1   986 122 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  4667  34 NEW INSIGHTS INTO ADULT AND PAEDIATRIC CHRONIC NON-BACTERIAL OSTEOMYELITIS CNO. PURPOSE OF REVIEW: TO DESCRIBE IN DETAIL THE CLINICAL SYNOPSIS AND PATHOPHYSIOLOGY OF CHRONIC NON-BACTERIAL OSTEOMYELITIS AND SAPHO SYNDROME. RECENT FINDINGS: CHRONIC NON-BACTERIAL OSTEOMYELITIS (CNO) HAS BEEN IDENTIFIED AS A DISEASE ENTITY FOR ALMOST 50 YEARS. THIS INFLAMMATORY BONE DISORDER IS CHARACTERIZED BY OSTEOLYTIC AS WELL AS HYPEROSTOTIC/OSTEOSCLEROTIC LESIONS. IT IS CHRONIC IN NATURE, BUT IT CAN PRESENT WITH EPISODIC FLAIRS AND PHASES OF REMISSION, WHICH HAVE LED TO THE DENOMINATION "CHRONIC RECURRENT OSTEOMYELITIS", WITH ITS SEVERE MULTIFOCAL FORM "CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS" (CRMO). FOR ALMOST THREE DECADES, AN INFECTIOUS AETIOLOGY HAD BEEN CONSIDERED, SINCE ESPECIALLY PROPIONIBACTERIUM ACNES HAD BEEN ISOLATED FROM BONE LESIONS OF INDIVIDUAL PATIENTS. HOWEVER, THIS CONCEPT HAS BEEN CHALLENGED SINCE LONG-TERM ANTIBIOTIC THERAPY DID NOT ALTER THE COURSE OF DISEASE AND MODERN MICROBIOLOGICAL TECHNIQUES (INCLUDING PCR) FAILED TO CONFIRM BONE INFECTION AS AN UNDERLYING CAUSE. OVER RECENT YEARS, A PROFOUND DYSREGULATION OF CYTOKINE EXPRESSION PROFILES HAS BEEN DEMONSTRATED IN INNATE IMMUNE CELLS OF CNO PATIENTS. A HALLMARK OF MONOCYTES FROM CNO PATIENTS IS THE FAILURE TO PRODUCE IMMUNE REGULATORY CYTOKINES INTERLEUKIN-10 (IL-10) AND IL-19, WHICH HAVE BEEN LINKED WITH GENETIC AND EPIGENETIC ALTERATIONS. SUBSEQUENTLY, A SIGNIFICANT UPREGULATION OF PRO-INFLAMMATORY, NLRP3 INFLAMMASOME-DEPENDENT CYTOKINES (IL-1BETA AND TNF-ALPHA), HAS BEEN DEMONSTRATED. THE CURRENT KNOWLEDGE ON CNO, THE UNDERLYING MOLECULAR PATHOPHYSIOLOGY, AND MODERN IMAGING STRATEGIES ARE SUMMARIZED; DIFFERENTIAL DIAGNOSES, TREATMENT OPTIONS, OUTCOME MEASURES, AS WELL AS QUALITY OF LIFE STUDIES ARE DISCUSSED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3   547  22 ATTENUATED TLR4/MAPK SIGNALING IN MONOCYTES FROM PATIENTS WITH CRMO RESULTS IN IMPAIRED IL-10 EXPRESSION. CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY BONE DISORDER OF UNKNOWN ORIGIN. WE PREVIOUSLY DEMONSTRATED THAT MONOCYTES FROM CRMO PATIENTS FAIL TO EXPRESS THE IMMUNE-MODULATORY CYTOKINE INTERLEUKIN-10 (IL-10) IN A CHROMATIN DEPENDENT MANNER. HERE, WE DEMONSTRATE THAT ATTENUATED EXTRACELLULAR-SIGNAL REGULATED KINASE (ERK)1 AND 2 SIGNALING IN RESPONSE TO TLR4 ACTIVATION RESULTS IN FAILURE TO INDUCE IL-10 EXPRESSION IN MONOCYTES FROM CRMO PATIENTS. ATTENUATED ERK1/2 ACTIVATION RESULTS IN 1) REDUCED LEVELS OF SP-1, A TRANSCRIPTION FACTOR THAT INDUCES IL-10 EXPRESSION IN MONOCYTES, AND 2) IMPAIRED H3S10 PHOSPHORYLATION OF THE IL10 PROMOTER, AN ACTIVATING EPIGENETIC MARK. THE PRO-INFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR (TNF)ALPHA AND IL-6 ARE NOT NEGATIVELY AFFECTED, RESULTING IN AN IMBALANCE TOWARDS PRO-INFLAMMATORY CYTOKINES. THUS, IMPAIRED ERK1/2 SIGNALING WITH SUBSEQUENTLY REDUCED SP-1 EXPRESSION AND H3S10 PHOSPHORYLATION OF THE IL10 PROMOTER MAY CENTRALLY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF CRMO.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4   969  21 CHRONIC NON-BACTERIAL OSTEOMYELITIS IS ASSOCIATED WITH IMPAIRED SP1 SIGNALING, REDUCED IL10 PROMOTER PHOSPHORYLATION, AND REDUCED MYELOID IL-10 EXPRESSION. CHRONIC NON-BACTERIAL OSTEOMYELITIS (CNO) IS AN AUTO-INFLAMMATORY DISORDER THAT AFFECTS THE SKELETAL SYSTEM. INTERLEUKIN (IL-)10 IS AN IMMUNE-MODULATORY CYTOKINE THAT CONTROLS INFLAMMATION, AND LIMITS INFLAMMATORY CYTOKINE RESPONSES. DYSREGULATION OF IL-10 EXPRESSION HAS BEEN SHOWN TO RESULT IN AUTOIMMUNE AND INFECTIOUS DISEASES. WE INVESTIGATED IL-10 EXPRESSION BY MONOCYTIC CELLS FROM CNO PATIENTS AND CONTROLS. IN RESPONSE TO STIMULATION WITH LPS, IL-10 EXPRESSION FROM CNO MONOCYTES WAS REDUCED (P<0.001). THIS WAS INDEPENDENT OF IL10 PROMOTER POLYMORPHISMS. THUS, WE INVESTIGATED SP1 RECRUITMENT TO THE IL10 PROMOTER AND SAW MARKEDLY REDUCED BINDING IN CNO MONOCYTES. THIS WAS ACCOMPANIED WITH REDUCED PHOSPHORYLATION OF HISTONE H3 SERINE 10 (H3S10), AN ACTIVATING EPIGENETIC MARK. IMPAIRED RECRUITMENT OF SP1 TO THE IL10 PROMOTER, AND REDUCED H3S10 PHOSPHORYLATION, MAY BE A REFLECTION OF DEFICIENT MAPK SIGNALING IN CNO MONOCYTES IN RESPONSE TO LPS STIMULATION. THUS, WE HAVE DISCOVERED A MECHANISM THAT MAY BE CENTRAL IN THE PATHOPHYSIOLOGY OF CNO.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5  2731  20 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  6254  22 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  4673  33 NEW INSIGHTS INTO THE PATHOGENESIS AND TREATMENT OF IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS ONE OF THE MOST COMMON FUNCTIONAL GASTROINTESTINAL DISORDERS (FGID), CHARACTERIZED BY ABDOMINAL PAIN AND A CHANGE IN STOOL FORM THAT CANNOT BE EXPLAINED BY STRUCTURAL ABNORMALITIES. ITS PREVALENCE RANGES FROM 9 TO 23% OF THE WORLDWIDE POPULATION. THE PATHOPHYSIOLOGY OF IBS IS DIVERSE AND NOT WELL UNDERSTOOD. BIOPSYCHOSOCIAL CONCEPT ASSUMES THAT THE DISEASE IS A PRODUCT OF PSYCHOSOCIAL FACTORS AND ALTERED AT MULTIPLE LEVELS OF GUT PHYSIOLOGY INTERACTIONS. SOME AETIOLOGICAL FACTORS HAVE BEEN IDENTIFIED, YET. ONE OF THE MOST IMPORTANT IS THE DISRUPTION OF BRAIN-GUT MUTUAL COMMUNICATION THAT LEADS TO VISCERAL HYPERSENSITIVITY. ALSO GENETIC AND EPIGENETIC FACTORS ARE INVOLVED. CHRONIC STRESS MAY PREDISPOSE TO IBS AS WELL AS EXACERBATE ITS SYMPTOMS. BOTH QUANTITATIVE AND QUALITATIVE DISORDERS OF THE GUT MICROBIOTA ARE OBSERVED. THERE IS ALSO A RELATIONSHIP BETWEEN THE IBS SYMPTOMS AND THE INTAKE OF A SPECIFIC TYPE OF FOOD PRODUCTS. IN THE DIARRHOEA TYPE OF IBS THE ROLE OF PREVIOUS GASTROINTESTINAL INFECTION IS DEMONSTRATED. RECENT STUDIES HAVE SUGGESTED THAT VISCERAL HYPERSENSITIVITY IN PATIENTS WITH IBS MAY BE SECONDARY TO THE ACTIVATION OF THE IMMUNE CELLS AND LOW-GRADE INFLAMMATION. CLINICAL SYMPTOMS OF IBS INCLUDE ABDOMINAL PAIN AND CHANGE IN BOWEL HABITS AS WELL AS SOMATIC AND PSYCHIATRIC COMORBIDITIES. IBS IS DIAGNOSED ON THE BASIS OF ROME DIAGNOSTIC CRITERIA. RECENTLY, THEIR NEWEST VERSION (ROME IV) HAS BEEN PRESENTED. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE PAST DECADE PROGRESS IN IBS DIAGNOSIS, MAIN PATHOPHYSIOLOGICAL ASPECTS AND THERAPEUTIC MANAGEMENT STRATEGY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  3821  20 INTRODUCTION: FROM PATHOGENESIS TO THERAPY, DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. A NUMBER OF THEORIES MAY EXPLAIN ITS PATHOGENESIS AND MANY ARGUMENTS SUPPORT THE HYPOTHESIS THAT GENETIC OR EPIGENETIC CHANGES ARE A PREREQUISITE FOR DEVELOPMENT OF LESIONS INTO DEEP ENDOMETRIOSIS. DEEP ENDOMETRIOSIS IS FREQUENTLY RESPONSIBLE FOR PELVIC PAIN, DYSMENORRHEA, AND/OR DEEP DYSPAREUNIA, BUT CAN ALSO CAUSE OBSTETRICAL COMPLICATIONS. DIAGNOSIS MAY BE IMPROVED BY HIGH-QUALITY IMAGING. THERAPEUTIC APPROACHES ARE A SOURCE OF CONTENTION AS WELL. IN THIS ISSUE'S VIEWS AND REVIEWS, MEDICAL AND SURGICAL STRATEGIES ARE DISCUSSED, AND IT IS EMPHASIZED THAT TREATMENT SHOULD BE DESIGNED ACCORDING TO A PATIENT'S SYMPTOMS AND INDIVIDUAL NEEDS. IT IS ALSO VITAL THAT REFERRAL CENTERS HAVE THE KNOWLEDGE AND EXPERIENCE TO TREAT DEEP ENDOMETRIOSIS MEDICALLY AND/OR SURGICALLY. THE DEBATE MUST CONTINUE BECAUSE EMERGING TRENDS IN THERAPY NEED TO BE FOLLOWED AND INVESTIGATED FOR OPTIMAL MANAGEMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9   105  27 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  4685  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  3286  41 HIDRADENITIS SUPPURATIVA: DETANGLING PHENOTYPES AND IDENTIFYING COMMON DENOMINATORS. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH A SEVERE IMPACT ON PATIENTS' QUALITY OF LIFE THROUGH ITS RECURRENT AND PAINFUL NATURE, AS WELL AS ITS COMORBIDITY BURDEN. THE SHIFT IN THE PATHOGENIC PARADIGM FROM A CONDITION OF THE APOCRINE GLANDS TO AN AUTOINFLAMMATORY DISEASE ASSOCIATED WITH FOLLICULAR DESTRUCTION HAS RENDERED ITS UNDERSTANDING DIFFICULT, AS THERE ARE STILL LARGE GAPS IN PINPOINTING THE UNDERLYING MECHANISMS, WHICH CANNOT CURRENTLY EXPLAIN THE EXISTING CLINICAL VARIATION AND AS A RESULT, TRANSLATE INTO SUBOPTIMAL THERAPY. MULTIFACTORIAL INVOLVEMENT IS HYPOTHESIZED, WITH AN IMPLICATION OF GENETIC MUTATIONS, MICROBIOME DYSBIOSIS, CYTOKINE UPREGULATION, AND ENVIRONMENTAL FACTORS. CLINICAL OBSERVATION IS FUNDAMENTAL FOR DIAGNOSIS, HOWEVER, THE MARKED HETEROGENEITY IN PRESENTATION LEADS TO DELAYS IN DETECTION AND CHALLENGES IN TREATMENT SELECTION, SHOWCASING CLEAR LIMITS IN DEFINING THE LINK BETWEEN GENETIC ASPECTS OF HS, THE ROLE OF EPIGENETIC FACTORS, AND ITS PATHOGENIC PATHWAYS. THERE HAVE BEEN ATTEMPTS TO FORMULATE PHENOTYPES THAT COULD AID IN PROGNOSTICATION AND MANAGEMENT, HOWEVER, CURRENT CLASSIFICATION SCHEMATA SHOW SIGNIFICANT OVERLAP AND NO VALIDATION THROUGH LONGITUDINAL STUDIES. IN THIS CONTEXT, NOMENCLATURE POSES A GREAT CHALLENGE DUE TO THE LACK OF GLOBAL AGREEMENT IN THE DEFINITION OF LESIONS, WHICH SHOULD BE ADDRESSED BY FUTURE RESEARCH TO ENABLE SIMPLIFIED RECOGNITION AND ALLOW FOR MORE PRECISE SEVERITY SCORING. THIS COULD BE COMPLEMENTED BY THE ADDITION OF EXTRA DERMATOLOGIC FINDINGS OR PARACLINICAL ASSESSMENT IN CONSTRUCTING PHENOTYPES. THE DEVELOPMENT OF VALID, PREDICTIVE, AND RELIABLE CLASSIFICATIONS OF HS MAY LEAD TO AN IMPROVEMENT IN COMPREHENDING ITS PATHOPHYSIOLOGY, FAVORING A MORE PERSONALIZED APPROACH IN MANAGEMENT. THIS COULD BE ACHIEVED THROUGH CONSENSUS IN THE CHARACTERIZATION OF CLINICAL FEATURES AND DATA GATHERING, AS WELL AS VALIDATION ATTEMPTS FOR DESCRIBED PHENOTYPES. ULTIMATELY, THE GENOTYPE-ENDOTYPE-PHENOTYPE CORRELATION IN HS REQUIRES TARGETED, SYSTEMATIC INQUIRIES AND SHOULD BE ADDRESSED MORE LARGELY TO BROADEN THE PERSPECTIVE ON THIS DEBILITATING ENTITY.	2023	

12  1055  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  4950  23 PATHOGENESIS OF ADENOMYOSIS: AN UPDATE ON MOLECULAR MECHANISMS. ADENOMYOSIS IS A UTERINE DISORDER BECOMING MORE COMMONLY DIAGNOSED IN WOMEN OF REPRODUCTIVE AGE BECAUSE OF DIAGNOSTIC IMAGING ADVANCEMENTS. THE NEW EPIDEMIOLOGICAL SCENARIO AND THE CLINICAL EVIDENCE OF PELVIC PAIN, ABNORMAL UTERINE BLEEDING AND INFERTILITY ARE CHANGING THE CLASSIC PERSPECTIVE OF ADENOMYOSIS AS A PREMENOPAUSAL DISEASE. IN THE LAST DECADE, THE EVALUATION OF MULTIPLE MOLECULAR MEDIATORS HAS IMPROVED OUR KNOWLEDGE OF PATHOGENIC MECHANISMS OF ADENOMYOSIS, SUPPORTING THAT THIS IS AN INDEPENDENT DISEASE FROM ENDOMETRIOSIS. ALTHOUGH THEY SHARE COMMON GENETIC MUTATIONS AND EPIGENETIC CHANGES IN SEX STEROID HORMONE RECEPTORS AND SIMILAR INFLAMMATORY MEDIATORS, AN INCREASING NUMBER OF RECENT STUDIES HAVE SHOWN PATHOGENIC PATHWAYS SPECIFIC FOR ADENOMYOSIS. A PUBMED SEARCH UP TO OCTOBER 2016 SUMMARIZES THE KEY MEDIATORS OF PAIN, ABNORMAL UTERINE BLEEDING AND INFERTILITY IN ADENOMYOSIS, INCLUDING SEX STEROID HORMONE RECEPTORS, INFLAMMATORY MOLECULES, EXTRACELLULAR MATRIX ENZYMES, GROWTH FACTORS AND NEUROANGIOGENIC FACTORS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  2556  21 EPIGENETICS IN RHEUMATOID ARTHRITIS. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA. IN MANY HUMAN DISEASES, ESPECIALLY IN CANCERS, BUT ALSO IN AUTOIMMUNE DISEASES, EPIGENETIC ABERRATIONS HAVE BEEN FOUND. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND DESTRUCTION OF SYNOVIAL JOINTS. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RHEUMATOID ARTHRITIS IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF GENETIC PREDISPOSITION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL INFLUENCES. TO GAIN A BETTER UNDERSTANDING OF THIS DISEASE, RESEARCHERS HAVE BECOME INTERESTED IN STUDYING EPIGENETIC CHANGES IN RHEUMATOID ARTHRITIS. HERE, WE WANT TO REVIEW THE CURRENT KNOWLEDGE ON EPIGENETICS IN RHEUMATOID ARTHRITIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15   631  25 BIOLOGICAL AND SYNTHETIC TARGET DMARDS IN PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC MULTI-FACETED IMMUNE-MEDIATED SYSTEMIC DISORDER, CHARACTERIZED BY ARTICULAR, CUTANEOUS, ENTHESIS, NAIL AND SPINE INVOLVEMENT. ARTICULAR MANIFESTATIONS OF PSA ARE PARTICULARLY COMMON AND HIGHLY DISABLING FOR PATIENTS, WHILE THE HETEROGENEOUS CLINICAL SUBSETS OF THE DISEASE ARE CHALLENGING FOR CLINICIANS. IN RECENT YEARS, RESEARCH HAS MADE MANY ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE FROM GENETIC, EPIGENETIC AND MOLECULAR POINTS OF VIEW. NEW DRUGS ARE NOW AVAILABLE FOR THE TREATMENT OF THIS CONDITION, AND, IN PARTICULAR, TNF-ALFA INHIBITORS, HISTORICALLY THE FIRST BIOLOGICALS APPROVED IN PSA, ARE NOW JUXTAPOSED BY NEW BIOLOGICAL DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (BDMARDS) WITH DIFFERENT MODES OF ACTION. TARGETING IL-12/IL-23 P40 COMMON SUBUNIT WITH USTEKINUMAB, IL-17A WITH SECUKINUMAB AND IXEKIZUMAB, T CELLS CO-STIMULATION WITH ABATACEPT, IS NOW POSSIBLE, SAFE AND EFFECTIVE. MOREOVER, TARGETED SYNTHETIC MOLECULES WITH ORAL ADMINISTRATION ARE AVAILABLE, WITH THE POSSIBILITY TO INTERFERE WITH PHOSPHODIESTERASE-4 AND JAK/STAT PATHWAYS. INDEED, NEW DRUGS ARE UNDER DEVELOPMENT, WITH THE POSSIBILITY TO TARGET SELECTIVELY IL-17 RECEPTOR, IL-23, AND OTHER KEY MOLECULAR TARGETS IN THE PATHOGENESIS OF THIS CONDITION. IN THIS NARRATIVE REVIEW, WE PROVIDE AN UP-TO-DATE OVERVIEW OF THE CURRENT APPLICATION OF BIOLOGICAL AND TARGETED SYNTHETIC DMARDS IN THE FIELD OF PSA, WITH PARTICULAR REGARD TO THE CLINICAL SIGNIFICANCE OF THIS POSSIBILITY TO TARGET A HIGHER NUMBER OF DISTINCT IMMUNE-PATHWAYS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  4518  19 MULTI-OMICS FOR BIOMARKER APPROACHES IN THE DIAGNOSTIC EVALUATION AND MANAGEMENT OF ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME: WHAT LIES AHEAD. RELIABLE BIOMARKERS FOR COMMON DISORDERS OF GUT-BRAIN INTERACTION CHARACTERIZED BY ABDOMINAL PAIN, INCLUDING IRRITABLE BOWEL SYNDROME (IBS), ARE CRITICALLY NEEDED TO ENHANCE CARE AND DEVELOP INDIVIDUALIZED THERAPIES. THE DYNAMIC AND HETEROGENEOUS NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS THAT UNDERLIE VISCERAL HYPERSENSITIVITY HAVE CHALLENGED SUCCESSFUL BIOMARKER DEVELOPMENT. CONSEQUENTLY, EFFECTIVE THERAPIES FOR PAIN IN IBS ARE LACKING. HOWEVER, RECENT ADVANCES IN MODERN OMICS TECHNOLOGIES OFFER NEW OPPORTUNITIES TO ACQUIRE DEEP BIOLOGICAL INSIGHTS INTO MECHANISMS OF PAIN AND NOCICEPTION. NEWER METHODS FOR LARGE-SCALE DATA INTEGRATION OF COMPLEMENTARY OMICS APPROACHES HAVE FURTHER EXPANDED OUR ABILITY TO BUILD A HOLISTIC UNDERSTANDING OF COMPLEX BIOLOGICAL NETWORKS AND THEIR CO-CONTRIBUTIONS TO ABDOMINAL PAIN. HERE, WE REVIEW THE MECHANISMS OF VISCERAL HYPERSENSITIVITY, FOCUSING ON IBS. WE DISCUSS CANDIDATE BIOMARKERS FOR PAIN IN IBS IDENTIFIED THROUGH SINGLE OMICS STUDIES AND SUMMARIZE EMERGING MULTI-OMICS APPROACHES FOR DEVELOPING NOVEL BIOMARKERS THAT MAY TRANSFORM CLINICAL CARE FOR PATIENTS WITH IBS AND ABDOMINAL PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  6827  22 [GILLES DE LA TOURETTE'S DISEASE. SYMPTOMS, ETIOPATHOGENESIS AND THERAPEUTIC APPROACHES]. THE GILLES DE LA TOURETTE SYNDROME IS A USUALLY CHRONIC NEUROPSYCHIATRIC DISORDER WITH AN EARLY CHILDHOOD ONSET FEATURING MAINLY MOTOR AND VOCAL TICS. IT SEEMS THAT STRONG GENETIC FACTORS MAKE A MAJOR CONTRIBUTION TO THE ETIOLOGY OF THIS DISORDER, BUT THERE ARE ALSO CLUES THAT EPIGENETIC FACTORS ARE INVOLVED IN THE PATHOGENESIS OF TOURETTE'S SYNDROME, SUCH AS MATERNAL STRESS DURING PREGNANCY, BIRTH COMPLICATIONS AND HORMONAL INFLUENCES. FIRST IN LINE FOR ADEQUATE TREATMENT ARE NEUROLEPTIC COMPOUNDS OF HIGH POTENCY, BESIDES, SEVERAL OTHER PSYCHOACTIVE DRUGS HAVE SHOWN SOME THERAPEUTIC EFFECTS. LESS EVIDENT IS THE EFFICACY OF NEUROSURGICAL AND PSYCHOTHERAPEUTIC INTERVENTIONS.	1997	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  5372  33 RECENT ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: NEW TREATMENT STRATEGIES. RHEUMATOID ARTHRITIS (RA) IS CONSIDERED A CHRONIC SYSTEMIC, MULTI-FACTORIAL, INFLAMMATORY, AND PROGRESSIVE AUTOIMMUNE DISEASE AFFECTING MANY PEOPLE WORLDWIDE. WHILE PATIENTS SHOW VERY INDIVIDUAL COURSES OF DISEASE, WITH RA FOCUSING ON THE MUSCULOSKELETAL SYSTEM, JOINTS ARE OFTEN SEVERELY AFFECTED, LEADING TO LOCAL INFLAMMATION, CARTILAGE DESTRUCTION, AND BONE EROSION. TO PREVENT JOINT DAMAGE AND PHYSICAL DISABILITY AS ONE OF MANY SYMPTOMS OF RA, EARLY DIAGNOSIS IS CRITICAL. AUTO-ANTIBODIES PLAY A PIVOTAL CLINICAL ROLE IN PATIENTS WITH SYSTEMIC RA. AS BIOMARKERS, THEY COULD HELP TO MAKE A MORE EFFICIENT DIAGNOSIS, PROGNOSIS, AND TREATMENT DECISION. BESIDES AUTO-ANTIBODIES, SEVERAL OTHER FACTORS ARE INVOLVED IN THE PROGRESSION OF RA, SUCH AS EPIGENETIC ALTERATIONS, POST-TRANSLATIONAL MODIFICATIONS, GLYCOSYLATION, AUTOPHAGY, AND T-CELLS. UNDERSTANDING THE INTERPLAY BETWEEN THESE FACTORS WOULD CONTRIBUTE TO A DEEPER INSIGHT INTO THE CAUSES, MECHANISMS, PROGRESSION, AND TREATMENT OF THE DISEASE. IN THIS REVIEW, THE LATEST RA RESEARCH FINDINGS ARE DISCUSSED TO BETTER UNDERSTAND THE PATHOGENESIS, AND FINALLY, TREATMENT STRATEGIES FOR RA THERAPY ARE PRESENTED, INCLUDING BOTH CONVENTIONAL APPROACHES AND NEW METHODS THAT HAVE BEEN DEVELOPED IN RECENT YEARS OR ARE CURRENTLY UNDER INVESTIGATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  6345  35 THE ROLE OF EPIGENETICS IN AUTOIMMUNE/INFLAMMATORY DISEASE. HISTORICALLY, SYSTEMIC SELF-INFLAMMATORY CONDITIONS WERE CLASSIFIED AS EITHER AUTOINFLAMMATORY AND CAUSED BY THE INNATE IMMUNE SYSTEM OR AUTOIMMUNE AND DRIVEN BY ADAPTIVE IMMUNE RESPONSES. HOWEVER, IT BECAME CLEAR THAT REALITY IS MUCH MORE COMPLEX AND THAT AUTOIMMUNE/INFLAMMATORY CONDITIONS RANGE ALONG AN "INFLAMMATORY SPECTRUM" WITH PRIMARILY AUTOINFLAMMATORY VS. AUTOIMMUNE CONDITIONS RESEMBLING EXTREMES AT EITHER END. EPIGENETIC MODIFICATIONS INFLUENCE GENE EXPRESSION AND ALTER CELLULAR FUNCTIONS WITHOUT MODIFYING THE GENOMIC SEQUENCE. METHYLATION OF CPG DNA DINUCLEOTIDES AND/OR THEIR HYDROXYMETHYLATION, POST-TRANSLATIONAL MODIFICATIONS TO AMINO TERMINI OF HISTONE PROTEINS, AND NON-CODING RNA EXPRESSION ARE MAIN EPIGENETIC EVENTS. THE PATHOPHYSIOLOGY OF AUTOIMMUNE/INFLAMMATORY DISEASES HAS BEEN CLOSELY LINKED WITH DISEASE CAUSING GENE MUTATIONS (RARE) OR A COMBINATION OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS ARISING FROM EXPOSURE TO THE ENVIRONMENT (MORE COMMON). OVER RECENT YEARS, PROGRESS HAS BEEN MADE IN UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION AND THE CONTRIBUTION OF INNATE AND ADAPTIVE IMMUNE RESPONSES. EPIGENETIC EVENTS HAVE BEEN IDENTIFIED AS (I) CENTRAL PATHOPHYSIOLOGICAL FACTORS IN ADDITION TO GENETIC DISEASE PREDISPOSITION AND (II) AS CO-FACTORS DETERMINING CLINICAL PICTURES AND OUTCOMES IN INDIVIDUALS WITH MONOGENIC DISEASE. THUS, A COMPLETE UNDERSTANDING OF EPIGENETIC CONTRIBUTORS TO AUTOIMMUNE/INFLAMMATORY DISEASE WILL RESULT IN APPROACHES TO PREDICT INDIVIDUAL DISEASE OUTCOMES AND THE INTRODUCTION OF EFFECTIVE, TARGET-DIRECTED, AND TOLERABLE THERAPIES. HERE, WE SUMMARIZE RECENT FINDINGS THAT SIGNIFY THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN AUTOIMMUNE/INFLAMMATORY DISORDERS ALONG THE INFLAMMATORY SPECTRUM CHOOSING THREE EXAMPLES: THE AUTOINFLAMMATORY BONE CONDITION CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO), THE "MIXED PATTERN" DISORDER PSORIASIS, AND THE AUTOIMMUNE DISEASE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE).	2019	
                                                                                                                                                                                                
20  5159  27 PRE-RHEUMATOID ARTHRITIS: PREDISPOSITION AND TRANSITION TO CLINICAL SYNOVITIS. MULTIPLE PROVEN AND POTENTIAL RISK FACTORS FOR THE DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA) HAVE BEEN IDENTIFIED, AND REPRESENT INTERACTIONS BETWEEN GENES AND THE ENVIRONMENT. PROVEN RISK FACTORS INCLUDE GENETIC INFLUENCES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS, SMOKING, ANTI-CITRULLINATED PROTEIN ANTIBODIES (ACPAS), AND RHEUMATOID FACTORS (RF). POTENTIAL RISK FACTORS INCLUDE EPIGENETIC CONTROL OF GENE EXPRESSION, THE MICROBIOME AND OTHER ENVIRONMENTAL FACTORS, TOLL-LIKE RECEPTORS, CYTOKINES, AND FC RECEPTORS. PRECLINICAL ABNORMALITIES SUCH AS CIRCULATING RF AND ACPAS MAY OCCUR MORE THAN 10 YEARS PRIOR TO THE ONSET OF CLINICAL DISEASE. HOWEVER, THE PRECISE MECHANISMS WHEREBY THESE RISK FACTORS LEAD TO CLINICAL DISEASE REMAIN UNCLEAR. IT IS POSSIBLE THAT, COMBINED WITH ACTIVATION OF THE INNATE IMMUNE SYSTEM, A SUBSET OF ACPAS INITIATES THE DISEASE IN THE CARTILAGE OR SYNOVIUM AFTER BINDING TO ENDOGENOUS CITRULLINATED PROTEINS. SUBSEQUENT ENGAGEMENT OF FC RECEPTORS AND COMPLEMENT ACTIVATION WOULD LEAD TO SECONDARY INFLAMMATION IN THE SYNOVIUM WITH INDUCTION OF A PERPETUATING CYCLE OF CHRONIC SYNOVITIS.	2012