1  553 48 AUTOINFLAMMATORY RETINOPATHY IN CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME. CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME IS A RARE AUTOSOMAL DOMINANT AUTOINFLAMMATORY DISEASE. WE REPORT THE CASES OF MONOZYGOTIC TWINS WITH CINCA SYNDROME WHOSE PREDOMINANT OCULAR MANIFESTATION WAS INFLAMMATORY ROD-CONE RETINAL DYSTROPHY. ATYPICALLY, THERE WERE SIGNIFICANT DIFFERENCES BETWEEN TWINS IN PHENOTYPE SEVERITY, SUGGESTIVE OF EPIGENETIC DIFFERENCES AND/OR INVOLVEMENT OF ENVIRONMENTAL FACTORS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2 4492 15 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 6603 18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4 3381 12 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5 1452 16 DISCORDANT INTESTINAL MALROTATION IN ADULT MONOZYGOTIC TWINS DISCOVERED INCIDENTALLY DURING LAPAROSCOPIC GASTRIC BYPASS: A CASE REPORT AND REVIEW OF THE LITERATURE. INTRODUCTION AND IMPORTANCE: INTESTINAL MALROTATION IS AN UNCOMMON ENTITY IN THE ADULT POPULATION; MORE SO IN MONOZYGOTIC TWINS, WHERE CONCORDANCE IS EXPECTED. IN LITERATURE, DISCORDANT INTESTINAL MALROTATION HAS ONLY BEEN DISCOVERED WHEN ONE TWIN BECAME SYMPTOMATIC, AND THE OTHER WAS SCREENED. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST DOCUMENTED CASE OF DISCORDANT ADULT TYPE INTESTINAL MALROTATION IN OTHERWISE ASYMPTOMATIC MONOZYGOTIC TWINS DISCOVERED INCIDENTALLY DURING LAPAROSCOPIC ROUX-EN-Y GASTRIC BYPASS (LRYGB). CASE PRESENTATION: TWINS A AND B MET THE NIH CRITERIA FOR BARIATRIC SURGERY, NEITHER HAVING SYMPTOMS OF ACUTE OR CHRONIC VOLVULUS OR HISTORY OF INTRAABDOMINAL SURGERY. TWIN A HAD A LRYGB PERFORMED BY A TRAINED BARIATRIC SURGEON, NOTING NO ANATOMIC ANOMALIES. 5 MONTHS LATER, TWIN B HAD LRYGB AND INTESTINAL MALROTATION WAS DIAGNOSED INCIDENTALLY. CLINICAL DISCUSSION: DIAGNOSIS OF INTESTINAL MALROTATION IS RARE IN ADULTS, USUALLY DISCOVERED AFTER BECOMING SYMPTOMATIC OR DURING ABDOMINAL IMAGING FOR ANOTHER INDICATION. TWO CASES OF DISCORDANT INTESTINAL MALROTATION IN MONOZYGOTIC TWINS HAVE BEEN DOCUMENTED, BOTH DISCOVERED WHEN ONE TWIN BECAME SYMPTOMATIC DUE TO ACUTE VOLVULUS, SUGGESTING EPIGENETIC PHENOMENA. WHEN DISCOVERED INCIDENTALLY DURING SURGERY, PATIENTS CAN SAFELY UNDERGO THEIR INTENDED PROCEDURE, BUT LITERATURE SUGGESTS PROPHYLACTIC DIVISION OF LADD'S BANDS, WHILE APPENDECTOMY IS LEFT TO THE DISCRETION OF THE SURGEON. CONCLUSIONS: INTESTINAL MALROTATION APPEARS TO BE ASSOCIATED WITH EPIGENETIC PHENOMENA AND IF DISCOVERED INCIDENTALLY DURING SURGERY, THE PROPOSED PROCEDURE CAN BE CARRIED OUT BY AN EXPERIENCED SURGEON, IN ADDITION TO DIVISION OF LADD'S BANDS AND APPENDECTOMY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 4665 15 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7 6351 14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 2818  9 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550).	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9 3074 14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10 6815 11 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 3899 17 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 6484 10 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13 5511 13 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 5153 14 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15 4834 17 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS.	2022	
                                                                                                                                                                                                                                                                                                                                               
16 6636 21 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	

17 1109 13 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18  820 16 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  645 15 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 3130 14 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