1 4465 169 MOLECULAR MECHANISMS OF POSTTRAUMATIC STRESS DISORDER (PTSD) AS A BASIS FOR INDIVIDUALIZED AND PERSONALIZED THERAPY: RATIONALE, DESIGN AND METHODS OF THE SOUTH EASTERN EUROPE (SEE)-PTSD STUDY. POSTTRAUMATIC STRESS DISORDER (PTSD) IS A MAJOR HEALTH PROBLEM IN SOUTH EASTERN EUROPE (SEE). AVAILABLE TREATMENT OPTIONS ARE NOT EFFICIENT ENOUGH AND THE COURSE IS OFTEN CHRONIC. LITTLE IS KNOWN ABOUT MOLECULAR MEDIATORS AND MODERATORS OF PATHOGENESIS AND THERAPY. GENETIC AND EPIGENETIC VARIATION MAY BE ONE CENTRAL MOLECULAR MECHANISM. WE THEREFORE ESTABLISHED A CONSORTIUM COMBINING CLINICAL EXPERTISE ON PTSD FROM SEE COUNTRIES BOSNIA-HERZEGOVINA (SARAJEVO, TUZLA AND MOSTAR), KOSOVO (PRISHTINA) AND CROATIA (ZAGREB) WITH GENETIC AND EPIGENETIC COMPETENCE FROM GERMANY (WURZBURG) IN 2011 WITHIN THE FRAMEWORK OF THE DAAD (DEUTSCHER AKADEMISCHER AUSTAUSCHDIENST)-FUNDED STABILITY PACT FOR SOUTH EASTERN EUROPE. AFTER OBTAINING ETHICAL VOTES AND PERFORMING RATER TRAININGS AS WELL AS TRAINING IN DNA EXTRACTION FROM EDTA BLOOD BETWEEN 2011 AND 2013, WE RECRUITED 747 INDIVIDUALS WHO HAD EXPERIENCED WAR-RELATED TRAUMA IN THE SEE CONFLICTS BETWEEN 1991 AND 1999. 236 PARTICIPANTS HAD CURRENT PTSD, 161 LIFETIME PTSD AND 350 DID NOT HAVE AND NEVER HAD PTSD. DEMOGRAPHIC AND CLINICAL DATA ARE CURRENTLY MERGED TOGETHER WITH GENETIC AND EPIGENETIC DATA IN A SINGLE DATABASE TO ALLOW FOR A COMPREHENSIVE ANALYSIS OF THE ROLE OF GENETIC AND EPIGENETIC VARIATION IN THE PATHOGENESIS AND THERAPY OF PTSD. ANALYSES WILL BE DONE TO A GREAT DEGREE BY PHD STUDENTS FROM PARTICIPATING SEE CENTERS WHO IN ADDITION TO PARTICIPATION IN THE PROJECT HAD AN OPPORTUNITY TO TAKE PART IN SPRING AND SUMMER SCHOOLS OF THE DFG (DEUTSCHE FORSCHUNGSGEMEINSCHAFT) FUNDED RESEARCH TRAINING GROUP (RTG) 1253 AND THUS MEET PHD STUDENTS FROM GERMANY AND OTHER COUNTRIES WE ARE CONFIDENT THAT OUR PROJECT WILL NOT ONLY CONTRIBUTE TO A BETTER UNDERSTANDING OF GENETIC AND EPIGENETIC MECHANISMS OF PTSD AS A BASIS FOR FUTURE INDIVIDUALIZED AND PERSONALIZED THERAPIES, BUT ALSO TO THE ACADEMIC DEVELOPMENT OF SOUTH EASTERN EUROPE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2 3883  33 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3 5353  30 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  645  31 BIRTH DEFECTS IN GAZA: PREVALENCE, TYPES, FAMILIARITY AND CORRELATION WITH ENVIRONMENTAL FACTORS. THIS IS THE FIRST REPORT OF REGISTRATION AT BIRTH, AND OF INCIDENCE OF MAJOR STRUCTURAL BIRTH DEFECTS (BD) OBTAINED IN GAZA AT AL SHIFA HOSPITAL, WHERE 28% OF TOTAL BIRTHS IN GAZA STRIP OCCUR. DOCTORS REGISTERED 4,027 DELIVERIES, WITH A PROTOCOL COMPREHENSIVE OF CLINICAL, DEMOGRAPHIC, KIN AND ENVIRONMENTAL QUESTIONS. PREVALENCE OF BD IS 14/1,000, WITHOUT ASSOCIATION WITH INTERMARRIAGE OR GENDER OF THE CHILD. PREVALENCE OF LATE MISCARRIAGES AND STILL BIRTHS ARE RESPECTIVELY 23.3/1,000 AND 7.4/1,000, AND OF PREMATURE BIRTHS 19.6/1,000. COUPLES WITH A BD CHILD HAVE ABOUT 10 TIMES HIGHER FREQUENCY OF RECURRENCE OF A BD IN THEIR PROGENY THAN THOSE WITH NORMAL CHILDREN, BUT NONE OF THEIR 694 SIBLINGS AND ONLY 10/1,000 OF THEIR 1,423 PROGENY HAD BD, SIMILAR TO THE FREQUENCY IN GENERAL POPULATION. THESE DATA SUGGEST OCCURRENCE OF NOVEL GENETIC AND EPIGENETIC EVENTS IN DETERMINATION OF BD. CHILDREN WITH BD WERE BORN WITH HIGHER FREQUENCY (P < 0 001) IN FAMILIES WHERE ONE OR BOTH PARENTS WERE UNDER "WHITE PHOSPHORUS" ATTACK, THAT IN THE GENERAL POPULATION. BOMBING OF THE FAMILY HOME AND REMOVAL OF THE RUBBLE WERE ALSO FREQUENTLY REPORTED BY COUPLES WITH BD OCCURRENCE. THESE DATA SUGGESTS A CAUSATIVE/FAVORING ROLE OF ACUTE EXPOSURE OF PARENTS TO THE WEAPONS-ASSOCIATED CONTAMINANTS, AND/OR OF THEIR CHRONIC EXPOSURE FROM THEIR PERSISTENCE IN THE ENVIRONMENT ON THE EMBRYONIC DEVELOPMENT OF THEIR CHILDREN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5 4492  26 MONOZYGOTIC TWINS DISCORDANT FOR ROHHAD PHENOTYPE. RAPID-ONSET OBESITY WITH HYPOTHALAMIC DYSFUNCTION, HYPOVENTILATION, AND AUTONOMIC DYSREGULATION (ROHHAD) FALLS WITHIN A GROUP OF PEDIATRIC DISORDERS WITH BOTH RESPIRATORY CONTROL AND AUTONOMIC NERVOUS SYSTEM DYSREGULATION. CHILDREN WITH ROHHAD TYPICALLY PRESENT AFTER 1.5 YEARS OF AGE WITH RAPID WEIGHT GAIN AS THE INITIAL SIGN. SUBSEQUENTLY, THEY DEVELOP ALVEOLAR HYPOVENTILATION, AUTONOMIC NERVOUS SYSTEM DYSREGULATION, AND, IF UNTREATED, CARDIORESPIRATORY ARREST. TO OUR KNOWLEDGE, THIS IS THE FIRST REPORT OF DISCORDANT PRESENTATION OF ROHHAD IN MONOZYGOTIC TWINS. TWIN GIRLS, BORN AT TERM, HAD CONCORDANT GROWTH AND DEVELOPMENT UNTIL 8 YEARS OF AGE. FROM 8 TO 12 YEARS OF AGE, THE AFFECTED TWIN DEVELOPED FEATURES CHARACTERISTIC OF ROHHAD INCLUDING OBESITY, ALVEOLAR HYPOVENTILATION, SCOLIOSIS, HYPOTHALAMIC DYSFUNCTION (CENTRAL DIABETES INSIPIDUS, HYPOTHYROIDISM, PREMATURE PUBARCHE, AND GROWTH HORMONE DEFICIENCY), RIGHT PARASPINAL/THORACIC GANGLIONEUROBLASTOMA, SEIZURES, AND AUTONOMIC DYSREGULATION INCLUDING ALTERED PAIN PERCEPTION, LARGE AND SLUGGISHLY REACTIVE PUPILS, HYPOTHERMIA, AND PROFOUND BRADYCARDIA THAT REQUIRED A CARDIAC PACEMAKER. RESULTS OF GENETIC TESTING FOR PHOX2B (CONGENITAL CENTRAL HYPOVENTILATION SYNDROME DISEASE-DEFINING GENE) MUTATIONS WERE NEGATIVE. WITH EARLY RECOGNITION AND CONSERVATIVE MANAGEMENT, THE AFFECTED TWIN HAD EXCELLENT NEUROCOGNITIVE OUTCOME THAT MATCHED THAT OF THE UNAFFECTED TWIN. THE UNAFFECTED TWIN DEMONSTRATED RAPID WEIGHT GAIN LATER IN AGE BUT NOT DEVELOPMENT OF SIGNS/SYMPTOMS CONSISTENT WITH ROHHAD. THIS DISCORDANT TWIN PAIR DEMONSTRATES KEY FEATURES OF ROHHAD INCLUDING THE IMPORTANCE OF EARLY RECOGNITION (ESPECIALLY HYPOVENTILATION), COMPLEXITY OF SIGNS/SYMPTOMS AND CLINICAL COURSE, AND IMPORTANCE OF INITIATING COMPREHENSIVE, MULTISPECIALTY CARE. THESE CASES CONFOUND THE HYPOTHESIS OF A MONOGENIC ETIOLOGY FOR ROHHAD AND INDICATE ALTERNATIVE ETIOLOGIES INCLUDING AUTOIMMUNE OR EPIGENETIC PHENOMENON OR A COMBINATION OF GENETIC PREDISPOSITION AND ACQUIRED PRECIPITANT.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 5356  24 REAC-INDUCED ENDOGENOUS BIOELECTRIC CURRENTS IN THE TREATMENT OF VENOUS ULCERS: A THREE-ARM RANDOMIZED CONTROLLED PROSPECTIVE STUDY. INTRODUCTION: ENDOGENOUS BIOELECTRIC FIELDS (EBFS) PLAY A FUNDAMENTAL ROLE IN PROMOTING REPAIR AND REGENERATION PROCESSES, INCLUDING IN LEG VENOUS ULCERS (LVUS). UNFORTUNATELY, THE MECHANISM UNDERLYING THE PRODUCTION OF EBFS IS EASILY ALTERED BY INFECTIOUS, TRAUMATIC, AND EPIGENETIC FACTORS. THIS ALTERATION IS ONE OF THE DETERMINING FACTORS FOR THE CHRONICITY OF LVUS. THIS STUDY INVESTIGATES HOW RADIOELECTRIC ASYMMETRIC CONVEYER (REAC) TECHNOLOGY TREATMENTS, SPECIFICALLY DESIGNED TO OPTIMIZE EBFS, AND IN PARTICULAR TISSUE OPTIMIZATION-REPARATIVE (TO-RPR) TREATMENT, CAN IMPROVE THE RESULTS OF STANDARD DRESSING WITH AND WITHOUT ELASTIC COMPRESSION IN LVU PATIENTS. METHODS: A TOTAL OF 30 PATIENTS WERE ENROLLED (12 MALES AND 18 FEMALES) AND RANDOMIZED INTO THREE GROUPS. ALL PATIENTS COMPLETED THE STUDY. GROUP A WAS TREATED WITH STANDARD DRESSING, ELASTIC COMPRESSION, AND REAC TO-RPR TREATMENT; GROUP B WAS TREATED WITH STANDARD DRESSING AND REAC TO-RPR TREATMENT; AND GROUP C WAS TREATED WITH STANDARD DRESSING AND ELASTIC COMPRESSION. RESULTS: THE RESULTS SHOW THAT THE COMBINATION OF REAC TREATMENT AND STANDARD DRESSING ASSOCIATED WITH ELASTIC COMPRESSION HAS THE GREATEST THERAPEUTIC EFFICACY IN PROMOTING THE HEALING PROCESS FOR ULCERS, REDUCING PERCEIVED PAIN, AND IMPROVING THE QUALITY OF LIFE OF THE PATIENTS TREATED. CONCLUSIONS: FURTHER STUDIES WILL BE USEFUL TO INVESTIGATE THESE PROSPECTIVE RESULTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7 6490  25 TRACING SLOW PHENOPTOSIS TO THE PRENATAL STAGE IN SOCIAL VERTEBRATES. VLADIMIR SKULACHEV'S COINING OF THE TERM "PHENOPTOSIS" 25 YEARS AGO (SKULACHEV, V. P., BIOCHEMISTRY (MOSCOW), 62, 1997) HIGHLIGHTED THE THEORETICAL POSSIBILITY THAT AGING IS A PROGRAMMED PROCESS TO SPEED THE EXIT OF INDIVIDUALS POSING SOME DANGER TO THEIR SOCIAL GROUP. WHILE RAPID "ACUTE PHENOPTOSIS" MIGHT OCCUR AT ANY AGE (E.G., TO PREVENT SPREAD OF DEADLY INFECTIONS), "SLOW PHENOPTOSIS" IS GENERALLY CONSIDERED TO OCCUR LATER IN LIFE IN THE FORM OF CHRONIC AGE-RELATED DISORDERS. HOWEVER, RECENT RESEARCH INDICATES THAT RISKS FOR SUCH CHRONIC DISORDERS CAN BE GREATLY RAISED BY EARLY LIFE ADVERSITY, ESPECIALLY DURING THE PRENATAL STAGE. MUCH OF THIS RESEARCH USES INDICATORS OF BIOLOGICAL AGING, THE SPEEDING OR SLOWING OF NATURAL PHYSIOLOGICAL DETERIORATION IN RESPONSE TO ENVIRONMENTAL INPUTS, LEADING TO DIVERGENCE FROM CHRONOLOGICAL AGE. STUDIES USING BIOLOGICAL AGING INDICATORS COMMONLY FIND IT IS ACCELERATED NOT ONLY IN OLDER INDIVIDUALS WITH CHRONIC DISORDERS, BUT ALSO IN VERY YOUNG INDIVIDUALS WITH HEALTH PROBLEMS. THIS REVIEW WILL EXPLAIN HOW ACCELERATED BIOLOGICAL AGING EQUATES TO SLOW PHENOPTOSIS. ITS OCCURRENCE EVEN IN THE PRENATAL STAGE IS THEORETICALLY SUPPORTED BY W. D. HAMILTON'S PROPOSAL THAT OFFSPRINGS DETECTING THEY HAVE DANGEROUS MUTATIONS SHOULD THEN AUTOMATICALLY SPEED THEIR DEMISE, IN ORDER TO IMPROVE THEIR INCLUSIVE FITNESS BY GIVING THEIR PARENTS THE CHANCE TO PRODUCE OTHER FITTER SIBLINGS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 5001  30 PERINATAL RISK FACTORS IN TOURETTE'S AND CHRONIC TIC DISORDERS: A TOTAL POPULATION SIBLING COMPARISON STUDY. ADVERSE PERINATAL EVENTS MAY INCREASE THE RISK OF TOURETTE'S AND CHRONIC TIC DISORDERS (TD/CTD), BUT PREVIOUS STUDIES HAVE BEEN UNABLE TO CONTROL FOR UNMEASURED ENVIRONMENTAL AND GENETIC CONFOUNDING. WE AIMED TO PROSPECTIVELY INVESTIGATE POTENTIAL PERINATAL RISK FACTORS FOR TD/CTD, TAKING UNMEASURED FACTORS SHARED BETWEEN FULL SIBLINGS INTO ACCOUNT. A POPULATION-BASED BIRTH COHORT, CONSISTING OF ALL SINGLETONS BORN IN SWEDEN IN 1973-2003, WAS FOLLOWED UNTIL DECEMBER 2013. A TOTAL OF 3 026 861 INDIVIDUALS WERE IDENTIFIED, 5597 OF WHICH HAD A REGISTERED TD/CTD DIAGNOSIS. WE THEN STUDIED DIFFERENTIALLY EXPOSED FULL SIBLINGS FROM 947 942 FAMILIES; OF THESE, 3563 FAMILIES INCLUDED SIBLINGS THAT WERE DISCORDANT FOR TD/CTD. PERINATAL DATA WERE COLLECTED FROM THE MEDICAL BIRTH REGISTER AND TD/CTD DIAGNOSES WERE COLLECTED FROM THE NATIONAL PATIENT REGISTER, USING A PREVIOUSLY VALIDATED ALGORITHM. IN THE FULLY ADJUSTED MODELS, IMPAIRED FETAL GROWTH, PRETERM BIRTH, BREECH PRESENTATION AND CESAREAN SECTION WERE ASSOCIATED WITH A HIGHER RISK OF TD/CTD, LARGELY INDEPENDENT FROM SHARED FAMILY CONFOUNDERS AND MEASURED COVARIATES. MATERNAL SMOKING DURING PREGNANCY WAS ASSOCIATED WITH RISK OF TD/CTD IN A DOSE-RESPONSE MANNER BUT THE ASSOCIATION WAS NO LONGER STATISTICALLY SIGNIFICANT IN THE SIBLING COMPARISON MODELS OR AFTER THE EXCLUSION OF COMORBID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. A DOSE-RESPONSE RELATIONSHIP BETWEEN THE NUMBER OF ADVERSE PERINATAL EVENTS AND INCREASED RISK FOR TD/CTD WAS ALSO OBSERVED, WITH HAZARD RATIOS RANGING FROM 1.41 (95% CONFIDENCE INTERVAL (CI): 1.33-1.50) FOR ONE EVENT TO 2.42 (95% CI: 1.65-3.53) FOR FIVE OR MORE EVENTS. THESE RESULTS PAVE THE WAY FOR FUTURE GENE BY ENVIRONMENT INTERACTION AND EPIGENETIC STUDIES IN TD/CTD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 1109  26 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 6914  23 [VITAMIN D DEFICIENCY IN PREGNANCY AND ITS IMPACT ON THE FETUS, THE NEWBORN AND IN CHILDHOOD]. OBJECTIVE: VITAMIN D DEFICIENCY (VDD) IN PREGNANT WOMEN AND THEIR CHILDREN IS AN IMPORTANT HEALTH PROBLEM WITH SEVERE CONSEQUENCES FOR THE HEALTH OF BOTH. THUS, THE OBJECTIVES OF THIS REVIEW WERE TO REASSESS THE MAGNITUDE AND CONSEQUENCES OF VDD DURING PREGNANCY, LACTATION AND INFANCY, ASSOCIATED RISK FACTORS, PREVENTION METHODS, AND TO EXPLORE EPIGENETIC MECHANISMS IN EARLY FETAL LIFE CAPABLE OF EXPLAINING MANY OF THE NON-SKELETAL BENEFITS OF VITAMIN D (VID). DATA SOURCE: ORIGINAL AND REVIEW ARTICLES, AND CONSENSUS DOCUMENTS WITH ELEVATED LEVEL OF EVIDENCE FOR VDD-RELATED CLINICAL DECISIONS ON THE HEALTH OF PREGNANT WOMEN AND THEIR CHILDREN, AS WELL AS ARTICLES ON THE INFLUENCE OF VID ON EPIGENETIC MECHANISMS OF FETAL PROGRAMMING OF CHRONIC DISEASES IN ADULTHOOD WERE SELECTED AMONG ARTICLES PUBLISHED ON PUBMED OVER THE LAST 20 YEARS, USING THE SEARCH TERM VITD STATUS, IN COMBINATION WITH PREGNANCY, OFFSPRING HEALTH, CHILD OUTCOMES, AND PROGRAMMING. DATA SYNTHESIS: THE FOLLOWING ITEMS WERE ANALYZED: VID PHYSIOLOGY AND METABOLISM, RISK FACTORS FOR VDD AND IMPLICATIONS IN PREGNANCY, LACTATION AND INFANCY, CONCENTRATION CUTOFF TO DEFINE VDD, THE VARIABILITY OF METHODS FOR VDD DETECTION, RECOMMENDATIONS ON VID REPLACEMENT IN PREGNANT WOMEN, THE NEWBORN AND THE CHILD, AND THE EPIGENETIC INFLUENCE OF VID. CONCLUSIONS: VDD IS A COMMON CONDITION AMONG HIGH-RISK PREGNANT WOMEN AND THEIR CHILDREN. THE ROUTINE MONITORING OF SERUM 25(OH)D3 LEVELS IN ANTENATAL PERIOD IS MANDATORY. EARLY PREVENTIVE MEASURES SHOULD BE TAKEN AT THE SLIGHTEST SUSPICION OF VDD IN PREGNANT WOMEN, TO REDUCE MORBIDITY DURING PREGNANCY AND LACTATION, AS WELL AS ITS SUBSEQUENT IMPACT ON THE FETUS, THE NEWBORN AND THE CHILD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11 6484  27 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC).	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 3074  26 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 6911  27 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 3381  25 HLA AND AUTOIMMUNE DISEASES: TYPE 1 DIABETES (T1D) AS AN EXAMPLE. AUTOIMMUNE DISEASES NEED TO BE CONSIDERED AT A GENETIC AND MECHANISTIC LEVEL. T1D IS AN AUTOIMMUNE, CHRONIC, MULTIFACTORIAL AND POLYGENIC DISEASE CHARACTERIZED BY THE DESTRUCTION OF THE PANCREATIC BETA-CELLS ASSOCIATED WITH LONG TERM DYSFUNCTION OF SEVERAL ORGANS AND TISSUES. MECHANISMS OF SUSCEPTIBILITY INCLUDE EPI-GENETIC AND POST-TRANSCRIPTIONAL EFFECTS THAT REGULATE TRANSMISSION AND EXPRESSION OF THE INHERITED GENES. THE HLA COMPLEX, CONSTITUTES THE MOST RELEVANT REGION CONTRIBUTING 50% OF THE INHERITED RISK FOR T1D. AN ADDITIONAL 17 GENES WITH VARIABLE BUT SMALL EFFECTS HAVE BEEN DESCRIBED. IN NON-CAUCASIANS, THE PRESENCE OF E-DRBETA1-74 AND/OR D-DRBETA1-57 ARE RELEVANT IN PREDISPOSITION. THE "DIABETOGENIC HAPLOTYPES" IN MEXICANS WERE DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) AND THE SAME DQA1/DQB1 WITH DRB1*0404/*0401 CONFERRING LOWER RISK, INCREASING (OR = 61.3) WITH AN EARLY AGE AT ONSET AND A HETEROZYGOTE DR3/DR4 GENOTYPE. IN MOST POPULATIONS, THE ABSENCE OF D-57 AND THE PRESENCE OF R-52 ARE IMPORTANT TO THE SUSCEPTIBILITY, BUT IN HISPANICS, ALL DR4S (INCLUDING THE PROTECTIVE DRB1*0403/*0407/*0411) ARE IN LINKAGE DISEQUILIBRIUM WITH DQA1/DQB1 SUSCEPTIBILITY ALLELES. THUS, SUSCEPTIBILITY ALLELES IN LATIN AMERICAN MESTIZOS ARE OF MEDITERRANEAN ANCESTRY WHEREAS PROTECTIVE ALLELES ARE OF AMERINDIAN ORIGIN. IN THIS REVIEW, WE DISCUSS THE COMPLEXITY OF T1D AND SOME ASPECTS OF PREVENTION/INTERVENTION BASED ON IMMUNOGENETICS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 1448  36 DIPEPTIDYL PEPTIDASE-4 INHIBITION AND NARROW-BAND ULTRAVIOLET-B LIGHT IN PSORIASIS (DINUP): STUDY PROTOCOL FOR A RANDOMISED CONTROLLED TRIAL. BACKGROUND: MODERATE TO SEVERE PSORIASIS IS A SYSTEMIC INFLAMMATORY DISEASE ASSOCIATED WITH INSULIN RESISTANCE, OBESITY AND TYPE 2 DIABETES (T2DM). SITAGLIPTIN IS A DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THAT IMPROVES GLYCAEMIA AND HAS A MARKETING AUTHORISATION FOR THE TREATMENT OF T2DM. NON-IMMUNOSUPPRESSIVE THERAPIES THAT ARE EFFECTIVE FOR PSORIASIS AND ITS ASSOCIATED COMORBIDITIES WOULD BE A SIGNIFICANT ADVANCE IN THE TREATMENT OF THIS CHRONIC DISEASE. METHODS/DESIGN: THIS IS A SINGLE CENTRE, 39-WEEK, PROSPECTIVE, RANDOMISED, OPEN LABEL, CLINICAL TRIAL OF ORAL SITAGLIPTIN (JANUVIA((R))) IN PSORIASIS PATIENTS WHO ARE DUE TO UNDERGO A COURSE OF NARROW-BAND ULTRAVIOLET-B (NB-UVB) PHOTOTHERAPY. WE PLAN TO ENROL 120 PARTICIPANTS AND ALLOCATE PARTICIPANTS ON A RANDOM AND 1:1 BASIS TO RECEIVE SITAGLIPTIN 100 MG DAILY FOR 24 WEEKS COMBINED WITH NB-UVB OR NB-UVB MONOTHERAPY. PARTICIPANTS WILL BE FOLLOWED UP FOR 12 WEEKS AFTER SITAGLIPTIN THERAPY IS DISCONTINUED. THE PRIMARY ENDPOINT IS THE CHANGE IN PSORIASIS AREA AND SEVERITY INDEX (PASI) 24 WEEKS AFTER TREATMENT INITIATION. SECONDARY ENDPOINTS INCLUDE CUMULATIVE NB-UVB DOSE, NUMBER OF NB-UVB TREATMENTS REQUIRED TO CLEAR PSORIASIS, PROPORTIONS OF PARTICIPANTS WHO ACHIEVE PASI-50 (50 % REDUCTION IN PASI FROM BASELINE), PASI-75, PASI-90 AND THE PROPORTION OF PARTICIPANTS WHO RELAPSE IN EACH GROUP. WE WILL ALSO ANALYSE CHANGES IN CARDIOVASCULAR DISEASE RISK FACTORS, SERUM CYTOKINE AND HORMONE LEVELS AND PERIPHERAL BLOOD MONONUCLEAR EXPRESSION OF IMMUNE PROTEINS AT 24 AND 36 WEEKS. A SUBGROUP OF PARTICIPANTS WILL HAVE SKIN BIOPSIES TAKEN AND ANALYSED FOR SKIN LEVELS AND EXPRESSION OF IMMUNE CELLS, RECEPTORS, HORMONES AND IMMUNE PROTEINS. THE GENETIC OR EPIGENETIC PROFILE THAT PREDICTS BEST RESPONSE TO DPP-4 INHIBITOR THERAPY WILL BE ANALYSED. THE SAFETY ENDPOINTS INCLUDE THE RATE AND SEVERITY OF ADVERSE EVENTS. DISCUSSION: THIS IS THE FIRST RANDOMISED CLINICAL TRIAL ASSESSING DIPEPTIDYL PEPTIDASE-4 INHIBITION THERAPY IN PSORIASIS. WE HYPOTHESISE THAT SITAGLIPTIN THERAPY IN COMBINATION WITH NB-UVB IMPROVES PSORIASIS SEVERITY COMPARED TO NB-UVB MONOTHERAPY. TRIAL REGISTRATION: CLINICALTRIALS.GOV IDENTIFIER NCT02347501 (DATE OF REGISTRATION: 27 JANUARY 2015).	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16 6351  30 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 3130  36 GLAST BUT NOT LEAST--DISTRIBUTION, FUNCTION, GENETICS AND EPIGENETICS OF L-GLUTAMATE TRANSPORT IN BRAIN--FOCUS ON GLAST/EAAT1. SYNAPTICALLY RELEASED L-GLUTAMATE, THE MOST IMPORTANT EXCITATORY NEUROTRANSMITTER IN THE CNS, IS REMOVED FROM EXTRACELLULAR SPACE BY FAST AND EFFICIENT TRANSPORT MEDIATED BY SEVERAL TRANSPORTERS; THE MOST ABUNDANT ONES ARE EAAT1/GLAST AND EAAT2/GLT1. THE REVIEW FIRST SUMMARIZES THEIR LOCATION, FUNCTIONS AND BASIC CHARACTERISTICS. WE THEN LOOK AT GENETICS AND EPIGENETICS OF EAAT1/GLAST AND EAAT2/GLT1 AND PERFORM IN SILICO ANALYSES OF THEIR PROMOTER REGIONS. THERE IS ONE CPG ISLAND IN SLC1A2 (EAAT2/GLT1) GENE AND NONE IN SLC1A3 (EAAT1/GLAST) SUGGESTING THAT DNA METHYLATION IS NOT THE MOST IMPORTANT EPIGENETIC MECHANISM REGULATING EAAT1/GLAST LEVELS IN BRAIN. THERE ARE TARGETS FOR SPECIFIC MIRNA IN SLC1A2 (EAAT2/GLT1) GENE. WE ALSO NOTE THAT WHILE DEFECTS IN EAAT2/GLT1 HAVE BEEN ASSOCIATED WITH VARIOUS PATHOLOGICAL STATES INCLUDING CHRONIC NEURODEGENERATIVE DISEASES, VERY LITTLE IS KNOWN ON POSSIBLE CONTRIBUTIONS OF DEFECTIVE OR DYSFUNCTIONAL EAAT1/GLAST TO ANY SPECIFIC BRAIN DISEASE. FINALLY, WE REVIEW EVIDENCE OF EAAT1/GLAST INVOLVEMENT IN MECHANISMS OF BRAIN RESPONSE TO ALCOHOLISM AND PRESENT SOME PRELIMINARY DATA SHOWING THAT ETHANOL, AT CONCENTRATIONS WHICH MAY BE REACHED FOLLOWING HEAVY DRINKING, CAN HAVE AN EFFECT ON THE DISTRIBUTION OF EAAT1/GLAST IN CULTURED ASTROCYTES; THE EFFECT IS BLOCKED BY BACLOFEN, A GABA-B RECEPTOR AGONIST AND A DRUG POTENTIALLY USEFUL IN THE TREATMENT OF ALCOHOLISM. WE ARGUE THAT MORE RESEARCH EFFORT SHOULD BE FOCUSED ON EAAT1/GLAST, PARTICULARLY IN RELATION TO ALCOHOLISM AND DRUG ADDICTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18 6835  22 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 6636  39 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	

20 6603  27 TWO SISTERS WITH FAMILIAL MEDITERRANEAN FEVER: LACK OF CORRELATION BETWEEN GENOTYPE AND PHENOTYPE? FAMILIAL MEDITERRANEAN FEVER (FMF) IS AN AUTOSOMAL RECESSIVE DISORDER CHARACTERIZED BY ATTACKS OF FEVER AND SEROSITIS. THE MOST IMPORTANT COMPLICATION OF FMF IS RENAL AMYLOIDOSIS, WHICH DETERMINES THE PROGNOSIS. THE GENE CODING THE DISEASE (MEFV) IS IDENTIFIED ON THE 16TH CHROMOSOME. THE MOST COMMON MEFV MUTATIONS ARE M694V, M680I, V726A AND M694I LOCATED ON EXON 10 AND E148Q LOCATED ON EXON 2. UNFORTUNATELY, GENOTYPE-PHENOTYPE CORRELATION IS NOT WELL ESTABLISHED AND THERE ARE UNEXPLAINED ETHNIC DIFFERENCES IN AMYLOIDOSIS RATES. WE REPORT TWO SISTERS WITH A COMMON GENOTYPE (M694V/M694V) PRESENTING WITH DIFFERENT PHENOTYPIC CHARACTERISTICS: ONE COMPLAINING OF INTERMITTENT ABDOMINAL PAIN, ARTHRITIS AND FEVER, WHILE THE OTHER WAS SUFFERING FROM INTERMITTENT PLEURITIS AND FEVER DURING ATTACKS. THE OBSERVATION OF DIFFERENT PHENOTYPIC PRESENTATIONS WITH A COMMON GENOTYPE IN TWO FAMILY MEMBERS SHOWS THAT DIFFERENT PHENOTYPES CANNOT BE EXPLAINED BY PARTICULAR MUTATIONS. TO UNDERSTAND THE CORRELATION BETWEEN GENOTYPIC AND PHENOTYPIC FMF VARIANTS THE EXISTENCE OF COMPLEX ALLELES, MODIFIER LOCI, GENETIC HETEROGENEITY AND POSSIBLE EPIGENETIC FACTORS SHOULD BE STUDIED EXTENSIVELY.	2006