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 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 3 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 4 6302 34 THE PUTATIVE ROLE OF VIRUSES, BACTERIA, AND CHRONIC FUNGAL BIOTOXIN EXPOSURE IN THE GENESIS OF INTRACTABLE FATIGUE ACCOMPANIED BY COGNITIVE AND PHYSICAL DISABILITY. PATIENTS WHO PRESENT WITH SEVERE INTRACTABLE APPARENTLY IDIOPATHIC FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY PRESENT A SIGNIFICANT THERAPEUTIC CHALLENGE. THE EFFECT OF PSYCHOLOGICAL COUNSELING IS LIMITED, WITH SIGNIFICANT BUT VERY SLIGHT IMPROVEMENTS IN PSYCHOMETRIC MEASURES OF FATIGUE AND DISABILITY BUT NO IMPROVEMENT ON SCIENTIFIC MEASURES OF PHYSICAL IMPAIRMENT COMPARED TO CONTROLS. SIMILARLY, EXERCISE REGIMES EITHER PRODUCE SIGNIFICANT, BUT PRACTICALLY UNIMPORTANT, BENEFIT OR PROVOKE SYMPTOM EXACERBATION. MANY SUCH PATIENTS ARE AFFORDED THE EXCLUSIONARY, NON-SPECIFIC DIAGNOSIS OF CHRONIC FATIGUE SYNDROME IF RUDIMENTARY TESTING FAILS TO DISCOVER THE CAUSE OF THEIR SYMPTOMS. MORE SOPHISTICATED INVESTIGATIONS OFTEN REVEAL THE PRESENCE OF A RANGE OF PATHOGENS CAPABLE OF ESTABLISHING LIFE-LONG INFECTIONS WITH SOPHISTICATED IMMUNE EVASION STRATEGIES, INCLUDING PARVOVIRUSES, HHV6, VARIANTS OF EPSTEIN-BARR, CYTOMEGALOVIRUS, MYCOPLASMA, AND BORRELIA BURGDORFERI. OTHER PATIENTS HAVE A HISTORY OF CHRONIC FUNGAL OR OTHER BIOTOXIN EXPOSURE. HEREIN, WE EXPLAIN THE EPIGENETIC FACTORS THAT MAY RENDER SUCH INDIVIDUALS SUSCEPTIBLE TO THE CHRONIC PATHOLOGY INDUCED BY SUCH AGENTS, HOW SUCH AGENTS INDUCE PATHOLOGY, AND, INDEED, HOW SUCH PATHOLOGY CAN PERSIST AND EVEN AMPLIFY EVEN WHEN INFECTIONS HAVE CLEARED OR WHEN BIOTOXIN EXPOSURE HAS CEASED. THE PRESENCE OF ACTIVE, REACTIVATED, OR EVEN LATENT HERPES VIRUS COULD BE A POTENTIAL SOURCE OF INTRACTABLE FATIGUE ACCOMPANIED BY PROFOUND PHYSICAL AND OR COGNITIVE DISABILITY IN SOME PATIENTS, AND THE SAME MAY BE TRUE OF PERSISTENT PARVOVIRUS B12 AND MYCOPLASMA INFECTION. A HISTORY OF CHRONIC MOLD EXPOSURE IS A FEASIBLE EXPLANATION FOR SUCH SYMPTOMS, AS IS THE PRESENCE OF B. BURGDORFERI. THE COMPLEX TROPISM, LIFE CYCLES, GENETIC VARIABILITY, AND LOW TITER OF MANY OF THESE PATHOGENS MAKES THEIR DETECTION IN BLOOD A CHALLENGE. EXAMINATION OF LYMPHOID TISSUE OR CSF IN SUCH CIRCUMSTANCES MAY BE WARRANTED. 2016 5 1057 40 CLINICAL MANIFESTATIONS AND EPIGENETIC REGULATION OF ORAL HERPESVIRUS INFECTIONS. THE ORAL CAVITY IS OFTEN THE FIRST SITE WHERE VIRUSES INTERACT WITH THE HUMAN BODY. THE ORAL EPITHELIUM IS A MAJOR SITE OF VIRAL ENTRY, REPLICATION AND SPREAD TO OTHER CELL TYPES, WHERE CHRONIC INFECTION CAN BE ESTABLISHED. IN ADDITION, SALIVA HAS BEEN SHOWN AS A PRIMARY ROUTE OF PERSON-TO-PERSON TRANSMISSION FOR MANY VIRUSES. FROM A CLINICAL PERSPECTIVE, VIRAL INFECTION CAN LEAD TO SEVERAL ORAL MANIFESTATIONS, RANGING FROM COMMON INTRAORAL LESIONS TO TUMORS. DESPITE THE CLINICAL AND BIOLOGICAL RELEVANCE OF INITIAL ORAL INFECTION, LITTLE IS KNOWN ABOUT THE MECHANISM OF REGULATION OF THE VIRAL LIFE CYCLE IN THE ORAL CAVITY. SEVERAL VIRUSES UTILIZE HOST EPIGENETIC MACHINERY TO PROMOTE THEIR OWN LIFE CYCLE. IMPORTANTLY, VIRAL HIJACKING OF HOST CHROMATIN-MODIFYING ENZYMES CAN ALSO LEAD TO THE DYSREGULATION OF HOST FACTORS AND IN THE CASE OF ONCOGENIC VIRUSES MAY ULTIMATELY PLAY A ROLE IN PROMOTING TUMORIGENESIS. GIVEN THE KNOWN ROLES OF EPIGENETIC REGULATION OF VIRAL INFECTION, EPIGENETIC-TARGETED ANTIVIRAL THERAPY HAS BEEN RECENTLY EXPLORED AS A THERAPEUTIC OPTION FOR CHRONIC VIRAL INFECTION. IN THIS REVIEW, WE HIGHLIGHT THREE HERPESVIRUSES WITH KNOWN ROLES IN ORAL INFECTION, INCLUDING HERPES SIMPLEX VIRUS TYPE 1, EPSTEIN-BARR VIRUS AND KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS. WE FOCUS ON THE RESPECTIVE ORAL CLINICAL MANIFESTATIONS OF THESE VIRUSES AND THEIR EPIGENETIC REGULATION, WITH A SPECIFIC EMPHASIS ON THE VIRAL LIFE CYCLE IN THE ORAL EPITHELIUM. 2021 6 556 41 AZACYTIDINE TREATMENT INHIBITS THE PROGRESSION OF HERPES STROMAL KERATITIS BY ENHANCING REGULATORY T CELL FUNCTION. OCULAR INFECTION WITH HERPES SIMPLEX VIRUS 1 (HSV-1) SETS OFF AN INFLAMMATORY REACTION IN THE CORNEA WHICH LEADS TO BOTH VIRUS CLEARANCE AND CHRONIC LESIONS THAT ARE ORCHESTRATED BY CD4 T CELLS. APPROACHES THAT ENHANCE THE FUNCTION OF REGULATORY T CELLS (TREG) AND DAMPEN EFFECTOR T CELLS CAN BE EFFECTIVE TO LIMIT STROMAL KERATITIS (SK) LESION SEVERITY. IN THIS REPORT, WE EXPLORE THE NOVEL APPROACH OF INHIBITING DNA METHYLTRANSFERASE ACTIVITY USING 5-AZACYTIDINE (AZA; A CYTOSINE ANALOG) TO LIMIT HSV-1-INDUCED OCULAR LESIONS. WE SHOW THAT THERAPY BEGUN AFTER INFECTION WHEN VIRUS WAS NO LONGER ACTIVELY REPLICATING RESULTED IN A PRONOUNCED REDUCTION IN LESION SEVERITY, WITH MARKEDLY DIMINISHED NUMBERS OF T CELLS AND NONLYMPHOID INFLAMMATORY CELLS, ALONG WITH REDUCED CYTOKINE MEDIATORS. THE REMAINING INFLAMMATORY REACTIONS HAD A CHANGE IN THE RATIO OF CD4 FOXP3(+) TREG TO EFFECTOR TH1 CD4 T CELLS IN OCULAR LESIONS AND LYMPHOID TISSUES, WITH TREG BECOMING PREDOMINANT OVER THE EFFECTORS. IN ADDITION, COMPARED TO THOSE FROM CONTROL MICE, TREG FROM AZA-TREATED MICE SHOWED MORE SUPPRESSOR ACTIVITY IN VITRO AND EXPRESSED HIGHER LEVELS OF ACTIVATION MOLECULES. ADDITIONALLY, CELLS INDUCED IN VITRO IN THE PRESENCE OF AZA SHOWED EPIGENETIC DIFFERENCES IN THE TREG-SPECIFIC DEMETHYLATED REGION (TSDR) OF FOXP3 AND WERE MORE STABLE WHEN EXPOSED TO INFLAMMATORY CYTOKINES. OUR RESULTS SHOW THAT THERAPY WITH AZA IS AN EFFECTIVE MEANS OF CONTROLLING A VIRUS-INDUCED INFLAMMATORY REACTION AND MAY ACT MAINLY BY THE EFFECTS ON TREG.IMPORTANCE HSV-1 INFECTION HAS BEEN SHOWN TO INITIATE AN INFLAMMATORY REACTION IN THE CORNEA THAT LEADS TO TISSUE DAMAGE AND LOSS OF VISION. THE INFLAMMATORY REACTION IS ORCHESTRATED BY GAMMA INTERFERON (IFN-GAMMA)-SECRETING TH1 CELLS, AND REGULATORY T CELLS PLAY A PROTECTIVE ROLE. HENCE, NOVEL THERAPEUTICS THAT CAN REBALANCE THE RATIO OF REGULATORY T CELLS TO EFFECTORS ARE A RELEVANT ISSUE. THIS STUDY OPENS UP A NEW AVENUE IN TREATING HSV-INDUCED SK LESIONS BY INCREASING THE STABILITY AND FUNCTION OF REGULATORY T CELLS USING THE DNA METHYLTRANSFERASE INHIBITOR 5-AZACYTIDINE (AZA). AZA INCREASED THE FUNCTION OF REGULATORY T CELLS, LEADING TO ENHANCED SUPPRESSIVE ACTIVITY AND DIMINISHED LESIONS. HENCE, THERAPY WITH AZA, WHICH ACTS MAINLY BY ITS EFFECTS ON TREG, CAN BE AN EFFECTIVE MEANS TO CONTROL VIRUS-INDUCED INFLAMMATORY LESIONS. 2017 7 4272 32 MICROBIOME AND BEHCET'S DISEASE: A SYSTEMATIC REVIEW. THE AIM OF THIS REVIEW WAS TO DESCRIBE THE CHANGES IN THE MICROBIOTA OF PATIENTS WITH BEHCET'S DISEASE (BD) AND THE MECHANISMS INVOLVED IN THE RELATIONSHIP BETWEEN THE MICROBIOME AND IMMUNITY IN BD. A SYSTEMATIC SEARCH FOR RELEVANT ARTICLES WAS MADE ON PUBMED AND THE COCHRANE LIBRARY DATABASE USING THE FOLLOWING TERMS: "MICROBIOTA AND BEHCET'S DISEASE" OR "MICROBIOME AND BEHCET'S DISEASE". SIXTEEN ARTICLES WERE INCLUDED IN A QUALITATIVE SYNTHESIS. THIS SYSTEMATIC REVIEW ON THE MICROBIOME AND BEHCET'S DISEASE UNDERLINES THE PRESENCE OF GUT DYSBIOSIS IN BD PATIENTS. THIS DYSBIOSIS IS MARKED BY (I) A DECREASE IN BUTYRATE-PRODUCING BACTERIA, WHICH COULD AFFECT T CELL DIFFERENTIATION AND EPIGENETIC REGULATION OF IMMUNE-RELATED GENES, (II) A MODIFICATION OF TRYPTOPHAN-METABOLISING BACTERIA, WHICH COULD BE LINKED TO DYSREGULATED IL-22 SECRETION, AND (III) A DECREASE IN BACTERIA KNOWN TO HAVE ANTI-INFLAMMATORY PROPERTIES. REGARDING ORAL MICROBIOTA, THIS REVIEW UNDERLINES THE POSSIBLE ROLE OF STREPTOCOCCUS SANGUINIS THROUGH MOLECULAR MIMICRY AND NETOSIS. CLINICAL STUDIES OF BD HAVE SHOWN THAT (I) NEED FOR DENTISTRY IS ASSOCIATED WITH A MORE SEVERE COURSE IN BD, AND (II) ANTIBIOTIC-SUPPLEMENTED MOUTHWASH REDUCES PAIN AND ULCERS. FECAL TRANSPLANTATION OF BD PATIENTS' MICROBIOTA INTO MOUSE MODELS LED TO DECREASED SCFA PRODUCTION, NEUTROPHIL ACTIVATION, AND TH1/TH17 RESPONSES.RECIPIENT MICE SHOWED EXACERBATED EXPERIMENTAL AUTOIMMUNE UVEITIS (EAU) AND EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE). IN HERPES VIRUS SIMPLEX-1 (HSV-1) INFECTED MICE MIMICKING BD, ADMINISTRATION OF BUTYRATEPRODUCING BACTERIA IMPROVED SYMPTOMS AND IMMUNE VARIABLES. THE MICROBIOME MAY THUS BE INVOLVED IN BD THROUGH IMMUNITY REGULATION AND EPIGENETIC MODIFICATIONS. 2023 8 6044 48 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022 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 5908 30 TARGETED DE-METHYLATION OF THE FOXP3-TSDR IS SUFFICIENT TO INDUCE PHYSIOLOGICAL FOXP3 EXPRESSION BUT NOT A FUNCTIONAL TREG PHENOTYPE. CD4+ REGULATORY T CELLS (TREGS) ARE KEY MEDIATORS OF IMMUNOLOGICAL TOLERANCE AND PROMISING EFFECTOR CELLS FOR IMMUNO-SUPPRESSIVE ADOPTIVE CELLULAR THERAPY TO FIGHT AUTOIMMUNITY AND CHRONIC INFLAMMATION. THEIR FUNCTIONAL STABILITY IS CRITICAL FOR THEIR CLINICAL UTILITY AND HAS BEEN CORRELATED TO THE DEMETHYLATED STATE OF THE TSDR/CNS2 ENHANCER ELEMENT IN THE TREG LINEAGE TRANSCRIPTION FACTOR FOXP3. HOWEVER, PROOF FOR A CAUSAL CONTRIBUTION OF THE TSDR DE-METHYLATION TO FOXP3 STABILITY AND TREG INDUCTION IS SO FAR LACKING. WE HERE ESTABLISHED A POWERFUL TRANSIENT-TRANSFECTION CRISPR-CAS9-BASED EPIGENETIC EDITING METHOD FOR THE SELECTIVE DE-METHYLATION OF THE TSDR WITHIN THE ENDOGENOUS CHROMATIN ENVIRONMENT OF A LIVING CELL. THE INDUCED DE-METHYLATED STATE WAS STABLE OVER WEEKS IN CLONAL T CELL PROLIFERATION CULTURES EVEN AFTER EXPRESSION OF THE EDITING COMPLEX HAD CEASED. EPIGENETIC EDITING OF THE TSDR RESULTED IN FOXP3 EXPRESSION, EVEN IN ITS PHYSIOLOGICAL ISOFORM DISTRIBUTION, PROVING A CAUSAL ROLE FOR THE DE-METHYLATED TSDR IN FOXP3 REGULATION. HOWEVER, SUCCESSFUL FOXP3 INDUCTION WAS NOT ASSOCIATED WITH A SWITCH TOWARDS A FUNCTIONAL TREG PHENOTYPE, IN CONTRAST TO WHAT HAS BEEN REPORTED FROM FOXP3 OVEREXPRESSION APPROACHES. THUS, TSDR DE-METHYLATION IS REQUIRED, BUT NOT SUFFICIENT FOR A STABLE TREG PHENOTYPE INDUCTION. THEREFORE, TARGETED DEMETHYLATION OF THE TSDR MAY BE A CRITICAL ADDITION TO PUBLISHED IN VITRO TREG INDUCTION PROTOCOLS WHICH SO FAR LACK FOXP3 STABILITY. 2020 11 1006 51 CHRONIC VIRAL INFECTION AND PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCY. PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS CAUSE SIGNIFICANT MORBIDITY AND MORTALITY IN BOTH ADULTS AND CHILDREN. WHILE SOME OF THE GENETIC AND MOLECULAR MECHANISMS OF NEURO-ONCOGENESIS ARE KNOWN, MUCH LESS IS KNOWN ABOUT POSSIBLE EPIGENETIC CONTRIBUTIONS TO DISEASE PATHOPHYSIOLOGY. OVER THE LAST SEVERAL DECADES, CHRONIC VIRAL INFECTIONS HAVE BEEN ASSOCIATED WITH A NUMBER OF HUMAN MALIGNANCIES. IN PRIMARY CNS MALIGNANCIES, TWO FAMILIES OF VIRUSES, NAMELY POLYOMAVIRUS AND HERPESVIRUS, HAVE BEEN DETECTED WITH VARIED FREQUENCIES IN A NUMBER OF PEDIATRIC AND ADULT HISTOLOGICAL TUMOR SUBTYPES. HOWEVER, ESTABLISHING A LINK BETWEEN CHRONIC VIRAL INFECTION AND PRIMARY CNS MALIGNANCY HAS BEEN AN AREA OF CONSIDERABLE CONTROVERSY, DUE IN PART TO VARIATIONS IN DETECTION FREQUENCIES AND METHODOLOGIES USED AMONG RESEARCHERS. SINCE A LATENT VIRAL NEUROTROPISM CAN BE SEEN WITH A VARIETY OF VIRUSES AND A WIDESPREAD SEROPOSITIVITY EXISTS AMONG THE POPULATION, IT HAS BEEN DIFFICULT TO ESTABLISH AN ASSOCIATION BETWEEN VIRAL INFECTION AND CNS MALIGNANCY BASED ON EPIDEMIOLOGY ALONE. WHILE DIRECT EVIDENCE OF A ROLE OF VIRUSES IN NEURO-ONCOGENESIS IN HUMANS IS LACKING, A MORE PLAUSIBLE HYPOTHESIS OF NEURO-ONCOMODULATION HAS BEEN PROPOSED. THE OVERALL GOALS OF THIS REVIEW ARE TO SUMMARIZE THE MANY HUMAN INVESTIGATIONS THAT HAVE STUDIED VIRAL INFECTION IN PRIMARY CNS TUMORS, DISCUSS POTENTIAL NEURO-ONCOMODULATORY MECHANISMS OF VIRAL-ASSOCIATED CNS DISEASE AND PROPOSE FUTURE RESEARCH DIRECTIONS TO ESTABLISH A MORE FIRM ASSOCIATION BETWEEN CHRONIC VIRAL INFECTIONS AND PRIMARY CNS MALIGNANCIES. 2010 12 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 13 6406 29 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 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 2662 38 EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS: A CONVOLUTED INTERACTION AND THE OPPORTUNITY TO UNRAVEL PREDICTIVE BIOMARKERS. SINCE THE EARLY 1980S, EPSTEIN-BARR VIRUS (EBV) INFECTION HAS BEEN DESCRIBED AS ONE OF THE MAIN RISK FACTORS FOR DEVELOPING MULTIPLE SCLEROSIS (MS), AND RECENTLY, NEW EPIDEMIOLOGICAL EVIDENCE HAS REINFORCED THIS PREMISE. EBV SEROCONVERSION PRECEDES ALMOST 99% OF THE NEW CASES OF MS AND LIKELY PREDATES THE FIRST CLINICAL SYMPTOMS. THE MOLECULAR MECHANISMS OF THIS ASSOCIATION ARE COMPLEX AND MAY INVOLVE DIFFERENT IMMUNOLOGICAL ROUTES, PERHAPS ALL RUNNING IN PARALLEL (I.E., MOLECULAR MIMICRY, THE BYSTANDER DAMAGE THEORY, ABNORMAL CYTOKINE NETWORKS, AND COINFECTION OF EBV WITH RETROVIRUSES, AMONG OTHERS). HOWEVER, DESPITE THE LARGE AMOUNT OF EVIDENCE AVAILABLE ON THESE TOPICS, THE ULTIMATE ROLE OF EBV IN THE PATHOGENESIS OF MS IS NOT FULLY UNDERSTOOD. FOR INSTANCE, IT IS UNCLEAR WHY AFTER EBV INFECTION SOME INDIVIDUALS DEVELOP MS WHILE OTHERS EVOLVE TO LYMPHOPROLIFERATIVE DISORDERS OR SYSTEMIC AUTOIMMUNE DISEASES. IN THIS REGARD, RECENT STUDIES SUGGEST THAT THE VIRUS MAY EXERT EPIGENETIC CONTROL OVER MS SUSCEPTIBILITY GENES BY MEANS OF SPECIFIC VIRULENCE FACTORS. SUCH GENETIC MANIPULATION HAS BEEN DESCRIBED IN VIRALLY-INFECTED MEMORY B CELLS FROM PATIENTS WITH MS AND ARE THOUGHT TO BE THE MAIN SOURCE OF AUTOREACTIVE IMMUNE RESPONSES. YET, THE ROLE OF EBV INFECTION IN THE NATURAL HISTORY OF MS AND IN THE INITIATION OF NEURODEGENERATION IS EVEN LESS CLEAR. IN THIS NARRATIVE REVIEW, WE WILL DISCUSS THE AVAILABLE EVIDENCE ON THESE TOPICS AND THE POSSIBILITY OF HARNESSING SUCH IMMUNOLOGICAL ALTERATIONS TO UNCOVER PREDICTIVE BIOMARKERS FOR THE ONSET OF MS AND PERHAPS FACILITATE PROGNOSTICATION OF THE CLINICAL COURSE. 2023 16 367 24 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM. 2014 17 3934 44 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 18 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 19 5497 43 REVIEW: ANIMAL MODELS OF ACQUIRED EPILEPSY: INSIGHTS INTO MECHANISMS OF HUMAN EPILEPTOGENESIS. IN MANY PATIENTS WHO SUFFER FROM EPILEPSIES, RECURRENT EPILEPTIC SEIZURES DO NOT START AT BIRTH BUT DEVELOP LATER IN LIFE. THIS HOLDS PARTICULARLY TRUE FOR EPILEPSIES WITH A FOCAL SEIZURE ORIGIN INCLUDING FOCAL CORTICAL DYSPLASIAS AND TEMPORAL LOBE EPILEPSY (TLE). TLE MOST FREQUENTLY HAS ITS SEIZURE ONSET IN THE HIPPOCAMPAL FORMATION. HIPPOCAMPAL BIOPSIES OF PHARMACORESISTANT TLE PATIENTS UNDERGOING EPILEPSY SURGERY FOR SEIZURE CONTROL MOST FREQUENTLY REVEAL THE DAMAGE PATTERN OF HIPPOCAMPAL SCLEROSIS, THAT IS, SEGMENTAL NEURONAL CELL LOSS AND CONCOMITANT ASTROGLIOSIS. MANY TLE PATIENTS REPORT ON TRANSIENT BRAIN INSULTS EARLY IN LIFE, WHICH IS FOLLOWED BY A 'LATENCY' PERIOD LACKING SEIZURE ACTIVITY OF MONTHS OR EVEN YEARS BEFORE CHRONIC RECURRENT SEIZURES START. THE PLETHORA OF STRUCTURAL AND CELLULAR MECHANISMS THAT CONVERT THE HIPPOCAMPAL FORMATION TO BECOME CHRONICALLY HYPEREXCITABLE AFTER A TRANSIENT INSULT TO THE BRAIN ARE SUMMARIZED UNDER THE TERM EPILEPTOGENESIS. IN CONTRAST TO THE OBSTACLES ARISING FOR EXPERIMENTAL STUDIES OF EPILEPTOGENESIS ASPECTS IN HUMAN SURGICAL HIPPOCAMPAL TISSUE, RECENT ANIMAL MODEL APPROACHES ALLOW INSIGHTS INTO MECHANISMS OF EPILEPTOGENESIS. RELEVANT MODELS OF TRANSIENT BRAIN INSULTS IN THIS CONTEXT COMPRISE SEVERAL DISTINCT TYPES OF LESIONS INCLUDING EXCITOXIC STATUS EPILEPTICUS (SE), ELECTRICAL SEIZURE INDUCTION, TRAUMATIC BRAIN INJURY, INDUCTION OF INFLAMMATORY PROCESSES BY HYPERTHERMIA AND VIRAL INFLAMMATION AND OTHERS. IN PATHOGENETIC TERMS, ABERRANT TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING, ACQUIRED CHANNEL- AND SYNAPTOPATHIES, NEURONAL NETWORK AND BLOOD-BRAIN BARRIER DYSFUNCTION AS WELL AS INNATE AND ADAPTIVE IMMUNITY-MEDIATED DAMAGE PLAY MAJOR ROLES. IN SUBSEQUENT STEPS, RESPECTIVE ANIMAL MODELS HAVE BEEN USED IN ORDER TO TEST WHETHER THIS DYNAMIC PROCESS CAN BE EITHER RETARDED OR EVEN ABOLISHED BY INTERFERING WITH EPILEPTOGENIC MECHANISMS. WELL-CONTROLLED SUBSEQUENT ANALYSES OF EPILEPTOGENIC CASCADES CHARACTERIZED IN ANIMAL MODELS USING CAREFULLY STRATIFIED HUMAN HIPPOCAMPAL BIOPSIES TO EXPLOIT THE UNIQUE OPPORTUNITIES GIVEN BY THESE RARE AND PRECIOUS BRAIN TISSUE SAMPLES AIM TO TRANSLATE INTO NOVEL ANTIEPILEPTOGENIC APPROACHES. RESPECTIVE PRECLINICAL TESTS CAN OPEN ENTIRELY NEW PERSPECTIVES FOR TAILOR-MADE TREATMENTS IN PATIENTS WITH THE POTENTIAL TO AVOID THE EMERGENCE OF CHRONIC FOCAL SEIZURE EVENTS. 2018 20 1253 33 CURRENT PROBLEMS AND FUTURE DIRECTIONS OF TRANSFUSION-INDUCED ALLOIMMUNIZATION: SUMMARY OF AN NHLBI WORKING GROUP. IN APRIL 2010, A WORKING GROUP SPONSORED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WAS ASSEMBLED TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE OUR UNDERSTANDING OF ALLOIMMUNIZATION CAUSED BY THE TRANSFUSION OF ALLOGENEIC BLOOD COMPONENTS AND TO EVALUATE POTENTIAL APPROACHES TO BOTH REDUCE ITS OCCURRENCE AND MANAGE ITS EFFECTS. SIGNIFICANT SEQUELAE OF ALLOIMMUNIZATION WERE DISCUSSED AND IDENTIFIED, INCLUDING DIFFICULTIES IN MAINTAINING CHRONIC TRANSFUSION OF RED BLOOD CELLS AND PLATELETS, HEMOLYTIC DISEASE OF THE NEWBORN, NEONATAL ALLOIMMUNE THROMBOCYTOPENIA, AND REJECTION OF TRANSPLANTED CELLS AND TISSUES. THE DISCUSSIONS RESULTED IN A CONSENSUS THAT IDENTIFIED KEY AREAS OF FUTURE RESEARCH AND DEVELOPMENTAL AREAS, INCLUDING GENETIC AND EPIGENETIC RECIPIENT FACTORS THAT REGULATE ALLOIMMUNIZATION, BIOCHEMICAL SPECIFICS OF TRANSFUSED PRODUCTS THAT AFFECT ALLOIMMUNIZATION, AND NOVEL TECHNOLOGIES FOR HIGH-THROUGHPUT GENOTYPING TO FACILITATE EXTENSIVE AND EFFICIENT ANTIGEN MATCHING BETWEEN DONOR AND RECIPIENT. ADDITIONAL AREAS OF IMPORTANCE INCLUDED ANALYSIS OF UNAPPRECIATED MEDICAL SEQUELAE OF ALLOIMMUNIZATION, SUCH AS CELLULAR IMMUNITY AND ITS EFFECT UPON TRANSPLANT AND AUTOIMMUNITY. IN ADDITION, SUPPORT FOR RESEARCH INFRASTRUCTURE WAS DISCUSSED, WITH AN EMPHASIS ON ENCOURAGING COLLABORATION AND SYNERGY OF ANIMAL MODELS BIOLOGY AND HUMAN CLINICAL RESEARCH. FINALLY, TRAINING FUTURE INVESTIGATORS WAS IDENTIFIED AS AN AREA OF IMPORTANCE. IN AGGREGATE, THIS COMMUNICATION PROVIDES A SYNOPSIS OF THE OPINIONS OF THE WORKING GROUP ON THE ABOVE ISSUES AND PRESENTS BOTH A LIST OF SUGGESTED PRIORITIES AND THE RATIONALE FOR THE TOPICS OF FOCUS. THE AREAS OF RESEARCH IDENTIFIED IN THIS REPORT REPRESENT POTENTIAL FERTILE GROUND FOR THE MEDICAL ADVANCEMENT OF PREVENTING AND MANAGING ALLOIMMUNIZATION IN ITS DIFFERENT FORMS AND MITIGATING THE CLINICAL PROBLEMS IT PRESENTS TO MULTIPLE PATIENT POPULATIONS. 2011