CHRONIC FATIGUE SYNDROME STUDIES ON CLINICAL …慢性疲劳综合征的临床的研究…精选文档文档资料.ppt

Myalgic encephalomyelitis:A highly prevalent debilitating disease,Persistent,debilitating fatigue associated with numerous physical and neurocognitive symptomsDisease severity can range from moderate to extremely severe:patients bedridden for years,totally caregiver dependent Prevalence estimates:0,3 to 0,6%;one million patients in the USA,two million patients in EuropeThis may just be the tip of the iceberg High socio-economic costCost to the society estimated as approximately$16 billion in the USA,20 billion in Europe,Patients usually present with multiple intestinal symptoms including:NauseaAbdominal painPoor appetiteAbnormal bowel motilityGastric refluxBloating Inflammation of the gastrointestinal tract Marked alteration of the intestinal microbial flora,Intestinal disorders in ME patients,Enterococcus and Streptococcus species are strongly over-represented in ME patients:,Henry Butt,University of Melbourne,Alterations of intestinal microflora(aerobes),Among anaerobic bacteria,Prevotella is the most consistently overgrown bacteria:,Henry Butt,University of Melbourne,Alterations of intestinal microflora(anaerobes),Henry Butt,University of Melbourne,Enterococcus spp.counts correlate with symptom expression:,Bacterial overgrowth correlates with symptoms severity,Henry Butt,University of Melbourne,Streptococcus spp.counts correlate with symptom expression:,Bacterial overgrowth correlates with symptoms severity,Hydrogen sulfide(H2S)has important physiological functions.H2S is produced by the cells and is an important gaseous signal molecule,involved in regulation of blood pressure,neurotransmission,muscle relaxation and regulation of inflammation,Hydrogen sulfide produced by bacteria works as a potent toxin for the body,.but exogeneous exposure can be extremely toxicIn excess,H2S acts as a mitochondrial poison.It can directly inhibit enzymes involved in the cellular production of energy.H2S also interferes with oxygen transport by blocking hemoglobin in the red blood cells.,Enterococcus,Streptococcus,Prevotella are strong H2S producers,E.coli,Strept,Fungi,Bacteria,Gut,Gut barrier,H2S,Mold,(metals),PRPC,PRPDX,Other gaseousmediators:NO.CO.,Cumulative effects of H2S and heavy metals,M,M,M,H2S,Mitochondria,ATP,Cell,Heavy metals interfere directly with energy production,Oxidase,Cu2+,Q10,NADH,Krebs cycle,NO.,Extracellular,Plasmamembrane,Intracellular,ATP,+,ONOO.,R-S-,Adapted from James Morr 2006 J Inorg Biochem 100 2140-2149,Genetic and environmental factors contribute to aberrant protein conformation,PRPC,PRPDX,Genetic,Acquired,Environmental,Mutations,Heavy Metals,PRP DX,Abnormal conformation can be transmitted from one cell to another,Cell,Metals,Cell,Cell,PRC,PRPDX,Increasing immune dysregulations(depressed T and NK cells,Th17 activation,opportunistic infections),Disease severity in ME is associated with different physiological dysfunctions,Immune alterations resulting from intestinal dysfunction,Nave T cells,TH1cells,TH2cells,TH17cells,Protection againstintracellular pathogens(viruses,bacteria),Protection againstextracellular pathogens(parasites,bacteria),Local immunity(mucosa,skin)Protection againstfungi,bacteria,IL-12,TGF-b+IL-6,IL-4,IFN-g,Dysbiosis causes a decreaseof CD8+cells and TH1 immunity,TH1 downregulation allowsincreased TH2 and TH17,Consequences of altered immunity,TH1 decrease favors the development of opportunistic viral infectionsHHV-6,Epstein-Barr,parvovirus B19,enterovirusesare found in ME patients.Gastro-intestinal mucosais a major site of infection TH2 increase favors the development of allergies TH17 increase promotes inflammation,autoimmunity,blood-brain barrier disruption,Genetic background plays a role in TH17 upregulationPolymorphisms of IL-17F,IL-6,TLR4,TGF-b genesare associated with ME and other intestinal diseases(Crohns disease,UC,IBS),Patient evaluation,Urine test for marker associated with H2S production Intestinal microflora evaluation Heavy metals analysis Presence of proteins with abnormal conformation Assays evaluating subsequent immune dysfunctions(immune dysregulations,opportunistic infections.),A marker associated with H2S production can be measured with a simple urine test,1.Collect urine,2.Open tube containing test reagent,3.Add a few drops of urine to the test reagent,4.Mix by shaking gently.Wait for two minutes,5.Observe color changes.Dark color=positive sample,Negative orPre-ME,Moderatedisease,Severedisease,A specific microbiological assay can determine gut microflora populations,Investigation of the microbial flora of the intestinal tract Quantifies major aerobic and anaerobic bacterial groups and yeast Focuses on dysbiosis(imbalance of the intestinal ecosytem)rather than digestive analysis to ascertain gut integrity Challenge:keep anaerobic bacteria viable for analysis-Validated oxygen-free,temperature controlled collection and shipping system,Microbiological assay:sample result,Patient presents increased Streptococcus,Enterococcus,and Prevotella,Heavy metal analysis:sample result,Patient presents mercury and nickel intoxication,Abnormal protein conformation assay,Aberrant luminescenceresponse indicates abnormal conformation,CONCLUSIONS,Gastro-intestinal dysfunctions play a central role in the pathogenesis of ME Dysbiosis detrimental effect mediated by increased production of H2S Immune dysfunctions and opportunistic infections arise as a consequence of pre-existing intestinal problemsOnce established,infections will contribute to the maintenance/aggravation of the disease,Acknowledgements,Henry Butt at the Bio21 Institute,University of Melbourne Marian Dix Lemle,Independent Researcher,Washington DCMed Hypotheses.2009 Jan;72(1):108-9.Epub 2008 Sep 16.Hypothesis:chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism.Lemle MD.,