1 40 182 A COMPARISON OF HERPES SIMPLEX VIRUS TYPE 1 AND VARICELLA-ZOSTER VIRUS LATENCY AND REACTIVATION. HERPES SIMPLEX VIRUS TYPE 1 (HSV-1; HUMAN HERPESVIRUS 1) AND VARICELLA-ZOSTER VIRUS (VZV; HUMAN HERPESVIRUS 3) ARE HUMAN NEUROTROPIC ALPHAHERPESVIRUSES THAT CAUSE LIFELONG INFECTIONS IN GANGLIA. FOLLOWING PRIMARY INFECTION AND ESTABLISHMENT OF LATENCY, HSV-1 REACTIVATION TYPICALLY RESULTS IN HERPES LABIALIS (COLD SORES), BUT CAN OCCUR FREQUENTLY ELSEWHERE ON THE BODY AT THE SITE OF PRIMARY INFECTION (E.G. WHITLOW), PARTICULARLY AT THE GENITALS. RARELY, HSV-1 REACTIVATION CAN CAUSE ENCEPHALITIS; HOWEVER, A THIRD OF THE CASES OF HSV-1 ENCEPHALITIS ARE ASSOCIATED WITH HSV-1 PRIMARY INFECTION. PRIMARY VZV INFECTION CAUSES VARICELLA (CHICKENPOX) FOLLOWING WHICH LATENT VIRUS MAY REACTIVATE DECADES LATER TO PRODUCE HERPES ZOSTER (SHINGLES), AS WELL AS AN INCREASINGLY RECOGNIZED NUMBER OF SUBACUTE, ACUTE AND CHRONIC NEUROLOGICAL CONDITIONS. FOLLOWING PRIMARY INFECTION, BOTH VIRUSES ESTABLISH A LATENT INFECTION IN NEURONAL CELLS IN HUMAN PERIPHERAL GANGLIA. HOWEVER, THE DETAILED MECHANISMS OF VIRAL LATENCY AND REACTIVATION HAVE YET TO BE UNRAVELLED. IN BOTH CASES LATENT VIRAL DNA EXISTS IN AN 'END-LESS' STATE WHERE THE ENDS OF THE VIRUS GENOME ARE JOINED TO FORM STRUCTURES CONSISTENT WITH UNIT LENGTH EPISOMES AND CONCATEMERS, FROM WHICH VIRAL GENE TRANSCRIPTION IS RESTRICTED. IN LATENTLY INFECTED GANGLIA, THE MOST ABUNDANTLY DETECTED HSV-1 RNAS ARE THE SPLICED PRODUCTS ORIGINATING FROM THE PRIMARY LATENCY ASSOCIATED TRANSCRIPT (LAT). THIS PRIMARY LAT IS AN 8.3 KB UNSTABLE TRANSCRIPT FROM WHICH TWO STABLE (1.5 AND 2.0 KB) INTRONS ARE SPLICED. TRANSCRIPTS MAPPING TO 12 VZV GENES HAVE BEEN DETECTED IN HUMAN GANGLIA REMOVED AT AUTOPSY; HOWEVER, IT IS DIFFICULT TO ASCRIBE THESE AS TRANSCRIPTS PRESENT DURING LATENT INFECTION AS EARLY-STAGE VIRUS REACTIVATION MAY HAVE TRANSPIRED IN THE POST-MORTEM TIME PERIOD IN THE GANGLIA. NONETHELESS, LOW-LEVEL TRANSCRIPTION OF VZV ORF63 HAS BEEN REPEATEDLY DETECTED IN MULTIPLE GANGLIA REMOVED AS CLOSE TO DEATH AS POSSIBLE. THERE IS INCREASING EVIDENCE THAT HSV-1 AND VZV LATENCY IS EPIGENETICALLY REGULATED. IN VITRO MODELS THAT PERMIT PATHWAY ANALYSIS AND IDENTIFICATION OF BOTH EPIGENETIC MODULATIONS AND GLOBAL TRANSCRIPTIONAL MECHANISMS OF HSV-1 AND VZV LATENCY HOLD MUCH PROMISE FOR OUR FUTURE UNDERSTANDING IN THIS COMPLEX AREA. THIS REVIEW SUMMARIZES THE MOLECULAR BIOLOGY OF HSV-1 AND VZV LATENCY AND REACTIVATION, AND ALSO PRESENTS FUTURE DIRECTIONS FOR STUDY. 2015 2 3839 38 IPSC-DERIVED NEURAL PRECURSOR CELLS: POTENTIAL FOR CELL TRANSPLANTATION THERAPY IN SPINAL CORD INJURY. A NUMBER OF STUDIES HAVE DEMONSTRATED THAT TRANSPLANTATION OF NEURAL PRECURSOR CELLS (NPCS) PROMOTES FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY (SCI). HOWEVER, THE NPCS HAD BEEN MOSTLY HARVESTED FROM EMBRYONIC STEM CELLS OR FETAL TISSUE, RAISING THE ETHICAL CONCERN. YAMANAKA AND HIS COLLEAGUES ESTABLISHED INDUCED PLURIPOTENT STEM CELLS (IPSCS) WHICH COULD BE GENERATED FROM SOMATIC CELLS, AND THIS INNOVATIVE DEVELOPMENT HAS MADE RAPID PROGRESSION IN THE FIELD OF SCI REGENERATION. WE AND OTHER GROUPS SUCCEEDED IN PRODUCING NPCS FROM IPSCS, AND DEMONSTRATED BENEFICIAL EFFECTS AFTER TRANSPLANTATION FOR ANIMAL MODELS OF SCI. IN PARTICULAR, EFFICACY OF HUMAN IPSC-NPCS IN NON-HUMAN PRIMATE SCI MODELS FOSTERED MOMENTUM OF CLINICAL APPLICATION FOR SCI PATIENTS. AT THE SAME TIME, HOWEVER, ARTIFICIAL INDUCTION METHODS IN IPSC TECHNOLOGY CREATED ALTERNATIVE ISSUES INCLUDING GENETIC AND EPIGENETIC ABNORMALITIES, AND TUMORIGENICITY AFTER TRANSPLANTATION. TO OVERCOME THESE PROBLEMS, IT IS CRITICALLY IMPORTANT TO SELECT ORIGINS OF SOMATIC CELLS, USE INTEGRATION-FREE SYSTEM DURING TRANSFECTION OF REPROGRAMMING FACTORS, AND THOROUGHLY INVESTIGATE THE CHARACTERISTICS OF IPSC-NPCS WITH RESPECT TO QUALITY MANAGEMENT. MOREOVER, SINCE MOST OF THE PREVIOUS STUDIES HAVE FOCUSED ON SUBACUTE PHASE OF SCI, ESTABLISHMENT OF EFFECTIVE NPC TRANSPLANTATION SHOULD BE EVALUATED FOR CHRONIC PHASE HEREAFTER. OUR GROUP IS CURRENTLY PREPARING CLINICAL-GRADE HUMAN IPSC-NPCS, AND WILL MOVE FORWARD TOWARD CLINICAL STUDY FOR SUBACUTE SCI PATIENTS SOON IN THE NEAR FUTURE. 2018 3 6697 67 VARICELLA-ZOSTER VIRUS HUMAN GANGLIONIC LATENCY: A CURRENT SUMMARY. VARICELLA-ZOSTER VIRUS (VZV) IS A UBIQUITOUS HUMAN HERPES VIRUS TYPICALLY ACQUIRED IN CHILDHOOD WHEN IT CAUSES VARICELLA (CHICKENPOX), FOLLOWING WHICH THE VIRUS ESTABLISHES A LATENT INFECTION IN TRIGEMINAL AND DORSAL ROOT GANGLIA THAT LASTS FOR THE LIFE OF THE INDIVIDUAL. VZV SUBSEQUENTLY REACTIVATES, SPONTANEOUSLY OR AFTER SPECIFIC TRIGGERING FACTORS, TO CAUSE HERPES ZOSTER (SHINGLES), WHICH MAY BE COMPLICATED BY POSTHERPETIC NEURALGIA AND SEVERAL OTHER NEUROLOGICAL COMPLICATIONS INCLUDING VASCULOPATHY. OUR UNDERSTANDING OF VZV LATENCY LAGS BEHIND OUR KNOWLEDGE OF HERPES SIMPLEX VIRUS TYPE 1 (HSV-1) LATENCY PRIMARILY DUE TO THE DIFFICULTY IN PROPAGATING THE VIRUS TO HIGH TITERS IN A CELL-FREE STATE, AND THE LACK OF A SUITABLE SMALL-ANIMAL MODEL FOR STUDYING VIRUS LATENCY AND REACTIVATION. IT IS NOW ESTABLISHED BEYOND DOUBT THAT LATENT VZV IS PREDOMINANTLY LOCATED IN HUMAN GANGLIONIC NEURONS. VIRUS GENE TRANSCRIPTION DURING LATENCY IS EPIGENETICALLY REGULATED, AND APPEARS TO BE RESTRICTED TO EXPRESSION OF AT LEAST SIX GENES, WITH EXPRESSION OF GENE 63 BEING THE HALLMARK OF LATENCY. HOWEVER, VIRAL GENE TRANSCRIPTION MAY BE MORE EXTENSIVE THAN PREVIOUSLY THOUGHT. THERE IS ALSO EVIDENCE FOR SEVERAL VZV GENES BEING EXPRESSED AT THE PROTEIN LEVEL, INCLUDING VZV GENE 63-ENCODED PROTEIN, BUT RECENT EVIDENCE SUGGESTS THAT THIS MAY NOT BE A COMMON EVENT. THE NATURE AND EXTENT OF THE CHRONIC INFLAMMATORY RESPONSE IN LATENTLY INFECTED GANGLIA IS ALSO OF CURRENT INTEREST. THERE REMAIN SEVERAL QUESTIONS CONCERNING THE VZV LATENCY PROCESS THAT STILL NEED TO BE RESOLVED UNAMBIGUOUSLY AND IT IS LIKELY THAT THIS WILL REQUIRE THE USE OF NEWLY DEVELOPED MOLECULAR TECHNOLOGIES, SUCH AS GEXPS MULTIPLEX POLYMERASE CHAIN REACTION (PCR) FOR VIRUS TRANSCRIPTIONAL ANALYSIS AND CHIP-SEQ TO STUDY THE EPIGENETIC OF LATENT VIRUS GENOME ( LIU ET AL, 2010 , BMC BIOL 8: 56). 2010 4 6615 35 ULTRAVIOLET-A1 IRRADIATION THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (LUPUS, SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES, WHICH BIND TO ANTIGENS AND ARE DEPOSITED WITHIN TISSUES TO FIX COMPLEMENT, RESULTING IN WIDESPREAD SYSTEMIC INFLAMMATION. THE STUDIES PRESENTED HEREIN ARE CONSISTENT WITH HYPERPOLARIZED, ADENOSINE TRIPHOSPHATE (ATP)-DEFICIENT MITOCHONDRIA BEING CENTRAL TO THE DISEASE PROCESS. THESE HYPERPOLARIZED MITOCHONDRIA RESIST THE DEPOLARIZATION REQUIRED FOR ACTIVATION-INDUCED APOPTOSIS. THE MITOCHONDRIAL ATP DEFICITS ADD TO THIS RESISTANCE TO APOPTOSIS AND ALSO REDUCE THE MACROPHAGE ENERGY THAT IS NEEDED TO CLEAR APOPTOTIC BODIES. IN BOTH CASES, NECROSIS, THE ALTERNATIVE PATHWAY OF CELL DEATH, RESULTS. INTRACELLULAR CONSTITUENTS SPILL INTO THE BLOOD AND TISSUES, ELICITING INFLAMMATORY RESPONSES DIRECTED AT THEIR REMOVAL. WHAT RESULTS IS "AUTOIMMUNITY." ULTRAVIOLET (UV)-A1 PHOTONS HAVE THE CAPACITY TO REMEDIATE THIS ABERRANCY. EXOGENOUS EXPOSURE TO LOW-DOSE, FULL-BODY, UV-A1 RADIATION GENERATES SINGLET OXYGEN. SINGLET OXYGEN HAS TWO MAJOR PALLIATIVE ACTIONS IN PATIENTS WITH LUPUS AND THE UV-A1 PHOTONS THEMSELVES HAVE SEVERAL MORE. SINGLET OXYGEN DEPOLARIZES THE HYPERPOLARIZED MITOCHONDRION, TRIGGERING NON-ATP-DEPENDENT APOPTOSIS THAT DETERS NECROSIS. NEXT, SINGLET OXYGEN ACTIVATES THE GENE ENCODING HEME OXYGENASE (HO-1), A MAJOR GOVERNOR OF SYSTEMIC HOMEOSTASIS. HO-1 CATALYZES THE DEGRADATION OF THE OXIDANT HEME INTO BILIVERDIN (CONVERTED TO BILIRUBIN), FE, AND CARBON MONOXIDE (CO), THE FIRST THREE OF THESE EXERTING POWERFUL ANTIOXIDANT EFFECTS, AND IN CONJUNCTION WITH A FOURTH, CO, PROTECTING AGAINST INJURY TO THE CORONARY ARTERIES, THE CENTRAL NERVOUS SYSTEM, AND THE LUNGS. THE UV-A1 PHOTONS THEMSELVES DIRECTLY ATTENUATE DISEASE IN LUPUS BY REDUCING B CELL ACTIVITY, PREVENTING THE SUPPRESSION OF CELL-MEDIATED IMMUNITY, SLOWING AN EPIGENETIC PROGRESSION TOWARD SLE, AND AMELIORATING DISCOID AND SUBACUTE CUTANEOUS LUPUS. FINALLY, A COMBINATION OF THESE MECHANISMS REDUCES LEVELS OF ANTICARDIOLIPIN ANTIBODIES AND PROTECTS DURING LUPUS PREGNANCY. CAPPING ALL OF THIS IS THAT UV-A1 IRRADIATION IS AN ESSENTIALLY INNOCUOUS, HIGHLY MANAGEABLE, AND COMFORTABLE THERAPEUTIC AGENCY. 2017 5 454 34 APPLICATIONS OF INDUCED PLURIPOTENT STEM CELL TECHNOLOGIES IN SPINAL CORD INJURY. NUMEROUS BASIC RESEARCH STUDIES HAVE SUGGESTED THE POTENTIAL EFFICACY OF NEURAL PRECURSOR CELL (NPC) TRANSPLANTATION IN SPINAL CORD INJURY (SCI). HOWEVER, IN MOST SUCH STUDIES, THE ORIGIN OF THE CELLS USED WAS MAINLY FETAL TISSUE OR EMBRYONIC STEM CELLS, BOTH OF WHICH CARRY POTENTIAL ETHICAL CONCERNS WITH RESPECT TO CLINICAL USE. THE DEVELOPMENT OF INDUCED PLURIPOTENT STEM CELLS (IPSCS) OPENED A NEW PATH TOWARD REGENERATIVE MEDICINE FOR SCI. IPSCS CAN BE GENERATED FROM SOMATIC CELLS BY INDUCTION OF TRANSCRIPTION FACTORS, AND INDUCED TO DIFFERENTIATE INTO NPCS WITH CHARACTERISTICS OF CELLS OF THE CENTRAL NERVOUS SYSTEM. THE BENEFICIAL EFFECT OF IPSC-DERIVED NPC TRANSPLANTATION HAS BEEN REPORTED FROM OUR GROUP AND OTHERS WORKING IN RODENT AND NON-HUMAN PRIMATE MODELS. THESE PROMISING RESULTS FACILITATE THE APPLICATION OF IPSCS FOR CLINICAL APPLICATIONS IN SCI PATIENTS. HOWEVER, IPSCS ALSO HAVE ISSUES, SUCH AS GENETIC/EPIGENETIC ABNORMALITIES AND TUMORIGENESIS BECAUSE OF THE ARTIFICIAL INDUCTION METHOD, THAT MUST BE ADDRESSED PRIOR TO CLINICAL USE. THE SELECTION OF SOMATIC CELLS, GENERATION OF INTEGRATION-FREE IPSCS, AND CHARACTERIZATION OF DIFFERENTIATED NPCS WITH THOROUGH QUALITY MANAGEMENT ARE ALL NEEDED TO ADDRESS THESE POTENTIAL RISKS. TO ENHANCE THE EFFICACY OF THE TRANSPLANTED IPSC-NPCS, ESPECIALLY AT CHRONIC PHASE OF SCI, ADMINISTRATION OF A CHONDROITINASE OR SEMAPHORIN3A INHIBITOR REPRESENTS A POTENTIALLY IMPORTANT MEANS OF PROMOTING AXONAL REGENERATION THROUGH THE LESION SITE. THE COMBINED USE OF REHABILITATION WITH SUCH CELL THERAPY APPROACHES IS ALSO IMPORTANT, AS REPETITIVE TRAINING ENHANCES NEURITE OUTGROWTH OF TRANSPLANTED CELLS AND STRENGTHENS NEURAL CIRCUITS AT CENTRAL PATTERN GENERATORS. OUR GROUP HAS ALREADY EVALUATED CLINICAL GRADE IPSC-DERIVED NPCS, AND WE LOOK FORWARD TO INITIATING CLINICAL TESTING AS THE NEXT STEP TOWARD DETERMINING WHETHER THIS APPROACH IS SAFE AND EFFECTIVE FOR CLINICAL USE. THIS ARTICLE IS PART OF THE MINI REVIEW SERIES "60TH ANNIVERSARY OF THE JAPANESE SOCIETY FOR NEUROCHEMISTRY". 2017 6 5879 35 SYNTHETIC MITOCHONDRIA AS THERAPEUTICS AGAINST SYSTEMIC AGING: A HYPOTHESIS. WE HYPOTHESIZE HEREIN THAT SYNTHETIC MITOCHONDRIA, ENGINEERED, OR REPROGRAMMED TO BE MORE ENERGETICALLY EFFICIENT AND TO HAVE MILDLY ELEVATED LEVELS OF REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, WOULD BE AN EFFECTIVE FORM OF THERAPEUTICS AGAINST SYSTEMIC AGING. THE FREE RADICAL AND MITOCHONDRIA THEORIES OF AGING HOLD THAT MITOCHONDRIA-GENERATED ROS UNDERLIES CHRONIC ORGANELLE, CELL AND TISSUES DAMAGES THAT CONTRIBUTE TO SYSTEMIC AGING. MORE RECENT FINDINGS, HOWEVER, COLLECTIVELY SUGGEST THAT WHILE ACUTE AND MASSIVE ROS GENERATION DURING EVENTS SUCH AS TISSUE INJURY IS INDEED DETRIMENTAL, SUBACUTE STRESSES, AND CHRONIC ELEVATION IN ROS PRODUCTION MAY INSTEAD INDUCE A STATE OF MITOCHONDRIAL HORMESIS (OR "MITOHORMESIS") THAT COULD EXTEND LIFESPAN. MITOHORMESIS APPEARS TO BE A CONVERGENT MECHANISM FOR SEVERAL KNOWN ANTI-AGING SIGNALING PATHWAYS. IMPORTANTLY, MITOHORMETIC SIGNALING COULD ALSO OCCUR IN A NON-CELL AUTONOMOUS MANNER, WITH ITS INDUCTION IN NEURONS AFFECTING GUT CELLS, FOR EXAMPLE. TECHNOLOGIES ARE OUTLINED THAT COULD LEAD TOWARDS TESTING OF THE HYPOTHESIS, WHICH INCLUDE GENETIC AND EPIGENETIC ENGINEERING OF THE MITOCHONDRIA, AS WELL AS INTERCELLULAR TRANSFER OF MITOCHONDRIA FROM TRANSPLANTED HELPER CELLS TO TARGET TISSUES. 2015 7 4964 31 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV. 2018 8 3280 39 HERPES ZOSTER OPHTHALMICUS FOLLOWING ONABOTULINUMTOXINA ADMINISTRATION FOR CHRONIC MIGRAINE: A CASE REPORT AND LITERATURE REVIEW. BACKGROUND: THERE IS A GROWING BODY OF LITERATURE DOCUMENTING LOCAL HERPES ZOSTER OUTBREAK FOLLOWING PROCEDURES. THE MECHANISM UNDERLYING THESE OUTBREAKS REMAINS ELUSIVE. WE PRESENT A CASE OF ZOSTER FOLLOWING ONABOTULINUMTOXINA (BTX) FOR MIGRAINE AND A LITERATURE REVIEW. METHODS: CHART AND LITERATURE REVIEW. CASE: A 72-YEAR-OLD WOMAN WITH CHRONIC MIGRAINE RECEIVED BTX INJECTIONS FOR 3 YEARS WITHOUT INCIDENT. SHE HAD A HISTORY OF THORACIC ZOSTER WITH SUBSEQUENT POST-HERPETIC NEURALGIA. IN AUGUST 2013, 48 HOURS AFTER RECEIVING BTX INJECTIONS, SHE DEVELOPED A PAINFUL RASH IN THE RIGHT V1 DISTRIBUTION CONSISTENT WITH HERPES ZOSTER OPHTHALMICUS. ONE WEEK LATER THE RASH HAD RESOLVED WITHOUT TREATMENT. LITERATURE REVIEW: WE IDENTIFIED 65 (INCLUDING 2 FROM JUEL-JENSON) CASES OF ZOSTER REACTIVATION FOLLOWING MINOR PROCEDURES. THESE CASES TEND TO BE IN YOUNG PATIENTS WITHOUT SPECIFIC RISK FACTORS. OUTBREAKS CHARACTERISTICALLY OCCUR AT THE LEVEL OF EXPOSURE TO LOCAL TRAUMA. DISCUSSION: OUR REVIEW SUGGESTS THAT LOCAL TRAUMA, REGARDLESS OF THE NATURE OF STIMULI, MAY BE SUFFICIENT FOR ZOSTER REACTIVATION. WE HYPOTHESIZE THAT THE STRESSORS IN THESE REPORTED CASES EXERT A LOCAL EPIGENETIC INFLUENCE ON VIRAL TRANSCRIPTION, ALLOWING FOR VIRAL REACTIVATION. CONCLUSION: ZOSTER IS A POTENTIAL COMPLICATION OF BTX ADMINISTRATION FOR CHRONIC MIGRAINE IN ADULTS. PHYSICIAN AWARENESS CAN REDUCE THE SIGNIFICANT MORBIDITY ASSOCIATED WITH THIS DISEASE. 2015 9 3380 40 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY. 2023 10 5912 27 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE. 2013 11 1716 33 DYSREGULATED CD4+ T CELLS AND MICRORNAS IN MYOCARDITIS. MYOCARDITIS IS A POLYMORPHIC DISEASE COMPLICATED WITH INDETERMINATE ETIOLOGY AND PATHOGENESIS, AND REPRESENTS ONE OF THE MOST CHALLENGING CLINICAL PROBLEMS LACKING SPECIFIC DIAGNOSIS AND EFFECTIVE THERAPY. IT IS CAUSED BY A COMPLEX INTERPLAY OF ENVIRONMENTAL AND GENETIC FACTORS, AND CAUSAL LINKS BETWEEN DYSREGULATED MICRORIBONUCLEIC ACIDS (MIRNAS) AND MYOCARDITIS HAVE ALSO BEEN SUPPORTED BY RECENT EPIGENETIC RESEARCHES. BOTH DYSREGULATED CD4+ T CELLS AND MIRNAS PLAY CRITICAL ROLES IN THE PATHOGENESIS OF MYOCARDITIS, AND THE CLASSIC TRIPHASIC MODEL OF ITS PATHOGENESIS CONSISTS OF THE ACUTE INFECTIOUS, SUBACUTE IMMUNE, AND RECOVERY/CHRONIC MYOPATHIC PHASE. CD4+ T CELLS ARE KEY PATHOGENIC FACTORS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF MYOCARDITIS, AND THE EFFECTOR AND REGULATORY SUBSETS, RESPECTIVELY, PROMOTE AND INHIBIT AUTOIMMUNE RESPONSES. FURTHERMORE, THE RECIPROCAL INTERPLAY OF THESE SUBSETS INFLUENCES THE PATHOGENESIS AS WELL. DYSREGULATED MIRNAS ALONG WITH THEIR MRNA AND PROTEIN TARGETS HAVE BEEN IDENTIFIED IN HEART BIOPSIES (INTRACELLULAR MIRNAS) AND BODY FLUIDS (CIRCULATING MIRNAS) DURING MYOCARDITIS. THESE MIRNAS SHOW PHASE-DEPENDENT CHANGES, AND CORRELATE WITH VIRAL INFECTION, IMMUNE STATUS, FIBROSIS, DESTRUCTION OF CARDIOMYOCYTES, ARRHYTHMIAS, CARDIAC FUNCTIONS, AND OUTCOMES. THUS, MIRNAS ARE PROMISING DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS IN MYOCARDITIS. IN THIS REVIEW, WE REVIEW MYOCARDITIS WITH AN EMPHASIS ON ITS PATHOGENESIS, AND PRESENT A SUMMARY OF CURRENT KNOWLEDGE OF DYSREGULATED CD4+ T CELLS AND MIRNAS IN MYOCARDITIS. 2020 12 5280 26 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 13 246 39 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016. 2017 14 537 31 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 15 5025 29 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 16 4411 26 MOLECULAR AND CELLULAR BASES OF IMMUNOSENESCENCE, INFLAMMATION, AND CARDIOVASCULAR COMPLICATIONS MIMICKING "INFLAMMAGING" IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN ARCHETYPE OF SYSTEMIC AUTOIMMUNE DISEASE, CHARACTERIZED BY THE PRESENCE OF DIVERSE AUTOANTIBODIES AND CHRONIC INFLAMMATION. THERE ARE MULTIPLE FACTORS INVOLVED IN LUPUS PATHOGENESIS, INCLUDING GENETIC/EPIGENETIC PREDISPOSITION, SEXUAL HORMONE IMBALANCE, ENVIRONMENTAL STIMULANTS, MENTAL/PSYCHOLOGICAL STRESSES, AND UNDEFINED EVENTS. RECENTLY, MANY AUTHORS NOTED THAT "INFLAMMAGING", CONSISTING OF IMMUNOSENESCENCE AND INFLAMMATION, IS A COMMON FEATURE IN AGING PEOPLE AND PATIENTS WITH SLE. IT IS CONCEIVABLE THAT CHRONIC OXIDATIVE STRESSES ORIGINATING FROM MITOCHONDRIAL DYSFUNCTION, DEFECTIVE BIOENERGETICS, ABNORMAL IMMUNOMETABOLISM, AND PREMATURE TELOMERE EROSION MAY ACCELERATE IMMUNE CELL SENESCENCE IN PATIENTS WITH SLE. THE MITOCHONDRIAL DYSFUNCTIONS IN SLE HAVE BEEN EXTENSIVELY INVESTIGATED IN RECENT YEARS. THE MOLECULAR BASIS OF NORMOGLYCEMIC METABOLIC SYNDROME HAS BEEN FOUND TO BE RELEVANT TO THE PRODUCTION OF ADVANCED GLYCOSYLATED AND NITROSATIVE END PRODUCTS. BESIDES, IMMUNOSENESCENCE, AUTOIMMUNITY, ENDOTHELIAL CELL DAMAGE, AND DECREASED TISSUE REGENERATION COULD BE THE RESULTS OF PREMATURE TELOMERE EROSION IN PATIENTS WITH SLE. HEREIN, THE MOLECULAR AND CELLULAR BASES OF INFLAMMAGING AND CARDIOVASCULAR COMPLICATIONS IN SLE PATIENTS WILL BE EXTENSIVELY REVIEWED FROM THE ASPECTS OF MITOCHONDRIAL DYSFUNCTIONS, ABNORMAL BIOENERGETICS/IMMUNOMETABOLISM, AND TELOMERE/TELOMERASE DISEQUILIBRIUM. 2019 17 6742 49 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 18 5326 33 PULP INNATE IMMUNE DEFENSE: TRANSLATIONAL OPPORTUNITIES. INTRODUCTION: THE IMPROVEMENT OF REGENERATIVE ENDODONTIC PROCEDURES REQUIRES AN UNDERSTANDING OF THE KEY CLINICAL QUESTIONS COMBINED WITH A FUNDAMENTAL BIOLOGICAL KNOWLEDGE OF HOW THE DENTAL TISSUES BEHAVE DURING HEALTH, DISEASE, AND REPAIR. THEREFORE, PARTNERSHIPS BETWEEN CLINICIANS AND BASIC SCIENTISTS ARE ESSENTIAL TO DRIVE THE FIELD FORWARD AND IMPROVE PATIENT OUTCOMES. METHODS: THIS REVIEW AIMED TO PROVIDE A BACKGROUND TO DENTIN-PULP BIOLOGY AND THE INTERACTION BETWEEN INFECTION, INFLAMMATION, AND REGENERATION. RESULTS: WE HAVE HIGHLIGHTED HOW THE RELEASE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) WITHIN THE PULP ARE DOUBLE-EDGED; WHILE THEY AIM TO LIMIT THE BACTERIAL INFECTION, THEY MAY ACTUALLY EXACERBATE CELL DEATH AND CHRONIC INFLAMMATION. ABERRANT LEVELS OF THESE STRUCTURES MAY OCCUR BECAUSE OF INEFFECTIVE HOST IMMUNOLOGIC PROCESSES, VIRAL INFECTIONS, OR IMPAIRED CLEARANCE CAUSED BY BACTERIAL VIRULENCE FACTORS. WE ALSO POSTULATE A PROINFLAMMATORY LINK IN THE PULP BETWEEN NETS AND THE INFLAMMASOME ACTIVATED BY PATHOGEN-ASSOCIATED MOLECULAR PATTERNS AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS. SUBSEQUENTLY, WE DISCUSS AREAS POTENTIALLY FRUITFUL FOR FUTURE CLINICAL EXPLOITATION INVOLVING NET INHIBITORS, INFLAMMASOME MODULATORS, PHOTOTHERAPIES, AND NOVEL EPIGENETIC APPROACHES. CONCLUSIONS: SUSTAINED SCIENTIST-CLINICIAN RESEARCH PARTNERSHIPS ALONG WITH AN INCREASED UNDERSTANDING OF THE ASSOCIATION BETWEEN INFLAMMATION AND REGENERATION WITHIN THE DENTIN-PULP COMPLEX WILL LEAD TO FUTURE PATIENT BENEFIT. 2020 19 6743 52 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2013 20 750 20 CARDIAC INVOLVEMENT IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AUTHORS HAVE REVIEWED LITERATURE ABOUT THE MANAGEMENT OF PATIENTS WITH CARDIOLOGIC DISEASE OCCURRING SECONDARY TO HEMATOLOGIC PATHOLOGY ITSELF OR ITS THERAPY, WITH A FOCUS ON INFILTRATION OF MYOCARDIUM IN ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MULTIPLE MYELOMA, AND HYPEREOSINOPHILIC SYNDROME. MOREOVER, THEY EVALUATED CHEMOTHERAPY-ASSOCIATED TOXICITY, PARTICULARLY FOR NEW DRUGS SUCH AS MONOCLONAL ANTIBODY THERAPY, TYROSINE KINASE INHIBITORS, ARSENIC TRIOXIDE, BORTEZOMIB, AND EPIGENETIC THERAPY. IN FACT, CARDIAC TOXICITY MAY RANGE FROM ASYMPTOMATIC SUBCLINICAL ABNORMALITIES, SUCH AS ELECTROCARDIOGRAPHIC CHANGES AND LEFT VENTRICULAR EJECTION DECLINE, TO LIFE-THREATENING EVENTS AND LEAD TO CHEMOTHERAPY DOSE REDUCTION AND DELAY AND, IN SOME CASES, FOR PATIENTS WITH SEVERE SIDE EFFECTS, DISCONTINUATION OF TREATMENT. FINALLY, THEY DISCUSSED ON THE IDENTIFICATION OF EARLY MARKERS OF CARDIAC INJURY AND ON CARDIAC STEM CELL THERAPY AS A PROMISING APPROACH TO FACILITATE MYOCARDIAL REGENERATION. 2010