usman mast cell and microglial activation -...

Stress and the Autonomic Nervous System

Anju Usman, M.D. True Health Medical Center.

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Dr.AnjuUsmanSingh,MD,FAAFP,ABIHM,Hom-C,FMAPS

Mast Cell and Microglial Activation

Implications for ASD

©TrueHealthMedicalCenter

Disclaimer

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• Clinicaltrialshavenotbeendoneonsometreatmentapproachesdiscussed

• Ideasandconceptsdiscussedareconsideredalternativetheoriesandnotstandardofcareyet

• Dr.UsmanSinghisMedicalDirectorofTrueHealthMedicalCenterandPureCompoundingPharmacy

• TrueHealthNaturals,Familyowned.

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HOPEism

It is difficult to say what is impossible, for the dream of yesterday is the hope of today and the reality of tomorrow. Robert H. Goddard

Neuroinflammation

• Neuroinflammationiswidelyregardedaschronic.• Acuteinflammationusuallyfollowsinjurytothecentralnervoussystemimmediately,andischaracterizedbyinflammatorymolecules,endothelialcellactivation,plateletdeposition,andtissueedema.

• Chronicinflammationisthesustainedactivationofglialcells,mastcellsandrecruitmentofotherimmunecellsintothebrain.

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Causes of Neuroinflammation

• Toxic metabolites • Autoimmunity • Allergens • Aging • Microbes/Infections • Viruses • Traumatic brain injury • Spinal cord injury • Air pollution • Passive smoke • Mycotoxins • Stress

The Unresolved Inflammatory Response aka Chronic Inflammation

• TheInnateImmuneresponseisactivated• MastCellsdegranulate• Microglialactivated• Glutamateisreleased• ExcessExcitationensues• Leadingto

• Dysautonomia• Mitochondrialdysfunction• Proteinaggregation(hyper-coaguablestate)• Oxidativestress• Abnormalneuronalconnectivity(choking)

Nicolas G. Bazan, ... Ludmila Belayev, in Basic Neurochemistry 2012

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n engl j med 373;2

PossibleSymptomsofMastCellActivation

• AtopicorAllergicSymptoms• Hives(urticaria),Feetingrashes,Flushing

• Angioedema• Itching• NasalCongestion• ShortnessofBreath• ChestTightness• Tachycardia• HighorLowBloodPressure

• Fatigue• MusculoskeletalPain• Nausea/Vomiting• Migraine• Difficultyconcentrating• Memoryloss• Anxiety

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Various triggers cause Mast Cells to degranulate And release a variety of inflammatory cells Mast Cells cause Microglial Activation

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http://www.frontiersin.org/files/Articles/112233/

Microglia release proinflammatory cells, that cause Glutamate release from neurons, Glutamate binds to the NMDA receptor, Allowing Calcium to flow into cells rapidly Excess Calcium excites the cells and causes damage to neurons

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The principle excitatory receptor, the N-Methyl-D-Aspartate (NMDA) receptor, and its associated calcium (Ca2+) permeable ion channel are activated by glutamate.

©TrueHealthMedicalCenter5/15/19 Copyright by Dr. TC Theoharides

Courtesy Dr. Theoharides

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Histamine,

IL-6, NGF,

CRH, NGF, NT, SP

IL-6, TNF Microglia

Neuron

Mast cell

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“IntegrativeApproachtoMastCell/MicroglialActivation”

• DietaryInterventions•  Anti-inflammatoryDiet:CF/GF/grain-free,lowglutamate,avoidexcitotoxins•  Considerlowlectindiet-nightshadefreeandlegumefree•  FAILSAFEDiet•  Antioxidant,phytonutrient,highcarotenoiddiet

•  Treatpotentialunderlyingcause!!!!!!-Toxin,Infection,Allergen*AddressMastCellActivation/MicroglialActivation*AddressGlutamateExcitation(Calciumdriven)*AddressDysautonomia/VagalNerveDysfunction•  Improvecirculationandhyper-coagulation/*HBOT• CellMembraneSupport-Omega3’sEPA/DHA-highdose,PC,PS*OtherAnti-inflammatoryagents

•  Spices•  Foods•  Herbs•  EssentialOils

ConsiderMastCellActivationwiththeseConditions

• ASD• AcuteRegressions

• SeasonalRegressions• AllergicDisorders• ReactionstoFood,Chemicals,Temperature,Stress

• Asthma• Eczema(rashes)• MultipleChemicalSensitivities• EhlersDanlosSyndrome

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LaboratoryWorkupImmune:InfectiousTriggers

•  Bacterial-Lyme,Bartonella,Babesia,Mycoplasma/Chlamydiapneumoniae,ASOTiter,AntiDNAseBAb

•  Parasitic-ToxoplasmosisAb•  Fungal•  ViralTiters-EBV,CMV,HHV6•  VaccineTiters-MMR,VZ•  OrganicAcidTest(OATS)Clostridia•  StoolTest-bacteria,yeast,parasites

LaboratoryWorkupImmune:InflammatoryMarkers

•  CBC•  CRP,SedimentationRate,PlateletCount•  Fecalcalprotectin,lactoferrin,lysozyme•  OxidativeStressMarkers

•  8OHDeoxyguanosine,LipidPeroxides,Malonodialdehyde•  TotalImmunoglobulinProfile

•  (totalIgE,IgM,IgA,IgAandIgGsubclasses)•  TLymphocytePanel-CD4/CD8•  Naturalkillercell,CD57

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Work - Up Inflammation

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LaboratoryWorkupImmune:AutoantibodiesandAllergy

•  Autoantibodytests(e.g.myelinbasicproteinantibodies,antidopamineAb,antigangliosideAb)

•  OtherAutoimmuneAb-NMDA,GAD65Ab•  ANA•  CeliacPanel•  MycotoxinPanel•  IgERASTorskintestingforinhalants,food,mold

•  IgGELISAtestingforfoodsensitivities

NaturalAgentstoDecreaseMicroglialActivation

• Resveratol-neuroprotective• Pycnogenol-antioxidant• Gastrodiaelata-braininjuryneuroprotective• Piperakadsura(Japanesepepper)-PGE2inhibitor• Ganodermalucidum(ReishiMushroom)-immunemodulatory

• Epimediumbrevicornum(HornyGoatWeed)-improvesbloodflow

• Fisetin-antiaging• PQQ(pyrroloquinolinequinone)-PGE2andCOX-2inhibitor

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NaturalAgentstoDecreaseMicroglialActivation

•  Luteolin-mastcellstabilizer• PEA(palmitylethanolamide)• Resveratol-neuroprotective• Pycnogenol-antioxidant• Gastrodiaelata-braininjuryneuroprotective• Piperakadsura(Japanesepepper)-PGE2inhibitor• Ganodermalucidum(ReishiMushroom)-immunemodulatory•  Epimediumbrevicornum(HornyGoatWeed)-improvesbloodflow•  Stephaniatetranda-Cachannelblocker•  Fisetin-antiaging• Benfotiamine/Biotin• Vinpocetine-PDEinhibitor,Caregulation• PQQ(pyrroloquinolinequinone)-PGE2andCOX-2inhibitor

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Natural and Pharmaceutical Agents for Mast Cell Activation

• StingingNettles• Quercetin• Luteolin-mastcellstabilizer,antiIL-6• PEA(palmitylethanolamide)• BlackCuminSeedOil• NRF2signaler/Antioxidants:sulfuraphane,DIM,EGCG• H1blockers:diphenhydramine,chlorpheniramine,cyproheptadine,hydroxyzine

• H2blockers:ranitidine,cimetidine,famotidine• MastCellStabilizers:ketotifen,rupatadine,cromolynsodium

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AvoidDietaryExcitotoxins

• Caffeine• MSG• NutraSweet• Red/yellowfooddyes• Nitrites• Sulfites• Glutamates• Propionates• Benzoates• Limitintakeofphenolics(apples,grapes,bananas,strawberries,…).

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LimitDietaryGlutamate

• Glutamate• MonosodiumGlutamate(MSG)

• HydrolyzedProtein• ModifiedFoodStarch• NaturalFlavors• Peas,Mushrooms,Tomatoes

• ParmesanCheese• ExcessProtein

GlutamateModulators

• Magnesium• P5P• Lithium• Leucine• Isoleucine • Lysine• L-Theanine• Taurine• Hypotaurine• Oxaloacetate• GABA• PQQ• Memantine/NamendaRx• Dextromethorphan/NudextaRx

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Glutamate Modulators

CalciumModulation- VitaminD3- VitaminK2- Vinpocetine -  Stephaniatetranda

Herbs- Gingkobiloba-  Silymarin-  Rosemary-LemonBalm-  Chamomile-  SkullCap-  Bacopa-  Pycnogenol

Address Dysautonomia

Down-regulateSympathetic•  AdaptogenicHerbs-Ginseng,Ashwaganda,Bacopa,Tulsi•  BetaBlockers-Propranolol•  Alpha2adenoreceptoragonists-Clonidine,Guafacine• NMDAreceptorantagonists-Memantine,Dextromethorphan• Upregulateinhibitoryneurotransmitters-GABA,L-theanine,Taurine,Glycine

•  Benfotiamine

Up-regulateParasympathetic•  Acetylcholine(phosphatidylcholine,phosphatidylserine)•  AcetylcholinesteraseInhibitors(galantamine,huperizineA,piracetam)

•  VagusNerveStimulation(TENSunit)

AddressGutIssues-especiallySIBO• NemecheckProtocol

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The Polyvagal Theory: Phylogenetic Contributions to Social Behavior

Stephen W. Porges

•  Vagal regulation of heart rate and heart rate variability

•  Vagal brake = modulates the visceral state

•  enables the individual to rapidly engage and disengage with objects and other individuals and to promote self-soothing behaviors and calm behavioral states

•  The vagal brake is obviously compromised in autism.

New conceptualization of the role of Vagus

Polyvagal Theory Cont’d

• TheVagusisinvolvedintheregulationoftheHPAaxis.

• VagalafferentsexhibitaninhibitoryinfluenceonHPAaxisandreducecortisolsecretion.

• TheafferentVagusmediatesbehavioraldepression.

• VagusnerveandAcetylcholinehelptomediategastrointestinalinflammation.

• Lossofvagaltonetotheheartcausesincreasedsympathetictoneandreleaseofcortisol.Highcortisolcausessuppressedimmunefunction.

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plant compounds that have a normalizing impact on the HPA axis under times of stress, help with blood sugar regulation, anxiety, immune modulation

• PanaxGinseng• SiberianGinseng• HolyBasil• Licorice/Glycyrrhizin• Rhodiolarosea• Ashwaganda• Bacopa• GotuKola• Moringaoleifera• Schisandra

Adaptogens

http://naturehacks.com/3-common-mistakes-made-when-taking-herbal-remedies/

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Medicinal Herbs

• Usedtraditionallybyallculturesforhealing• Complexstructures• Numerousqualities• Multiplecomponents• Availableasdriedherb,tinctures,decoction,oils• Canbeeateninfoodsorasteas• Carefulwithdrugandvitamininteractions• Carefulwithphenolandoxalateissues• Irecommendtorotateandpulsewhenusinglongterm• Manydrugstodayareoriginallyderivedfromherbs

Role of Plant Based Therapies in ASD

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Licorice/Glycyrrhizin

• Preventsbreakdownofcortisoltocortisone

• Increaseshalflifeofcortisol• Selectiveestrogenreceptormodulator

• Immune• Antiviral• Isoflavinoid:antimicrobial,antifungal

• Preventulcerformation• Stimulateshealingofmucosa

Holy Basil (Tulsi)

• Adaptogenicherb• Antianxiety• Bloodsugarregulation• Antibacterial,antiviral• Anti-inflammatory• Helpswithheadaches• Reducesfever• GoodsourceofVitaminK• Activecompounds:eugenol,rosmarinicacid,apigenin,myretenal,luteolin,β-sitosterol,andcarnosicacid

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Ashwaganda Withania somnifera

• Anti-inflammatory• Antitumor• Antistress

•  Modulatescortisol

• Exerciseintolerance• Fatigue• Antioxidant

•  Brainlipidperoxidation• Immunomodulatory

•  Mobilizationandactivationofperitonealmacrophages,phagocytosis,andincreasedactivityofthelysosomalenzymes

• Hemopoetic“ScientificBasisfortheTherapeuticUseofWithaniasomnifera(Ashwagandha):AReview”Lakshmi-ChandraMishra,MD(Ayur).AltMedReview2000

Buhner Herbs (anti-inflammatory)

• Polygonumcuspidatum(JapaneseKnotweed)–protectstheendotheliallining

• Scutellariabaicalensis(ChineseSkullcap)-inhibitscytokinecascade

• Salviamiltiorrhiza(RedSage/Danshen)-inhibitscytokinecascade

• ImmuneModulators• Cordyceps• Reishi• Rhodiola• Scutellariabaicalensis(ChineseSkullcap)• Unicariatomentosa(Cat’sclaw)• Eleutherococcussenticosus(SiberianGinseng)• Withaniasomnifera(Ashwaganda)

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Effect of Propranolol on Verbal

Problem Solving in Autism Spectrum

Neurocase:TheNeuralBasisofCognition2008,Beversdorf

• DrugsdecreasingnoradrenergicactivityarebeneficialinASD.

• Beneficialfordifficultnetworkflexibility-dependentproblems.

• Benefitsperformanceforsimpleproblems.• DecreasedflexibilityofaccesstonetworksinASD.• ASDsubjectsbenefitedfrompropranololonsimpleanagrams,whereascontrolsubjectswereimpairedbypropranolol.

A Prospective, Open-Label Trial of Galantamine in Autistic Disorder

Dr. Rob Nicolson, Beth Craven-Thuss, and Judy Smith. Journal of Child and Adolescent Psychopharmacology.

October 2006, 16(5): 621-629.

• Thirteenchildrenwithautism(meanage,8.8±3.5years)participatedina12-week,open-labeltrialofgalantamine

• Results:Patientsshowedasignificantreductioninparent-ratedirritabilityandsocialwithdrawalontheABC

• SignificantimprovementsinemotionallabilityandinattentionontheConners’ParentRatingScale—Revised

• Clinicianratingsshowedreductionsintheangersubscale• Eightof13participantswereratedasrespondersonthebasisoftheirimprovementscoresontheClinicalGlobalImpressionsscale

• Overall,galantaminewaswell-tolerated,withnosignificantadverseeffectsapartfromheadachesinonepatient

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Phosphadityl Serine

• Lowerscortisol• Increasescellularmetabolism• Antioxidant• Improvesmood• Improvesmotivation• Decreasesanxiety• Improvesmemoryandcognition• Preventshippocampaldamagefromhighcortisol

Phosphatidyl Serine

• Supportsthefunctionofmanyvitalenzymes.• Actsasanantioxidant,andquellsinflammationinthebrain.• InEuropeandJapan,phosphatidylserineissoldasaprescriptiondrugtotreatmemoryandlearningdysfunction.

• Agedratswithcognitivedeficitshavedemonstrateddecreasedphosphatidylserineinthehippocampus.

• Helpswithstressinduceddamageinthebrain.

•  UlmannL.Brainandhippocampusfattyacidcompositioninphospholipidclassesofaged-relativecognitivedeficitrats.ProstaglandinsLeukotEssentFattyAcids.2001Mar;64(3):189-95.

•  LomnitskiL.DistinctalterationsinphospholipidmetabolisminbrainsofapolipoproteinE-deficientmice.JNeurosciRes.1999Nov15;58(4):586-92.

•  SuzukiS.Oraladministrationofsoybeanlecithintransphosphatidylatedphosphatidylserineimprovesmemoryimpairmentinagedrats.JNutr.2001Nov;131(11):2951-6.

•  CastilhoJC.Phosphatidylserine:anantidepressiveoracognitiveenhancer?ProgNeuropsychopharmacolBiolPsychiatry.2004Jul;28(4):731-8.

•  PepeuG.Nootropicdrugsandbraincholinergicmechanisms.ProgNeuropsychopharmacolBiolPsychiatry.1989;13SupplS77-S88.

•  SchreiberS.Anopentrialofplant-sourcederivedphosphatydilserinefortreatmentofage-relatedcognitivedecline.IsrJPsychiatryRelatSci.2000;37(4):302-7.

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Hyperbaric Oxygen Reduces Neuroinflammation

HBOT Decreases Neuroinflammation in Rat Model of TBI

(2.8 ATA, 2 sessions for 45 min each)

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Hyperbaric treatment for children with autism: a multicenter randomized, double blind, controlled

BMCPediatr.2009RossignolDA,RossignolLW,SmithS,SchneiderC,LogerquistS,UsmanA,NeubranderJ,MadrenEM,HintzG,GrushkinB,MumperEA.

Childrenwithautismwhoreceivedhyperbarictreatmentat1.3atmand24%oxygenfor40hourlysessionshadsignificantimprovementsinoverallfunctioning,receptivelanguage,socialinteraction,eyecontact,andsensory/cognitiveawarenesscomparedtochildrenwhoreceivedslightlypressurizedroomair.PMID:19284641

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Anti-inflammatory Herbs, Spices and Foods

DecreaseIL-6•  Allspice•  Apple•  Basil•  Bayleaves•  Blackpepper•  Caraway•  Chilipepper•  Cinnamon•  Clove•  Ginger•  Holybasil•  Licorice•  Nutmeg•  Paprika•  Sage•  Oregano•  Rooibostea•  Thyme

DecreaseTNF-alpha•  Billberry•  Caraway•  ChiliPepper•  Licorice•  Nutmeg•  Oregano•  Sage•  Thyme•  Bayleaf•  Cinnamon•  BlackPepper

Increase IL-10

•  Allspice•  Basil•  Cardomom•  ChiliPepper•  Ginseng•  Marjoram•  Oregano•  Paprika•  Pomegranate

Decrease COX-2

•  BayLeaf•  Nutmeg•  BlackPepper•  Basil•  Thyme•  Apple•  Clove•  Anise

Decrease iNOS

•  Licorice•  Sage•  Fenugreek•  Oregano

Common Anti-inflammatory Herbs

Curcumin-Turmeric•  COX-2inhibitor,anti-prostaglandin•  Similartoibuprofen•  Antimicrobial•  Breaksdownbiofilms•  Preventsbloodclots•  Helpsjointpain•  NRF2stimulator•  Poororalabsorption•  InhibitsCOMTandMAOagenes

Boswellia–Indianfrankincense•  5-LOX(lipoxygenaseinhibitor)•  TNFalphainhibitor•  Antibacterial•  Helpswithjointpain•  Improvesspatialmemory

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Other Anti-inflammatory Herbs

• Cat’sclaw/Samento(Unicariatomentosa)• NaturalCalciumChannelBlocker• Antiviral,Antibacterial• Immunemodulator• ProtectsDNAfromdamage

• MilkThistle(Silymarin)• IncreasesSODandincreasesglutathioneproduction• Protectsliverandkidney

• Ginger• InhibitsNO,COX-2,andPGE2• Helpswithnausea

www.2bucketscleaning.com/2017/12/5-useful-essential-oils/

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Essential Oils

• Usegoesbacktoancientcivilizations2000BC• Usedbyallcultures,traditionallyasperfumes,cosmeticsandformedicinalproperties

• Volatilearomaticcompounds• Changestatequicklyfromliquidtogasatroomtemperature

• Lipophilic,fatsolublecompounds,canpenetratetissueandcells

• Potent,maycauseirritationtoskinandmucosa• Extractedfromfruits,plants,herbs,flowers,stems,leaf,seed,rootorbarkbysteamdistillation

EgyptianMedicinalEssentialOilFormulas

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Using Essential Oils Safely

•  Topical-Maybeappliedinsmallquantitieswithacarrieroil•  AccupuncturePoints•  ReflexologyPoints•  Massage•  Triggerpoints•  Carefulwithcitrusoils,maycausephotosensitivity

•  Aromatic-Maybeinhaled,diffusedornebulized•  Internal-Someoilscanbeconsumed(teas,water)andusedincooking

•  Lessismore•  Rotatevariousoils•  Avoidprolongeduseofthesameoil•  Readlabelsregardinguse

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NeuroprotectiveOils

• CholinesteraseInhibitors•  Polygonumhydropiper–Marshpepperknotweed•  Rumexhastatus-Arrowleafdock•  Narcissuspoeticus-Daffodil•  Salvialevifolia-sagefamily•  Marlierearacemose-BidiLeafTree•  Cistusfamily-RockRose

•  SustainedAttention•  Eucalyptusglobulus•  Lavandulaaugustifolia•  Rosemarinusofficinalis•  Methapeperita•  Jasmine

AntioxidantOils

•  Lavender–increaseGSH•  Thyme•  Coriander-increaseGSHinhippocampus•  Clove•  Eucalyptus•  Cinnamon•  Juniper•  Basil–anticonvulsant,helpswithsleep•  Chamomile•  Cumin•  Coriander•  Thyme•  Oregano•  CommonYarrow•  Salviamulticaulis

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Antimicrobial,AntioxidantandAnti-InflammatoryActivityofEssentialOils

•  EucalyptusOil•  LemongrassOil•  ThymeOil•  LinderniaOil• GeraniumOil•  TeaTreeOil

• Antimicrobial•  E.Coli-All•  Staphylococcus-All•  GramNegbacteria-notgeranium•  Candida-lemongrass,thyme,lindernia•  Pseudomonas-none

• DecreasedTNF-alpha–notgeranium• DecreasedLOX-5• DecreasedIL-1Beta• DecreasedIL-8• DecreasedNO•  Lemongrassmostpotentantimicrobial•  Thymemostpotentantioxidant

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Bitters/HOPS in Beer Have an Anti-inflammatory Effect in Alzheimer’s Mice

Consider incorporating more herbs and oils in your daily routine

drinking, eating, sleeping, bathing…

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