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« R eal»- B iological P roposals for

« R eal»- B iological P roposals for new paths to bipolarity, mixity, fibromyalgia, and migraine. G.Treviranus, Berne (CH). www.biposuisse.ch.

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« R eal»- B iological P roposals for

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  1. «Real»-Biological Proposals for new paths to bipolarity, mixity, fibromyalgia, and migraine. G.Treviranus, Berne (CH) www.biposuisse.ch  CNS regulates itself: its «psychosomatoses» occur after breach of mast cell-guarded barriers under conjointco-evolved pluri-site microbial «influence»  PNE-Immunology matures from «Solutes» to «Conduits, Cauldrons & Pellets» monitored by PNS to explain LOCAL small-arterial «change» by Mast cells Concatenated Conduits: lymphatics, fascial spaces, adventitial nerves and neural vessels, vessel-vessels, micro-conduits, nerves, sinus cavernosus …  Carrying: fluid signals,cells, MCs and their cytokine pellets (Kunder 2008) Mast cells (MCs) are "kanban-hubs" at every stage. 1.) PterygoPalatineGanglion: calmsBRAIN MAST CELLs (MCs)-2.) BRAIN MCs:in meninges, thalamus, putamen, habenulaare «psychodynamicmigrants»,damage & heal theBBBand Gray matter & White mattter. 3.) Peripheral MC-borne TNFa- «XR» pellets leak from final curve of THORACIC DUCT& reach centripetal adventitial vessels of CAROTIDE Art. & VETEBRAL branches causing local BBB damage e.g. from MCs4.) MC-made pelletsbeforehandtricklefromPNS-influencedLYMPHATIC CAULDRONScause FIBROMYALGIA/other psycho-SOMATIC STRESS DISORDERS5.)BARTONELLA  unguealCatscratch Disease,Morgellons etc. a Genome-hijacker & -modifier  ?CNV , Chromosome anoma-lies, MASTOCYTE mutations? Present CRISIS OF RESEARCH: Glahn DC (2008): pathways, through which .. remote risk-conferring and … influence on brain … are unknown. Maes M (1995, 2012): a bad, chronic … (neuro)inflammation and (neuro) degenerativeprocesses following less well defined triggers.Whalley (2012) polygenetic risk profiling, … model… in vitro, individuals from the extremes .. to identify the cellular process that underlie imaging findings. 500+ Mio. Yrs. old a MC from Malaga

  2. Bartonella-caused mutation triple hypothesis: a genetic link to Mastocyte activation syndromes & BPAD? 2012: PPG calms brain MCs? A “NEW TWIST for BPAD?” (Hagop) 2013:“Mastocyte Activation Syndromes” – a PARADIGM DISORDER for BPAD? 2014 ? Peru-Brazil migrants mission for Bartonella bac. with additional B.henselae -PCR & HCl-33 for BPAD? ? Infect MCs w/ Bartonella ? ? Skin test for BH in Mastocyte Activation Syndromes ? HCl-33 in common depression SYSTEMIC MAST CELL ACTIVATION Syndrome 1991 Metcalfe: MILD Systemic MASTOCYTOSIS with NORMAL SKIN 2007 Akin: aberrant mast cell population with idiopathic ANAPHYLAXIS 2009Bonadonna: CLONAL mast cell disorders in systemic reactions to BEE-stings and serum TRYPTASE 2010 Alvarez-Twose: … with SYSTEMIC MAST CELL ACTIVATION Various mutations in Mastocyte activation syndrome (with anaphylaxia) • Full circle? • ImmuneR weak • BART-like germs invade, lymphatics, • CNS…  Behavior: «thrive & don’t fear cats» • & BONE MARROW  mutations •  MC-activation syndrome & IR MC D •  IR-deficiency  more infections. Rogers MP, HMS 1985

  3. Angioma & Zoonoticpsychosis(sheep). Periunguealtenderness & ascendingalonglymphaticsis «difficultdata» … Where is your clinical data? pyodermagangrenosum «Mickey’scheek» lesionsof DORSALMIDBRAIN : 1 BartonellahenselaeBH Peri rednucleus =O SCAR or ? ongoingBartonellosis ? with+potential forangiomas? P. Grof What kind of rhinosinusitis? Lhermitte . Alice In Wonderland Syndrome PEDUNCULAR HALLUCINOSIS M, 1977: Italian.RC-BPAD1 since childhood, CSA, OH++, sex++ Spectacular hallucinations: devils all around him, micro- / macropsia,TLE-like. Talented. NOT psychotic , insight. Univ. depart.: F20 & Xeplion i.m. rTMS: L DFPC: halluc. STOPPED ! He refuses further TMS because ”I NEED the “Fire in my legs”as FEEDBACK from GOD” MC extracelluar traps? M, 1964: TY-KurdAnergic BPAD-2 Cthymia, OH ++ Thoracic duct & Venositis? M, 1936: Generalized, clinical, serological, antibiotic- responsive Bartonella henselae: Early vertebralis arteriitis SCAR? BH caused oculo-glandular syn-drome of dorsal midbrain of Parinaud 1898 ! Small serie’s clusters are chance, but 5 independent recent cases had clinico-serological and/or MRT signs ++ suggestive of BARTONELLA

  4. 1. BPAD  SYSTEMIC AUTOINFLAMMATION Leboyer 2012 CONFLICT =trigger Grunze 2012 - ? via MAST CELLS (MCs) ? 2. Classical dimensions THOUGHT-ACTION-MOODMAP ONTOCortico-SubCortical-Circuits Anderson 1986 which are BUNDLED at the THALAMUSGT. IRBD 2012? in order to receive MC-signals? 3.NASAL Ganglion [PPG] ?exerts TONIC A.Ch-anti-inflammatory PARASYMPATHETIC BRAKE ON MC otherwhise opening BBB? IRBD 2012 4. TRIGEMINAL afferents or STOP of biting (TG mot)? inhibit NASAL PPG-brake ? MCs open BBBACUTE SHAME: STOPS ostracism. 5.HABENULAR MCs brakeVTA/SEARCH-systemCHRONIC SHAME: STOPS rivalry.GT. IRBD 2013 Can ISTDP (H.Davanloo) REVERT SHAME TO GUILT ? 6.MRI: LEFT hemisphere-LITHIUM-rescue: does it STOP MCs ? 7.THREAT signals of co-evolved microbes act via LYMPH-conduitsthrough MC-pellets on ? own vessels of Carotide etc. MCs open BBBalong SMALL ARTERIES 8. MRI reveils “environmental” GM-losses :HIPPOCAMPUS xxxMCs ? RIGHT:    non-shared (mostly) environmental damage APPROACH CYCLES Bearden: CX 2007 GM loss & rescue LITHIUM acts asMC- Inhibitor ? R Li ÷ no LEFT HC 2008 R R R HIPPOCAMPUS Szabo 2009 Bundled GM x BPAD in TWINS Lenticulostriate SMALL ARTERY MIDBRAIN ? NON-shared environmentVan den Schot, 2010 TAM

  5. C1)i. Parasympathetic PPG = 2 x 70T cells, of which 5.6T to brain ARTERIES: ? APPROACH network: its VTA has 2 x 400T cellsMIGRAINE: ii.Cortex is hyper-responsive because of lowThalamo-Cortical drive– bc. of MCs?ii. ET1 or kynurenin CSD-oligemia via ? Pericytes Chauvel 2012iii.CGRP-receptorsonly on MCs(but NO axon reflex!)iv. CAUSE of MIG.= Unknown trouble of TG! brainstem! PPG Dont BITE ’ Dreier 2002, OUTPUT= 2 x 2.8T cells  BRAIN ARTERIES (? MCs) minor part opens to liquid ? from CAROTIS ALL HEADACHES show LOCAL GM-loss& WM-losscorr. general COGNITIVE  & Sinus Cavernosus Ggl. PPG-brake of BBB-MCs braked by ?TG-baskets  Frequent MIGRAINEURS PUTAMEN  GM May 2009 MIG TENS CLUST Maleki 2011 CFS HealthyControls • COGNITION • / Memory  • Headaches Severity MIG±AURA Subj. severe TENSION Ravindran 2011

  6. lung r & LEFT Thoracic ducts Post-nodal Collectors Initial LV 0.03 mm Rat tail Hagedoorn 2004 THREAT signal COLLECTING vessel Margaris 2012 L~ NODE NALT, BALT, GALT, GERALT Rat tail Suami 2011 Cell migration can overcome interstitial flow ~.1-4 µm/s TNF-a fosters : lymphatic growth leukocyte & MCtransmigration - MCattraction in lung: Baluk 2009 BARRIERS PATHOGENS PHYSICAL needs &threats Could pellets cross the barrier of lymphatic collectors or ducts? NO? YES, IF neurogenic nerves & MCs OPEN LYMPHATICS to hasten the SIGNAL DELIVERIES to LYMPH-NODES required for immune response - at the expense of FLUID DRAINAGE– WHILE microbes are present.

  7. Conduits for lymph-borne signals to the BRAINSTEM? LEFT – more than right - Thoracic DUCT drains a «cauldron» FROM LYMPHATIC «catchment areas»: face, skin, GIT/UGT, CNS Why this curve? VA Thoracic duct Thoracic duct Seeger 2009 Subclavia Subclavia VAGAL N. through cephalad curves the thoracic DUCTS come to lie within the carotide sheath close to the CAROTIDE and VERTEBRAL art. and to the VAGAL N.: here TNFa-pellets could cross from the LYMPHATICS to the former’s micro-arteries

  8. Pellet TNFaacts on the vasa vasorum of the CAROTIDE branches and causes ? MC-modifying «arteriitis» of BBB.. The VERTEBRAL ARTERIES fuse to the Basilar Art. preserving LATERALITY of ist walls. The left VA is crossed by the Thoracic Duct, which lies inside the carotid sheath with the IJV and the vagal nervewhich are also inflamed via the proper micro-arteries. The transversa colli Art. could inflame the brachial plexus. thoracic duct pellet-leaks maybe reach the brachial plexus perineural veins behind the ant. scalene, then the radicular veins and Bateson’s plexus. MC-mediated ?Reversible cerebral vaso-constriction syndrome Inflammatory VEIN stenosesof IJV in MSclerosis?91% or of Azygos 86%(Zamboni 2009) with  Type III collagen; but no myofibroblast (Coen 2013). Lymphatic & MC-mediated? VARICOSE VEINS driven by C-fibres & mast cells (Vital 2010) ;C5a activation (deVries 2013). Seeger 2009 MC-mediated? inflammatory VASA VASORUM dissections R Thorac duct MC-mediated? Rupture of atherosclerotic plaque Willems 2013

  9. micro biomechanics nano biomechanics LYMPHATIC microvalves Good or bad guy ? KLC2 lowers AMPA: TAT-KLCpCDK inhibitsGSK3b-P~ylation of KLC2needed for (rat) AMPAR-trafficking and «mood-stabilizing» in the rat (Du, Manji 2009). But KLC2 is ALSO needed to fetch the pump Na+/K+-ATPase when MCs fill with Na+ after any release (± IgE). Trzewik 2001 Trzewik 2001 OH intake  in amygdalar k.o.-14-3-3ζ which is needed by KLC2 … LYMPHATIC «open end» Particle inside! BARTONELLA Mphage media  EC prolif via HIF-1, VEGF.. Scheidegger 2011 F10 & BP «The pump» Na+/K+-ATPase neuro-ISO-FORM 3 is candidate for mood swings El-Mailakh 1983. Only BPAD patients already stabilized on LI:  the pump and  oxidative stress Bannerjee 2012 Ouabaïne-like cardenolides from adrenals e.g. INHIBIT the pump causing TNF-related (TRAIL) apoptosis Panayiotidis 2010 brain-slice «irritability», stress-hypertension and damages healed by LITHIUM (not VPA) Hennion, El-Mailakh 2002 Icv.-Ouabaïne-Mania-rats release more DA in mPFC – LI no use! Sui (Shanghai) 2013 AMPH the pump in rats – unless on LI or VPA MAMPH and pro-inflammatory CKs  pump isoform3 bc. of downstream Erk Pendyala 2012 «pump» ISOFORM 3 is related to MIGRAINE Bonghan Rabbit ventricle Bonghan «primo-ves-sels» slide freely on brain surfaces & within vessels ABC-C1 trans-porter = multi-drug-resistance MDR1: carries S1P – Fingolimod – targeted prime modulator of MC functions.

  10. MC & BBB: MC are longlived (wks-mo), but migrate within hour from blood to brain:TNF-a essential 1st contact with EC (Kneilling 2009) MCs Basophils Paul Ehrlich 1854- 1915 BBB MCs steer Leukocyte & ownentry ± similarly Leuk TNFa Leuk EC Leuk ONGOING CAUSE  OLD or NEW SYMPTOMS Theoharides N.Y. MCs in ASD MCs in MS etc. RR-MS: Flares: days, Remission: weeks; 70% progressive TREAT ONGOING CAUSE  RECOVERY BPAD R. Post

  11. B.2) BRAIN MCs: open, damage & seal BBB: are hubs Rudich et 2012 MCs are long-living hubs w/ convergent divergent signals on ~100 /  ~40 receptors resonating with Stress-axes HPA, HThyrA,Ntroph/peptA Selye Addictive signals calm (CB, Nicotine, BZD) or release + H (OH, Op.) or via MKLC (OH) AMPH ??

  12. Bartonella H-like bacteria CAUSE «epigenetic» hijacking of the histone acetylase and repair systems & genetic changes to the human genome incl. CNV Schizophr Bull. 1995;21(2):167-71. BIPOLAR & Rheumatism “Gelenkrheumatismus”: E. Kraepelin SCHIZOPHRENIA & RA: Fuller Torrey & Yolken ++ >HCO cats in childhood Similarities: class II HLA Ag. ? infectious etiology: retroviruses, HERPES viruses (EBV, HSV) Toxoplasma gondii Inverse correlation “once a person gets one (..)  relatively immune to the other.” Torrey EF, Yolken RH, 2001

  13. Ceko, Bushnell, Gracely (2012) Tran, Casey 2010 Potvin 2008, 2009 Lévesque2012 r= - 0.70 PANNS+ Ceko et al.(McGill) 2012 «4 possible factors»: 1) ongoing peripheral source of input from C nociceptors other than applied S ; 2) sensitized NMDA-R (Staud: Can be dampened in HCO too: post-NMDA-R .. 3) (..) descending modulation of DH DNICMOR, a2ADR etc. pp.!; 4) supraspinal level. FM:  sensitivity(detection ok) in noxious & multiplesensory modes: sounds; even pleasant odors, which parallels tenderness – and ? Irritability ? Thalamic MCs? ? ANTICIPATION F20 Qrost-v. BRAIN gyrus rectus {SHAME – GUILT} Qpost.-d. BRAIN QThalamus CR QThalamus 5, 10, 20 s & 20 s HEAT perception intensity MCs unleashed by PPG … LI case reports; VALP: none. LIMBIC DA Striatal D2/D3+:pain; COMTval/val (DA -):pain .- FM: DRD3-SNP.

  14. www.bipoSuisse.ch Research Gate www.Prezi.com MC MC TNF-a Muchas gracias! PC EC AC

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