1  6160 115 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  1797  26 EFFECT OF HELICOBACTER PYLORI ERADICATION ON GASTRIC PRECANCEROUS LESIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: THE QUESTION OF WHETHER ERADICATION OF HELICOBACTER PYLORI (HP) CAN REVERSE GASTRIC PRECANCEROUS LESIONS, INCLUDING INTESTINAL METAPLASIA, REMAINS UNCERTAIN, LEADING TO ONGOING DEBATE. THEREFORE, A META-ANALYSIS WAS PERFORMED TO EVALUATE THE EFFECT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. MATERIALS AND METHODS: PUBMED, EMBASE, COCHRANE LIBRARY, WEB OF SCIENCE, SCOPUS DATABASE, AND CLINICALTRIALS.GOV WERE SYSTEMATICALLY SEARCHED FROM INCEPTION TO APRIL 2023 FOR STUDIES THAT EXPLORED THE IMPACT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. RISK RATIOS (RRS) AND THEIR 95% CONFIDENCE INTERVALS (95% CIS) WERE SELECTED AS THE EFFECT SIZE. WE USED THE RANDOM-EFFECTS MODEL TO ASSESS POOLED DATA. WE ALSO PERFORMED QUALITY ASSESSMENTS, SUBGROUP ANALYSES, AND SENSITIVITY ANALYSES. RESULTS: FIFTEEN STUDIES WERE INCLUDED. COMPARED WITH PLACEBO, HP ERADICATION COULD SIGNIFICANTLY PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS (RR = 0.87, 95% CI: 0.81-0.94, P < 0.01) AND REVERSE THEM (RR = 1.32, 95% CI: 1.17-1.50, P < 0.01). THEN, SPECIFIC PRECANCEROUS LESIONS WERE FURTHER EXPLORED. THE PROGRESSION OF INTESTINAL METAPLASIA WAS SIGNIFICANTLY PREVENTED BY HP ERADICATION COMPARED TO PLACEBO OR NO TREATMENT (RR = 0.80, 95% CI: 0.69-0.94, P < 0.01). MOREOVER, COMPARED WITH PLACEBO OR NO TREATMENT, HP ERADICATION ALSO IMPROVED CHRONIC ATROPHIC GASTRITIS (RR = 1.84, 95% CI: 1.30-2.61, P < 0.01) AND INTESTINAL METAPLASIA (RR = 1.41, 95% CI: 1.15-1.73, P < 0.01). HOWEVER, IN TERMS OF PREVENTING DYSPLASIA PROGRESSION (RR = 0.86, 95% CI: 0.37-2.00) AND IMPROVING DYSPLASIA (RR = 0.89, 95% CI: 0.47-1.70), HP ERADICATION HAD NO ADVANTAGE COMPARED TO PLACEBO OR NO TREATMENT. CONCLUSIONS: HP ERADICATION THERAPY COULD PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS AND REVERSE THEM. NOTABLY, INTESTINAL METAPLASIA CAN BE REVERSED, BUT THIS MAY ONLY BE APPROPRIATE FOR PATIENTS WITH EPIGENETIC ALTERATIONS AND MILDER LESIONS.	2023	

3  1391  30 DIAGNOSTIC APPROACH TO PATIENTS WITH LOW SERUM ALKALINE PHOSPHATASE. INCREASED SERUM LEVELS OF ALKALINE PHOSPHATASE (ALP) ARE WIDELY RECOGNIZED AS A BIOCHEMICAL MARKER OF MANY DISORDERS AFFECTING THE LIVER OR BONE. HOWEVER, THE APPROACH FOR PATIENTS WITH LOW ALP PHOSPHATASE IS NOT WELL-ESTABLISHED. LOW SERUM ALP IS AN EPIPHENOMENON OF MANY SEVERE ACUTE INJURIES AND DISEASES. PERSISTENTLY LOW SERUM ALP MAY BE SECONDARY TO DRUG THERAPY (INCLUDING ANTIRESORPTIVES) OR A VARIETY OF ACQUIRED DISORDERS, SUCH AS MALNUTRITION, VITAMIN AND MINERAL DEFICIENCIES, ENDOCRINE DISORDERS, ETC. HYPOPHOSPHATASIA, DUE TO PATHOGENIC VARIANTS OF THE ALPL GENE, WHICH ENCODES TISSUE NON-SPECIFIC ALP, IS THE MOST COMMON GENETIC CAUSE OF LOW SERUM ALP. MARKED BONE HYPOMINERALIZATION IS FREQUENT IN SEVERE PEDIATRIC-ONSET CASES. HOWEVER, ADULT FORMS OF HYPOPHOSPHATASIA USUALLY PRESENT WITH MILDER MANIFESTATIONS, SUCH AS SKELETAL PAIN, CHONDROCALCINOSIS, CALCIFIC PERIARTHRITIS, DENTAL PROBLEMS, AND STRESS FRACTURES. THE DIAGNOSTIC APPROACH TO THESE PATIENTS IS DISCUSSED. MEASURING SEVERAL ALP SUBSTRATES, SUCH AS PYROPHOSPHATE, PYRIDOXAL PHOSPHATE, OR PHOSPHOETHANOLAMINE, MAY HELP TO ESTABLISH ENZYME DEFICIENCY. GENE ANALYSIS SHOWING A PATHOGENIC VARIANT IN ALPL MAY CONFIRM THE DIAGNOSIS. HOWEVER, A SUBSTANTIAL PROPORTION OF PATIENTS SHOW NORMAL RESULTS AFTER SEQUENCING ALPL EXONS. IT IS STILL UNKNOWN IF THOSE PATIENTS CARRY UNIDENTIFIED MUTATIONS IN REGULATORY REGIONS OF ALPL, EPIGENETIC CHANGES, OR ABNORMALITIES IN OTHER GENES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  4101  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  3339  26 HISTONE DEACETYLASE ISOFORMS DIFFERENTIALLY MODULATE INFLAMMATORY AND AUTOANTIBODY RESPONSES IN A MOUSE MODEL OF MYASTHENIA GRAVIS. MYASTHENIA GRAVIS (MG) IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC MUSCLE FATIGUE AND WEAKNESS CAUSED BY AUTOANTIBODIES AND COMPLEMENT-MEDIATED DAMAGE AT NEUROMUSCULAR JUNCTIONS. HISTONE DEACETYLASES (HDACS) ARE CRUCIAL EPIGENETIC REGULATORS OF PROINFLAMMATORY GENE EXPRESSION; HOWEVER, IT IS UNCLEAR WHETHER HDACS MODULATE CHRONIC INFLAMMATION OR AUTOANTIBODY PRODUCTION ASSOCIATED WITH MG PATHOGENESIS. WE EXAMINED EXPRESSION PROFILES AND SERUM LEVELS OF KEY INFLAMMATORY CYTOKINES (IL-6 AND IL-21) AND ACETYLCHOLINE RECEPTOR (ACHR)-SPECIFIC AUTOANTIBODIES FOLLOWING PHARMACOLOGICAL INHIBITION OF KEY HDAC ISOFORMS IN A MOUSE MODEL OF MG. WE FOUND THAT HDAC INHIBITION SIGNIFICANTLY REDUCED THE PRODUCTION OF IL-6, BUT NOT IL-21, IN ACHR-STIMULATED PBMCS AND SPLENOCYTES (N = 5 PER GROUP). TRICHOSTATIN (PAN-HDAC INHIBITOR) TREATMENT OF MG-PBMCS (N = 2) ALSO EXHIBITED REDUCED PRODUCTION OF INDUCED IL-6. ALTHOUGH HDAC1 INHIBITION LOWERED IL-6 LEVELS THE MOST, HDAC2 INHIBITION DEPLETED INTRACELLULAR IL-6 AND MARKEDLY REDUCED SERUM ANTI-ACHR IGG2B IN EAMG MICE. THE TRANSCRIPTOMIC PROFILING AND PATHWAY MAPPING ALSO REVEALED THAT AUTOIMMUNITY-LINKED, MAJOR CELL SIGNALING PATHWAYS WERE DIFFERENTIALLY ALTERED BY HDAC1/2 INHIBITION. HDAC INHIBITION-MEDIATED REDUCTION IN IL-6 AND AUTOANTIBODY LEVELS ALSO CORRELATED WITH MILDER DISEASE AND PRESERVATION OF MUSCLE ACHR IN THE TREATED MICE. OVERALL, OUR FINDINGS REVEALED ISOFORM-SPECIFIC FUNCTIONAL VARIANCE OF HDACS IN REDUCING INFLAMMATION AND IDENTIFIED HDAC-REGULATED MANY GENES UNDERLYING SPECIFIC INFLAMMATORY AND AUTOANTIBODY PATHWAYS IN EAMG. THUS, THE STUDY PROVIDES A RATIONALE FOR FURTHER RESEARCH TO EVALUATE THE HDACS OR THEIR GENE TARGETS AS A POTENTIAL ADJUNCT TREATMENT FOR MG.	2021	
                                                                                                                                                                                                       
6  6140  22 THE ETIOLOGY OF AUTOIMMUNE DISEASES: THE CASE OF MYASTHENIA GRAVIS. AUTOIMMUNE DISEASES COMPRISE A WIDE VARIETY OF DISORDERS, FROM THOSE THAT ARE ACUTE AND SPONTANEOUSLY REGRESSIVE TO CHRONIC DISEASES. THEIR OCCURRENCE IS THE SIGN OF A LOSS OF TOLERANCE TO SELF-ANTIGENS. WITH FEW EXCEPTIONS, THE ETIOLOGY OF AUTOIMMUNE DISEASES HAS NOT BEEN CLEARLY ESTABLISHED. IN ALL CASES, IT IS COMPLEX, INVOLVING GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IN THIS ARTICLE I WILL ATTEMPT TO ANALYZE THE VARIOUS FACTORS THAT HAVE A TRIGGERING OR PROTECTING ROLE, WITH PARTICULAR REFERENCE TO MYASTHENIA GRAVIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  1055  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  4161  22 MECP2 REGULATES ETHANOL SENSITIVITY AND INTAKE. WE HAVE INVESTIGATED THE EXPRESSION OF CHROMATIN-REGULATING GENES IN THE PREFRONTAL CORTEX AND IN THE SHELL SUBDIVISION OF THE NUCLEUS ACCUMBENS DURING PROTRACTED WITHDRAWAL IN MICE WITH INCREASED ETHANOL DRINKING AFTER CHRONIC INTERMITTENT ETHANOL (CIE) VAPOR EXPOSURE AND IN MICE WITH A HISTORY OF NON-DEPENDENT DRINKING. WE OBSERVED THAT THE METHYL-CPG BINDING PROTEIN 2 (MECP2) WAS ONE OF THE FEW CHROMATIN-REGULATING GENES TO BE DIFFERENTIALLY REGULATED BY A HISTORY OF DEPENDENCE. AS MECP2 HAS THE POTENTIAL OF ACTING AS A BROAD GENE REGULATOR, WE INVESTIGATED SENSITIVITY TO ETHANOL AND ETHANOL DRINKING IN MECP2(308/) (Y) MICE, WHICH HARBOR A TRUNCATED MECP2 ALLELE BUT HAVE A MILDER PHENOTYPE THAN MECP2 NULL MICE. WE OBSERVED THAT MECP2(308/) (Y) MICE WERE MORE SENSITIVE TO ETHANOL'S STIMULATORY AND SEDATIVE EFFECTS THAN WILD-TYPE (WT) MICE, DRANK LESS ETHANOL IN A LIMITED ACCESS 2 BOTTLE CHOICE PARADIGM AND DID NOT SHOW INCREASED DRINKING AFTER INDUCTION OF DEPENDENCE WITH EXPOSURE TO CIE VAPORS. ALCOHOL METABOLISM DID NOT DIFFER IN MECP2(308/) (Y) AND WT MICE. ADDITIONALLY, MECP2(308/) (Y) MICE DID NOT DIFFER FROM WT MICE IN ETHANOL PREFERENCE IN A 24-HOUR PARADIGM NOR IN THEIR INTAKE OF GRADED SOLUTIONS OF SACCHARIN OR QUININE, SUGGESTING THAT THE MECP2(308/) (Y) MUTATION DID NOT ALTER TASTE FUNCTION. LASTLY, USING THE GENE SET ENRICHMENT ANALYSIS ALGORITHM, WE FOUND A SIGNIFICANT OVERLAP IN THE GENES REGULATED BY ALCOHOL AND BY MECP2. TOGETHER, THESE RESULTS SUGGEST THAT MECP2 CONTRIBUTES TO THE REGULATION OF ETHANOL SENSITIVITY AND DRINKING.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  6791  34 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10  4559  39 MUTATIONS OF THE TRANSCRIPTIONAL COREPRESSOR ZMYM2 CAUSE SYNDROMIC URINARY TRACT MALFORMATIONS. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) CONSTITUTE ONE OF THE MOST FREQUENT BIRTH DEFECTS AND REPRESENT THE MOST COMMON CAUSE OF CHRONIC KIDNEY DISEASE IN THE FIRST THREE DECADES OF LIFE. DESPITE THE DISCOVERY OF DOZENS OF MONOGENIC CAUSES OF CAKUT, MOST PATHOGENIC PATHWAYS REMAIN ELUSIVE. WE PERFORMED WHOLE-EXOME SEQUENCING (WES) IN 551 INDIVIDUALS WITH CAKUT AND IDENTIFIED A HETEROZYGOUS DE NOVO STOP-GAIN VARIANT IN ZMYM2 IN TWO DIFFERENT FAMILIES WITH CAKUT. THROUGH COLLABORATION, WE IDENTIFIED IN TOTAL 14 DIFFERENT HETEROZYGOUS LOSS-OF-FUNCTION MUTATIONS IN ZMYM2 IN 15 UNRELATED FAMILIES. MOST MUTATIONS OCCURRED DE NOVO, INDICATING POSSIBLE INTERFERENCE WITH REPRODUCTIVE FUNCTION. HUMAN DISEASE FEATURES ARE REPLICATED IN X. TROPICALIS LARVAE WITH MORPHOLINO KNOCKDOWNS, IN WHICH EXPRESSION OF TRUNCATED ZMYM2 PROTEINS, BASED ON INDIVIDUAL MUTATIONS, FAILED TO RESCUE RENAL AND CRANIOFACIAL DEFECTS. MOREOVER, HETEROZYGOUS ZMYM2-DEFICIENT MICE RECAPITULATED FEATURES OF CAKUT WITH HIGH PENETRANCE. THE ZMYM2 PROTEIN IS A COMPONENT OF A TRANSCRIPTIONAL COREPRESSOR COMPLEX RECENTLY LINKED TO THE SILENCING OF DEVELOPMENTALLY REGULATED ENDOGENOUS RETROVIRUS ELEMENTS. USING PROTEIN-PROTEIN INTERACTION ASSAYS, WE SHOW THAT ZMYM2 INTERACTS WITH ADDITIONAL EPIGENETIC SILENCING COMPLEXES, AS WELL AS CONFIRMING THAT IT BINDS TO FOXP1, A TRANSCRIPTION FACTOR THAT HAS ALSO BEEN LINKED TO CAKUT. IN SUMMARY, OUR FINDINGS ESTABLISH THAT LOSS-OF-FUNCTION MUTATIONS OF ZMYM2, AND POTENTIALLY THAT OF OTHER PROTEINS IN ITS INTERACTOME, AS CAUSES OF HUMAN CAKUT, OFFERING NEW ROUTES FOR STUDYING THE PATHOGENESIS OF THE DISORDER.	2020	
                                                                                                                                                                                                                                                                                                                                            
11  4381  29 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  6165  31 THE GLOBAL DIABETES EPIDEMIC AS A CONSEQUENCE OF LIFESTYLE-INDUCED LOW-GRADE INFLAMMATION. THE RECENT MAJOR INCREASE IN THE GLOBAL INCIDENCE OF TYPE 2 DIABETES SUGGESTS THAT MOST CASES OF THIS DISEASE ARE CAUSED BY CHANGES IN ENVIRONMENT AND LIFESTYLE. ALL MAJOR RISK FACTORS FOR TYPE 2 DIABETES (OVERNUTRITION, LOW DIETARY FIBRE, SEDENTARY LIFESTYLE, SLEEP DEPRIVATION AND DEPRESSION) HAVE BEEN FOUND TO INDUCE LOCAL OR SYSTEMIC LOW-GRADE INFLAMMATION THAT IS USUALLY TRANSIENT OR MILDER IN INDIVIDUALS NOT AT RISK FOR TYPE 2 DIABETES. BY CONTRAST, INFLAMMATORY RESPONSES TO LIFESTYLE FACTORS ARE MORE PRONOUNCED AND PROLONGED IN INDIVIDUALS AT RISK OF TYPE 2 DIABETES AND APPEAR TO OCCUR ALSO IN THE PANCREATIC ISLETS. CHRONIC LOW-GRADE INFLAMMATION WILL EVENTUALLY LEAD TO OVERT DIABETES IF COUNTER-REGULATORY CIRCUITS TO INFLAMMATION AND METABOLIC STRESS ARE COMPROMISED BECAUSE OF A GENETIC AND/OR EPIGENETIC PREDISPOSITION. HENCE, IT IS NOT THE LIFESTYLE CHANGE PER SE BUT A DEFICIENT COUNTER-REGULATORY RESPONSE IN PREDISPOSED INDIVIDUALS WHICH IS CRUCIAL TO DISEASE PATHOGENESIS. NOVEL APPROACHES OF INTERVENTION MAY TARGET THESE DEFICIENT DEFENCE MECHANISMS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  1477  33 DIVERSE PHENOTYPIC EXPRESSION OF NPHP4 MUTATIONS IN FOUR SIBLINGS. NEPHRONOPHTHISIS (NPHP) IS AN AUTOSOMAL RECESSIVE DISEASE CHARACTERIZED BY RENAL TUBULAR BASEMENT MEMBRANE DISRUPTION, INTERSTITIAL FIBROSIS AND TUBULAR CYSTS THAT PROGRESSES TO END-STAGE KIDNEY DISEASE (ESKD). THERE ARE ALSO CHARACTERISTIC EXTRARENAL MANIFESTATIONS. MUTATIONS OF MORE THAN THIRTEEN GENES THAT CAN CAUSE NPHP HAVE BEEN IDENTIFIED. WE HEREIN REPORT FOUR SIBLINGS FROM A CONSANGUINEOUS FAMILY, WHO CARRIED THE SAME NPHP4 MUTATIONS BUT PRESENTED WITH DIFFERENT DISEASE PHENOTYPES RANGING FROM ENURESIS NOCTURNA TO ESKD. DILUTED URINE AND ECHOGENIC KIDNEYS IN ULTRASOUND EXAMINATION WERE CONSISTENT, WHICH IS TYPICAL FOR 100% OF THE NPHP CASES THAT HAVE BEEN DESCRIBED. CHRONIC KIDNEY DISEASE DEVELOPED IN THE OLDER TWO BROTHERS. THE OBSERVED PHENOTYPIC DIFFERENCES ARE LIKELY TO BE RELATED TO ENVIRONMENTAL AND EPIGENETIC FACTORS, OLIGOGENIC INHERITANCE AND MODIFIER GENES AFFECTING THE AGE OF PRESENTATION OF SIGNS AND SYMPTOMS. NPHP SHOULD BE CONSIDERED AS AN IMPORTANT CAUSE OF CKD IN CHILDREN, WHICH INSIDIOUSLY PROGRESSES TO ESKD, WITH NO SPECIFIC THERAPY AVAILABLE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  3985  20 LONG-TERM MAINTENANCE OF THE MUCOSAL HEALING INDUCED BY AZACITIDINE THERAPY IN A PATIENT WITH INTESTINAL BEHCET'S-LIKE DISEASE ACCOMPANIED WITH MYELODYSPLASTIC SYNDROME INVOLVING TRISOMY 8. MYELODYSPLASTIC SYNDROMES (MDSS) ARE A GROUP OF MYELOID NEOPLASMS CHARACTERIZED BY BLOOD CELL DEFORMATION AND DYSFUNCTION, AND MDS WITH TRISOMY 8 IS CLOSELY LINKED WITH INTESTINAL BEHCET'S-LIKE DISEASES. INTESTINAL BEHCET'S-LIKE DISEASE IS REFRACTORY TO CONVENTIONAL THERAPIES, INCLUDING PREDNISOLONE, IMMUNOMODULATORS, AND ANTI-TUMOR NECROSIS FACTOR ALPHA AGENTS. HERE, WE DESCRIBE A 56-YEAR-OLD WOMAN WITH INTESTINAL BEHCET'S-LIKE DISEASE ASCRIBED TO MDS WITH TRISOMY 8 WHO HAD MULTIPLE INTRACTABLE INTESTINAL ULCERS. SHE PRESENTED WITH PERIODIC FEVER AND ABDOMINAL PAIN. THE GENETIC ANALYSIS SHOWED A HETEROZYGOUS E148Q MUTATION IN THE MEDITERRANEAN FEVER GENE. THE PATIENT DID NOT TOLERATE TREATMENT WITH COLCHICINE BECAUSE OF DIARRHEA; THEREFORE, AZACITIDINE THERAPY WAS INITIATED. ONE CYCLE OF AZACITIDINE THERAPY IMPROVED THE MULTIPLE INTESTINAL ULCERS, AND THE PERIODIC FEVER AND ABDOMINAL PAIN GRADUALLY DISAPPEARED. AFTER EIGHT CYCLES OF AZACITIDINE THERAPY, ILEOCOLONOSCOPY, HISTOLOGICAL ASSESSMENT AND CAPSULE ENDOSCOPY REVEALED MUCOSAL HEALING. AZACITIDINE THERAPY WAS CONTINUED, AND MUCOSAL HEALING WAS MAINTAINED FOR MORE THAN 2 YEARS. THIS CASE SUGGESTS THAT AZACITIDINE THERAPY WHICH HAS IMMUNOREGULATORY EFFECTS AND EPIGENETIC MODULATIONS, MIGHT CONTROL INTESTINAL BEHCET'S-LIKE DISEASE ASSOCIATED WITH MDS INVOLVING TRISOMY 8.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  6884  24 [RHEUMATOID ARTHRITIS]. RHEUMATOID ARTHRITIS ABSTRACT. RHEUMATOID ARTHRITIS (RA) IS THE MOST FREQUENT CHRONIC INFLAMMATORY JOINT DISEASE WITH A PREVALENCE OF APPROXIMATELY 1% WORLDWIDE. THE PATHOGENESIS IS A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS, WHICH ARE STILL INCOMPLETELY UNDERSTOOD. THE DISEASE IS CHARACTERIZED BY A POLYARTICULAR SYNOVITIS WITH SYMMETRICAL INVOLVEMENT OF SMALL AND LARGE JOINTS. THE MAJORITY OF PATIENTS HAS DETECTABLE AUTOANTIBODIES IN THE SERUM, RHEUMATOID FACTOR AND ANTI-CCP ANTIBODIES WHICH ARE SPECIFIC FOR RA. THE UNCONTROLLED CHRONIC JOINT INFLAMMATION RESULTS IN DESTRUCTIVE CHANGES OF JOINT CARTILAGE AND BONE. AN EARLY DIAGNOSIS AND INITIATION OF TREATMENT IS THEREFORE OF CENTRAL IMPORTANCE. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARD) ARE ABLE TO INHIBIT JOINT DESTRUCTION AND SHOULD BE STARTED AS SOON AS POSSIBLE. THERAPY SHOULD BE TARGETED TO REACH A STATE OF REMISSION. THE INTRODUCTION OF HIGHLY EFFECTIVE BIOLOGIC AND TARGETED SYNTHETIC DMARD HAS ALLOWED TO REACH THIS GOAL OF THERAPY IN MANY PATIENTS AND TO PREVENT DISABILITY. HOWEVER, RISKS OF MEDICATION NEED TO BE CONSIDERED, AS WELL AS COMORBIDITIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  5218  28 PREVENTION OF HEPATOCELLULAR CARCINOMA. PREVENTION IS THE ONLY REALISTIC APPROACH FOR REDUCING MORTALITY RATES ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. VACCINATION AGAINST HEPATITIS B AND SCREENING OF BLOOD DONATIONS ARE EFFECTIVE MEASURES OF PRIMARY PREVENTION. SCREENING OF BLOOD DONATIONS HAS LED TO A SUBSTANTIAL REDUCTION IN VIRAL HEPATITIS TRANSMISSION AMONG THE GENERAL POPULATION, AND IN TAIWAN VACCINATION AGAINST HEPATITIS B CAUSED A SIGNIFICANT REDUCTION IN HCC INCIDENCE AMONG INFANTS. PRIMARY PREVENTION ALSO INCLUDES APPROACHES THAT ALTER EPIGENETIC AND GENETIC CHANGES IN HEPATOCYTES, KNOWN TO INCREASE SUSCEPTIBILITY TO HCC, AS WELL AS TREATMENTS SLOWING PROGRESSION TO CIRRHOSIS. THE ONLY EVIDENCE THAT CHEMOPREVENTION REDUCES HCC RISK IS A MULTICENTER RANDOMIZED PROSPECTIVE STUDY IN ASIAN PATIENTS WITH ADVANCED HEPATITIS B WHO RECEIVED THE ORAL NUCLEOSIDE ANALOGUE LAMIVUDINE. CIRCUMSTANTIAL EVIDENCE SUGGESTS THAT HCC RISK IS ALSO REDUCED IN PATIENTS WITH CHRONIC HEPATITIS C WHO HAVE HAD A SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON THERAPY. HCC IS NOT SUBSTANTIALLY REDUCED IN PATIENTS WITH HEPATITIS B TREATED WITH INTERFERON AND PATIENTS WITH HEPATITIS C WHO DID NOT RESPOND TO INTERFERON. SECONDARY PREVENTION, THAT IS, PREVENTION OF TUMOR RECURRENCE AFTER HEPATIC RESECTION OR LOCAL ABLATIVE THERAPIES, HAS BEEN PURSUED WITH DIFFERENT APPROACHES. RETINOIDS, HEPATIC EMBOLIZATION WITH (131)I LIPIODOL, AND ADOPTIVE ADJUVANT IMMUNOTHERAPY HAVE YIELDED ENCOURAGING RESULTS. OTHER APPROACHES, INCLUDING THOSE BASED ON INTERFERON ALFA OR BETA, PROVIDED INCONCLUSIVE EVIDENCE FOR SECONDARY PROPHYLAXIS OF HCC, MAINLY BECAUSE OF THE POOR METHODOLOGIES AND SCIENTIFIC BACKGROUND OF THE STUDIES. DIETARY INTERVENTIONS AND ANTIAFLATOXIN AGENTS MIGHT HELP TO PREVENT HCC IN SUSCEPTIBLE INDIVIDUALS, BUT THE REAL EFFICACY OF THESE APPROACHES IS FAR FROM BEING DEMONSTRATED.	2005	
                                                                                                                                                                             
17  4685  28 NEW TARGETS AND STRATEGIES FOR RHEUMATOID ARTHRITIS: FROM SIGNAL TRANSDUCTION TO EPIGENETIC ASPECT. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT CAN LEAD TO JOINT DAMAGE AND EVEN PERMANENT DISABILITY, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. AT PRESENT, THE COMPLETE CURE FOR RA IS NOT ACHIEVABLE, ONLY TO RELIEVE THE SYMPTOMS TO REDUCE THE PAIN OF PATIENTS. FACTORS SUCH AS ENVIRONMENT, GENES, AND SEX CAN INDUCE RA. PRESENTLY, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DRMADS, AND GLUCOCORTICOIDS ARE COMMONLY USED IN TREATING RA. IN RECENT YEARS, SOME BIOLOGICAL AGENTS HAVE ALSO BEEN APPLIED IN CLINICAL PRACTICE, BUT MOST HAVE SIDE EFFECTS. THEREFORE, FINDING NEW MECHANISMS AND TARGETS FOR TREATING RA IS NECESSARY. THIS REVIEW SUMMARIZES SOME POTENTIAL TARGETS DISCOVERED FROM THE PERSPECTIVE OF EPIGENETICS AND RA MECHANISMS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  4975  26 PATHOPHYSIOLOGICAL MECHANISMS OF AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC DISORDERS CHARACTERIZED BY INFLAMMATORY REACTIONS AGAINST SELF-ANTIGENS THAT CAN BE EITHER SYSTEMIC OR ORGAN SPECIFIC. AIDS CAN DIFFER IN THEIR EPIDEMIOLOGIC FEATURES AND CLINICAL PRESENTATIONS, YET ALL SHARE A REMARKABLE COMPLEXITY. AIDS RESULT FROM AN INTERPLAY OF GENETIC AND EPIGENETIC FACTORS WITH ENVIRONMENTAL COMPONENTS THAT ARE ASSOCIATED WITH IMBALANCES IN THE IMMUNE SYSTEM. MANY OF THE PATHOGENIC MECHANISMS OF AIDS ARE ALSO IMPLICATED IN MYASTHENIA GRAVIS (MG), AN AID IN WHICH INFLAMMATION OF THE THYMUS LEADS TO A NEUROMUSCULAR DISORDER. OUR GOAL HERE IS TO HIGHLIGHT THE SIMILARITIES AND DIFFERENCES BETWEEN MG AND OTHER AIDS BY REVIEWING THE COMMON TRANSCRIPTOME SIGNATURES AND THE DEVELOPMENT OF GERMINAL CENTERS AND BY DISCUSSING SOME UNRESOLVED QUESTIONS ABOUT AUTOIMMUNE MECHANISMS. THIS REVIEW WILL PROPOSE HYPOTHESES TO EXPLAIN THE ORIGIN OF REGULATORY T (T(REG) ) CELL DEFECTS AND THE CAUSES OF CHRONICITY AND SPECIFICITY OF AIDS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19   220  33 ACUTE KIDNEY DISEASE: AN OVERVIEW OF THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT. ACUTE KIDNEY INJURY (AKI) INCREASES THE RISK OF CHRONIC KIDNEY DISEASE (CKD), AND AKI AND CKD ARE SEEN AS INTERCONNECTED SYNDROMES. ACUTE KIDNEY DISEASE (AKD) IS DEFINED AS SUBACUTE DAMAGE AND/OR LOSS OF KIDNEY FUNCTION OCCURRING 7 TO 90 DAYS AFTER AKI, DURING WHICH PERIOD KEY INTERVENTIONS MAY BE INITIATED TO HINDER THE DEVELOPMENT OF CKD. WHILE AKD IS USUALLY UNDER-RECOGNIZED, IT IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY GLOBALLY. THIS REVIEW ARTICLE AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE CONCERNING THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT OF AKD WITH THE AIM TO DEVELOP MONITORING STRATEGIES AND THERAPEUTIC AGENTS OF AKD. GENERALLY, AKD TENDS TO OCCUR MORE FREQUENTLY IN THE ELDERLY AND THOSE WITH CHRONIC DISEASES, SUCH AS HYPERTENSION, DIABETES MELLITUS, AND METABOLIC SYNDROME. IN ADDITION, THE SEVERITY, DURATION, AND FREQUENCY OF AKI ARE INDEPENDENT RISK FACTORS FOR AKD. INVESTIGATIONS OF SEVERAL MECHANISMS OF AKD, SUCH AS RENAL TUBULAR EPITHELIUM CELL-CYCLE ARREST, EPIGENETIC CHANGE, CHRONIC INFLAMMATION, MITOCHONDRIA DYSFUNCTION, FAILED REGENERATION OF TUBULAR CELLS, METABOLIC REPROGRAMMING, AND RENIN-ANGIOTENSIN SYSTEM (RAS) ACTIVATION, HAVE IDENTIFIED ADDITIONAL POTENTIAL PHARMACOTHERAPY TARGETS. MANAGEMENT OF AKD INCLUDES PREVENTION OF REPEATED AKI, EARLY AND REGULAR FOLLOW-UP BY A NEPHROLOGIST, RESUMPTION AND ADJUSTMENT OF ESSENTIAL MEDICATION, OPTIMIZATION OF BLOOD PRESSURE CONTROL AND NUTRITION MANAGEMENT, AND DEVELOPMENT OF NEW PHARMACEUTICAL AGENTS INCLUDING RAS INHIBITORS. FINALLY, WE OUTLINE A CARE BUNDLE FOR AKD PATIENTS BASED ON IMPORTANT LESSONS LEARNED FROM STUDIES AND REGISTRIES AND IDENTIFY THE NEED FOR CLINICAL TRIALS OF RAS INHIBITORS OR OTHER NOVEL AGENTS TO IMPEDE ENSUING CKD DEVELOPMENT.	2023	
                                                                                                                                                                                                                                          
20  6821  34 [GASTROINTESTINAL MANIFESTATIONS IN IMMUNODEFICIENCIES WITH MONOGENIC ORIGIN]. ALTHOUGH VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE THAT DEVELOPS IN EARLY CHILDHOOD (BEFORE THE AGE OF 6 YEARS) HAS A DIFFERENT ETIOLOGY FROM CROHN'S DISEASE AND ULCERATIVE COLITIS, IT IS ALSO CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT. BASICALLY, VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE SHOULD BE CONSIDERED AS AN IMMUNODEFICIENCY WITH MONOGENIC ORIGIN WHERE BOTH GASTROINTESTINAL MANIFESTATIONS AND SYMPTOMS OF IMMUNODEFICIENCIES MAY DEVELOP IN VARIABLE COMBINATIONS. HOWEVER, IN THE FUTURE, THE EVALUATION OF GENETIC ALTERATIONS IN THE BACKGROUND OF THE DISEASE WILL PROBABLY BE PERFORMED BY NEXT-GENERATION SEQUENCING TECHNOLOGY; ONE SHOULD ALSO CONSIDER THAT THE SEQUENCE OF THE DNA STANDS IN CONTINUOUS INTERACTION WITH A WIDE VARIETY OF ENVIRONMENTAL EFFECTS, AMONG WHICH NUTRITION SHOULD BE EMPHASIZED BY ALL MEANS. EPIGENETIC ALTERATIONS THAT ARE INDUCED BY ENVIRONMENTAL FACTORS, COULD CONTRIBUTE TO THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES THAT DEVELOP DURING CHILDHOOD, THEREFORE, THEY SHOULD ALSO BE IDENTIFIED DURING FURTHER RESEARCH. IT HAS A KEY SIGNIFICANCE TO ESTABLISH THE DIAGNOSIS OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE AS EARLY AS POSSIBLE, BECAUSE THIS COULD GIVE THE OPPORTUNITY TO START THE ADEQUATE TREATMENT WHICH IS BONE MARROW TRANSPLANTATION IN THE CASE OF MONOGENIC IMMUNODEFICIENCIES. ORV HETIL. 2018; 159(49): 2050-2056.	2018