1 3934 260 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 2 3803 60 INTESTINAL METAPLASIA OF THE STOMACH. A STATUS REPORT. INTESTINAL METAPLASIA IN THE STOMACH INCREASES THE RISK OF GASTRIC CANCER, AND THE INCREASED RISK IS PROPORTIONAL TO THE EXTENT OF THE METAPLASIA. THIS RISK COULD BE GENERATED BY ONE OR MORE MECHANISMS: (1) THE METAPLASTIC TISSUE IS AN EARLY STEP IN A MULTISTEP INDUCTION PROCESS; (2) THE METAPLASTIC TISSUE IS AN EPIGENETIC CHANGE THAT RAISES THE PH OF GASTRIC JUICE BY REPLACING OXYNTIC MUCOSA, FAVORING THE GROWTH OF A BACTERIA CAPABLE OF GENERATING ENDOGENOUS MUTAGENS; AND/OR (3) THE METAPLASIA IS ONLY A MARKER FOR CHRONIC GASTRITIS DUE TO H. PYLORI INFECTION OR PERNICIOUS ANEMIA. WITH THE LAST MECHANISM, THE INFLAMMATORY RESPONSE FAVORS INTRAMURAL MUTAGENESIS THAT MIGHT RESULT IN METAPLASIA OR NEOPLASIA AS INDEPENDENT EVENTS. FINDING GENE REARRANGEMENTS COMMON TO BOTH METAPLASTIC AND NEOPLASTIC TISSUE MAY ESTABLISH A DIRECT LINK BETWEEN THEM, BUT TOO FEW HAVE BEEN IDENTIFIED TO ACCOUNT FOR THE LARGE NUMBER OF STOMACH CANCERS THAT DEVELOP IN HIGH RISK POPULATIONS. HISTOCHEMICAL AND IMMUNOCHEMICAL STAINS THAT IDENTIFY ENZYMES OR MUCOSUBSTANCES MAY SUGGEST THAT METAPLASTIC EPITHELIAL CELLS RESEMBLE SMALL OR LARGE INTESTINAL CELLS, BUT THEY ARE DISTINCTLY DIFFERENT FROM BOTH. MOREOVER, THESE STAINS DO NOT INDICATE WHETHER A GIVEN CYTOLOGIC CHANGE IS GENETIC OR EPIGENETIC; THEREFORE, THEY CANNOT BE USED TO DEFINE THE RELATIONSHIP BETWEEN METAPLASIA AND NEOPLASIA. IT IS UNNECESSARY FOR PRACTICING PHYSICIANS TO AWAIT RESOLUTION OF THIS QUESTION. IT CAN BE ASSUMED THAT ANY PERSON WITH EXTENSIVE METAPLASIA IS AT HIGH RISK FOR GASTRIC CANCER AND SHOULD BE SUBJECT TO PERIODIC SCREENING. THE EXTENT OF THE METAPLASTIC PROCESS IS PROBABLY MORE IMPORTANT THAN THE METAPLASTIC SUBTYPE. 1994 3 5051 40 PHARMACOLOGICAL RESCUE OF NOCICEPTIVE HYPERSENSITIVITY AND OXYTOCIN ANALGESIA IMPAIRMENT IN A RAT MODEL OF NEONATAL MATERNAL SEPARATION. OXYTOCIN (OT), KNOWN FOR ITS NEUROHORMONAL EFFECTS AROUND BIRTH, HAS RECENTLY BEEN SUGGESTED FOR BEING A CRITICAL DETERMINANT IN NEURODEVELOPMENTAL DISORDERS. THIS HYPOTHALAMIC NEUROPEPTIDE EXERTS A POTENT ANALGESIC EFFECT THROUGH AN ACTION ON THE NOCICEPTIVE SYSTEM. THIS ENDOGENOUS CONTROL OF PAIN HAS AN IMPORTANT ADAPTIVE VALUE BUT MIGHT BE ALTERED BY EARLY LIFE STRESS, POSSIBLY CONTRIBUTING TO ITS LONG-TERM CONSEQUENCES ON PAIN RESPONSES AND ASSOCIATED COMORBIDITIES. WE TESTED THIS HYPOTHESIS USING A RAT MODEL OF NEONATAL MATERNAL SEPARATION (NMS) KNOWN TO INDUCE LONG-TERM CONSEQUENCES ON SEVERAL BRAIN FUNCTIONS INCLUDING CHRONIC STRESS, ANXIETY, ALTERED SOCIAL BEHAVIOR, AND VISCERAL HYPERSENSITIVITY. WE FOUND THAT ADULT RATS WITH A HISTORY OF NMS WERE HYPERSENSITIVE TO NOXIOUS MECHANICAL/THERMAL HOT STIMULI AND TO INFLAMMATORY PAIN. WE FAILED TO OBSERVE OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND OT ANTIHYPERALGESIA AFTER CARRAGEENAN INFLAMMATION. THESE ALTERATIONS WERE PARTIALLY RESCUED IF NMS PUPS WERE TREATED BY INTRAPERITONEAL DAILY INJECTION DURING NMS WITH OT OR ITS DOWNSTREAM SECOND MESSENGER ALLOPREGNANOLONE. THE INVOLVEMENT OF EPIGENETIC CHANGES IN THESE ALTERATIONS WAS CONFIRMED SINCE NEONATAL TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR SAHA, NOT ONLY NORMALIZED NOCICEPTIVE SENSITIVITIES BUT ALSO RESTORED OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND THE ENDOGENOUS ANTIHYPERALGESIA IN INFLAMED NMS RATS. THERE IS GROWING EVIDENCE IN THE LITERATURE THAT EARLY LIFE STRESS MIGHT IMPAIR THE NOCICEPTIVE SYSTEM ONTOGENY AND FUNCTION. THIS STUDY SUGGESTS THAT THESE ALTERATIONS MIGHT BE RESTORED WHILE STIMULATING OT RECEPTOR SIGNALING OR HISTONE DEACETYLASE INHIBITORS, USING MOLECULES THAT ARE CURRENTLY AVAILABLE OR PART OF CLINICAL TRIALS FOR OTHER PATHOLOGIES. 2018 4 4402 42 MODULATION OF NOCICEPTION BY SOCIAL FACTORS IN RODENTS: CONTRIBUTION OF THE OPIOID SYSTEM. RATIONALE: THE OPIOID SYSTEM IS INVOLVED IN THE REGULATION OF SEVERAL BEHAVIORAL AND PHYSIOLOGICAL RESPONSES, CONTROLLING PAIN, REWARD, AND ADDICTIVE BEHAVIORS. OPIOID ADMINISTRATION, DEPENDING ON DRUGS AND DOSES, USUALLY AFFECTS SOCIABILITY REDUCING INTERACTIONS BETWEEN CONSPECIFICS, WHEREAS SOME AFFILIATIVE BEHAVIORS SUCH AS SEXUAL ACTIVITY, SOCIAL GROOMING, AND PLAY BEHAVIOR INCREASE THE ENDOGENOUS OPIOID ACTIVITY. OBJECTIVES: THE POSSIBLE INTERACTION BETWEEN ENDOGENOUS OPIOIDS RELEASED DURING SOCIO/SEXUAL BEHAVIOR AND THEIR ANALGESIC EFFECT ON PAIN RESPONSE IS REVIEWED IN THE RODENT LITERATURE. RESULTS: DIRECT EVIDENCE FOR SOCIALLY MEDIATED OPIOID CHANGES RESULTING IN INCREASE IN NOCICEPTIVE THRESHOLD DERIVES FROM STUDIES EXPLORING THE EFFECTS OF DEFEAT EXPERIENCES, SOCIAL ISOLATION, MATERNAL, SEXUAL BEHAVIOR, AND SOCIAL REUNION AMONG KIN OR FAMILIAR ANIMALS IN LABORATORY RODENTS. INDIRECT EVIDENCE FOR ENDOGENOUS ACTIVATION OF THE OPIOID SYSTEM, POSSIBLY AFFECTING PAIN SENSITIVITY, DERIVES FROM STUDIES INVESTIGATING THE RELEVANCE OF NATURAL SOCIAL REWARD USING THE CONDITIONED PLACE PREFERENCE PROTOCOLS OR ANALYZING ULTRASONIC VOCALIZATIONS ASSOCIATED TO POSITIVE AFFECTIVE CONTEXTS. FINALLY, GENETIC AND EPIGENETIC FACTORS THAT AFFECT THE OPIOID SYSTEM DURING DEVELOPMENT ARE REPORTED TO BE INVOLVED IN MODULATING THE RESPONSE TO SOCIAL STIMULI AS WELL AS NOCICEPTION. CONCLUSIONS: ALL STUDIES HIGHLIGHT THE RELEVANCE OF AFFILIATIVE CONTACT BEHAVIOR BETWEEN CONSPECIFICS THAT IS RESPONSIBLE FOR THE ACTIVATION OF THE ENDOGENOUS MU-OPIOID SYSTEM, INDUCING NOCICEPTIVE THRESHOLD INCREASE. 2012 5 835 56 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 6 3973 42 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 7 495 72 ASSESSMENT OF THE HEALTH EFFECTS OF TRICHLOROETHYLENE. THE EPIDEMIOLOGICAL STUDIES PERFORMED THUS FAR HAVE PRESENTED ONLY LIMITED EVIDENCE FOR THE CARCINOGENICITY OF TRICHLOROETHYLENE (TRI) TO HUMANS. HOWEVER, THESE STUDIES HAD DRAWBACKS SUCH AS INSUFFICIENT SIZE OF COHORT, SHORT OBSERVATION PERIOD, AND INADEQUATE TRI EXPOSURE ASSESSMENT; THEREFORE, NO CONCRETE CONCLUSION HAS BEEN REACHED CONCERNING TRI CARCINOGENICITY TO HUMANS. DESPITE THE LIMITED EPIDEMIOLOGICAL EVIDENCE AS TO THE CARCINOGENICITY OF TRI, THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS CHANGED THE CARCINOGENICITY CLASSIFICATION OF TRI FROM GROUP 3 (NOT CLASSIFIABLE AS TO CARCINOGENICITY TO HUMANS) TO GROUP 2A (PROBABLY CARCINOGENIC TO HUMANS). IN REGARD TO THE NEW CLASSIFICATION BY THE IARC, THE COMMITTEE FOR OCCUPATIONAL EXPOSURE LIMITS OF THE JAPAN SOCIETY FOR OCCUPATIONAL HEALTH HAS MADE A PROPOSAL THAT IT IS TOO EARLY TO CLASSIFY THE CARCINOGENICITY OF TRI AS GROUP 2A AND THAT IT IS PROPER TO PROMOTE EXPOSURE CONTROL WITH THE CARCINOGENICITY BEING CLASSIFIED AS 2B FOR THE MOMENT. THERE ARE SPECIES DIFFERENCES IN TRI CARCINOGENICITY, PARTICULARLY BETWEEN RATS AND MICE. ALTHOUGH EXPERIMENTAL STUDIES HAVE FOUND NO EVIDENCE THAT TRI INDUCES LIVER CANCER IN RATS, THERE IS AMPLE EVIDENCE THAT TRI PROMOTES THE DEVELOPMENT OF LIVER CANCER IN MICE, PARTICULARLY IN B6C3F1 MICE. THE CARCINOGENICITY OF TRI IN THIS STRAIN OF MICE MAY BE BASED ON AN EPIGENETIC MECHANISM RATHER ON A GENOTOXIC MECHANISM AND THE LIVER CANCER MAY BE INDUCED ONLY AFTER TRI HAS BEEN INHALED FOR A LONG PERIOD OF TIME AT CONCENTRATIONS HIGH ENOUGH TO CAUSE CYTOTOXICITY. CONVERSELY, WITH NO REPORTS SHOWING TRI-INDUCED RENAL TUMORS IN MICE, THE POSSIBILITY HAS BEEN SUGGESTED THAT THIS CHEMICAL INDUCES SUCH TUMORS IN MALE RATS. THE SPECIES DIFFERENCES ARE MAINLY ACCOUNTED FOR BY DIFFERENCES IN THE METABOLISM OF TRI BETWEEN RATS AND MICE. FROM A GENERAL SURVEY OF THE LITERATURE, IT CAN BE CONCLUDED THAT TRI ITSELF IS NOT MUTAGENIC. HOWEVER, THE CONJUGATION OF TRI WITH GLUTATHIONE (GSH), A MINOR PATHWAY OF TRI METABOLISM, RESULTS IN MUTAGENIC METABOLITES IN THE KIDNEY OF RATS. THE ACUTE TOXICITY OF TRI IS NEUROTOXICITY BASED ON ITS ANESTHETIC ACTION. AN EXPOSURE TO EXTREMELY HIGH LEVELS OF TRI MAY CAUSE THE LIVER AND KIDNEY DISORDERS. REPEATED EXPOSURES TO HIGH LEVELS OF TRI MAY RESULT IN NEURO-, HEPATO-, AND/OR NEPHROTOXICITY. THE MAIN SYMPTOMS APPEARING AFTER CHRONIC EXPOSURE AT LOW LEVELS ARE NEUROLOGICAL CHANGES REPRESENTED BY SUBJECTIVE SYMPTOMS RELATING TO CENTRAL AND AUTONOMIC NERVOUS SYSTEMS, OR BY A LOWERED CONDUCTION VELOCITY OF THE NERVES OR A PROLONGED LATENCY OF THE NERVE RESPONSES. FOR THE PRESENT, IT IS REASONABLE TO USE THE NEUROLOGICAL FINDINGS FOR ESTABLISHING THE REFERENCE VALUES OF TRI FOR BOTH WORK AND GENERAL ENVIRONMENTS. A VALUE OF 25 PPM (135 MG/M3) IS PROPOSED AS A REFERENCE VALUE FOR WORK ENVIRONMENTS, AND 25-50 PPB (135-270 MICROGRAMS/M3) FOR THE GENERAL ENVIRONMENT (1/1,000 OF THE VALUE FOR WORK ENVIRONMENT). 1997 8 5786 44 SPORT AND MALE SEXUALITY. THE RELATIONSHIPS BETWEEN SPORT AND SEXUALITY IN MALES ARE OF GREAT SOCIAL AND CLINICAL INTEREST, BECAUSE OF SPORTS AND MOTOR ACTIVITIES THAT HIGHLY PROMOTE SOCIAL AND SEXUAL RELATIONSHIPS. EVEN IF FEW LITERATURE EXIST, TWO MAIN QUESTIONS SHOULD BE TAKEN INTO ACCOUNT: WHETHER AND HOW PHYSICAL EXERCISE AND SPORT POSITIVELY OR NEGATIVELY INFLUENCE SEXUAL HEALTH AND BEHAVIOR AND/OR WHETHER AND HOW SEXUAL BEHAVIOR MAY AFFECT A SUB-SEQUENT SPORT PERFORMANCE. PHYSICAL EXERCISE AND SPORT PER SE CAN INFLUENCE, POSITIVELY OR NEGATIVELY, THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FUNCTION AND, CONSEQUENTLY, THE INDIVIDUAL'S REPRODUCTIVE AND/OR SEXUAL HEALTH. THIS DEPENDS ON INDIVIDUAL FACTORS SUCH AS GENETIC AND EPIGENETIC ONES AND ON DIFFERENT VARIABLES INVOLVED IN THE PRACTICE OF SPORT ACTIVITIES (TYPE OF SPORT, INTENSITY AND DURATION OF TRAINING, DOPING AND DRUG USE AND ABUSE, NUTRITION, SUPPLEMENTS, PSYCHOLOGICAL STRESS, ALLOSTATIC LOAD, ETC.). IF WELL CONDUCTED, MOTOR AND SPORT ACTIVITIES COULD HAVE BENEFICIAL EFFECTS ON SEXUAL HEALTH IN MALES. AMONG DIFFERENT LIFESTYLE CHANGES, INFLUENCING SEXUAL HEALTH, REGULAR PHYSICAL ACTIVITY IS FUNDAMENTAL TO ANTAGONIZE THE ONSET OF ERECTILE DYSFUNCTION (ED). HOWEVER, COMPETITIVE SPORT CAN LEAD BOTH REPRODUCTIVE AND/OR SEXUAL TRACT DAMAGES AND DYSFUNCTIONS, TRANSIENT (GENITAL PAIN, HYPOESTHESIA OF THE GENITALIA, HYPOGONADISM, DE, ALTERED SEXUAL DRIVE, ETC.) OR PERMANENT (HYPOGONADISM, DE, ETC.), BY ACTING DIRECTLY (TRAUMAS OF THE EXTERNAL GENITALIA, SADDLE-RELATED DISORDERS IN CYCLISTS, ETC.) OR INDIRECTLY (EXERCISE-RELATED HYPOGONADISM, DRUG ABUSE, DOPING, STRESS, ETC.). SEXUAL ACTIVITIES SHORTLY PERFORMED BEFORE A SPORT COMPETITION COULD DIFFERENTLY INFLUENCE SPORT PERFORMANCE. DUE TO THE FEW EXISTING DATA, IT IS ADVISABLE TO AVOID AN ABSOLUTE PRE-COMPETITION SEXUAL ABSTINENCE. 2017 9 5331 60 PUTTING THE PIECES TOGETHER IN GILLES DE LA TOURETTE SYNDROME: EXPLORING THE LINK BETWEEN CLINICAL OBSERVATIONS AND THE BIOLOGICAL BASIS OF DYSFUNCTION. GILLES DE LA TOURETTE SYNDROME IS A COMPLEX, IDIOPATHIC NEUROPSYCHIATRIC DISORDER WHOSE PATHOPHYSIOLOGICAL MECHANISMS HAVE YET TO BE ELUCIDATED. IT IS PHENOTYPICALLY HETEROGENEOUS AND MANIFESTS MORE OFTEN THAN NOT WITH BOTH MOTOR AND BEHAVIORAL IMPAIRMENT, ALTHOUGH TICS ARE ITS CLINICAL HALLMARK. TICS THEMSELVES PRESENT WITH A COMPLEX PROFILE AS THEY CHARACTERISTICALLY WAX AND WANE AND ARE OFTEN PRECEDED BY PREMONITORY SOMATOSENSORY SENSATIONS TO WHICH IT IS SAID A TIC IS THE RESPONSE. HIGHLY COMORBID WITH OBSESSIVE-COMPULSIVE DISORDER AND ATTENTION DEFICIT-HYPERACTIVITY DISORDER, IT IS PURPORTED TO BE AN EPIGENETIC, NEURODEVELOPMENTAL SPECTRUM DISORDER WITH A COMPLEX GENETIC PROFILE. IT HAS A CHILDHOOD ONSET, OCCURS DISPROPORTIONATELY IN MALES, AND SHOWS SPONTANEOUS SYMPTOMATIC ATTENUATION BY ADULTHOOD IN THE MAJORITY OF THOSE AFFLICTED. ALTHOUGH NOT FULLY UNDERSTOOD, ITS NEUROBIOLOGICAL BASIS IS LINKED TO DYSFUNCTION IN THE CORTICO-BASAL GANGLIA-THALAMO-CORTICAL NETWORK. TREATMENT MODALITIES FOR TOURETTE SYNDROME INCLUDE BEHAVIORAL, PHARMACOLOGICAL AND SURGICAL INTERVENTIONS, BUT THERE IS PRESENTLY NO CURE FOR THE DISORDER. FOR THOSE SEVERELY AFFECTED, DEEP BRAIN STIMULATION (DBS) HAS RECENTLY BECOME A VIABLE THERAPEUTIC OPTION. A KEY FACTOR TO ATTAINING OPTIMAL RESULTS FROM THIS SURGERY IS TARGET SELECTION, A TOPIC STILL UNDER DEBATE DUE TO THE COMPLEX CLINICAL PROFILE PRESENTED BY GTS PATIENTS. DEPENDING ON ITS PHENOTYPIC EXPRESSION AND THE MOST PROBLEMATIC ASPECT OF THE DISORDER FOR THE INDIVIDUAL, ONE OF THREE BRAIN REGIONS IS MOST COMMONLY CHOSEN FOR STIMULATION: THE THALAMUS, GLOBUS PALLIDUS, OR NUCLEUS ACCUMBENS. NEUROPHYSIOLOGICAL ANALYSES OF INTRA- AND POST-OPERATIVE HUMAN ELECTROPHYSIOLOGICAL RECORDINGS FROM CLINICAL DBS STUDIES SUGGEST A LINK BETWEEN TIC BEHAVIOR AND ACTIVITY IN BOTH THE THALAMUS AND GLOBUS PALLIDUS. IN PARTICULAR, CHRONIC RECORDINGS FROM THE THALAMUS HAVE SHOWN A CORRELATION BETWEEN SYMPTOMATOLOGY AND (1) SPECTRAL ACTIVITY IN GAMMA BAND POWER AND (2) THETA/GAMMA CROSS FREQUENCY COHERENCE. THESE RESULTS SUGGEST GAMMA OSCILLATIONS AND THETA/GAMMA CROSS CORRELATION DYNAMICS MAY SERVE AS BIOMARKERS FOR DYSFUNCTION. WHILE ACUTE AND CHRONIC RECORDINGS FROM HUMAN SUBJECTS UNDERGOING DBS HAVE PROVIDED BETTER INSIGHT INTO TIC GENESIS AND THE NEUROPATHOPHYSIOLOGICAL MECHANISMS UNDERLYING TOURETTE SYNDROME, THESE STUDIES ARE STILL SPARSE AND THE FIELD WOULD GREATLY BENEFIT FROM FURTHER INVESTIGATIONS. THIS REVIEW REPORTS DATA AND DISCOVERIES OF SCIENTIFIC AND CLINICAL RELEVANCE FROM A WIDE VARIETY OF METHODS AND PROVIDES UP-TO-DATE INFORMATION ABOUT OUR CURRENT UNDERSTANDING OF THE PATHOMECHANISMS UNDERLYING TOURETTE SYNDROME. IT GIVES A COMPREHENSIVE OVERVIEW OF THE CURRENT STATE OF KNOWLEDGE AND ADDRESSES OPEN QUESTIONS IN THE FIELD. 2017 10 4848 28 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 11 4937 44 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 12 6736 54 WHAT IS A PSYCHOSIS AND WHERE IS IT LOCATED? KRAEPELIN'S DICHOTOMY, MANIC-DEPRESSIVE INSANITY AND DEMENTIA PRAECOX, ARE CONTRASTING AND TRUE ENDOGENOUS DISEASE ENTITIES WHICH AFFECT EXCITABILITY, THE FUNDAMENTAL PROPERTY OF THE CNS. KRAEPELIN WANTED TO ESTABLISH A VALID CLASSIFICATION AND HIT THE EXTREMES IN BRAIN STRUCTURE AND FUNCTION AT A TIME WHEN WE HAD NO KNOWLEDGE OF BRAIN DYSFUNCTION IN "FUNCTIONAL" PSYCHOSES. THE AETIOLOGY IS NOW KNOWN: THE PSYCHOSES ARE PART OF HUMAN GROWTH AND MATURATION AND MIGHT BE CLASSIFIED ACCORDING TO THEIR BRAIN DYSFUNCTION, WHICH IS EXACTLY WHAT KRAEPELIN WANTED. HOWEVER, PRESUMABLY TO REDUCE THE STIGMA ATTACHED TO THE WORD "PSYCHOSIS", THERE IS CURRENTLY A STRONG INITIATIVE TO ELIMINATE THE CONCEPT. BUT KNOWLEDGE OF WHAT IS HAPPENING IN THE BRAIN IN A PSYCHOSIS MIGHT BE MORE HELPFUL IN REDUCING STIGMA. IT IS SUGGESTED THAT PSYCHOSIS IS DUE TO AN AFFECTION OF THE SUPPLEMENTARY MOTOR AREA (SMA), LOCATED AT THE CENTRE OF THE MEDIAL FRONTAL LOBE NETWORK. THE SMA IS ONE OF THE RARE UNIVERSALLY CONNECTED AREAS OF THE BRAIN, AS SHOULD BE THE CASE FOR SUCH A KEY STRUCTURE THAT MAKES DECISIONS AS TO THE RIGHT MOMENT FOR ACTION. THIS IMPORTANT NETWORK, WHICH PARTLY HAS CONTINUOUS NEUROGENESIS, HAS SUFFICIENTLY WIDESPREAD CONNECTIONS. THE SMA, A PREMOTOR AREA LOCATED ON THE MEDIAL SIDE OF THE FRONTAL LOBES, IS ONE OF THE LAST REGIONS TO REACH A CONCURRENCE OF SYNAPTOGENESIS. AN AFFECTION OF THE SMA, A DEFICIENT OR ABOLISHED DELAYED RESPONSE TASK, SERIOUSLY DISTURBS OUR RELATION AND ADAPTATION TO THE SURROUNDINGS. WE USUALLY MASTER THE DELAYED RESPONSE TASK AROUND THE AGE OF 7 MONTHS, A TIME AT WHICH THE SECOND CNS REGRESSIVE EVENT TAKES PLACE, WHICH PROCEEDS FROM THE POSTERIOR TO THE ANTERIOR OF THE BRAIN. IN VERY LATE MATURATION, A PERSISTENT AFFECTION OF THE SMA MIGHT OCCUR. WE EXPERIENCE A CHRONIC PSYCHOSIS: INFANTILE AUTISM (IA), A CHRONIC INABILITY TO ACT CONSCIOUSLY, WHICH CONTRASTS WITH THE EPISODIC SMA AFFECTION POST-PUBERTY, WHEN EXCITATION IS REDUCED DUE TO EXCESSIVE PRUNING OF EXCITATORY SYNAPSES. SILENT SPOTS ARE THE RESULT OF INSUFFICIENT FILL-IN MECHANISMS FOLLOWING A BREAKDOWN OF CIRCUITRY. THEY MAY AFFECT THE SMA IN THE CASE OF VERY LATE PUBERTY. AN ACUTE REDUCTION IN EXCITATION AND CONCOMITANTLY A MARKED INCREASE IN SILENT SPOTS MIGHT LEAD TO AN ACUTE PSYCHOSIS. A FRONTAL PREFERENCE IS LIKELY, GIVEN THAT A REDUCTION MIGHT OCCUR ANYWHERE IN THE CORTEX, BUT PARTICULARLY IN THE AREAS MATURING LATEST. THE VARYING LOCALISATIONS PROBABLY EXPLAIN THE DIFFICULTY IN ACCEPTING SCHIZOPHRENIA AS A DISEASE ENTITY. THE MULTIFACTORIAL INHERITANCE OF THE DICHOTOMY IMPLIES THAT THE GENETICS ARE NOT FATE, A PSYCHOTIC DEVELOPMENT MIGHT BE PREVENTED GIVEN ENOUGH EPIGENETIC FACTORS: BRAIN FOOD (OMEGA 3). MIGHT THE PRESENT DIETARY ADVERSITY, WITH ITS LACK OF BRAIN FOOD, BE RESPONSIBLE FOR A RISING INCIDENCE IN PSYCHOSIS? A PSYCHOSIS IS AN UNDERSTANDABLE AND PREVENTABLE DYSFUNCTION OF THE BRAIN, AND ITS MECHANISMS ARE KNOWN. PRIMARILY A DISORDER OF REDUCED EXCITATION IN AN ATTENUATED CNS, THIS EXPLAINS WHY ALL THE NEUROLEPTICS ARE CONVULSANTS, RAISING EXCITATION, IN CONTRAST TO ALL ANTIDEPRESSIVES, WHICH ARE ANTI-EPILEPTIC. 2008 13 5057 47 PHENOBARBITAL MECHANISTIC DATA AND RISK ASSESSMENT: ENZYME INDUCTION, ENHANCED CELL PROLIFERATION, AND TUMOR PROMOTION. CHRONIC EXPOSURE TO HIGH DOSES OF PHENOBARBITAL (PB) CAUSES HEPATOCELLULAR ADENOMAS IN BOTH MICE AND RATS AND HEPATOCELLULAR CARCINOMAS IN SOME STRAINS OF MICE. LONG-TERM PB THERAPY HAS NOT BEEN FOUND TO CAUSE HUMAN TUMORS. PB IS NOT DNA REACTIVE, AND MOST GENOTOXICITY TESTS HAVE YIELDED NEGATIVE RESULTS. PB HAS BEEN EXTENSIVELY STUDIED AS AN EPIGENETIC, RODENT LIVER TUMOR PROMOTER. AT EXPOSURES CAUSING RODENT LIVER TUMORS, PB HAS MEASURABLE EFFECTS ON HEPATOCYTES: PB INHIBITS CELL-TO-CELL COMMUNICATION; PB INDUCES ENZYMES, INCLUDING P450 CYTOCHROMES; PB STIMULATES PROLIFERATION AND INHIBITS APOPTOSIS OF HEPATOCYTES IN NEOPLASTIC FOCI. THRESHOLD EXPOSURES FOR SOME OF THESE ENDPOINTS COINCIDE WITH THE THRESHOLD EXPOSURE FOR TUMORIGENESIS. 1996 14 5712 39 SIRT1 MEDIATES DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS. DEPRESSION IS A RECURRING AND LIFE-THREATENING ILLNESS THAT AFFECTS UP TO 120 MILLION PEOPLE WORLDWIDE. IN THE PRESENT STUDY, WE SHOW THAT CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MODEL OF DEPRESSION IN MICE, INCREASES SIRT1 LEVELS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. INCREASES IN SIRT1, A WELL CHARACTERIZED CLASS III HISTONE DEACETYLASE, AFTER CHRONIC SOCIAL DEFEAT SUGGEST A ROLE FOR THIS ENZYME IN MEDIATING DEPRESSION-LIKE BEHAVIORS. WHEN RESVERATROL, A PHARMACOLOGICAL ACTIVATOR OF SIRT1, WAS DIRECTLY INFUSED BILATERALLY INTO THE NAC, WE OBSERVED AN INCREASE IN DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. CONVERSELY, INTRA-NAC INFUSIONS OF EX-527, A SIRT1 ANTAGONIST, REDUCED THESE BEHAVIORS; EX-527 ALSO REDUCED ACUTE STRESS RESPONSES IN STRESS-NAIVE MICE. NEXT, WE INCREASED SIRT1 LEVELS DIRECTLY IN NAC BY USE OF VIRAL-MEDIATED GENE TRANSFER AND OBSERVED AN INCREASE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS WHEN MICE WERE ASSESSED IN THE OPEN-FIELD, ELEVATED-PLUS-MAZE, AND FORCED SWIM TESTS. USING A CRE-INDUCIBLE VIRAL VECTOR SYSTEM TO OVEREXPRESS SIRT1 SELECTIVELY IN DOPAMINE D1 OR D2 SUBPOPULATIONS OF MEDIUM SPINY NEURONS (MSNS) IN THE NAC, WE FOUND THAT SIRT1 PROMOTES DEPRESSIVE-LIKE BEHAVIORS ONLY WHEN OVEREXPRESSED IN D1 MSNS, WITH NO EFFECT SEEN IN D2 MSNS. CONVERSELY, SELECTIVE ABLATION OF SIRT1 IN THE NAC USING VIRAL-CRE IN FLOXED SIRT1 MICE RESULTED IN DECREASED DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. TOGETHER, THESE RESULTS DEMONSTRATE THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN THE NAC IN REGULATING MOOD-RELATED BEHAVIORAL ABNORMALITIES AND IDENTIFIES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT MAJOR DEPRESSIVE DISORDERS. SIGNIFICANCE STATEMENT: IN THIS STUDY, WE DEMONSTRATE A PIVOTAL ROLE FOR SIRT1 IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW THAT STRESS STABLY INDUCES SIRT1 EXPRESSION IN THIS BRAIN REGION AND THAT ALTERING SIRT1 ACTIVITY USING A PHARMACOLOGICAL OR GENETIC APPROACH REGULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIORS. THESE RESULTS SUGGEST THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN REGULATING MOOD-RELATED BEHAVIORS AND INTRODUCES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT DEPRESSION AND OTHER STRESS-RELATED DISORDERS. A RECENT GROUNDBREAKING PUBLICATION BY THE CONVERGE CONSORTIUM (2015) IDENTIFIED A REPRODUCIBLE ASSOCIATION OF THE SIRT1 LOCUS WITH MAJOR DEPRESSION IN HUMANS. THEREFORE, OUR RESULTS ARE TIMELY AND HAVE SIGNIFICANT TRANSLATIONAL RELEVANCE. 2016 15 6267 41 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM. 2008 16 837 81 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS. 2004 17 4944 35 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 18 4860 36 OREXIN SIGNALING MEDIATES THE ANTIDEPRESSANT-LIKE EFFECT OF CALORIE RESTRICTION. DURING PERIODS OF REDUCED FOOD AVAILABILITY, ANIMALS MUST RESPOND WITH BEHAVIORAL ADAPTATIONS THAT PROMOTE SURVIVAL. DESPITE THE FACT THAT MANY PSYCHIATRIC SYNDROMES INCLUDE DISORDERED EATING PATTERNS AS A COMPONENT OF THE ILLNESS, LITTLE IS KNOWN ABOUT THE NEUROBIOLOGY UNDERLYING BEHAVIORAL CHANGES INDUCED BY SHORT-TERM CALORIE RESTRICTION. PRESENTLY, WE DEMONSTRATE THAT 10 D OF CALORIE RESTRICTION, CORRESPONDING TO A 20-25% WEIGHT LOSS, CAUSES A MARKED ANTIDEPRESSANT-LIKE RESPONSE IN TWO RODENT MODELS OF DEPRESSION AND THAT THIS RESPONSE IS DEPENDENT ON THE HYPOTHALAMIC NEUROPEPTIDE OREXIN (HYPOCRETIN). WILD-TYPE MICE, BUT NOT MICE LACKING OREXIN, SHOW LONGER LATENCY TO IMMOBILITY AND LESS TOTAL IMMOBILITY IN THE FORCED SWIM TEST AFTER CALORIE RESTRICTION. IN THE SOCIAL DEFEAT MODEL OF CHRONIC STRESS, CALORIE RESTRICTION REVERSES THE BEHAVIORAL DEFICITS SEEN IN WILD-TYPE MICE BUT NOT IN OREXIN KNOCK-OUT MICE. ADDITIONALLY, CHRONIC SOCIAL DEFEAT STRESS INDUCES A PROLONGED REDUCTION IN THE EXPRESSION OF PREPRO-OREXIN MRNA VIA EPIGENETIC MODIFICATION OF THE OREXIN GENE PROMOTER, WHEREAS CALORIE RESTRICTION ENHANCES THE ACTIVATION OF OREXIN CELLS AFTER SOCIAL DEFEAT. TOGETHER, THESE DATA INDICATE THAT OREXIN PLAYS AN ESSENTIAL ROLE IN MEDIATING REDUCED DEPRESSION-LIKE SYMPTOMS INDUCED BY CALORIE RESTRICTION. 2008 19 4948 42 PATERNAL STRESS EXPOSURE ALTERS SPERM MICRORNA CONTENT AND REPROGRAMS OFFSPRING HPA STRESS AXIS REGULATION. NEUROPSYCHIATRIC DISEASE FREQUENTLY PRESENTS WITH AN UNDERLYING HYPOREACTIVITY OR HYPERREACTIVITY OF THE HPA STRESS AXIS, SUGGESTING AN EXCEPTIONAL VULNERABILITY OF THIS CIRCUITRY TO EXTERNAL PERTURBATIONS. PARENTAL LIFETIME EXPOSURES TO ENVIRONMENTAL CHALLENGES ARE ASSOCIATED WITH INCREASED OFFSPRING NEUROPSYCHIATRIC DISEASE RISK, AND LIKELY CONTRIBUTE TO STRESS DYSREGULATION. WHILE MATERNAL INFLUENCES HAVE BEEN EXTENSIVELY EXAMINED, MUCH LESS IS KNOWN REGARDING THE SPECIFIC ROLE OF PATERNAL FACTORS. TO INVESTIGATE THE POTENTIAL MECHANISMS BY WHICH PATERNAL STRESS MAY CONTRIBUTE TO OFFSPRING HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, WE EXPOSED MICE TO 6 WEEKS OF CHRONIC STRESS BEFORE BREEDING. AS EPIDEMIOLOGICAL STUDIES SUPPORT VARIATION IN PATERNAL GERM CELL SUSCEPTIBILITY TO REPROGRAMMING ACROSS THE LIFESPAN, MALE STRESS EXPOSURE OCCURRED EITHER THROUGHOUT PUBERTY OR IN ADULTHOOD. REMARKABLY, OFFSPRING OF SIRES FROM BOTH PATERNAL STRESS GROUPS DISPLAYED SIGNIFICANTLY REDUCED HPA STRESS AXIS RESPONSIVITY. GENE SET ENRICHMENT ANALYSES IN OFFSPRING STRESS REGULATING BRAIN REGIONS, THE PARAVENTRICULAR NUCLEUS (PVN) AND THE BED NUCLEUS OF STRIA TERMINALIS, REVEALED GLOBAL PATTERN CHANGES IN TRANSCRIPTION SUGGESTIVE OF EPIGENETIC REPROGRAMMING AND CONSISTENT WITH ALTERED OFFSPRING STRESS RESPONSIVITY, INCLUDING INCREASED EXPRESSION OF GLUCOCORTICOID-RESPONSIVE GENES IN THE PVN. IN EXAMINING POTENTIAL EPIGENETIC MECHANISMS OF GERM CELL TRANSMISSION, WE FOUND ROBUST CHANGES IN SPERM MICRORNA (MIR) CONTENT, WHERE NINE SPECIFIC MIRS WERE SIGNIFICANTLY INCREASED IN BOTH PATERNAL STRESS GROUPS. OVERALL, THESE RESULTS DEMONSTRATE THAT PATERNAL EXPERIENCE ACROSS THE LIFESPAN CAN INDUCE GERM CELL EPIGENETIC REPROGRAMMING AND IMPACT OFFSPRING HPA STRESS AXIS REGULATION, AND MAY THEREFORE OFFER NOVEL INSIGHT INTO FACTORS INFLUENCING NEUROPSYCHIATRIC DISEASE RISK. 2013 20 6742 57 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