOCIATED WITH BE, AND MAY CONTRIBUTE TO HUMAN SUSCEPTIBILITY TO BE. 2014