Puas yog SARS-CoV-2 Infection Lead To Neurodegeneration And Parkinson's Disease? Ntu 2
Apr 28, 2024
3.2. SARS-CoV-2 Neuropathology
Feem ntau, cov cim neuropathological ntawm COVID-19 cov neeg mob hauv lub cev tuag yog diffuse edema, gliosis nrog rau kev ua kom cov microglia thiab astrocytes, cov kab mob ischemic, intracranial los ntshav, arteriosclerosis, hypoxic-ischemic raug mob, encephalitis / meningitis, thiab diffuse o [34, 35 ].
Vim tias diffuse edema tuaj yeem ua rau muaj cov tsos mob ntawm lub cev, suav nrog kev qaug zog, ua tsis taus pa, mob taub hau, kiv taub hau, thiab lwm yam, tib neeg feem ntau tsis quav ntsej txog nws qhov kev nco. Qee cov kev tshawb fawb tau pom tias cov tsos mob ntawm edema feem ntau ua rau cov neeg tsis nco qab vim nws cuam tshuam rau lub hlwb thiab cov ntshav ncig.
Ua ntej, peb yuav tsum to taub tias diffuse edema yog dab tsi. Nws yog ib qho mob tshwm sim los ntawm cov kua dej ntau dhau hauv lub cev. Nws tuaj yeem tshwm sim los ntawm kab mob plawv, teeb meem raum, kab mob siab, lossis qee yam tshuaj. Cov tsos mob ntawm diffuse edema muaj xws li edema, o ntawm tes thiab pob taws, plab edema, thiab lwm yam.
Kev tshawb fawb qhia tau hais tias cov tsos mob edema tuaj yeem ua rau muaj kev cuam tshuam ntau hauv tib neeg lub hlwb, ua rau poob qis hauv kev txawj ntse thiab kev nco. Piv txwv li, cov tsos mob ntawm edema tuaj yeem ua rau ischemia thiab hypoxemia hauv lub hlwb, uas tuaj yeem ua rau tuag ntawm cov paj hlwb hauv lub hlwb thiab tom qab ntawd cuam tshuam rau tib neeg lub hlwb kev ua haujlwm. Nyob rau tib lub sijhawm, cov tsos mob edema kuj tseem yuav ua rau cov kua dej ntau ntau hauv tib neeg lub cev, uas yuav cuam tshuam rau qhov sib npaug ntawm cov ntsev, cov tshuaj hormones, thiab lwm yam tshuaj, cuam tshuam rau tib neeg lub peev xwm thiab kev nco.
Txawm li cas los xij, kev siv cov kev xav zoo tuaj yeem pab peb txhim kho qhov tsis zoo ntawm diffuse edema, yog li txhim kho peb lub cim xeeb. Piv txwv li, peb tuaj yeem txhim kho cov tsos mob edema los ntawm kev noj qab nyob zoo, xws li kev noj zaub mov kom tsim nyog thiab kev tawm dag zog. Tsis tas li ntawd, qee cov tswv yim los tswj kev xav, xws li ua pa tob tob, yoga, thiab kev xav, kuj tuaj yeem pab peb txo cov tsos mob ntawm edema thiab yog li txhim kho kev nco.
Tsis tas li ntawd, peb kuj tuaj yeem txhim kho kev nco los ntawm qee qhov kev txawj ntse, xws li kev nyeem ntawv, kawm yam tshiab, ua si kev txawj ntse, thiab lwm yam. Cov kev tawm dag zog no tuaj yeem pab peb txhim kho peb txoj kev xav thiab kev xav, yog li txhim kho qhov tsis zoo ntawm cov tsos mob edema.
Diffuse edema cuam tshuam rau tib neeg lub cim xeeb, tab sis peb tuaj yeem kov yeej nws cov teebmeem nrog kev xav zoo thiab kev ua neej. Los ntawm cov kev siv zog no, peb tuaj yeem tuav lub cev noj qab haus huv thiab nco ntsoov, txhim kho peb lub neej zoo, thiab ua rau peb ua tiav thiab zoo siab. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kab mob. kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv kev loj hlob ntawm kev paub tsis meej thiab kab mob neurodegenerative.
Nyem paub txoj hauv kev los txhim kho lub hlwb
Cov neeg mob uas raug mob hnyav los ntawm COVID-19 tau pom qhov txo qis ntawm cov neurons thiab nce siab ntawm cov kab mob microglial hlwb thiab astrocytes, nrog rau qib siab ntawm proinflammatory cytokines ntsuas los ntawm qPCR [36].Matching lub hypothesis ntawm hematogenous ntxeem tau rau hauv lub hlwb, Paniz-Mondolfiet al. kuaj pom tus kab mob hauv capillary endothelium thiab neurons nyob rau hauv cov ntaub so ntswg frontal lobe los ntawm tus neeg mob nrog COVID-19 [11,37].
Tus kab mob no tsis tau pom nyob rau hauv glial hlwb hauv vivo [11].Lwm pab pawg zoo sib xws tau pom SARS-CoV-2 los txhawb CNS endothelial hlwb nrog ACE2-receptor qhia hauv cov leeg nqaij leeg ntawm cov hlab ntsha [38 ].
Cov kab mob me me tau txheeb pom nyob rau hauv tsib ntawm cuaj tus kab mob COVID-19 tus neeg mob cev nqaij daim tawv; Txawm li cas los xij, SARS-CoV-2 tsuas yog kuaj pom hauv ib kis uas siv immunohistochemistry [39]. Kev kuaj pom ntawm SARS-CoV-2 hauv lub hlwb siv PCR yog qhov nyuaj sib npaug; tus kab mob siab tshaj plaws tau sau tseg rau hauv lub qhov muag olfactory, thaum SARS-CoV-2 PCR tau rov qab tsis zoo hauv substantianigra [30,34,40].
Viral muaj, txawm li cas los xij, tsis tshua pom muaj tus kab mob encephalitis feem ntau (piv txwv li, hauv herpesvirus-, arbovirus- lossis enterovirus-induced encephalitis) [6].Lub hlwb ntawm COVID-19 cov neeg mob hauv lub cev tau pom tias muaj microglial activation hauv lub qhov muag olfactory. , frontal cortex, hippocampus, thiab feem ntau prominently nyob rau hauv lub hlwb, whereaslymphocytes tsis tshwm sim kom qhib tau [39].
Interestingly, cov neeg mob uas muaj keeb kwm ntawm delirium thaum lub sij hawm COVID-19 tau ua kom pom ntau dua microglial ua rau hauv hippocampus [39]. Cov neeg mob uas muaj thiab tsis muaj sepsis tsis tuaj yeem paub qhov txawv neuropathologically, tawm tsam qhov kev xav tias neuropathology txhim kho theem nrab mus rau cytokine cua daj cua dub thaum muaj kab mob septic [39].
3.3. SARS-CoV-2 Neuroinflammation/Biomarkers
Sib nrug los ntawm kev cuam tshuam ncaj qha ntawm SARS-CoV-2 ntawm lub paj hlwb los ntawm kev nkag mus rau hauv CNS, cov kev cuam tshuam thib ob ntawm kev ua haujlwm ntawm lub paj hlwb vim muaj kev hloov pauv hauv cov kab mob tau sib tham dav dav.
Kev tshawb xyuas ntawm cov ntaub so ntswg ntawm lub hlwb, biofluids, thiab cov txheej txheem systemicreaction tau pom tias muaj cov lus teb (neuro-) inflammatory teb tshwm sim los ntawm COVID-19.Ntau cov cytokines tau pom tias tau nce siab hauv cov ntshav thaum mob COVID-19, thaum nce qib ntawm Pro-inflammatory markers tsis pom nyob rau hauv cerebrospinalfluid (CSF) [41]. Qib ntshav ntawm IL-4, IL-10, IL-6 thiab IL1 tau nce siab hauv COVID-19 cov neeg mob [33,42,43]. IL-1- thiab IL-6 paub tias ua rau neuroinflamation [9].
SARS-CoV-2 cov tshuaj tiv thaiv tau nquag tshawb pom hauv CSF ntawm cov neeg mob COVID-19, txawm hais tias qhov no tsis ua pov thawj intrathecal antibody ntau lawm [41,44,45]. Kev kuaj pom tus kab mob ntawm PCR los ntawm CSF yog tsis yooj yim sua nyob rau hauv feem ntau [41,44,45].
Tsuas yog ob peb tus kws sau ntawv piav qhia qhov tshwm sim tsis zoo hauv SARS-CoV-2 PCR los ntawm CSF hauv cov neeg mob uas muaj cov tsos mob hnyav [46–48].
Kev soj ntsuam ntawm cov cim qhia txog CNS qhov txhab tau qhia txog qib siab ntawm cov kab mob neurofilamentlight (NfL) thiab glial fibrillary acidic protein (GFAP) hauv cov ntshav ntawm cov neeg mob uas muaj mob hnyav rau COVID-19 [17,49]. Tsis tas li ntawd, peb ntawm yim tus neeg mob uas muaj tus kab mob COVID hnyav-19 muaj cov tsos mob ntawm kev cuam tshuam cov ntshav-hlwb hlwb, ib tus muaj cov tshuaj tiv thaiv kab mob hauv lub cev thiab plaub tus neeg tau txais txiaj ntsig zoo rau 14-3-3 hauv CSF [44].
The data on CSF pleocytosis are controversial so far. A case series of 15 patients and a review summarizing CSF white blood cell counts of 409 COVID-19 patients with neurological symptoms observed frequent pleocytosis (defined as >5 hlwb / µL) hauv 36% ntawm 15 thiab 17% ntawm 409 tus neeg mob [30,50].
Ntawm qhov tod tes, cov xwm txheej ntawm 13 tus neeg mob nrog COVID-19 thiab encephalopathy lossis qaug dab peg tau tshaj tawm CSF pleocytosis hauv ib kis, zoo ib yam li kev tshawb fawb nrog 18 tus neeg mob nrog COVID-19 thiab cov teeb meem neurological uas pom pleocytosis hauv plaub kis. thiab tshaj tawm tag nrho plaub qhov yuav tshwm sim vim muaj ntshav paug [51,52].
Sun et al. tshawb xyuas cov khoom thauj ntawm neuronal-enriched extracellular vesicles thiab txaus siab pom nce NfL, amyloid- , neurogranin, tau, thiab phosphorylated tau inCOVID-19 cov neeg mob cuam tshuam txog cov txheej txheem neurodegenerative [42].
Nqa cov lus hauv tsev ntawm Tshooj 1 (Tshooj 3): 1. Nws zoo li SARS-CoV-2 tuaj yeem yog neurotropic txij li qhov no tau tshwm sim rau lwm tus kabmob humancoronaviruses (HCov-OC43, Hcov-229E, SARS-CoV, MERS-Cov) yav dhau los.2.
Muaj peb txoj hauv kev ntawm SARS-CoV-2 neuroinvasion: Lub transneuronal routevia olfactory paj hlwb, txoj kev hematogenous ntawm vascular endothelium los yog permeable ntshav-hlwb barrier, thiab "Trojan-horse-mechanism" los ntawm infiltration ntawm immunecells. thiab tom qab ntxeem tau rau hauv CNS ntawm diapedesis.3. Neuropathologically, SARS-CoV-2 leads to microglial activation in distinct CNS area.4. SARS-CoV-2 ua rau cov lus teb neuroinflammatory nrog nce qib ntshav ntawm ntau cytokines (piv txwv li, IL-1, IL-6) thiab cov cim siab xws li NfL thiab GFAP hauv CSF qhia txog CNS qhov txhab.
4. Tshooj 2
Kab mob Viral thiab Neurodegeneration
Dhau li ntawm COVID-19 kev sib kis, muaj cov pov thawj dav dav (kev kis kabmob) txuas nrog lwm tus kabmob kis mus rau cov kabmob neurodegenerative, tshwj xeeb tshaj yog PD thiab AD, uas yuav raug tshuaj xyuas hauv tshooj hauv qab no.
Lub tswv yim, hais tias cov kab mob kis tau tuaj yeem txhawb nqa neurodegeneration thawj zaug tsim nrogencephalitis lethargica tom qab kis mob khaub thuas Spanish thaum pib ntawm lub xyoo pua 20th [53]. Txij thaum ntawd los, kev sib txuas ntawm cov kab mob thiab cov kab mob neurodegenerative tau rov ua dua.Ib qho kev tshuaj ntsuam xyuas ntawm 287,773 PD cov neeg mob thiab 7,102,901 tswj tau qhia tias cov tib neeg uas muaj kab mob yav dhau los tau muaj kev pheej hmoo siab rau PD (pawg piv, 1.20) [54].
Cov txiaj ntsig no yog qhov tseem ceeb tshaj plaws rau cov kab mob kab mob [54]. Nyob rau hauv txoj kab nrog qhov no, kev tshawb fawb tsis ntev los no tau pom tias "lub nra hnyav dua" txhais los ntawm kev muaj ntau cov tshuaj tiv thaiv kab mob sib txawv thiab cov kab mob hauv cov ntshav ntawm cov neeg mob PD [55]. Tshwj xeeb tshaj yog, PD qhov kev pheej hmoo tau pom tias yuav nce siab tom qab VZV kab mob (hloov qhov phom sij, 1.17) thiab PD cov neeg mob feem ntau seropositive rau EBV [56,57].
HCV yog qhov tsim muaj kev pheej hmoo zoo rau PD raws li yog HSV-1 kab mob rau kev txhim kho AD [58–61]. Cov kab mob khaub thuas tau coj los rau hauv cov ntsiab lus nrog PD txij li encephalitis lethargicahad a Parkinsonian phenotype, thiab tus kab mob khaub thuas tau npaj raws li tus kab mob khaub thuas Spanish [53].
Tsis tas li ntawd, kev kis kab mob H1N1 tau ua rau muaj kev pheej hmoo microglialactivation ua ib qho cim ntawm kev mob ntsws ntev hauv cov nas qus [62]. H5N1 ua raws li kev ua kom microglial thiab -synuclein aggregation hauv cov nas uas ua rau poob ntawm dopaminergic neurons hauv substantia nigra, uas tau lees paub tias yog tus kab mob pathological ntawm PD [63]. Tsis tas li ntawd, tus kab mob khaub thuas A tau kuaj pom tom qab tuag hauv substantia nigra ntawm PD cov neeg mob [64].
Ib txoj kev tshawb fawb txog kev tswj xyuas tsis ntev los no uas siv cov ntaub ntawv los ntawm Danish National Patient Registry tau qhia tias qhov kev kuaj mob ua npaws tau cuam tshuam nrog kev txhim kho ntawm PD mus txog kaum xyoo tom qab (qhov txawv ntawm qhov sib txawv 1.73) [65].
Yog li, lub koom haum muaj zog ntawm cov kab mob khaub thuas thiab PD yog xav tias tab sis yuav tsum tau piav qhia ntxiv.Japanese encephalitis tus kab mob ua rau muaj tus kab mob parkinsonian thaum muaj tus kab mob hnyav, tab sis txawm tias mob parkinsonism nrog MRI qhov mob hauv substantia nigra tau pom peb mus rau tsib xyoos tom qab kis kab mob. ].West Nile tus kab mob no tuaj yeem ua rau muaj tus kab mob Parkinsonism thaum kis tus kab mob.
Hauv postmortemstudies, qib siab -synuclein tau kuaj pom hauv cov neeg mob uas muaj kab mob West Nilevirus [57,67,68]. Ib qho kev xav zoo txog kev ua haujlwm ntawm -synuclein tau tsim nyob rau hauv -synuclein-knockout nas qauv tom qab West Nile kab mob [67].
Qhov tsis muaj -synuclein hauv tus qauv no ua rau muaj kev puas tsuaj loj zuj zus, qhia txog kev tiv thaiv lub luag haujlwm ntawm -synuclein tiv thaiv kab mob kis [57,67]. Nws tau tshaj tawm tias -synuclein entrapsviral hais raws li kev tiv thaiv cellular mechanism, uas txuas ntxiv tom qab tus kab mob ua rau nws cov kab mob sib sau ua ke thiab cov teebmeem neurotoxic tom qab.
Tib lub tswv yim tau npaj rau -amyloid, uas tuaj yeem nkag rau HSV-1 thiab inhibit nws cov kab mob sib kis thiab nkag hauv vitro thiab hauv vivo [69,70]. HSV-1 tus kab mob tau cuam tshuam los ntawm tus kab mob uas muaj feem cuam tshuam rau AD tab sis kuj tseem nyob hauv PD hauv qhov sib txawv hauv vitro thiab hauv vivo kev tshawb nrhiav [71,72]. A2.
Ib theem 2 kawm tshawb xyuas seb valaciclovir tuaj yeem ua rau qeeb ntawm AD hauv cov neeg mob HSV-1 tam sim no tsis tu ncua (clinicaltrials.gov NCT03282916) [70].
Muaj cov kev tshawb fawb sib txawv qhia txog kev koom tes ntawm kev hloov kho lub cev tiv thaiv kab mob hauv kev txhim kho neurodegeneration. Cov kev tshawb fawb genome-wide koom haum tau pom muaj kev koom tes ntawm qhov tshwj xeeb histocompatibility complex II gene alleles nrog PD thiab T-hlwb ntawm PD cov neeg mob tau pom tias muaj kev cuam tshuam rau -synuclein epitopes [73].
Lwm pab pawg tau qhia tias Th17-T-cells pab txhawb rau PD pathogenesis hauv cov qauv kab lis kev cai ntawm PD siv induced pluripotent qia hlwb (iPSCs) [74]. Tsis ntev los no, T-hlwb tau pom tias nyob ib sab ntawm Lewy lub cev thiab dopaminergic neurons nyob rau hauv lub hlwb ntawm Lewy-lub cev-dementia cov neeg mob thiab stimulation ntawm CD4+ T-cells nrog ib tug phosphorylated -synuclein epitope ua rau muaj zog IL-17 ntau lawm ua ib qho kos npe ntawm Th17- teb [75].
Nqa cov lus hauv tsev ntawm Tshooj 2 (Tshooj 4): 1. Ntau qhov kev tshawb fawb txog kab mob sib kis sib txawv (kab mob) kis mus rau PD, vim tias cov tib neeg muaj qee yam kab mob muaj kev pheej hmoo siab rau PD.
2. Cov protein -synuclein tuaj yeem ua lub cev ua haujlwm raws li kev tiv thaiv kab mob, nkag mus rau cov kab mob, uas tuaj yeem ua rau nws cov kab mob sib sau ua ke thiab cov teebmeem neurotoxic PD tom qab.
3. Kev koom tes ntawm kev hloov lub cev tiv thaiv kab mob hauv kev txhim kho cov kab mob neurodegenerative tau nce ntxiv los txhawb kev xav tias kev kis kab mob, thiab yog li kev ua kom lub cev tiv thaiv kab mob tuaj yeem ua rau cov kab mob neurodegenerativecascades.
5. Tshooj 3
5.1. General Implications of SARS-CoV-2 in Neurodegeneration
Cov kev sib tham yav dhau los ntawm cov kab mob neurotropism thiab neuroinflamation tsa cov lus nug ntawm seb puas yuav tsum muaj kev xav mus sij hawm ntev neurodegeneration tom qab COVID-19 kab mob.
SARS-CoV-2 thiab cov proteins uas muaj peev xwm ua rau muaj kev cuam tshuam hauv neurodegeneration tau txuas los ntawm kev tshawb fawb sib txawv. Nws tau pom tias qhov sib npaug ntawm cov protein receptor bindingdomain khi rau heparin thiab heparin-binding proteins nrog rau amyloid- , -synuclein, tau, prion, thiab TDP-43, uas tuaj yeem pib cov kab mob sib sau ua ke ntawm cov proteins uas ua rau muaj kev cuam tshuam ntawm neurodegeneration [76, 77] ib.
Tib lub tshuab tau piav qhia rau HSV-1, uas ua rau muaj kev sib sau ntawm amyloid- hauv vitro thiab hauv vivo thiab yog qhov tsim muaj kev pheej hmoo zoo rau AD [76,78]. Tsis ntev los no, nws tau pom tias cov kab mob sib kis (xws li SARSCoV-2 spike protein) pab txhawb kev sib kis ntawm cov noob protopathic los ntawm kev hloov pauv ntawm cov cellularcargo hloov pauv [79].Viruses siv cov tswv yim sib txawv los tswj hwm lub zog ntawm tes, xws li cuam tshuam nrog autophagy thiab mitochondrial lossis lysosomal ua haujlwm, uas cuam tshuam rau kev txhim kho cov kab mob neurodegenerative zoo li [80].
SARS-CoV-2 altersautophagy thiab mitochondrial thiab lysosomal functions nyob rau hauv cov mob ntsws hlwb [81]. Tsis tas li ntawd, cov kab mob hloov pauv hauv proteostasis ntawm lub xov tooj ntawm tes tuaj yeem ua rau kom nrawm "aging" ntawm cov ntaub so ntswg, uas tej zaum yuav txhawb cov txheej txheem neurodegenerative. uas muaj ntau nyob rau hauv senescent hlwb [80].
Ferrosenescence yog cov txheej txheem kev laus ntawm cov hlau ua ntej ntawm cov hlwb uas ua rau muaj kev cuam tshuam ntawm cov hlau uas cuam tshuam rau DNA kho thiab, yog li, hauv neurodegeneration [82]. Ib qho tseem ceeb ntawm kev muaj peev xwm kis kab mob yog qhov cuam tshuam ntawm ferrosenescence hauv cov tswv tsev cell kom yooj yim rau tus kab mob rov ua dua tshiab [82].Cov ntaub ntawv no txhawb kev xav tias SARS-CoV-2 kab mob tuaj yeem ua rau muaj kev hloov pauv ntawm cov kab mob neurodegenerative cascades.
5.2. COVID-19 thiab cov cuab yeej ua tau txuas mus rau Parkinson's Disease
Ntau qhov txuas ntawm COVID-19 thiab kev txhim kho ntawm PD tau piav qhia hauv ntu no.
Xyoo 1985, nws tau pom tias kev kis kab mob ntawm nas nrog tus kab mob siab nas (thathas raug txheeb xyuas tias yog murine analog ntawm tib neeg Coronaviridae) ua rau mob mildencephalitis thiab tso tawm ntawm cov kab mob antigens feem ntau hauv cov nucleus subthalamic thiab substantia nigra [83].
Qhov no tau ua rau gliosis tom qab hauv cov cheeb tsam ntawd, qhia txog kev sib txuas ntawm tus kab mob thiab PD / postencephalitic parkinsonism [83]. Cov tshuaj tiv thaiv tiv thaiv Coronaviridae tau pom tias tau nce siab hauv CSF ntawm cov neeg mob PD piv rau kev tswj hwm asearly li xyoo 1992 [84].Tam sim no, peb cov ntaub ntawv tshaj tawm ntawm PD pib tshwm sim raws sij hawm sib raug zoo rau COVID-19 kab mob tau tshaj tawm; Txawm li cas los xij, tsis tuaj yeem tsim qhov sib txuas kom pom tseeb [85].
Ob qhov xwm txheej ntawm cov neeg mob tsim COVID-19-kev cuam tshuam encephalitis nrog kev loj hlob ntawm tus kab mob parkinsonism thiab FDG-PET alterations reminiscent ntawm postencephalitic parkinsonism tau luam tawm tsis ntev los no [86].Muaj ntau lub tswv yim uas COVID-19 tuaj yeem pab txhawb rau txoj kev loj hlob ntawm PD tau raug tshuaj xyuas yav dhau los thiab sib tham: Kev thuam ntawm cov hlab ntsha hauv cov kab mob nigrostriatal tuaj yeem ua rau Parkinsonism tom ntej [87].
Tsis tas li ntawd, cov cua daj cua dub cytokine cuam tshuam nrog qhov mob hnyav COVID-19 ua rau cov kab mob neuroinflammation thiab, tom qab ntawd, neurodegeneration [33,87]. Cov theem ntawm cov txheej txheem ntawm IL-6 tau nce siab hauv COVID-19, thiab kev tshawb fawb me me tau pom tias qib siab dua ntawm IL-6 cuam tshuam nrog kev pheej hmoo ntawm kev tsim PD [88].
For more information:1950477648nn@gmail.com
