1 5854 112 SUBSTANCE P AND NEPRILYSIN IN CHRONIC PANCREATITIS. BACKGROUND/AIMS: WE AIMED TO ANALYZE SUBSTANCE P (SP) AND NEPRILYSIN (NEP), THE MEMBRANE METALLOPEPTIDASE THAT DEGRADES SP, IN CHRONIC PANCREATITIS (CP). METHODS: SP AND NEP MRNA LEVELS WERE ANALYZED BY QRT-PCR IN TISSUE SAMPLES FROM 30 PATIENTS WITH CP AND 8 ORGAN DONORS. IN ADDITION, SP SERUM LEVELS WERE DETERMINED BEFORE AND AFTER SURGERY IN THE SAME PATIENTS, BY MEANS OF A COMPETITIVE ELISA ASSAY. GENETIC AND EPIGENETIC ANALYSES OF THE NEP GENE WERE ALSO PERFORMED. RESULTS: SP MRNA EXPRESSION LEVELS WERE HIGHER IN CP TISSUES COMPARED TO CONTROLS (P = 0.0152), WHILE NEP MRNA SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN CP AND HEALTHY SUBJECTS (P = 0.2102). IN CP PATIENTS, SP SERUM LEVELS CORRELATED WITH THOSE IN TISSUE, AND AFTER SURGICAL RESECTION SP SERUM LEVELS WERE REDUCED COMPARED TO THE PREOPERATIVE VALUES. FAILURE OF NEP TO OVEREXPRESS IN CP TISSUES WAS ASSOCIATED WITH SIGNIFICANT MIR-128A OVEREXPRESSION (P = 0.02), RATHER THAN WITH MUTATIONS IN THE NEP CODING REGION OR THE PRESENCE OF HYPERMETHYLATION SITES IN THE NEP PROMOTER REGION. CONCLUSION: TISSUE AND SERUM LEVELS OF SP WERE INCREASED IN CP, WHILE NEP LEVELS REMAINED UNALTERED. IN AN SP/NEP-MEDIATED PATHWAY, IT WOULD APPEAR THAT NEP FAILS TO PROVIDE ADEQUATE SURVEILLANCE OF SP LEVELS. FAILURE OF NEP TO OVEREXPRESS COULD BE ASSOCIATED WITH MIRNA REGULATION. 2012 2 965 19 CHRONIC NEURODEGENERATIVE CONSEQUENCES OF TRAUMATIC BRAIN INJURY. TRAUMATIC BRAIN INJURY (TBI) IS A SERIOUS PUBLIC HEALTH CONCERN AND A MAJOR CAUSE OF DEATH AND DISABILITY WORLDWIDE. EACH YEAR, AN ESTIMATED 1.7 MILLION AMERICANS SUSTAIN TBI OF WHICH ~52,000 PEOPLE DIE, ~275,000 PEOPLE ARE HOSPITALIZED AND 1,365,000 PEOPLE ARE TREATED AS EMERGENCY OUTPATIENTS. CURRENTLY THERE ARE ~5.3 MILLION AMERICANS LIVING WITH TBI. TBI IS MORE OF A DISEASE PROCESS THAN OF AN EVENT THAT IS ASSOCIATED WITH IMMEDIATE AND LONG-TERM SENSOMOTOR, PSYCHOLOGICAL AND COGNITIVE IMPAIRMENTS. TBI IS THE BEST KNOWN ESTABLISHED EPIGENETIC RISK FACTOR FOR LATER DEVELOPMENT OF NEURODEGENERATIVE DISEASES AND DEMENTIA. PEOPLE SUSTAINING TBI ARE ~4 TIMES MORE LIKELY TO DEVELOP DEMENTIA AT A LATER STAGE THAN PEOPLE WITHOUT TBI. SINGLE BRAIN INJURY IS LINKED TO LATER DEVELOPMENT OF SYMPTOMS RESEMBLING ALZHEIMER'S DISEASE WHILE REPETITIVE BRAIN INJURIES ARE LINKED TO LATER DEVELOPMENT OF CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE) AND/OR DEMENTIA PUGILISTICA (DP). FURTHERMORE, GENETIC BACKGROUND OF SS-AMYLOID PRECURSOR PROTEIN (APP), APOLIPOPROTEIN E (APOE), PRESENILIN (PS) AND NEPRILYSIN (NEP) GENES IS ASSOCIATED WITH EXACERBATION OF NEURODEGENERATIVE PROCESS AFTER TBI. THIS REVIEW ENCOMPASSES ACUTE EFFECTS AND CHRONIC NEURODEGENERATIVE CONSEQUENCES AFTER TBI. 2014 3 253 23 ADVANCES AND PERSPECTIVES FROM GENETIC RESEARCH: DEVELOPMENT OF BIOLOGICAL MARKERS IN ALZHEIMER'S DISEASE. DESPITE IMPORTANT RECENT ADVANCES, A FULL UNDERSTANDING OF THE (GENETIC) ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS STILL A LONG WAY OFF. LARGE COLLABORATIVE EFFORTS ARE ONGOING, AS WELL AS THE EXPLORATION OF VARIOUS SOURCES OF GENETIC VARIATION. EVIDENCE SUPPORTS THE VIEW THAT MENDELIAN EARLY-ONSET FAMILIAL FORMS OF AD ARE CAUSED BY RARE AND USUALLY HIGHLY PENETRANT MUTATIONS IN THREE GENES (APP, PSEN1 AND PSEN2). CONSIDERING SPORADIC LATE-ONSET AD (LOAD), THE APOE EPSILON4 ALLELE IS BY FAR THE BEST-ESTABLISHED RISK GENE. RECENTLY PUBLISHED LARGE-SCALE GENOME-WIDE ANALYSES POINT TO ADDITIONALLY RELEVANT GENETICALLY ASSOCIATED LOCI, PARTICULARLY CLU, PICALM AND CR1. THESE SUSCEPTIBILITY LOCI SUPPORT EXISTING HYPOTHESES ABOUT THE AMYLOID, LIPID, CHAPERONE AND CHRONIC INFLAMMATORY MECHANISMS IN AD PATHOGENESIS, AND ARE THEREFORE LIKELY TO PROVIDE THE BASIS FOR THE DEVELOPMENT OF HYPOTHESIS-DRIVEN NOVEL BIOMARKER CANDIDATES. ADDITIONAL GENES, LISTED ONLINE IN ALZGENE (E.G., GAB2 OR SORL1) HAVE REPEATEDLY SHOWN RISK EFFECTS IN LOAD, AND MAY BE TRUE RISK GENES, BUT THIS IS MUCH LESS CERTAIN. NEW EPIGENETIC RESEARCH PROVIDED SOME EVIDENCE THAT DNA MODIFICATIONS MAYBE INVOLVED IN LOAD (E.G., POST-MORTEM STUDIES DESCRIBED BOTH HYPO- AND HYPER-METHYLATION IN AD-RELATED SUSCEPTIBILITY GENES). WITH RESPECT TO BIOMARKERS, ELDERLY NONDEMENTED APOE EPSILON4 CARRIERS DEMONSTRATED DISTINCT CEREBROSPINAL FLUID BIOMARKER SIGNATURES AND ALTERATIONS OF BRAIN GLUCOSE METABOLISM SIMILAR TO THOSE OBSERVED IN AD. FUTURE RESEARCH SHOULD EVALUATE THE USEFULNESS OF NEWLY DETECTED AD RISK GENES AND EPIGENETIC CHANGES AS POTENTIAL BIOMARKERS TOWARDS GENETIC PROFILING OF AD OR FOR CORRELATION WITH ENDOPHENOTYPES AND THERAPEUTIC OUTCOME. 2010 4 810 35 CHANGES IN DNA METHYLATION IN APOE AND ACKR3 GENES IN MULTIPLE SCLEROSIS PATIENTS AND THE RELATIONSHIP WITH THEIR HEAVY METAL BLOOD LEVELS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE WITH DEMYELINATED LESIONS IN THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION AS AN EPIGENETIC CHANGE INFLUENCED BY ENVIRONMENTAL FACTORS, INCLUDING HEAVY METALS HAS BEEN IMPLEMENTED IN MS DISEASE. WE INVESTIGATED THE CORRELATION OF DNA METHYLATION CHANGES IN APOE AND ACKR3 GENES IN MS PATIENTS AND THE POSSIBLE ASSOCIATION WITH BLOOD CONCENTRATION OF ARSENIC (AS), CADMIUM (CD) AND LEAD (PB) AS MAJOR HEAVY METAL POLLUTANTS. THIS STUDY INCLUDED 69 RELAPSING-REMITTING MULTIPLE SCLEROSIS (RR-MS) PATIENTS AND 69 AGE/GENDER-MATCHED HEALTHY SUBJECTS. THE HRM REAL-TIME PCR METHOD WAS USED TO INVESTIGATE THE CHANGES IN DNA METHYLATION AND HEAVY METAL CONCENTRATIONS WERE MEASURED BY ELECTROTHERMAL ATOMIC ABSORPTION SPECTROMETRY. OUR RESULTS SHOWED THAT THE METHYLATION PATTERN IN THE ACKR3 GENE OF THE PATIENT GROUP WAS MORE HYPOMETHYLATED, WHILE IN THE CASE OF THE APOE GENE, THIS PATTERN WAS MORE TOWARDS HYPERMETHYLATION COMPARED TO HEALTHY SUBJECTS. MOREOVER, THE BLOOD LEVELS OF AS AND CD METALS, BUT NOT PB, WERE SIGNIFICANTLY HIGHER IN THE PATIENT GROUP COMPARE TO THE CONTROL GROUP (P