1  4101 78 MDCT AND MR UROGRAM SPECTRUM OF CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT DIAGNOSED IN ADULTHOOD. OBJECTIVE: CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) ENCOMPASS A SPECTRUM OF ANOMALIES THAT RESULT FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND MOLECULAR SIGNAL ABERRATIONS AT KEY STAGES OF URINARY TRACT DEVELOPMENT. CAKUT CAN BE SEEN INCIDENTALLY ON CROSS-SECTIONAL IMAGING OF THE ABDOMEN OR CAN BE A CAUSE FOR ADULT-ONSET CHRONIC KIDNEY DISEASE, POSING NEW CHALLENGES FOR NEPHROLOGISTS, UROLOGISTS, AND RADIOLOGISTS. CONCLUSION: AWARENESS OF CAKUT AND FAMILIARITY WITH THEIR IMAGING FINDINGS PERMIT OPTIMAL PATIENT MANAGEMENT AND THOROUGH WORKUP TO PREVENT HYPERTENSION AND PROGRESSION FROM CAKUT TO RENAL FAILURE. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE CROSS-SECTIONAL IMAGING FINDINGS OF CAKUT THAT MAY PRESENT IN ADULTHOOD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  6817 21 [FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY: REPORT OF SEVEN PATIENTS]. BACKGROUND: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY IS THE THIRD MOST COMMON MUSCULAR DYSTROPHY WITH AN ESTIMATED PREVALENCE OF 1 PER 20.000 AND A NORMAL LIFE EXPECTANCY IN THE MAJORITY OF PATIENTS. HOWEVER, APPROXIMATELY 15% OF PATIENTS BECOME WHEELCHAIR BOUND IN THE COURSE OF THEIR LIFE. IT IS A HEREDITARY AUTOSOMAL DOMINANT DISEASE WITH HIGH (95%) PENETRANCE BY THE AGE OF 20, BUT WITH VARIABLE DEGREE OF PHENOTYPIC EXPRESSION EVEN IN THE SAME FAMILY GROUP. SYMPTOMS FREQUENTLY START IN THE SECOND DECADE OF LIFE, WITH FACIAL AND SCAPULAR WEAKNESS. AIM: TO REPORT THE CLINICAL FEATURES OF SEVEN PATIENTS WITH THE DISEASE, SEEN AT A PUBLIC HOSPITAL. MATERIAL AND METHODS: ANALYSIS OF SEVEN PATIENTS WITH GENETIC STUDY SEEN IN A PUBLIC HOSPITAL IN SANTIAGO. RESULTS: THE AGE OF PATIENTS FLUCTUATED FROM 18 TO 61 YEARS AND FOUR WERE FEMALES. THE MEAN AGE AT ONSET OF SYMPTOMS WAS 29 YEARS AND FOUR HAD A FAMILY HISTORY OF THE DISEASE. THE USUAL PRESENTING COMPLAINT WAS ARM OR SHOULDER ASYMMETRIC WEAKNESS. FOUR PATIENTS HAD BONE PAIN. FACIAL INVOLVEMENT WAS PRESENT IN FOUR. A GENETIC STUDY WAS DONE IN FIVE PATIENTS, THE OTHER TWO PATIENTS WERE RELATIVES, CONFIRMING THE CONTRACTION OR LOWER NUMBER OF REPETITIONS IN D4Z4 REGION. AFTER 12 YEARS OF FOLLOW UP ONLY 2 PATIENTS OLDER THAN 60 YEARS CANNOT WORK AND ONE FEMALE PATIENTS IS IN A SEMI DEPENDENT STATE AT THE AGE OF 30. CONCLUSIONS: THE CLINICAL WORKUP IN THE DIAGNOSIS AND THE TIMELY INDICATION OF GENETIC STUDIES ARE HIGHLIGHTED, TO AVOID UNNECESSARY AND INVASIVE PROCEDURES. THE VARIABILITY IN THE PHENOTYPIC EXPRESSION IN A SIMILAR GENETIC DEFECT IS DISCUSSED AND THE GENETIC OR EPIGENETIC MECHANISMS OF THIS MUSCULAR DYSTROPHY ARE DESCRIBED.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  4052 19 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  6160 33 THE GENETICS AND PATHOGENESIS OF CAKUT. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) COMPRISE A LARGE VARIETY OF MALFORMATIONS THAT ARISE FROM DEFECTIVE KIDNEY OR URINARY TRACT DEVELOPMENT AND FREQUENTLY LEAD TO KIDNEY FAILURE. THE CLINICAL SPECTRUM RANGES FROM SEVERE MALFORMATIONS, SUCH AS RENAL AGENESIS, TO POTENTIALLY MILDER MANIFESTATIONS, SUCH AS VESICOURETERAL REFLUX. ALMOST 50% OF CASES OF CHRONIC KIDNEY DISEASE THAT MANIFEST WITHIN THE FIRST THREE DECADES OF LIFE ARE CAUSED BY CAKUT. EVIDENCE SUGGESTS THAT A LARGE NUMBER OF CAKUT ARE GENETIC IN ORIGIN. TO DATE, MUTATIONS IN ~54 GENES HAVE BEEN IDENTIFIED AS MONOGENIC CAUSES OF CAKUT, CONTRIBUTING TO 12-20% OF THE AETIOLOGY OF THE DISEASE. PATHOGENIC COPY NUMBER VARIANTS HAVE ALSO BEEN SHOWN TO CAUSE CAKUT AND CAN BE DETECTED IN 4-11% OF PATIENTS. FURTHERMORE, ENVIRONMENTAL AND EPIGENETIC FACTORS CAN INCREASE THE RISK OF CAKUT. THE DISCOVERY OF NOVEL CAKUT-CAUSING GENES IS CHALLENGING OWING TO VARIABLE EXPRESSIVITY, INCOMPLETE PENETRANCE AND VARIABLE GENOTYPE-PHENOTYPE CORRELATION. HOWEVER, SUCH A DISCOVERY COULD ULTIMATELY LEAD TO IMPROVEMENTS IN THE ACCURATE MOLECULAR GENETIC DIAGNOSIS, ASSESSMENT OF PROGNOSIS AND MULTIDISCIPLINARY CLINICAL MANAGEMENT OF PATIENTS WITH CAKUT, POTENTIALLY INCLUDING PERSONALIZED THERAPEUTIC APPROACHES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  3788 16 INTERLEUKIN 1 ALPHA (IL1A) POLYMORPHISMS AND RISK OF ENDOMETRIOSIS IN IRANIAN POPULATION: A CASE-CONTROL STUDY. ENDOMETRIOSIS IS ONE OF THE MOST COMMON GYNECOLOGICAL DISEASES AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS INFLUENCED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. RECENTLY, GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED A STRONG ASSOCIATION BETWEEN IL1A SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND INCREASED RISK OF ENDOMETRIOSIS IN JAPANESE WOMEN. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ASSOCIATION OF THREE IL1A SNPS, RS17561, RS1304037, AND RS2856836 WITH THE RISK OF ENDOMETRIOSIS IN IRANIAN POPULATION. TOTALLY, 105 WOMEN WITH DIAGNOSIS OF ENDOMETRIOSIS AND 102 HEALTHY WOMEN AS CONTROL GROUP WERE INCLUDED. THREE SNPS OF THE IL1A, RS17561 G/T, RS1304037 A/G, AND RS2856836 T/C, WERE GENOTYPED BY PCR AND RFLP. THE RS2856836 TC GENOTYPE WAS SIGNIFICANTLY HIGHER (P = .002; OR = 3.1, 95% CI: 1.5-6.5) IN THE PATIENTS (28.1%) THAN THE CONTROL GROUP (12.7%). THE RS2856836 CC GENOTYPE WAS SIGNIFICANTLY HIGHER (P = .047; OR = 2.3, 95% CI: 1.0-5.3) IN THE PATIENTS (17.5%) THAN THE CONTROL GROUP (10.8%). THE RS2856836 C ALLELE WAS SIGNIFICANTLY HIGHER (P = .001; OR = 2.2, 95% CI: 1.4-3.6) IN THE PATIENTS (31.6%) THAN THE CONTROL GROUP (17.2%). THE IL1A RS2856836 T/C SNP WAS ASSOCIATED WITH SUSCEPTIBILITY TO ENDOMETRIOSIS AND THE RS2856836 C ALLELE MAY INCREASE THE RISK OF ENDOMETRIOSIS IN IRANIAN WOMEN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6  1452 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  3903 21 LEP, LDLR AND APOA4 GENE POLYMORPHISMS AND THEIR RELATIONSHIP WITH THE RISK OF OVERWEIGHT, OBESITY AND CHRONIC DISEASES IN ADULTS OF THE STATE OF SUCRE, VENEZUELA. INTRODUCTION: OVERWEIGHT, OBESITY AND SOME CHRONIC DISEASES HAVE BECOME MORE PREVALENT RECENTLY. IT IS WELL KNOWN THAT THEIR CAUSES MAY BE GENETIC, EPIGENETIC, ENVIRONMENTAL, OR A MIXTURE OF THESE. OBJECTIVE: TO ANALYZE THE RELATIONSHIP BETWEEN NINE SINGLE NUCLEOTIDE POLYMORPHISMS OF GENES LEP (RS2167270), LDLR (RS885765, RS688, RS5925, RS55903358, RS5742911) AND APOA4 (RS5095, RS675, RS5110) WITH OBESITY-RELATED PHENOTYPES AND OTHER COMORBIDITIES. MATERIAL AND METHODS: WE RECRUITED 144 ADULTS (76 MALES AND 68 FEMALES, WITH AVERAGE AGES OF 29.93+/-8.29 AND 32.49+/-11.15 YEARS, RESPECTIVELY) IN THE STATE OF SUCRE, VENEZUELA. CLINICAL AND ANTHROPOMETRIC PARAMETERS WERE OBTAINED. GENOTYPE-RISK ASSOCIATIONS WERE STUDIED. WE THEN COMPARED THE AVERAGES REGISTERED FOR ANTHROPOMETRIC AND BIOCHEMICAL VARIABLES PREVIOUSLY ADJUSTED FOR BIOLOGICAL AND ENVIRONMENTAL FACTORS. RESULTS: ACCORDING TO THE BODY MASS INDEX, 38.9% OF THE INDIVIDUALS IN THE SAMPLE WERE OVERWEIGHT (25</=BMI</=29.9 KG/M2) AND 20.1% WERE OBESE (BMI>/=30 KG/M2). GENOTYPE AND ALLELE FREQUENCIES DID NOT DIFFER STATISTICALLY FOR GROUPS WITH NORMAL AND HIGH BODY MASS INDEX (OVERWEIGHT PLUS OBESITY). THE ASSOCIATION BETWEEN LDLR RS5742911 ANCESTRAL GENOTYPE A/A AND HIGH RISK CONDITION RELATED TO HDL-CHOLESTEROL WAS THE ONLY ONE FOUND TO BE SIGNIFICANT (OR=2.944, 95% CI: 1.446-5.996; P=0.003). THE DIFFERENCE IN ADJUSTED MEAN HDL-CHOLESTEROL FOR LDLR RS5742911 GENOTYPES WAS STATISTICALLY SIGNIFICANT (P=0.005) (A/A: 41.50+/-14.81 MG/DL; A/G: 45.00+/-12.07 MG/DL; G/G: 47.17+/-9.43 MG/DL). CONCLUSIONS: FOR MOST OF THE GENETIC VARIANTS STUDIED, THERE WAS AN ASSOCIATION WITH THE PRESENCE OF OVERWEIGHT AND OBESITY AMONG ANCESTRAL GENOTYPE CARRIERS, ALTHOUGH THIS WAS NOT STATISTICALLY SIGNIFICANT. THE RS5742911 POLYMORPHISM MAY BE USEFUL AS AN INDICATOR OF A RISK OF CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  3879 15 KERATIN 19-EXPRESSING HEPATOCELLULAR CARCINOMA AND SMALL-DUCT TYPE INTRAHEPATIC CHOLANGIOCARCINOMA SHOW A SIMILAR POSTOPERATIVE CLINICAL COURSE BUT HAVE DISTINCT GENETIC FEATURES. AIMS: THE PRESENT STUDY AIMED TO SYSTEMATICALLY COMPARE CLINICOPATHOLOGICAL AND GENETIC FEATURES BETWEEN KERATIN 19 (K19)-EXPRESSING HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICCA). METHODS AND RESULTS: CONSECUTIVE CASES OF HCC (N = 430) WERE CLASSIFIED INTO K19(+) AND K19(-) USING IMMUNOHISTOCHEMISTRY. ICCA CASES WERE ALSO SEPARATED INTO SMALL-(S-ICCA; N = 36) AND LARGE-DUCT TYPES (N = 22) BASED ON RECENTLY PROPOSED CRITERIA, WITH THE FORMER BEING USED IN THE PRESENT STUDY. MUTATIONAL HOT-SPOTS IN TERT, CTNNB1, KRAS AND IDH1 WERE SEQUENCED. TWENTY-SIX CASES (6%) OF HCC EXPRESSED K19. K19(+) HCC WAS MORE STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B THAN K19(-) HCC AND S-ICCA (46% VERSUS 17% AND 6%; BOTH P < 0.001). LYMPH NODE METASTASIS WAS OBSERVED IN K19(+) HCC (8%) AND S-ICCA (22%), BUT WAS EXCEPTIONAL IN K19(-) HCC (1%). K19(+) HCC HAD TERT PROMOTER MUTATIONS LESS FREQUENTLY THAN K19(-) HCC (31% VERSUS 59%; P = 0.022), AND LACKED ALTERATIONS IN KRAS AND IDH1. CTNNB1 MUTATIONS WERE SIMILARLY OBSERVED IN K19(+) AND K19(-) HCC (23% AND 19%, RESPECTIVELY), BUT RARE IN S-ICCA (3%). THE POSTOPERATIVE SURVIVAL CURVE OF K19(+) HCC WAS ALMOST IDENTICAL TO THAT OF S-ICCA IN THE FIRST 5 YEARS (APPROXIMATELY 50% AT 5 YEARS), AND SIGNIFICANTLY WORSE THAN THAT OF K19(-) HCC (P = 0.040). EXTRAHEPATIC RECURRENCE WAS MORE COMMON IN K19(+) HCC (50%) AND S-ICCA (35%) THAN IN K19(-) HCC (15%) (P = 0.001). CONCLUSIONS: ALTHOUGH K19(+) HCC AND S-ICCA SHOWED SIMILAR BIOLOGICAL BEHAVIOURS, THEY DID NOT SHARE ANY DRIVER GENE MUTATIONS, SUGGESTING THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ICCA-LIKE FEATURES OF K19(+) HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  5001 18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  2814 24 FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: MIDDLE-AGE ONSET OF HETEROTOPIC OSSIFICATION FROM A UNIQUE MISSENSE MUTATION (C.974G>C, P.G325A) IN ACVR1. FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP) IS THE RARE MENDELIAN DISEASE CHARACTERIZED BY CONGENITAL MALFORMATION OF THE GREAT TOES PRECEDING HETEROTOPIC OSSIFICATION (HO) AND CAUSED BY HETEROZYGOUS ACTIVATING MUTATION OF THE ACVR1 GENE, WHICH ENCODES THE ALK2 RECEPTOR FOR BONE MORPHOGENETIC PROTEINS. EARLY ADULT LIFE IS THE LATEST REPORTED PRESENTATION FOR THE HO OF FOP. THE PATIENT OF OUR REPORT FIRST DEVELOPED HO FROM FOP AT 47 YEARS OF AGE. SHE HAD CONGENITAL HALLUX VALGUS DEFORMITY BUT DESPITE VARIOUS TRAUMAS WAS PREVIOUSLY WELL. HO BEGAN SEVERAL MONTHS AFTER A BRIEF, SEEMINGLY VIRAL, ILLNESS. SUDDEN AND PROGRESSIVE PAIN, REDNESS, WARMTH, AND SWELLING APPEARED OVER A SCAPULA. COMPUTED TOMOGRAPHY WAS REMARKABLE FOR ASYMMETRICAL THICKENING OF MUSCLES AND FASCIAL PLANES. AT FIRST, THE SIGNIFICANCE OF THE GREAT TOE ABNORMALITIES WENT UNRECOGNIZED ELSEWHERE, AND BIOPSY FOR SUSPECTED INFLAMMATORY FASCIITIS REVEALED PROLIFERATING FIBROBLASTS WITH SCATTERED INFLAMMATORY CELLS. PREDNISONE IMPROVED HER SYMPTOMS BUT, WHEN TAPERED, SWELLINGS DEVELOPED ON HER CHEST, POSTERIOR THORAX, AND FLANK, AND FOP WAS DIAGNOSED. METHYLPREDNISOLONE, METHOTREXATE, AND ALENDRONATE SEEMED TO HELP HER SYMPTOMS, BUT THE LESIONS WORSENED AND HO APPEARED AND RAPIDLY PROGRESSED. MUTATION ANALYSIS OF THE ACVR1 GENE REVEALED HETEROZYGOSITY FOR A UNIQUE MISSENSE DEFECT (C.974G>C, P.G325A) THAT PREDICTED A CONSERVATIVE (MILD) AMINO ACID CHANGE WITHIN THE KINASE DOMAIN OF ALK2. HENCE, HO IN FOP CAN BE DELAYED UNTIL MIDDLE-AGE, AND PERHAPS PROVOKED BY A VIRAL ILLNESS. NEVERTHELESS, PROGRESSION OF HO CAN THEN BE RAPID DESPITE BISPHOSPHONATE AND HIGH-DOSE IMMUNOSUPPRESSIVE THERAPY. POSSIBLY, OUR PATIENT'S LATE-ONSET HO REFLECTS HER MILD ALTERATION OF ALK2 OR SOME PROTECTIVE AND THERAPEUTICALLY USEFUL GENETIC, EPIGENETIC, OR NONGENETIC FACTOR. RECOGNITION OF PRESYMPTOMATIC INDIVIDUALS OR LATE-ONSET HO IN FOP SHOULD HAVE THESE PATIENTS AVOID TRAUMAS, TREATMENTS, AND MAYBE VIRAL ILLNESSES THAT CAN INITIATE OR EXACERBATE THE HO. IF THE DIAGNOSIS OF FOP IS UNCLEAR, ACVR1 MUTATION ANALYSIS IS AVAILABLE AT CERTIFIED LABORATORIES.	2012	
                                                                                                                                                                                                                                                                                                                        
11  6507 13 TRAINING VOCATIONAL REHABILITATION COUNSELORS WHO WORK WITH CHRONIC MENTAL PATIENTS. BECAUSE OF THE INEFFICACY OF DISPARATE PSYCHIATRIC AND REHABILITATIVE APPROACHES TO PSYCHOSOCIAL RESTORATION OF CHRONIC MENTAL PATIENTS, THE AUTHORS DESIGNED THE NEW ENGLAND PSYCHIATRIC REHABILITATION TRAINING PROGRAM FOR VOCATIONAL REHABILITATION COUNSELORS WHO WORK WITH THESE PATIENTS. THE PROGRAM EXTENDS ERIKSON'S EPIGENETIC SEQUENCE TO DEVELOPMENT OF WORK CAPACITY AND EMPHASIZES A COMPREHENSIVE, MULTIAXIAL APPROACH TO PSYCHOPATHOLOGY AND VOCATIONAL REHABILITATION. AFTER 6 WEEKS OF SEMINARS, CLINICAL WORK, AND SUPERVISION, COUNSELORS RETURN TO THEIR AGENCIES AND RECEIVE AN ADDITIONAL 8 WEEKS OF PART-TIME SUPPORT FROM FIELD FACULTY INSTRUCTORS.	1981	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12   820 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  1265 28 CYSTINURIA POORLY RESPONDING TO TREATMENT - THE RISK OF CHRONIC KIDNEY DISEASE. CYSTINURIA IS THE GENETIC CONDITION FOR THE INCREASED EXCRETION OF CYSTINE IN THE URINE. PATIENTS MAINLY SUFFER FROM AFFLICTIONS RELATED TO THE PRESENCE AND PASSAGE OF KIDNEY STONES. THE CURRENTLY AVAILABLE TREATMENT METHODS INCLUDE CONSERVATIVE TREATMENT BASED ON INCREASED FLUID INTAKE, APPROPRIATE DIET, MEDICATIONS AND UROLOGICAL PROCEDURES. THE CAUSAL TREATMENT HAS NOT YET BEEN INVENTED. A CASE REPORT: A PATIENT CASE WAS DESCRIBED WHOSE FIRST SYMPTOMATIC KIDNEY STONES APPEARED AFTER THE SECOND YEAR OF LIFE. URINARY CYSTINE EXCRETION WAS SIGNIFICANTLY INCREASED - 25,431 MUMOL/1G CREATININE (NORM: 167-333 MUMOL/1G CREATININE), WHICH WAS ALSO SHOWN, BUT LOWER, IN BOTH PARENTS OF THE PATIENT. DESPITE THE EARLY INITIATION OF THERAPY INCLUDING LOW SODIUM DIET, ABUNDANT HYDRATION, ALKALIZATION, CAPTOPRIL AND COMPLIANCE WITH STRINGENT RESTRICTIONS, THE LEVEL OF URINARY CYSTINE EXCRETION WAS STILL NOT WITHIN THE NORMAL RANGE. THERE HAVE BEEN MANY MODIFICATIONS TO THE THERAPY AND DOSE INCREASES OF DRUGS, BUT WITHOUT VISIBLE RESULTS. THE PATIENT UNDERWENT SEVERAL UROLOGICAL PROCEDURES, INCLUDING: ESWL (EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY), URSL (URETEROSCOPIC LITHOTRIPSY), PCNL (PERCUTANEOUS NEPHROLITHOTOMY) AND OPEN SURGERY TO REMOVE CYSTINE DEPOSITS THAT WERE STILL PRODUCED IN THE KIDNEYS. IN ADDITION, FOR MANY YEARS THE DISEASE WAS COMPLICATED BY RECURRENT URINARY TRACT INFECTIONS, UNDERWEIGHT AND LESIONS LIKE EPITHELIAL METAPLASIA IN THE BLADDER. RENAL PARAMETERS WERE REPEATEDLY EXAMINED. ELEVATED RESULTS SUCH AS: SERUM CREATININE 0.9 MG/DL, CYSTATIN C CONCENTRATION 1.10 MG/L, ALBUMIN-CREATININE INDEX 0.197, CREATININE CLEARANCE 50.7 ML/MIN /1.73 M2 AND EGFR 73 ML/MIN/1.73 M2 ALLOWED FOR THE DIAGNOSIS OF CHRONIC KIDNEY DISEASE BEFORE THE AGE OF 18. AFTER MANY YEARS OF CONSERVATIVE TREATMENT, ONLY THE INTRODUCTION OF THIOPRONINE, STILL LITTLE KNOWN IN POLAND, REDUCED THE LEVEL OF CYSTINE EXCRETED IN THE URINE. THE INCLUSION OF THE DRUG REDUCED THE TENDENCY TO PRODUCE KIDNEY STONES, WHICH ALLOWED TO INHIBIT THE PROGRESSION OF RENAL FAILURE. CONCLUSIONS: DESPITE MANY YEARS OF RESEARCH AND MODERN DRUGS, CYSTINURIA IS STILL A DISEASE WITH WHICH PATIENTS ARE ASSOCIATED FOR THE REST OF THEIR LIVES. THE ONGOING RESEARCH, ALONG WITH ATTEMPTS TO UNDERSTAND THE GENETIC AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE EMERGENCE OF MUTATIONS IN THE MAIN GENES CAUSING THE DISEASE AND THE COURSE OF THE DISEASE, GIVES HOPE FOR FINDING A METHOD OF CAUSAL TREATMENT FOR CYSTINURIA.	2021	

14   553 11 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15    81 14 A NEW TYPE OF DENTAL ANOMALY: MOLAR-INCISOR MALFORMATION (MIM). A MOLAR-INCISOR MALFORMATION (MIM) IS A NEWLY DISCOVERED TYPE OF DENTAL ANOMALY OF THE PERMANENT FIRST MOLARS, DECIDUOUS SECOND MOLARS, AND PERMANENT MAXILLARY CENTRAL INCISORS. MIM ANOMALIES OF THE PERMANENT FIRST MOLARS AND DECIDUOUS SECOND MOLARS MAY INCLUDE NORMAL CROWNS WITH A CONSTRICTED CERVICAL REGION AND THIN, NARROW, AND SHORT ROOTS, WHEREAS THE AFFECTED MAXILLARY CENTRAL INCISORS MAY EXHIBIT A HYPOPLASTIC ENAMEL NOTCH NEAR THE CERVICAL THIRD OF THE CLINICAL CROWN. ALTHOUGH THE ETIOLOGY OF MIM REMAINS TO BE DETERMINED, IT IS THOUGHT TO BE ATTRIBUTABLE TO AN EPIGENETIC FACTOR LINKED TO BRAIN- AND CENTRAL NERVOUS SYSTEM-RELATED SYSTEMIC DISEASES AT AROUND AGE 1 TO 2 YEARS. MIM TEETH ARE ASSOCIATED WITH CLINICAL PROBLEMS SUCH AS IMPACTION, EARLY EXFOLIATION, SPACE LOSS, SPONTANEOUS PAIN, PERIAPICAL ABSCESS, AND POOR INCISOR ESTHETICS. CHILDREN WITH MIM TEETH SHOULD BE OBSERVED CLOSELY WITH RESPECT TO THEIR MEDICAL HISTORY, AND DENTISTS SHOULD FORMULATE A WIDER-RANGING TREATMENT PLAN.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  6813 21 [EPILEPSY-ASSOCIATED TUMORS OF THE CENTRAL NERVOUS SYSTEM: EPILEPSY SURGERY AND ONCOLOGICAL ASPECTS]. BACKGROUND: AMONG THE TUMORS ASSOCIATED WITH CHRONIC EPILEPSY, DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND GANGLIOGLIOMA ARE THE MOST COMMON BESIDES ANGIOCENTRIC GLIOMA, PLEOMORPHIC XANTHOASTROCYTOMA AND PILOCYTIC ASTROCYTOMA. THESE TUMORS ARE USUALLY CONSIDERED AS BEING BENIGN. OBJECTIVE: TO DETERMINE THE BEST CONSERVATIVE AND SURGICAL TREATMENT OF TUMORS ASSOCIATED WITH EPILEPSY. MATERIAL AND METHODS: THIS ARTICLE PRESENTS CASE REPORTS OF MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND OF A TUMOR INITIALLY DIAGNOSED AS A GANGLIOGLIOMA BASED ON MAGNETIC RESONANCE IMAGING (MRI) CRITERIA. DESCRIPTION OF REFERENCES IN THE LITERATURE ON EPILEPSY SURGERY AND THE NEURO-ONCOLOGY OF EPILEPSY-ASSOCIATED TUMORS. RESULTS: IN THE CASE OF THE INITIALLY HISTOPATHOLOGICALLY DIAGNOSED DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR, A MALIGNANT TRANSFORMATION OCCURRED 5 YEARS AFTER INCOMPLETE RESECTION. THE DIFFERENTIATION FROM A GLIOBLASTOMA WAS POSSIBLE THROUGH THE ANALYSIS OF THE METHYLATION PROFILE. IN ANOTHER CASE A TUMOR ASSUMED TO BE A GANGLIOGLIOMA SHOWED AN INCREASE IN SIZE AFTER 6 YEARS. INITIAL HISTOPATHOLOGICAL RESULTS REVEALED A GLIOBLASTOMA. THE ANALYSIS OF THE METHYLATION PROFILE SUGGESTED THE DIAGNOSIS OF AN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA AND AS A DIFFERENTIAL DIAGNOSIS AN ANAPLASTIC GANGLIOGLIOMA. TUMOR PROGRESS CORRELATED WITH THE WORSENING OF SEIZURES. CONCLUSION: RECENT STUDIES HAVE SHOWN THAT IN THE TREATMENT OF PREDOMINANTLY BENIGN EPILEPSY-ASSOCIATED TUMORS NEURO-ONCOLOGICAL ASPECTS SHOULD ALSO BE TAKEN INTO ACCOUNT IN ADDITION TO THE EPILEPTOLOGICAL CONSIDERATIONS. IN THE CASE OF MALIGNANT TRANSFORMATION EPIGENETIC SCREENING (METHYLATION PROFILES) CAN HELP TO CLASSIFY THE TUMOR ENTITY MORE PRECISELY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17   645 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  1419 17 DIFFERENT CLINICAL FORMS OF HEREDITARY TYROSINEMIA (TYPE I) IN PATIENTS WITH IDENTICAL GENOTYPES. HEREDITARY TYROSINEMIA TYPE I (HTI, MCKUSICK 276700) IS AN AUTOSOMAL RECESSIVE DISEASE CAUSED BY DEFICIENT FUMARYLACETOACETATE HYDROLASE (FAH, EC 3.7.1.2) ACTIVITY. HTI IS CHARACTERIZED BY PROGRESSIVE LIVER DYSFUNCTION WITH NODULAR CIRRHOSIS OFTEN LEADING TO HEPATOCELLULAR CARCINOMA. TWO EXTREMES OF THE CLINICAL PHENOTYPE HAVE BEEN DESCRIBED: THE "ACUTE" (SEVERE, EARLY ONSET AND DEATH) AND "CHRONIC" (DELAYED ONSET AND SLOW COURSE) PHENOTYPE. ALLELIC HETEROGENEITY AND/OR MUTATION REVERSION IN HEPATIC CELLS HAVE BEEN PROPOSED EARLIER TO EXPLAIN THE CLINICAL HETEROGENEITY. TWO PROBANDS (ONE "ACUTE," ONE "CHRONIC") FROM THE FRENCH-CANADIAN ISOLATE WHERE HTI IS PREVALENT WERE STUDIED. BOTH WERE HOMOZYGOUS (GERM LINE) FOR THE SEVERE SPLICE MUTATION IVS12 + 5G --> A; BOTH SHOWED LIVER MOSAICISM FOR FAH IMMUNOREACTIVITY WITH EVIDENCE FOR MUTATION REVERSION TO HETEROZYGOSITY (IVS12 + 5G --> A/+) IN FAH-STAINED NODULES AS SHOWN BY AMPLIFICATION OF DNA EXTRACTED FROM MICRODISSECTED NODULES. WESTERN BLOT ANALYSIS OF PROTEINS FROM A REVERTED FAH-EXPRESSING NODULE SHOWED 29 +/- 3% FAH IMMUNOREACTIVE MATERIAL AS COMPARED TO AN AVERAGE NORMAL LIVER. THIS WAS CONSISTENT WITH THE MEASURED FAA HYDROLYTIC ACTIVITY (25%) IN THIS LARGE REGENERATING NODULE. THESE FINDINGS SHOW THAT GENOTYPIC HETEROGENEITY IS NOT A SUFFICIENT EXPLANATION FOR CLINICAL HETEROGENEITY AND IMPLICATE EPIGENETIC AND OTHER FACTORS MODIFYING THE PHENOTYPE IN HTI.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  1055 31 CLINICAL INTEGRATION OF GENOME DIAGNOSTICS FOR CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT. REVOLUTIONS IN GENETICS, EPIGENETICS, AND BIOINFORMATICS ARE CURRENTLY CHANGING THE OUTLINE OF DIAGNOSTICS AND CLINICAL MEDICINE. FROM A NEPHROLOGIST'S PERSPECTIVE, INDIVIDUALS WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) ARE AN IMPORTANT PATIENT CATEGORY: NOT ONLY IS CAKUT THE PREDOMINANT CAUSE OF KIDNEY FAILURE IN CHILDREN AND YOUNG ADULTS, BUT THE STRONG PHENOTYPIC AND GENOTYPIC HETEROGENEITY OF KIDNEY AND URINARY TRACT MALFORMATIONS HAS HAMPERED STANDARDIZATION OF CLINICAL DECISION MAKING UNTIL NOW. HOWEVER, PATIENTS WITH CAKUT MAY BENEFIT FROM PRECISION MEDICINE, INCLUDING AN INTEGRATED DIAGNOSTICS TRAJECTORY, GENETIC COUNSELING, AND PERSONALIZED MANAGEMENT TO IMPROVE CLINICAL OUTCOMES OF DEVELOPMENTAL KIDNEY AND URINARY TRACT DEFECTS. IN THIS REVIEW, WE DISCUSS THE PRESENT UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF CAKUT AND THE CURRENTLY AVAILABLE GENOME DIAGNOSTIC MODALITIES IN THE CLINICAL CARE OF PATIENTS WITH CAKUT. FINALLY, WE DISCUSS HOW CLINICAL INTEGRATION OF FINDINGS FROM LARGE-SCALE GENETIC, EPIGENETIC, AND GENE-ENVIRONMENT INTERACTION STUDIES MAY IMPROVE THE PROGNOSIS OF ALL INDIVIDUALS WITH CAKUT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  5353 24 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