Premise:
I-Estrogen receptor-α (ER-α), ehlanganiswe ne-ESR1, itholakala ngokuhlolwa kwe-immunohistochemistry cishe ku-70% yamacansi omkhoma avundla ubisi futhi isebenza njengesibonakalisi esiqinile. Ukuguquka kwe-ESR1 okuvuselayo endaweni ye-ligand-binding kubikwe kufinyelela ku-35-40% yamakhensa e-ER-positive metastatic futhi ahambisana nokumelana nokwelashwa kwe-endocrine kanye nokwanda kwesifo. Okwamanje, akucacile ukuthi ukuguquka kwe-ESR1 kuguqula yini ukubonakala kwe-ER okwenziwa nge-immunohistochemical ekusetshenzisweni kwansuku zonke. Kulolu cwaningo, ukuguquka kwe-ESR1 emkhomeni wobisi kutholakale ngokusebenzisa i-Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), i-hybridization capture-based next-generation sequencing assay evunywe yi-Food and Drug Administration. Amakhensa angama-586 obisi avela ezigulini ezinesimo esithuthukile noma esihambayo sihlaziyiwe ngokusebenzisa i-MSK-IMPACT ngesikhathi socwaningo. Ukuguquka kwe-ESR1 somatic kutholakale kumasampula angama-67 amakhensa obisi avela kuziguli ezingu-66. Ukuhlaziywa kwe-immunohistochemical kwe-ER, i-progesterone receptor, kanye ne-human epidermal growth factor receptor 2 kwenziwa emkhomeni wokuqala kanye nemkhoma ethintekile yalezi ziguli ngesikhathi sokuhlolelwa. Ukuguquka okungama-20 okwahlukene kwe-ESR1 kutholakale ekuthinteni indawo ye-ligand-binding, konke kumasampula amakhensa obisi avela kuziguli ezike zelashwa nokwelashwa kwe-endocrine. Ukuguquka okuhlangene kakhulu kube yi-D538G (n = 22), i-Y537S (n = 7), kanye ne-E380Q (n = 7). Wonke amasampula amakhensa obisi anokuguquka kwe-ESR1 abe ne-ER-positive ngokuhlolwa kwe-immunohistochemistry. Ukubuyekezwa kwe-ER immunohistochemistry kumkhoma wokuqala ongalashelwe kanye nomkhoma oselashiwe ovela ezigulini ezingu-34 akutholanga ukuguquka okubonakala esimeni se-ER-positive immunohistochemical (iphesenti lesilinganiso samaseli ahlasela umkhoma anokukhuthazwa kwe-nuclear: umkhoma wokuqala ongalashelwa 90%, umkhoma oselashiwe 95%).

Hypothesis:
Siphetha ngokuthi ukuguquka kwe-ESR1 akubuthakathisi ngendlela ebonakalayo ukubonakala kwe-ER okuphawulekile ngokusebenzisa i-immunohistochemistry.


Premise:
Umdlavuza wesofegi (EC) uyisifo esihlasela kakhulu, esinezinhlobo ezimbili ezinkulu zama-histology: i-adenocarcinoma (EAC) ne-squamous cell carcinoma (ESCC). Lezi zinhlobo ezimbili ze-EC zihluka kakhulu mayelana nako konke okuphathelene nazo. Ukuphuhla kwe-ESCC kuhlobene kakhulu nokubhema kanye nokuphuza utshwala, kanti ukuba nesisindo esikhulu kanye nesifo se-gastroesophageal reflux (GERD) kuyizinto ezinkulu ezilethela ubungozi hhayi nje kuphela kwe-EAC, kodwa naku-Barrett's esophagus (BE), okuyinto yokuguqulwa kwamangqamuzana asohlotsheni lwamathumbu olwandulela i-EAC. Ukuba nesisindo esikhulu kubangela ukuqoqana kwamathonsi amafutha (LD) ezindaweni ezingafanele emzimbeni, okungezizo izindawo zamafutha. I-LD iyizingxenyekazi zamangqamuzana ezibandakanyeka ekunikezeleni ukudla emangqamuzaneni, ekuxhumaneni kwamagqamuzana, ekwandiseni amanqqamuzana kanye nasekukhiqizeni izakhi ezilethela ukuvuvukala. Ngakho-ke, inhloso yalolu cwaningo kwakuwukuphenya ukubakhona kanye neqhaza le-LD kumdlavuza wesofegi. Lolu cwaningo lukhombisa ukwenyuka kwenzinga le-LD ekuthuthukeni kwe-EAC, emasampulini esofegi kusukela kubantu abangenazo izinkinga zesisindo kuya kwabanezisindo ezikhulu, kanye nakubantu abanesifo se-BE, kanye neziguli ze-EAC, kanti akukho zinguquko ezibonakalayo ezibonakalayo emasampulini e-ESCC, uma kuqhathaniswa namasampula angenamdlavuza. Ukwengeza, ukuze kulinganiswe ukuhlangabezana nezinto eziyingozi ze-BE ne-EAC, isigaba samangqamuzana esofegi angenayo umdlavuza safakwa ku-oleic acid (OA) kanye nesikhutha esiwumphumela wamasidi kanye/noma i-deoxycholic acid (DCA), okwaveza ukwenyuka okubalulekile ngobuningi be-LD kanye nokubonakalisa kwe-COX-2 ne-CXCL-8, kanye nokukhiqizwa kwe-IL-8. Ngaphezu kwalokho, ukubonakalisa kwe-COX-2 kanye nenani le-LD kwakhombisa uxhumano oluhle olubalulekile futhi kwabonakala ndawonye e-EAC, kodwa hhayi e-ESCC, okwenza sicabange ukuthi i-LD ingaba yindawo yokukhiqizwa kwe-eicosanoid e-EAC.

Hypothesis:
Okokugcina, lolu cwaningo lukhombisa ukuthi ukukhuluphala, kanye nokuvuvuka okuhambisana ne-BE kanye ne-EAC kuholela ekuncipha kancane kwe-LD, okungaba nomsebenzi wokuhlela ukukhiqizwa kanye/noma ukusebenza kwezakhi zokuvuvuka, ngaleyo ndlela kube nomthelela ekuqaleni nasekuqhubekeni kwe-BE kanye ne-EAC.


Premise:
Ukuqhubeka komdlavuza wesitho sangasese kuya esikhathini lapho ushintshela ekulimeleni ezindaweni ezahlukahlukene zomzimba kanye nasekubeni amandla okuphila asheshe ahambe kuyisinyathelo esisemqoka kakhulu. Sike sakuveza phambilini ukuthi ukushukuma kweprotheyini kinase C (PKC) okulandelwa i-Twist1 kanye nesivuseleli sehomoni yesilisa (AR) kubamba iqhaza elibalulekile ekumeleni ukudluliswa kwamahomoni yesilisa, kodwa umshini wezingxenye ophathekayo usasele ungakaziwa ngokugcwele. Lolu cwaningo luhlose ukucacisa umshini wezingxenye ofanelekile, lugxile kunzikandaweni yokubhala ye-NF-κB. Sihlolisise umsebenzi we-NF-κB ngemva kokulwa ne-PKC, kanye nokubonakalisa kwe-Twist1 ne-AR ngemva kokulwa ne-NF-κB emasosheni omdlavuza wesitho sangasese somuntu. Siphinde sahlola isimo se-PKC/NF-κB ngemva kokulwa nomyalezo we-AR emasosheni amelana nokwelashwa ngamahomoni. Ngenxa yalokho, ukulwa nemiyalezo ye-PKC kusetshenziswa ukucindezela nokuvinjelwa kwezingxenye ezincane ze-PKC, kunciphise umsebenzi we-RelA, kanti ukuvimba i-NF-κB kucindezele ukusetshenziswa kwe-Twist1 ne-AR. Ngokuphambene nalokho, ukuvimba umyalezo we-AR ngokukhipha ihomoni yesilisa kanye nesibulali samahomoni esisha enzalutamide kubangele ukushukuma kwe-PKC nokuqinisa kwamandla kwe-RelA, okuholele ekukhuleni kwe-Twist1/AR ezingeni lomhlahlandlela. Ngaphezu kwalokho, ukuvimbela umyalezo we-NF-κB kuvimbele ukuphakama okubangwa enzalutamide kwe-Twist1 ne-AR. Okokugcina, i-NF-κB iqiniswe emasosheni amelana namahomoni kanye namelana nenzalutamide.

Hypothesis:
Okokuphetha, i-NF-κB signaling yayibhekene nokwanda kwe-Twist1 nge-PKC ngenxa yokuthuthukiswa kwe-AR, okuholela ekusebenzeni okungafanele kwe-AR.


Premise:
Amaseli omdlavuza athanda i-glycolysis ukuze athole amandla, ngisho noma kukhona umoya owanele ukwenza lokhu kungadingeki. Lokhu kubizwa ngephuzu le-Warburg, futhi kukhuthaza ukuvela komdlavuza kanye nokwanda kwawo emzimbeni. Kulolu cwaningo, sikhombise ukuthi i-EZH2, i-protein eyandisa umdlavuza enezindima eziningi ekwandeni komdlavuza, ukuhlasela kanye nokusabalala, ikhuthaza ukuvela komdlavuza weglioblastoma kanye nokwanda kwawo ngokusebenzisa iphuzu le-Warburg. Siqaphele ukuthi i-HIF1α iyinto ehlosiwe yi-EZH2 nokuthi ukusebenza kwayo kudingeka ukuze i-EZH2 ikwazi ukushintsha indlela umzimba osebenzisa ngayo izakhi, nokuthi i-HIF1α iyasebenza uma i-EZH2 ikhiqizwa ngokweqile. I-EZH2 inciphisa ukukhiqizwa kwe-EAF2, okubese kwandisa amazinga e-HIF1α.

Hypothesis:
Siphetha kulemi miphumela ukuthi i-EZH2 ivimba ukubumbeka kwamatumo kanye nokudlondlobala kwesifo ngokwengxenye ngokuqalisa i-glycolysis ngokusebenzisa umgudu we-EAF2-HIF1α.


Premise:
I-Intramitochondrial Sr2+, efana ne-Ca2+, ivimba i-oxidative phosphorylation ku-intact rat-liver mitochondria. Kokubili i-Ca2+ ne-Sr2+ zivimba umsebenzi we-hydrolytic we-ATPase kumahlulana e-submitochondrial. Ukuvimba okuhhafu-maksimum komsebenzi we-ATPase kwafinyelelwa elinganisweni le-2.5 mM Ca2+ noma 5.0 mM Sr2+ uma ilinganiselwa le-Mg2+ kulendawo kwakuyi-1.0 mM. Ukuvinjelwa komsebenzi we-ATPase yi-cations zombili kwakuncishiswe kakhulu ukwanda kwe-Mg2+ concentration endaweni yokusebenza. Ngaphezu kwalokho, idatha ye-kinetical kanye nokuboniswa kwe-concentration ye-MgATP, i-substrate ye-ATPase, ebukhoneni bamalinganiselwa ahlukene e-Ca2+ noma e-Sr2+ akhombisa kakhulu ukuthi lama-cations avimba i-ATP hydrolysis ngokuncintisana ne-Mg2+ ekwakhiweni kwe-MgATP.

Hypothesis:
Ngokusekelwe esivumelwaneni esihle phakathi kwalezi ziphumo kanye nama-submitochondrial particles kanye nemiphumela yokuhlanganiswa kwe-oxidative phosphorylation ne-carboxyatractyloside noma i-oligomycin kuma-mitochondria agcwaliswe nge-Sr2+ kungaphetha ngokuthi i-intramitochondrial Ca2+ noma i-Sr2+ ivimba i-oxidative phosphorylation kuma-mitochondria aphelele ngokunciphisa ukutholakala kwama-adenine nucleotides kokubili ku-ADP/ATP carrier kanye ne-ATP synthase.


Premise:
I-calcium ye-mitochondria ingumshukumisi obalulekile we-metabolism yamaseli. I-CCDC90A yabikwa njengomhleli we-mitochondrial calcium uniporter (MCU) complex, isitshetsho esikhethayo esilawula ukuthatha i-calcium kwe-mitochondria, ngakho-ke yaqanjwa kabusha i-MCUR1. Lapha sibonisa ukuthi ukucindezelwa kwe-CCDC90A kumafibroblast abantu kukhiqiza inkinga eqondile yokuhlanganiswa kwe-cytochrome c oxidase (COX), okuholela ekuncipisweni kwe-mitochondrial membrane potential kanye nokukhinyabezeka komkhawulo wokuthatha i-calcium ye-mitochondria. Amafibroblast eziguli ezinezinkinga zokuhlanganiswa kwe-COX ngenxa yemithente kuma-TACO1 noma i-COX10 nawo akhombisa ukunciphisa kwe-mitochondrial membrane potential kanye nokukhinyabezeka komkhawulo wokuthatha i-calcium, kokubili okwasindiswa ngokufakwa kwe-cDNA ezejwayelekile ezihambisanayo. Ukususwa kwe-fmp32, i-homolog ye-CCDC90A ku-Saccharomyces cerevisiae, isidalwa esingenayo i-MCU, nako kukhiqiza ukungasebenzi kahle kwe-COX, okubonisa ukuthi umsebenzi we-CCDC90A ulondolozekile ekuthuthukeni kwempilo.

Hypothesis:
Siphethela ngokuthi i-CCDC90A idlala indima ekuhlanganiseni i-COX futhi ayilawuli ngqo i-MCU.


Premise:
Ama-mitochondria akhiqiza inani elikhulu le-ATP emasosheni amaningi, kufaka phakathi amaseli obuchopho. Ukulawula le mishini eyinkimbinkimbi ukuze ivumelane nezidingo zamandla eseli kuyinqubo eyinkimbinkimbi esingakakaqondi ngokuphelele. Kulesi simo, i-3',5'-cyclic AMP (cAMP) iphakanyiswe ukuthi idlala indima ebalulekile ekuxhumaneni kwezinhlelo zokukhipha imiyalezo nokudla kanye nokulawulwa kokukhiqizwa kwe-ATP yi-mitochondria. Emasosheni, izimpawu ze-cAMP zingathinta ama-mitochondria ohlangothini lwe-cytosolic kodwa kamuva nje, uphawu lwe-cAMP olukhiqizwe ngaphakathi kwe-matrix yama-mitochondria yi-soluble adenylyl cyclase (sAC) kuphakanyiswe ukuthi ilawula ukuphefumula kanjalo nokukhiqizwa kwe-ATP. Nokho, kulwazi oluncane mayelana nalezi zinqubo ema-mitochondria obuchopho, futhi izinto ezisebenza kophawu lwe-cAMP olukhiqizwe ngaphakathi kwe-matrix azicacile ngokuphelele njengoba kokubili i-protein kinase A (PKA) kanye ne-exchange protein activated by cAMP 1 (EPAC1) kuphakanyiswe ukuthi kubandakanyekile. Lapha, sibuyekeza ulwazi lwamanje futhi sihlobisana ne-mitochondria yobuchopho. Ngaphezu kwalokho, ngokuya ngezikalo zokuphefumula, i-membrane potential, nokukhiqizwa kwe-ATP kuma-mitochondria ahlukanisiwe ekhaleni lobuchopho begundane, sitshengisa ukuthi izivimbeli ze-sAC, i-PKA, noma i-EPAC zithinta ukusebenza kwe-mitochondria ngezindlela ezahlukene.

Hypothesis:
Ekugcineni, siphakamisa ukuthi ama-mitochondria obuchopho alawula ukusebenza kwawo ngezinkomba ze-cAMP ezidluliselwa nge-sAC nokuthi kokubili i-PKA ne-EPAC kungahle kubandakanyeke emva kwe-cAMP.


Premise:
I-ADP ayisiyo kuphela okuyingxenye ebalulekile ekukhiqizeni i-ATP, kodwa futhi ingumvimbi onamandla wesikhala sokudlula kwamangqamuzana e-mitochondrial (mPTP). Kulolu cwaningo, sihlola ukuthi ingcindezi ye-oxidative ithinta kanjani amandla e-ADP njengomvimbi we-mPTP futhi nokuthi ukuncishiswa kwayo kokubakhona kwama-reactive oxygen species (ROS) kungaba nendima. Sinqume ngokulinganisa imiphumela ye-ADP ekukwazini kuka-mitochondrial ukukhulisa i-calcium (CRC) kuze kufike ekungenisweni kwe-mPTP kumamitochondria ahlukene enhliziyweni. Sisebenzise izinhlelo ezimbili zeminyaka yobudala yengcindezi ye-oxidative (amagundane amadala nanasifo sikashukela) nezinhlelo ezimbili ezintsha zengcindezi ye-oxidative (i-ischemia reperfusion (IR) ne-tert-butyl hydroperoxide (t-BH)). Kumamitochondria okulawula, i-CRC yayingu 344 ± 32 nmol/mg yeprotheni. I-ADP engu-500 μmol/L yenyusa i-CRC yafika ku-774 ± 65 nmol/mg yeprotheni. Lo miphumela ye-ADP ibonakala ihlangene nesilinganiso sayo ngoba engu-50 μmol/L ibe nomthelela omncane kakhulu. Futhi, i-oligomycin, evimba ukuguqulwa kwe-ADP ibe yi-ATP nge-F0F1ATPase, yenyusa kakhulu umthelela we-ADP engu-50 μmol/L. Ingcindezi ye-oxidative eyiminyaka eminingi ayizange ibe nomthelela ku-CRC noma emiphumeleni ye-ADP engu-500 μmol/L. Ngemva kokuvela kwe-IR noma i-t-BH, i-CRC yehliswa kakhulu yafika ku-1 ± 0.2 no-32 ± 4 nmol/mg weprotheni, ngokulandelana. Ngokumangalisa, i-ADP yenyusa i-CRC yafika ku-447 ± 105 kanye no-514 ± 103 nmol/mg yeprotheni kwi-IR nakwi-t-BH, ngokulandelana. Ngakho-ke, yanyusa i-CRC ngesilinganiso esifanayo njengasekuphathweni. Kumamitochondria okulawula, i-ADP yehlisa kokubili i-substrate kanye nokunyuka kwe-calcium okubangelwe yi-ROS. Kodwa-ke, kumamitochondria e-t-BH, umthelela we-ADP kwi-ROS wawuncane kakhulu.

Hypothesis:
Siphetha ngokuthi i-ADP ibuyisela ngamandla amakhono e-CRC emithonjeni ecindezeleke kakhulu.


Premise:
Abacwaningi bangaphambili baye babonisa ukuthi 3,4-methylenedioxymethamphetamine (MDMA) edalayo i-hyperthermia, emisipha yamathambo yezilwane, iya ncike kwi-uncoupling protein 3 (UCP3). Ngokulinda uphenyo lwethu ukuthi in vivo phosphorylation ye-UCP1 yandiswa ngaphansi kwezimo zokujwayela amakhaza, saqala ukuphenya ukuthi (a) ingabe i-UCP3 yayiphosphorylated in vivo kanye (b) ukuthi ingabe in vivo phosphorylation ye-UCP3 kwakuphumela ekuvuzeni okukhulu kwe-proton ngemuva kokunika i-MDMA ezilwaneni. Idatha yethu ibonisa ukuthi ukwelashwa nge-MDMA (kodwa hhayi ukwelashwa nge-PBS) kwezilwane kuphumela kokubili in vivo serine kanye ne-tyrosine phosphorylation ye-UCP3 emitochondria yemisipha yamathambo, ehlukaniswe phambi kwe-phosphatase inhibitors ukugcina in vivo phosphorylation. Ngaphezu kwalokho, ukuvuza kwe-proton kuphela kwenyuka emitochondria yemisipha yamathambo ehlukanisiwe kusuka ezilwaneni ezelashwe nge-MDMA (ebakhona ye-phosphatase inhibitors) kanye nokuvuza kwe-proton okukhulile kungenxa ye-UCP3 ephosphorylated. Ubuningi be-UCP3 emitochondria yemisipha yamathambo abuphazamiseki ngokuphathwa kwe-MDMA. Ukugcinwa kwe-UCP3 phosphorylation nokwanda kokuvuza kwe-proton kuyalahleka lapho imitochondria yemisipha yamathambo ihlukaniswa ngaphandle kwe-phosphatase inhibitors.

Hypothesis:
Siphetha ngokuthi ukwelashwa kwe-UCP3 kwezilwane kwandisa ukukhipha kwama-proton emithambo yamathambo emikhakhayi yesikhumba ngokuvusa i-MDMA ngokushintsha okuzibophayo kwe-MDMA ngaphakathi emzimbeni ngokufaka ifosfeti (phosphorylation).


Premise:
I-CsrA (umlawuli wokulondoloza i-carbon A) iwumhleli wogqoko lwe-RNA obaktheria osakazeke kabanzi olawula ukuqala kokutolika nezinga le-mRNA emibhalweni ethize. Kumabaktheria angu-γ-proteobacteria, umsebenzi we-CsrA uphikiswa ngokuncintisana yi-RNA encane eyodwa noma ngaphezulu (ama-sRNA) equkethe izindawo eziningi zokubophela i-CsrA, kodwa i-CsrA emabakteriya angaphandle kwe-γ-proteobacteria iphikiswa uphroteni obizwa nge-FliW. Lapha sibonisa ukuthi i-FliW yase-Bacillus subtilis ayibopheli ezinsaleni ezifanayo ze-CsrA ezidingekayo ekubopheni i-RNA. Esikhundleni salokho, izinguquko ze-CsrA ezingazweli ukuphikiswa kwe-FliW (crw) zishintsha izinsalela ze-CsrA ebusweni be-allosteric obungamele umsebenzi ongazange wachazwa ngaphambilini. Ezinye izinguquko ze-crw zisusa ukubophana kwe-CsrA-FliW, kodwa ezinye azikususi, okusho ukuthi ukuhlangana kwe-FliW ne-RNA akufanele kucatshangwe ngokumelana.

Hypothesis:
Siphetha ngokuthi i-FliW ivimba ihomoni ye-parathyroid ngendlela engenamncintisano, eyehlukile kakhulu kuleyo eyaziwayo yezivimbi ze-sRNA.


Premise:
Umphathi jikelele wokuhumusheka kwe-Spx we-Bacillus subtilis ulawulwa emazingeni amaningi enqubo yokuveza ijini. Ugcinwa emazingeni aphansi ngesikhathi sokukhula okungahlukunyezwanga yi-ATP-dependent protease ClpXP. Ngaphansi kokwengama kwe-disulfide, amazinga e-Spx ayenyuka ngenxa yokwehla kwe-ClpXP-catalyzed proteolysis. Izifundo zakamuva zika-Larsson nabasebenzi bakhe (Mol. Microbiol. 66:669-684, 2007) zabonisa ukuthi umkhiqizo wejini i-yjbH udingeka ekulawuleni i-proteolytic ye-Spx. Esifundweni samanje, ukuhlaziywa kwe-yeast two-hybrid kanye nokuxhumanisa kwe-protein-protein kubonise ukuthi i-Spx ixhumana ne-YjbH. In vitro i-YjbH yaboniswa ukuthi ithuthukisa i-proteolysis ye-Spx ezingxubeni zemisebenzisi equkethe i-ClpXP protease kodwa hhayi i-ClpCP protease. Isimo se-YjbH esinqunyulwe eningini eliphambili esinokususa kwehlukanisa 1 ukuya 24 (YjbH(Delta1-24)) asibonisanga umsebenzi wokuthuthukisa i-proteolysis. I-YjbH ikhethekile kwe-Spx njengoba ingalisheshisanga i-proteolysis ye-substrate ye-ClpXP i-green fluorescent protein (GFP)-SsrA, isimumethe se-GFP esinophawu lwe-C-terminal SsrA olubonakala yi-ClpXP. Kusetshenziswa i-inductively coupled plasma atomic emission spectroscopy kanye ne-4-(2-pyridylazo) resorcinol release experiments, i-YjbH yatholakala iqukethe ama-atom e-zinc. Ukuhlaziywa kwe-zinc ye-YjbH(Delta1-24) kwaveza ukuthi isifunda esi-N-terminal esicebile nge-histidine asibalulekile ekuhlanganisweni kwe-atom elilodwa lokungenani le-Zn. I-atom le-Zn elihlanganiselwe esifundeni se-N-terminal lakhululwa ngokushesha ephrothinini ngokusebenzisa i-oxidant enamandla.

Hypothesis:
Siphetha ngokuthi i-YjbH iyisibambiso samadimande esithuthukisa ukubulawa kwe-proteini i-Spx okwenzeka nge-ClpXP.


Premise:
Ukukhiqizwa kwe-exoprotease ku-Bacillus subtilis kulawulwa ngokuqinisekile yisistimu elawula izingxenye ezimbili, i-DegS-DegU, futhi, ngaphezu kwalokho, ngezinye izinto ezincane. Umkhiqizo wegene elingu-degR ungena eqenjini lesibili futhi unikeza umthelela omuhle ngendlela eyencike ku-DegS-DegU. Sithole ukuthi ukubhalwa kwe-degR kwavinjelwa ukuphazamiseka kokuthi i-mecA noma i-mecB kodwa kwakhululwa ngokuphazamiseka okuqhubekayo kwe-comK. Ukuphazamiseka kwe-comK yodwa, nokho, akuzange kushintsha ukubhalwa kwe-degR. Siphinde sathola ukuthi ukuguqulwa kwe-mecA kudinga indawo ezungeze isikhundla esingu-52 esiphathelene nendawo yokuqala yokubhalwa kwe-degR ukuze kube nomthelela wayo. Sesikhombisile ngaphambilini ukuthi ukubhalwa kwe-degR kuholwa yisici esihlukahlukene se-sigma, i-sigmaD. Lapho ukuzibonakalisa kwe-degR kuholwa yisiqalisi se-sigmaA esakhiwe ngobuchwepheshe, ukuphazamiseka kwe-mecA/B akuzange kuholele kunoma yikuphi ukwehla okubalulekile ekuzibonakalisa kwe-degR, okukhombisa ukuthi umthelela ongemuhle wokuguqulwa kwe-mec usebenza ngokubhalwa okuholwa yi-sigmaD. Sekukhombisiwe ukuthi i-MecA ne-MecB zilawula ngokuphikisana ne-ComK, futhi ukuguqulwa kwe-mecA/B okungekho kuholela ekuzibonakalisa kwe-comK okuphezulu.

Hypothesis:
Kulemi miphumela siphetha ngokuthi i-ComK ilawula ngendlela engemihle ukuvokalwa kwe-degR ngokuvimbela umshini we-sigmaD osiqhuba ukubhalwa kwe-degR, kungenzeka ngobudlelwano nendawo elawulayo.


Premise:
Ukuvezwa kwesikhanyiso okuncike ekuphakathi kwebaningi kwe-Vibrio fischeri kulawulwa yi-autoinducer N-3-oxohexanoyl-L-homoserine lactone (autoinducer 1 [AI-1]), okuthi ngokusebenzisa i-LuxR kuqale ukubhalwa kwe-lux operon (luxICDABEG, ekhoda i-autoinducer synthase esuselwayo [LuxI] kanye nama-enzyme esikhanyiso). Kamuva sathola indawo entsha ye-V. fischeri, i-ainS, edingeka ekwakhiweni kwe-autoinducer yesibili, i-N-octanoyl-L-homoserine lactone (AI-2), engakwazi ngokusebenzisa i-LuxR ukuqalisa ukubhalwa kwe-lux operon uma kungekho i-AI-1. Ukuze kuchaziwe iqhaza lokulawula le-AI-2, kwakhiwa umutanti we-luxI ainS owawunakekelwa kabili; ngokuphambene nesizinda sabazali kanye nomutanti we-luxI, umutanti we-luxI ainS awuzange uveze ukushuba kwesikhanyiso futhi awuzange ukhiqize i-autoinducer yesikhanyiso etholakalayo, okukhombisa ukuthi i-V. fischeri ayenzi ama-autoinducer esikhanyiso ngaphandle kwalawa okwakhiwa kwawo okuqondiswa yi-luxI ne-ainS. Umutanti owonakele kuphela ku-ainS ukhombise ukushuba kwesikhanyiso okusheshayo uma kuqhathaniswa nesizinda sabazali, okukhombisa ukuthi i-AI-2 isebenza ku-V. fischeri ukuhlehlisa ukushuba kwesikhanyiso. Ngokuvumelana nalokho okubonisiwe, ukwengezwa kwangaphandle kwe-AI-2 kunqande ukusheshisa ngendlela encike esikhalini ku-V. fischeri kanye ne-Escherichia coli ethwele amagene e-lux. I-AI-2 ayizange ilamule i-luxR negative autoregulation, yodwa noma ikhona i-AI-1, futhi yanqanda ukushuba kwesikhanyiso ku-E. coli ngaphandle kokuthi ngabe i-luxR ilawulwa yi-promoter yayo yendabuko noma eyomuntu wangaphandle. Ukunyuka kwezinga le-AI-1 kunqobe umthelela onqandayo we-AI-2, futhi ukukhuthazwa okulinganayo kwesikhanyiso kudinge i-AI-2 engaphezulu ngokuphindwe ka-25 kuya ku-45 uma kuqhathaniswa ne-AI-1.

Hypothesis:
Siphetha ngokuthi i-AI-1 ivimba ukubhalwa kwe-lux operon.


Premise:
I-Mycobacterium smegmatis, imbewu yokhula ngokushesha engenalo isifo se-mycobacterium, isetshenziswa njengomfuziselo ukufunda ngofuzo lwe-mycobacterial. I-Acetamidase ye-M. smegmatis iyona enzyme ekhiqizeka kakhulu ye-Mycobacteria, esebenzisa izinhlobo eziningana ze-amide njengomthombo obalulekile wekhabhoni kanye ne-nitrogen. I-operon ye-acetamidase inendlela elawulwa ngokuphindaphindiwe, okuquka amaprotheni amathathu okulawula, abakhiqizi abane, namaelementi amathathu e-operator. Esifundweni sethu esidlule, sikhombise ukuthi ukuphinda-phindeka kwe-AmiA kuhola ekulawulweni okungemuhle kwe-acetamidase ngokuvimba umkhiqizi i-P2. Kulolu cwaningo, sithole i-protein entsha elawula ngendlela enhle, i-AmiC exhumana ne-AmiA ngokuhlangana kwe-protein ne-protein. Ukuhlaziywa kwe-Gel mobility shift kukhombise ukuthi i-protein ye-AmiC ivimba i-AmiA ekubophezeleni kwayo kumkhiqizi i-P2. Ukuxhumana kwe-AmiC namaelementi e-cis-acting kukhombise amandla ayo okubophezela ezindaweni eziningi zokulawula ze-operon njenge-P3, i-OP3, nomkhiqizi/operator ye-P1. Ngokunjalo, ukwengeza isikhuthazi i-acetamide ku-AmiC kuphazamisa izinhlangano, okwenza i-AmiC ibonakale njenge-protein yokuzwa kwamaamides. Ukufana komfanekiso nemifanekiso yokuxhumana emakhemikhalini kusikisela ukuthi i-AmiC iyilungu lama-Periplasmic binding proteins, abophezela ngokukhethekile kubazikhuthazi kodwa hhayi kuma-suppressor. Ukwanda kwe-AmiC kuthola ukwehla kokulawulwa kwe-negative regulator, i-amiA, kanye nokwenyuka okuqhubekayo kwe-acetamidase.

Hypothesis:
Ngokususela kulezi zimo ezitholakele, siphetha ngokuthi i-AmiC ilawula ngendlela eyiyo i-operon ye-acetamidase.


Premise:
Kuphakanyiswe ukuthi isivimbeli samatissue se-metalloproteinases-1 (TIMP-1) sibandakanyeka ekuxazululeni kwembobo yesibindi ngokuzenzakalelayo. Inhloso yalolu cwaningo kwakuwukuphenya ukuthi ngabe i-TIMP-1 iyashintsha yini ukuxazululwa kwembobo yesibindi ngokuzenzakalelayo ngokuhambisana nokuvimbelwa kwe-matrix metalloproteinases (MMP) kanye nokuvuselelwa kwamaseli ama-hepatic stellate (HSC). Izibindi zezilwane ezinjengamagundane ezinguqulo ze-TIMP-1 ezihlosiwe esibindini (TIMP-Tg) kanye namahayibridi okulawula (Cont) zaqoqwa ezinsukwini ezingu-0, 3, 7, kanye nama-28 ngemuva kokusinda okuzenzakalelayo emanyaleni yesibindi edalwe yi-CCl(4). Izinga lokuxazululwa kwembobo, ukuvela kwe-MMP, amaseli aphozithivu e-alpha-smooth-muscle actin (alpha-SMA), kanye ne-procollagen-(I) messenger RNA (mRNA) esibindini zahlolwa ngezinkathi ezifanele kuwo womabili amaqembu. Saphinda sahlola umthelela we-TIMP-1 ekufeni kwamaseli e-HSC. Amagundane e-TIMP-Tg akhombisa ukwehla okubalulekile ekuxazululweni kwembobo yesibindi ezenzakalelayo uma kuqhathaniswa namagundane e-Cont. Iqophelo le-hydroxyproline, inani lamaseli aphozithivu e-alpha-SMA, kanye ne-procollagen-(I) mRNA kwehla ngokushesha ngesikhathi kumagundane e-Cont, kanti lezi zimpawu zashintsha kancane kumagundane e-TIMP-Tg. Izinga lefomu elivelele le-metalloproteinases-2 (MMP-2) kumagundane e-TIMP-Tg lalincane kunalelo emagundaneni e-Cont. I-TIMP-1 yehlisa kakhulu amaseli angezona izicubu zesibindi afayo emodeli yokuxazululwa kwembobo yesibindi, futhi ivimbela ukufa kwamaseli e-HSC okuhambisana nokucindezela umsebenzi we-caspase-3 ngaphakathi kwetissue.

Hypothesis:
Okokugcina, i-fibrosis yanciphisa kakhulu ukuguquka kwesiqu se-TIMP-1 esibizini ngokuhlanganisa ukuncishiswa kwemisebenzi ye-MMP kanye nokucindezela i-apoptosis ku-HSC.


Premise:
I-liver fibrosis, okuyinqubo ye-pathophysiologic yesibindi ngenxa yokulimala okuphilayo okuqhubekayo njengempendulo yokulimala kwesibindi okuyisifo esikhona isikhathi eside, ekugcineni izothuthukela ibe yi-cirrhosis. I-Puerarin, i-isoflavone glucoside ebioactive etholakala emthini wesintu waseShayina obizwa nge-pueraria, ibikwe ukuthi inezici eziningi ezilwa nokuvuvukala kanye nezilwa ne-fibrosis. Kodwa-ke, izindlela ezijulile azikacwaningwa kahle. Lolu cwaningo luhlose ukuphenya imiphumela ye-puerarin ekusebenzeni kwesibindi kanye nenqubo ye-fibrosis kumagundane abangelwe i-CCl4. Amagundane e-C57BL/6J ajovwe ngaphakathi kwesikhwama sesisu nge-10% ye-CCl4 kwi-olive oil (2mL/kg) ngaphandle noma ne-puerarin ehlangene nayo (100 no-200mg/kg ngaphakathi kwesikhwama sesisu kanye ngosuku) amaviki amane alandelanayo. Njengoba kukhombisiwe i-ameliorative serum hepatic enzymes kanye nokuncishiswa kwezinto ezingajwayelekile kwe-histopathologic, idatha eqoqiwe ikhombise ukuthi i-puerarin ingavikela ekuhlukumezekeni kwesibindi okuyisifo esibangelwe yi-CCl4. Ngaphezu kwalokho, ukuthuthuka kwe-fibrosis okubangelwe yi-CCl4, njengoba kufakazelwa ukukhula kokuvezwa kwe-alpha smooth muscle actin (α-SMA), i-collagen-1, i-transforming growth factor (TGF)-尾 kanye ne-connective tissue growth factor (CTGF) esibindini, kuncishiswe yi-puerarin. Izindlela ezingahlobana nalezi zithonya zokucindezela zaqondakala ngokuvimbela indlela yokudlulisa umyalezo ye-NF-κB, ukukhiqizwa kwe-reactive oxygen species (ROS) kanye nokuphazamiseka komsebenzi wama-mitochondria ku-vivo. Ngaphezu kwalokho, lokhu kuvikelwa okubaliwe ngenhla kwaholwa yikwehla kokulawulwa kwe-PARP-1 ngenxa ye-puerarin ngoba i-puerarin ingaphucula ukuvezwa kwe-PARP-1 esibindini esicekelwe phansi yi-CCl4 kanye ne-PJ34, uhlobo oluthile lwe-PARP-1 inhibitor, ilingise ukuvikeleka kwe-puerarin.

Hypothesis:
Njengesiphetho, i-puerarin ibambe indima yokuvikela ekuvuvukaleni kwesibindi okubangelwa yi-CCl4 kungenzeka ngokuvimba i-PARP-1 kanye nokulandelayo ukunciphisa i-NF-κB, ukukhiqizwa kwe-ROS kanye nokungasebenzi kahle kwama-mitochondria.


Premise:
I-Polyenylphosphatidylcholine (PPC), okuyi-phospholipid extract eningi kumasoya, ivimbela ukuthuthuka kwesirhosha sesibindi kumamodeli ezilwane. Indlela yokusebenza kwayo ayaziwa. Ngokususela ohlotyeni lokuthi i-PPC ingasebenza ngokunciphisa ukwanda kwamaseli e-hepatic stellate, safunda umthelela we-PPC nezingxenye zayo ezinkulu, i-dilinoleoylphosphatidylcholine (DLPC) ne-palmitoyl-linoleoylphosphatidylcholine (PLPC), ekwandeni kwamaseli e-stellate okukhuthazwa yi-PDGF nasekudlulisweni kwesignali engaphakathi kweseli. Amaseli e-hepatic stellate ajwayelekile emagundaneni ekulimeni kwamaselula, alandelwa ukungasondleki, futhi agcinwa ne-10ng/ml ye-PDGF ngaphandle noma ngokukhona kwama-phospholipid. Ukwanda kwamaseli kwakalwa nge-3H-thymidine incorporation. Ukusebenza kwe-P44MAPK kwakalwa nge-kinase assay, kanti i-AP-1 binding yakalwa nge-electrophoretic mobility shift assay. I-PPC (200 ng/ml) yavinjelwa ngokuphumelele ukwanda okukhuthazwa yi-PDGF (p < 0.05; ANOVA, n = 3) futhi yaphikisana nokusebenza kwe-P44MAPK okukhuthazwa yi-PDGF kanye ne-AP-1 binding. Lo mphumela wawulingiswa yi-DLPC kodwa hhayi yi-PLPC. Akukho nakuyiphi phakathi kwe-DLPC noma i-PLPC eyavimba ukusebenza kwamaresepta e-PDGF.

Hypothesis:
Siphetha ngokuthi i-PPC inomthelela ongakaze wabonwa ngaphambilini ekwandeni kwamaseli e-stellate okukhuthazwa yi-mitogen okungase kube yimiphumela ye-DLPC.


Premise:
Iseli esisebenzayo somdlandla webhilibhili (HSC) sibalulekile ekubambekeni kwesibindi njengomthombo omkhulu wecollagen I kanye ne-III kanye nezivimbelanqamulajuqu zemetalloproteinase-1 (TIMP-1). Ngesikhathi sokuzilungisa okungahleliwe kokubambeka kwesibindi, kunokunciphisa kokuvakashiswa kwe-TIMP, ukwanda komsebenzi wecollagenase, kanye nokwanda kokubulawa kwamaseli e-HSC, okukhombisa iqhaza elingaba khona le-TIMP-1 ekuphileni kwe-HSC. Kulo mbiko, sisebenzisa amasampula okulima amaseli kanye namaphethini empilweni ukubonisa ukuthi i-TIMP-1 ngokuqondile ivimba ukubulawa kwamaseli e-HSC. I-TIMP-1 ibonise imphumela eyiqiniso, ebalulekile, nokuya ngezinga lokuvikela ukubulawa kwamaseli e-HSC eqaliswe emasampuleni okulima amaseli futhi yakhuthazwa ukuba ibulale amaseli ngokuncipha kweserum, ukuhlangabezana ne-cycloheximide, kanye nokukhuthazwa kokukukhula kwemizwa. I-TIMP-1 eguqulwe engasebenzi (i-T2G mutant) lapho zonke ezinye izindawo zigcinwe khona ayizange ivimbe ukubulawa kwamaseli, okukhombisa ukuthi ukuvimba ukubulawa kwamaseli kwakuhlelwe ngokuvimba i-MMP. Izivimbelanqamulajuqu ze-MMP ezenziwe ngabantu nazo zavimba ukubulawa kwamaseli e-HSC. Izifundo zesifo sesibindi esibambekile zabonisa ukuthi ukuvakashiswa okuqhubekayo kwe-TIMP-1 mRNA okuqinisekiswe nge-PCR kuhlobene nokuqhubeka kwe-HSC esebenzayo equndwe ukuhlobana kwe-alpha smooth muscle actin, kanti ekubambekeni, ukulahleka kwe-HSC esebenzayo kuhlobene nokuncishiswa kwe-TIMP-1 mRNA.

Hypothesis:
Sinquma ukuthi i-TIMP-1 ivimba i-apoptosis yamasosha omzimba angu-CD14dim avusiwe ngokuvimba i-MMP.


Premise:
Ukwakhiwa kwamaseli estellate esibindini (ama-HSCs) kudlala indima ebalulekile ekuthuthukiseni i-fibrosis yesibindi. I-C1q/tumor necrosis factor-related protein 3 (CTRP3), ilungu lama-CTRPs, ibandakanyeka kwi-fibrosis. Kodwa-ke, kulwazi oluncane mayelana nendima ye-CTRP3 kwi-fibrosis yesibindi. Lolu cwaningo luhlose ukuthola indima yalo kwi-fibrosis yesibindi kanye nokuhlola indlela okungenzeka ukuthi kusebenze ngayo. Imiphumela yethu ikhombise ukuthi i-CTRP3 ibivezwe kancane emathuphini e-fibrosis yesibindi kanye nama-HSCs avuselelwe. Ukwandiswa kwe-CTRP3 kuvinjelwe ukwanda nokuhamba kwamaseli e-HSCs, kanye nokucindezela ukuvela kwama-extracellular matrix (ECM) kumaseli e-HSC-T6 akhuthazwa yi-transforming growth factor-尾1 (TGF-尾1). Ngaphezu kwalokho, ukwandiswa kwe-CTRP3 kuvimbele kakhulu izinga lokuvela kwe-phosphorylation ye-Smad3 kumaseli e-HSC-T6 akhuthazwa yi-TGF-尾1.

Hypothesis:
Ekuphetheni, ucwaningo lwamanje lukhombise ukuthi i-CTRP3 inqanda ukwanda kanye nokuhamba kwamaseli e-HSC-T6 akhuthazwe yi-TGF-尾 1 futhi yanciphisa i-liver fibrosis, okungenani ingxenye, ngokuvimba indlela yokusakaza ye-Smad.


Premise:
Isidingo sokuphucuzwa kokucacisa ekwelashweni okusendaweni yezifo ezivuvukele emathunjini (IBD) sisiholele ekusebenziseni amasomu anegciwane elinegesi eliwuphawu olubi ukulungisa amahlandla avuvukelwe emathunjini. Inhloso yalolu cwaningo kwakuwukucacisa imbangela yalokho esikubonile ngaphambilini ukuthi la masomu aqoqeka, ikakhulukazi, embozweni eyivuvukele yamagundane akhishwe kucolitis yokuhlola, ngemuva kokuphathwa kwegolo. Ukuhlaziya kwamaphroteni (tandem mass spectrometry, kuqinisekiswe ngeWestern blot) kwezibonelo zombozo evuvukele, ekhishwe ku-pH 3, 5 no-7, kwaveza ukwanda kokuvela kwetransferrin (TF) ku-pH 3. Ukuhlolwa kwehistoloji kubonise ukuthi i-TF yayisengxenyeni egolo lomboza evuvukele. Amasomu anegciwane elinegesi eliwuphawu olubi (kodwa hhayi aphakathi nendawo) ananela kokuyi-TF kokubili okuthengwayo nokwemboza ku-pH ephansi, kodwa hhayi ku-pH ephakathi nendawo. Ngaphezu kwalokho, ukuhlala ngaphambili kwamasomu anegciwane elinegesi eliwuphawu olubi ne-TF kwanciphisa kakhulu ukunamathela kwawo embedeni evuvukele yegolo lekati.

Hypothesis:
Kungashiwo ukuthi, ku-pH ephansi, efanayo naleyo esetshenziswa ekoloni elungelweni olunobubomvu (ulcerative colitis), i-TF ihlanganyela ukuze inamathele ezakudliweni kwamandla ezicucu emanzini (liposomes) ezinegciwane elibi eliphuma esikudeni esibomvile.


Premise:
I-Curcumin (i-diferulolylmethane) ikhombisa imiphumela enamandla okulwa nokuvuvukala emasosheni amathumbu (IEC) kanye namasosha okulwa nezifo emzimbeni kulabo abazohloliwe futhi ibukeka iphephisa ezilokazaneni ezifakwe izinto zamakhemikhali zomgogodla, ngokomcansi wokusebenza okucatshangwayo ngokuvimba i-NF-kappaB. Yize kukhombisiwe ukuthi kuyasebenza ekunciphiseni izinga lokubuyisa enkingeni yokuvuvukala kwomathumbu ezigulini, ukusebenza kwe-curcumin kwisifo sika-Crohn (CD) noma kuma-model okulwa nezifo angu-Th-1/Th-17 e-CD akukaze kuhlolwe. Ngakho-ke, saphenyisisa imiphumela ye-curcumin yokudla (0.1-1%) ekuthuthukisweni kokuvuvukala kwomathumbu, ukuvuseleleka kokulwa nezifo, kanye nokusebenza kwe-NF-kappaB emzimbeni kumantshontsho angenagciwane e-IL-10(-/-) noma e-IL-10(-/-);NF-kappaB(EGFP) ahlanganiswe nemicroflora ehlanzekile ekhethekile. I-morphology yamathumbu angaphambili nangasemuva ikhombise umthelela omncane wokuvikela we-curcumin kuphela ku-0.1%. Ukuvakashwa kwe-IFN-gamma yomathumbu kanye ne-IL-12/23p40 mRNA kulandele indlela efanayo (mayelana noku-50% ukuvimba ku-0.1%). Ukukhishwa kwe-IL-12/23p40 kanye ne-IFN-gamma ngomthombo wokukhiqiza amathumbu kanye namasosha ezindawo ezivuvukele zamadlebe kwakuphakeme emantshontshweni e-IL-10(-/-) futhi akuncishiswanga yi-curcumin yokudla. Ngokumangalisayo, ukuvuseleleka kwe-NF-kappaB emantshontshweni e-IL-10(-/-) (i-phospho-NF-kappaBp65) noma kwi-IL-10(-/-);NF-kappaB(EGFP) emantshontshweni (isitho sonke noma ukuthwebula kwezithombe ze-confocal) akuzange kuvinjwe yi-curcumin. Ngaphezu kwalokho, siyakhombisa ukuthi i-IL-10 kanye ne-curcumin zisebenza ngokuhlanganyela ukunciphisa ukusebenza kwe-NF-kappaB ku-IEC kanye nokukhiqizwa kwe-IL-12/23p40 amasosha omphimbo kanye namasosha okuhambisa ulwazi.

Hypothesis:
Siphetha ngokuthi indlela eyinhloko yokusebenza kwe-curcumin ekuvimbeleni i-colitis eyenziwa ngamakhemikhali kungokuvimba i-NF-kappaB.


Premise:
Ukukhuluphala kuyisici sobungozi bokuthuthuka kwesifo esikhathazayo semithombe. I-Pea iyingqayizivele nokuqukethwe kwayo okuphakeme kokudla okusingethe amafayibha, ama-polyphenolics, kanye nama-glycoproteins, konke okwaziwa ngokuba nomphumela omuhle empilweni. Sihlose ukuphenya umthelela wokuhlanganyela kwe-green pea (GP) ekuthintekeni kwamagundane adliwa ukudla okunokunono okuphakeme (HFD) kwe-colitis ebangelwe yi-dextran sulfate sodium (DSS). Amagundane esifazane anezinsuku eziyisithupha ubudala we-C57BL/6J adliwa i-45% HFD noma i-HFD ehlanganyele ngo-10% GP. Ngemuva kwezonto eziyisikhombisa zokungezelela ukudla, i-colitis iveleliswe ngokungeza 2.5% DSS emanzini okuphuza izinsuku eziyisikhombisa kulandelwa isikhathi sokubuyisa ezinye izinsuku eziyisikhombisa. Ukwengeza i-GP kusizile esikhaleni sesikali somthelela wesifo kumagundane adla i-HFD ngesikhathi sokubuyisa, futhi kwehlisa ukungena kwama-neutrophil, umbono we-mRNA we-monocyte chemoattractant protein-1 (MCP-1) nezimpawu zokukhathazeka i-interleukin (IL)-6, i-cyclooxygenase-2 (COX-2), i-IL-17, i-interferon-γ (IFN-γ), kanye ne-inducible nitric oxide synthase (iNOS) emagundaneni adla i-HFD. Ngaphezu kwalokho, ukwengeza i-GP kwandise okuqukethwe kwemucin 2 nokukhuluma kwe-mRNA kwezimpawu zokuhlukaniswa kweseli le-goblet kufaka phakathi i-Trefoil factor 3 (Tff3), i-Kr眉ppel-like factor 4 (Klf4), kanye ne-SAM pointed domain ETS factor 1 (Spdef1) emagundaneni adla i-HFD. Ngaphezu kwalokho, i-GP yanciphisa i-endoplasmic reticulum (ER) stress njengoba kukhombiswe ukwehliswa kokukhuluma kweprotheni ye-Activating transcription factor-6 (ATF-6) namagene ayo aqondiswe i-chaperone protein glucose-regulated protein 78 (Grp78), i-CCAAT-enhancer-binding protein homologous protein (CHOP), i-ER degradation-enhancing α-mannosidase-like 1 protein (Edem1), kanye ne-X-box binding protein 1 (Xbp1) emagundaneni adla i-HFD.

Hypothesis:
Ekugcineni, ukunikezwa kwe-GP kwanciphisa ubunzima be-colitis eyenziwe yi-DSS kumagundane afunzwe yi-HFD, okwakuhambisana nokucindezela ukuvuvukala, ukuncipha kwe-mucin, kanye nokucindezela i-ER stress kukholo.


Premise:
I-Bilirubin icatshangwa ukuthi inomthelela wokuvikela ukuvuvukala ngokuvimba ukuhamba kwamaseli amhlophe egazi elixhumene nesakhiwo seselula sokujiyisa amathambo (VCAM-1) nangokucindezela ukuvela kwe-inducible nitric oxide synthase (iNOS). Njengoba i-VCAM-1 ne-iNOS zingabalamuli abalulekile bokulimala kwamatissue emodeli yemouse ye-dextran sodium sulfate (DSS) yesifo sokuqumba sesibumbu, sihlolile ukuthi i-bilirubin ivikela yini ukulimala kwekholo ezimpondweni eziphathwa nge-DSS. Izimpondwa zesilisa ze-C57BL/6 zanikwa i-2.5% ye-DSS emanzini okuphuza izinsuku eziyi-7, ngesikhathi ezithola imijovo yesikhathi esisodwa ye-bilirubin (30 mg/kg) noma i-potassium phosphate vehicle. Umsebenzi wesifo waqashelwa, izibalo zegazi lasemithanjeni nokuhlolwa kwamazinga amanitrate egazini kwanqunywa, namasu esitho somphimbo ahlaziywa ngokulimala kwe-histological, ukuhlasela kwamaseli amhlophe, nokuzibonakalisa kwe-iNOS. Umthelela we-bilirubin ekukhiqizweni kwe-IL-5 ngamaseli e-HSB-2 kanye nokuhamba kwamaseli e-Jurkat transendothelial nawo wanqunywa. Izimpungushe eziphathwe nge-DSS ezithole i-bilirubin ngesikhathi esisodwa zilahlekelwe yisisindo somzimba esingaphansi, zinamazinga amanitrate aphansi egazini, futhi zibonakalisa ukusinda kwesifo okunciphile kunesilwane esihlanzwe nge-vehicle. Ngokuhambisana, izinhlolovo ze-histopathological zembule ukuthi izimpungushe ezinye i-bilirubin ziveze ukulimala okuncane kwekholo, okuhlanganisa ukuncishiswa kwamaeosinophils, amalymphocytes, namasosha, kanye nokuncipha kokuzibonakalisa kwe-iNOS. Ukunikwa kwe-bilirubin kuye kwahlotshaniswa nokuncipha kokuhlasela kwamaeosinophil namasosha amathumbu amancane, nokukhula okuhambisanayo kwe-eosinophilia yegazi lasemithanjeni. I-Bilirubin ivimbe ukuhamba kwe-Jurkat kodwa ayizange ishintshe ukukhiqizwa kwe-IL-5.

Hypothesis:
Ngokuphethayo, i-bilirubin ivimbela i-colitis eyenziwa yi-DSS ngokuvimba ukuhamba kwamasosha omzimba (ama-leukocyte) ukuwela endleleni yegazi (i-vascular endothelium) nangokucindezelela isiqubulo se-iNOS.


Premise:
Izinga lokuvela kwezifo ezinokuqubuka kwemilalazi linyuke eminyakeni yakamuva. Ngaphakathi kwekholo, imindeni yama-mucin (MUC) nama-trefoil factor (TFF) isiza ekuvikeleni kwemilalazi. Ukusetshenziswa kwamagciwane amahle (probiotic) kunomthelela esigabeni se-MUC semathumbu. Ngaphezu kwalokho, izingxenye zokudla zingaba nomthelela ezinhlayiyeni zemilalazi noma zibe nemiphumela eqondile esivikela se-MUC. Inhloso yethu kwakuwukuthola ukuthi ngabe ukudla kanye/noma i-Lactobacillus rhamnosus GG (LGG) kungaxazulula yini ukuqubuka kwesigujana esibangwa yidextran sodium sulfate (DSS) ngokushintsha ukuvezwa kwama-gene e-MUC ne-TFF. Amagundane e-C57BL/6 adliswa ukudla okunamaphroteni e-casein, esoy, noma ewhey ngo-20% (wt:wt) kanye noma ngaphandle kwe-LGG isikhathi esiyizinsuku eziyi-12. Ezinsukwini eziyisikhombisa ngemuva kokuqala ukudla kwe-LGG, amagundane anikwa i-DSS engu-2% emanzini okuphuza izinsuku ezine. Amaqembu amabili engeziwe e-casein enakanye noma kungekho i-LGG anikwa amanzi empompi, kwaba yizigaba eziyisishiyagalombili sezephelele. Usuku olulodwa ngemuva kokunikwa i-DSS, amagundane abulawa kwase kuqoqwa amathishu ekholo nekhekham neziqulatho zekhekhamu kwase kuhlolwa nge-qRT-PCR. Amaphroteni ewhey akhuphule kakhulu izinga le-LGG ekhekhamu uma kuqhathaniswa nokudla okunye. Emaqenjini endla ye-casein, ukuvezwa kwe-MUC1 ne-TFF-3 ekholoni kwanyuswa kakhulu yi-DSS ngaphandle kokuncika kwi-LGG. Uma kuqhathaniswa namaqembu aphathwe nge-DSS, amaphroteni esoy anciphise i-MUC-1 ne-TFF-3 ekholoni. Ngokufanayo, amaphroteni esoy anciphise umthelela we-DSS ezilinganisweni zokuqubuka, ukuvezwa kwe-gene yeTNFα, kanye nokufinyezwa kwekholo. Bekungenamthelela ophelele we-LGG kulezi zilinganiso.

Hypothesis:
Ekupheleni, iprotheni yesoya inciphise ukuvela kwegeni le-TNFα okubangelwa ukuphehla ngokwamandla kwe-MUC, i-TFF, kanye ne-DSS ngaphandle kwe-LGG.


Premise:
I-Hypoxia inducible factor 1α (HIF1α) iwumgcini omkhulu okhokhelela ekuhlelelaneni kwemethabholizimi, inqubo yefiziyoloji ebalulekile ukugcina ukuphila kwamaseli ezisekelo ngaphansi kwe-hypoxia. Nokho, akuqondisiseki kahle ukuthi i-HIF1α idlulisela kanjani ekungeneni enyukliyasi kumaseli ezisekelo ngaphansi kwe-hypoxia. Lapha, siphenye indima ye-protein adaptor yemota ebizwa nge-Bicaudal D homolog 1 (BICD1) ekuthuthweni kwe-HIF1α okwenziwa yi-dynein ukuya enyukliyasi kanye nomthelela wokulawulwa kwe-BICD1 ekuzijwayezeni kwe-hypoxia kanyenomthombo wokwelapha kumaseli ezisekelo asuka kwi-human umbilical cord blood (UCB-MSCs). Emiphumeleni yethu, ukucishwa kwe-BICD1 kodwa hhayi i-BICD2 kwashabalalisa ukudluliselwa kwe-HIF1α enyukliyasi kanye nomsebenzi wayo. Ukungezeleka kwe-BICD1 kwaqhubeka kwathuthukisa ukudluliselwa kwe-HIF1α enyukliyasi okubangelwa yi-hypoxia. I-hypoxia yavuselela ukuboshelwa okuqondile kwe-HIF1α kwe-BICD1 kanye ne-chain ethile ye-dynein (i-Dynein IC), okwashabalaliswa ukucishwa kwe-BICD1. Ukuvikelwa kwe-Akt kwanciphisa ukubosheleka kwe-BICD1 kwe-HIF1α kanye nokudluliselwa kwe-HIF1α enyukliyasi. Ngokuphambene, ukusebenza kwe-Akt noma ukucishwa kwe-GSK3尾 kwaqhubeka kwathuthukisa ukudluliselwa kwe-HIF1α enyukliyasi okubangelwa yi-hypoxia. Phezu kwalokho, ukucishwa kwe-BICD1 kwashabalalisa ukuhlelwa kabusha kwe-glycolytic okubangelwa yi-hypoxia futhi kwandisa ukuqoqeka kwe-mitochondrial ROS kanye ne-apoptosis kuma-UCB-MSCs ngaphansi kwe-hypoxia. Kwimodeli yokwelapha isilonda sesikhumba sikagundane, ukuphila kwamaseli atshaliwe kanye namandla okwelapha isilonda sesikhumba e-UCB-MSCs ezilungiselelwe nge-hypoxia kuncishiswe ukucishwa kwe-BICD1 futhi kwaqhubeka kwakhuliswa ukucishwa kwe-GSK3尾.

Hypothesis:
Okokugcina, sivezile ukuthi ukuhanjiswa kwe-FGF okubangelwe ukuthi i-HIF1 α ingene emhlahlandeleni kubalulekile ekulungiseleleni okuphathelene nokusweleka komoya, okuyinto enquma amandla okuzidalulula kabusha kwe-UCB-MSCs.


Premise:
I-Von Hippel-Lindau protein (pVHL) ivame isebenza ekudaleni i-ubiquitin-mediated degradation ye-hypoxia-inducible factor-1alpha (HIF-1alpha) ngaphansi kwezimo ze-normoxic kodwa hhayi ngaphansi kwezimo ze-hypoxic, futhi ikhuthaza ukuhlukaniswa kwamanyuroni kwamaseli angaphambili emzimbeni. Nokho, indima ye-pVHL ekuhlukanisweni kwamaseli angaphambili emzimbeni ngaphansi kwanoma yisiphi isimo ayikahlolisiswa ngokugcwele. Lapha, sibonisa ukuthi ngaphansi kwesimo se-anoxic ukuqhamuka kwe-pVHL kanye nezimpawu zamanyuroni kwamaseli angaphambili emzimbeni kuvinjelwa, kanti i-HIF-1alpha iyakhuthazwa. Ngaphezu kwalokho, amaseli angaphambili emzimbeni akhombisa i-pVHL ngemuva kokudluliswa kwegene akhombisa ukuhlukana okucacile kwamanyuroni kanye nokungakhuthazwa kwe-HIF-1alpha ngaphansi kwesimo se-normoxic kodwa hhayi ngaphansi kwesimo se-anoxic.

Hypothesis:
Ngakho-ke, siphetha ngokuthi i-pVHL ivimba ukuhlukaniswa kwama-neural ngaphansi kwesimo se-anoxic.


Premise:
Inhlangano eyenza amafektha ahoxekayo (HIF) iwumlawuli osemqoka wokusabela kweseli kumazinga aphansi e-oxygen okugqugquzela ukunikezwa kwe-oxygen nokuhlela kabusha indlela yokusebenza kweseli uma kungekho i-oxygen eyanele. Nokho, izinga nesikhathi sokuvela kwe-HIF-1α ekuhoxeni kufanele kulinganiswe ngokucophelela emasosheni ukuze kugwenywe imiphumela engafuneki ehambisana nomsebenzi omningi. Ukuvela kwe-HIF-1α mRNA kucindezelwa ekuhoxeni isikhathi eside, okukhombisa ukuthi ukulawulwa kokubhalwa kwe-HIF1A gene kulawulwa kanzima yizindlela zokubuyisela emuva eziphefumulo. Kukhona okuncane okwaziwa ngokuxazululwa kwesabelo se-HIF-1α protein kanye nokucindezela kwe-HIF-1α mRNA ekuhoxeni isikhathi eside. Lapha, sikhombisa ukuthi i-Repressor Element 1-Silencing Transcription factor (REST) ibophekela ku-HIF-1α promoter ngendlela eyencike ekuhoxeni. Ukwehliswa kwe-REST kusetshenziswa i-RNAi kwandisa ukuvela kwe-HIF-1α mRNA, protein kanye nomsebenzi wokubhala. Ngaphezu kwalokho, ukwehliswa kwe-REST kwandisa ukusetshenziswa kwe-glucose kanye nokukhiqizwa kwe-lactate ngendlela eyencike ku-HIF-1α (kodwa hhayi ku-HIF-2α). Okokugcina, i-REST ithuthukisa ukuxazululwa kokuvela kwe-HIF-1α protein ekuhoxeni isikhathi eside.

Hypothesis:
Okokuphetha, siphakamisa umqondo wokuthi i-hypoxia inqanda umsebenzi we-transcription ye-HIF-1α ngesikhathi eside se-REST, ngalokho ifaka isandla ekuxazululeni umsebenzi we-HIF-1α.


Premise:
Ukubonakala kwe-core autophagy kinase, i-Unc51-like kinase 1 (ULK1), kulawulwa ngezinga lokuqamba nokutolika ukudla kwethuba elide elikhuthaza i-autophagy. Kodwa-ke, ukuthi i-ULK1 ilawulwa kanjani ngesikhathi sophoxo akuqondakali kahle. Ngaphambilini, sibonise ukuthi ukuvela kwe-ULK1 kukhuthazwa ingcindezi yophoxo. Lapha, sibika i-microRNA entsha elungisa i-ULK1, i-miR-93; ukuqanjwa kwayo kuhlobene ngendlela engathandeki nokutolika kwe-ULK1 ngaphansi kwesimo sokweswela umoya. I-miR-93 ihloshe i-ULK1 futhi inciphisa amazinga ayo eprotheni ngaphansi kwesimo sokweswela umoya. I-miR-93 ivimba futhi i-autophagy ekhuthazwa ukweswela umoya ngokuvimbela i-LC3-I ukuya kwi-transition ye-LC3-II kanye nokubhidlizwa kwe-P62; lezi zinqubo ziguqulwa ukweqiswa komvimbi wendabuko we-miR-93. Ukuphinde kuqanjwe i-ULK1 ngaphandle kwezinto zokusabela ze-miR-93 kubuyisela i-autophagy ekhuthazwa ukweswela umoya evinjwe yi-miR-93. Okokugcina, sithole imiphumela ye-miR-93 ekuphileni kwamaseli nasekufeni kwamaseli ezinhlobeni zamaseli angezona ezomdlavuza namaseli omdlavuza. Sithole ukuthi i-miR-93 igcina ukuphila kwe-MEFs (amafibroblasts omlingatshana wegundane) futhi ivimba ukufa kwawo ngaphansi kweswela umoya.

Hypothesis:
Ngakho-ke, sifika esiphethweni sokuthi i-miR-93 inendima eyidlalayo ekuqaleni kwe-autophagy ebangelwa yi-hypoxia ngokukulawula i-ULK1.


Premise:
Izimo ze-hypoxic ziphakanyiswa ukuthi ziyathinta isimo sokwehlukana kwamabunzi esitolo (SC), kufaka phakathi namabunzi esitolo embryonic (ESC). I-Hypoxia inducible factor (HIF) ingomunye wamamolecule amakhulu angaphakathi kweseli onokuziphendulela ekuphenduleni kweseli kwi-hypoxia. I-Hypoxia istabiliza i-HIF ngokuvimba umsebenzi we-HIF prolyl-hydroxylases (PHD), eyaziwayo ngenhloso ye-HIF-alpha subunits yokubhidlizwa kwe-proteosomal. Ukuze sibhekane nomthelela wokustabiliza kwe-HIF ekugcineni i-stemness signature ye-mouse ESC (mESC), sihlole umthelela wokuvimba kwama-PHD ne-hypoxia (1% O2 no-5% O2) ekwehlukaneni okuzenzakalelayo kwe-ESC okuqalwe ukuhlaziywa kwe-leukemia inhibitory factor isikhathi esingamahora angu-24 nama-48. Isivimbi esisaziwa kakhulu se-panhydroxylase i-dimethyloxaloylglycine (DMOG) nesivimbi se-PHD i-JNJ-42041935 (JNJ) esiphakanyiswe se-specificity esingcono se-PHDs kusetshenzisiwe. Lezi zivimbi zombili namazinga womabili e-hypoxia enyuse kakhulu amazinga e-protein e-HIF-1alpha ne-HIF-2alpha kanye nomsebenzi we-transcriptional we-HIF kwi-mESC ehlukana ngokuzenzakalela. Lokhu kwakuhambelana nokwehla okubalulekile kokwanda kwamaseli okuvezwe ukuvimba okuphelele kokuhlanganiswa kwe-DNA kanye nokuboshwa kwengxenye kwi-S phase emva kwamahora angu-48. Ngaphezu kwalokho, ukustabiliza kwe-HIF kuqinise ukwehla kokuvakaliswa kwezinye izimpawu zokukhiqiza (OCT-4, NANOG, ZFP-42, TNAP) kwi-mESC ehlukana ngokuzenzakalela. Kodwa, ngesikhathi esifanayo, kwakukhona ukwehla okubalulekile ekuvakaleni kwezinye zama-gene akhethwe njengezimpawu zokwehlukana kwamaseli (isibonelo: SOX1, BRACH T, ELF5).

Hypothesis:
Ngokuphetha, ukusimama kwesikhashana kwe-hypoxia kusetshenziswa izinqando ze-PHD i-JNJ ne-DMOG kanye ne-HIF akuzange kuvimbele ukulahleka okuzenzekelayo kwezimpawu ze-pluripotency ku-mESC.


Premise:
I-BTK inhibitor ibrutinib ibonise umthelela wokwelashwa ovelele kwi-mantle cell lymphoma (MCL). Kodwa-ke, cishe ingxenye eyodwa kwezintathu yeziguli ayiphenduli kumuthi ekuqaleni. Ukuze sithole izindlela eziyisisekelo zokumelana ne-ibrutinib eqalayo kwi-MCL, sihlaziye izinguquko ze-transcriptome emazingeni amaseli ahlukahlukene anesimiso se-ibrutinib kanye nalawo amelana nayo ngesikhathi sokwelashwa nge-ibrutinib. Sithole ukuthi isignesha yegene ye-MYC yayicindezelwe yi-ibrutinib ezinhlosweni ezizwelayo kodwa hhayi emazingeni amaseli amelanayo. Sikhombisile ukuthi igene ye-MYC ayilungile ngokwesakhiwo futhi iphrotheni ye-MYC yayikhiqizwe ngokweqile kumaseli e-MCL. Ngaphezu kwalokho, ukucekelwa phansi kwe-MYC nge-RNA interference kuvinjelwe ukukhula kwamaseli ezinhlosweni ezizwelayo ze-ibrutinib kanye nalawo amelana nayo. Sihlolile amathuba okuvimbela i-MYC ngokusebenzisa ukuvinjelwa kwe-HSP90. Iphrotheni ye-chaperon ikhiqizwe ngokweqile kuwo womabili amazinga amaseli kanye namaseli e-MCL asuselwa ezigulini. Sikhombisile ukuthi i-MYC iyikhasimende yangempela ye-HSP90 ekuhlanganisweni kwe-MCL ngokusebenzisa kokubili i-immunoprecipitation kanye ne-chemical precipitation. Ngaphezu kwalokho, ukuvimbelwa kwe-HSP90 ngokusebenzisa i-PU-H71 kukhuthaze i-apoptosis futhi kubangele ukumiswa kwesayikili yamaseli. I-PU-H71 ibuye ikhombise ukuvinjelwa okunamandla futhi okuhlobene ngqo nohlelo lwe-MYC transcriptional uma kuqhathaniswa nezinye izindlela ze-oncogenic. Esimweni se-xenograft esitholakala esigulini se-MCL, i-HSP90 inhibitor ivinjelela ukukhula kwesimila futhi yelulela ukuphila. Okokugcina, sikhombisile ukuthi i-PU-H71 ikhuthaze i-apoptosis futhi yehlise iphrotheni ye-MYC kumaseli e-MCL atholakala ezigulini ezazingamelana ne-ibrutinib ngokwemithetho yokwelashwa.

Hypothesis:
Nesiphetho, umsebenzi we-MYC ungaphansi kokwenqaba kwangaphakathi kwe-ibrutinib ku-MCL.


Premise:
I-Activation-induced cytidine deaminase (AID) iyadingeka ekuguquleni amaseli okushisa angaphezu kwesisindo kanye nokuhlanganiswa kabusha kwesigaba se-immunoglobulin (Ig) emaseliheni e-B asesikhungweni esivuthayo (GC). Ngezinye izikhathi, i-AID ingahlosela amagene angewona awe-Ig ngaleyo ndlela iqhubele phambili isifo somdlavuza wamaselikha e-B we-GC. Kamuva nje sibonise ukuthi i-kinase edlala indima enkulu ye-BCR-ABL1 iqala ukubonakalisa i-AID ngendlela engafanele ku-pre-B acute lymphoblastic leukemia (ALL) kanye ne-lymphoid chronic myelogenous leukemia esesikhungweni sokuqhuma. Ukucacisa ukubaluleka kwezinto eziphilayo zokubonakalisa i-AID ngendlela engafanele, sifunde ukulahleka komsebenzi we-AID ohlelweni olulingisayo lwe-BCR-ABL1 ALL emanyane. Amagundane ahlonjisiwe ngesitho somgogodla esihlaselwe nge-BCR-ABL1 AID(-/-) ayephila isikhathi eside uma eqhathaniswa namagundane ahlonjiswe namaseli esifo somdlavuza egcinwe kumaseli e-AID(+/+) esithweni somgogodla. Ngokuhambelana nendima ebangela ye-AID ekungathembeki kwezofuzo, i-AID(-/-) leukemia yayinezinga eliphansi lokwengezeka kanye nokusulwa nokudlulisa nokwengeza kwezinga eliphansi lokushintsha kwamagene angewona awe-Ig, kufaka i-Pax5 kanye ne-Rhoh uma kuqhathaniswa ne-AID(+/+) leukemias. Amaseli e-AID(-/-) ne-AID(+/+) ALL abonisa ukuhlukana kwephetheni ye-gene expression, futhi amaseli e-AID(-/-) ALL ahlulekile ukwehlisa inani lamagene afiphela isifo kufaka ne-Rhoh, i-Cdkn1a (p21), kanye ne-Blnk (SLP65).

Hypothesis:
Siqeda ngokuthi i-ALL isheshisa ukuguquka kwama-clone kwi-BCR-ABL1 AID ngokuqinisa ukungastabili kwamajini nokushintsha okungafanele somatic hypermutation, kanye ngokuqondisa okungemuhle kwamajini alwa nezifo.


Premise:
Izinguquko ezivuselelayo ze-c-Kit zitholakala kaningi ezigulini ze-acute myeloid leukemia (AML) ezinegciwane le-t(8;21) chromosomal translocation eyenza i-fusion protein ye-AML1-ETO. Lapha sibonisa ukuthi i-mutant esebenzayo ye-c-Kit isebenzisana ne-AML1-ETO ukwenza i-AML ezinhlolweni zokulungiswa komgogodla wamathambo empondweni. Amaseli e-leukemic akhombisa i-AML1-ETO nge-c-Kit(D814V) ayedluliselwa ngokulandelana. Izivivinyo zokudlulisela zibonise ukuthi amaseli e-leukemic i-lineage(-)c-Kit(+)Sca-1(+) (KSL), kodwa hhayi amaseli e-leukemic lineage(+), angamele kakhulu amaseli e-leukemia stem (LSCs). Ukuqhathaniswa kwama-profile wokubonakala kwamajini phakathi kwe-KSL leukemic namaseli avamile kuveze ukuthi i-CD200R1 yayivezwe kakhulu kumaseli e-KSL leukemic uma kuqhathaniswa namaseli e-KSL avamile. Ukunyuswa kwe-CD200R1 kuqinisekiwe kumaseli e-leukemic lineage(-), kodwa hhayi kumaseli e-leukemic lineage(+). Ukuvezwa kwe-CD200R1 kumaseli e-leukemic lineage(-) akuhambisani nokuvamisa kwe-LSCs, okukhombisa ukuthi i-CD200R1 akuyona inkomba esebenzisekayo ye-LSCs kulezi zinhlelo. Okukhuthazayo, i-CD200R1 yanyuswa kumaseli e-KSL adluliselwa nge-AML1-ETO, kodwa hhayi kwezinye izinguquko ezenza i-leukemia, kufaka i-c-Kit(D814V), i-AML1(D171N), kanye ne-AML1(S291fsX300). Ngokuhambisana, ukunyuswa kwe-CD200R1 kumaseli e-leukemic lineage(-) kubonwe kuphela ku-BM yezimpuku eziphethwe yi-leukemia ene-AML1-ETO positive.

Hypothesis:
Ekugcineni, i-AML1-ETO yenyusa i-CD200R1 emasosheni angenayo (lineage(-)), okwakuyimpawu ye-AML1-ETO eyayikhombisa i-leukemia kumagundane.


Premise:
Ukuze sifunde indima yohlobo lwe-oncogene ye-NRAS (NRAS(G12V)) esimweni sokuba ne-acute myeloid leukemia (AML), sisebenzise uhlelo lwe-Vav promoter-tetracycline transactivator (Vav-tTA) oluhambisana nezinga le-TRE-NRAS(G12V) transgene ezimpukwini ze-Mll-AF9 knock-in ezithuthukisa i-AML. Ukucindezela okuhleliwe kokuvela kwe-NRAS(G12V) kwanciphisa kakhulu isibalo samasosha amhlophe egazini (WBC) ezimpukwini ezinalesi sifo futhi kwabangela ukufa kwamaseli e-AML afakiwe okuhambelana nokwehliswa kwesibonakaliso se-Ras/Erk. Emva kokuphela okukhulu kwamaseli e-AML, isifo se-myeloproliferative (MPD) esifana ne-AML savela kabusha esabonakaliswa amaseli angazange aveze i-NRAS(G12V). Uma kuqhathaniswa ne-AML yokuqala, i-AML efana ne-MPD yabonisa ukwehliswa okubalulekile kobuhlasimulisi, ukwehliswa kwe-myelosuppression, nendlela yokukhiqiza ehlukile.

Hypothesis:
Siphetha ngokuthi, ku-AML ebangelwe i-transgene ye-Mll-AF9, ukuvakashwa kwe-NRAS(G12V) kunikela ekulondolozeni i-leukemia ebucayi ngokucindezela i-apoptosis kanye nokunciphisa ukuhlukaniswa kwamacells e-leukemia.


Premise:
Ukuphindaphinda kwangaphakathi okuhlelekile (ITD) engxenyeni ye-juxtamembrane ye-Fms-efana ne-tyrosine kinase 3 (FLT3), uhlobo lwesithathu lwe-receptor tyrosine kinase (RTK), kungukungahambi kahle kwemolekhuli okuvame kakhulu okuhambisana ne-acute myeloid leukemia (AML). Ukuvela kakhulu kwalolu guquko olwenziwayo kukwenza kube yinto ephambili ekwelashweni okusekelwe kwimolekhuli. Izivimbeli ze-indolinone tyrosine kinase zinomsebenzi owaziwa ngokumelene ne-KIT, olunye ilungu lomndeni wesithathu we-RTK. Ngenxa yokufana okugcinekile phakathi kwamalungu alomndeni, saqagela ukuthi umsebenzi wezinye izivimbeli ze-KIT uzokwanda kuze kube yi-FLT3. Sisebenzise imizila eyahlukene yamaseli e-leukemia (BaF3, MV 4-11, RS 4;11) ukuhlola umsebenzi wezakhi ze-indolinone ngokumelene nomsebenzi we-FLT3 kinase kokubili, uhlobo lwendalo (WT) kanye ne-ITD isoforms. Kokubili i-SU5416 ne-SU5614 bekunamandla okuvimba i-autophosphorylation ye-ITD ne-WT FLT3 (i-SU5416 izinga elivimba u-50% [IC(50)], 100 nM; kanye ne-SU5614 IC(50) 10 nM). Ukusebenza kwe-FLT3 okuncikile ekuvuselelweni kwezakhi zezimpawu ezehlukanisiwe ze-mitogen-activated protein kinase (MAPK) kanye ne-signal transducer and activator of transcription 5 (STAT5) kwavinjelwa futhi ngokwelashwa kwamazinga afanayo. Ukuvinjelwa kwe-FLT3 nge-SU5416 kanye ne-SU5614 kwaholela ekunciphiseni ukukhula (IC(50), 250 nM kanye ne-100 nM, ngokulandelana) kanye nokuqalisa i-apoptosis yemizila yamaseli e-leukemia ane-FLT3 ITD. Ukwelashwa kwalama seli ngesici sokukhula esihlukile (i-granulocyte-macrophage colony-stimulating factor [GM-CSF]) kubuyisele izimpawu ze-MAPK nokukhula kwamaseli, okukhombisa ukuqonda kwemiphumela evimbelayo eboniwe.

Hypothesis:
Siphetha ngokuthi i-SU5416 ne-SU5614 ziyizinqamlajuqu ezinamandla ze-FLT3.


Imibhalo nge-Cardiac amyloidosis (isifo senhliziyo esibangwa ukuqoqana kwamaphrotheni). Ngicela ungazise ukuthi ngingayithola kuphi imibhalo nge-Cardiac amyloidosis. Umalume wami ushone izolo ngenxa yalesi sifo. Njengoba lesi kuyisifo esitholakala kancane, futhi ukuze ngihloniphe isikhumbuzo sakhe, ngingathanda ukusabalalisa imibhalo emngcwabeni wakhe. Ngingumsebenzi omdala wesikhungo sezokwelapha sikazwelonke (i-National Institutes of Health) osethathiwe, ngakho-ke ngiyawazi amagceke uma unayo imibhalo engingayilanda khona. Ngiyabonga.

I-cardiac amyloidosis (isifo sokuqoqana kwamaphrotheni enhliziyweni) isimo sokuphazamiseka esidalwa ukubekwa kweiprotheni engajwayelekile (i-amyloid) kwizicubu zomzimba zenhliziyo. Lezi zinto ezifakwayo zenza kube nzima ukuthi inhliziyo isebenze ngendlela efanele.


Imibhalo emayelana ne-Cardiac amyloidosis (isifo senhliziyo esibangwa ukuqoqana kwamaphrotheni). Ngicela ungazise ngendlela ehloniphekile ukuthi ngingayithola kuphi imibhalo emayelana nalesi sifo. Umalume wami ushone izolo ngenxa yalesi sifo. Njengoba lesi kuyisifo esingajwayelekile, futhi ukuze ngihloniphe isikhumbuzo sakhe, ngingathanda ukusabalalisa imibhalo emkhosini womngcwabo wakhe. Ngingumsebenzi osathatha umhlalaphansi we-National Institutes of Health (NIH), ngakho-ke ngiyayazi indawo uma unayo imibhalo e-NIH engingayilanda. Ngiyabonga kakhulu.

Igama elithi "amyloidosis" (isifo sokugqwala kweprotheni) alibhekisele esifo esisodwa kodwa iqoqo lezigulo lapho ukugqwala okususelwa kuprotheni kubekeka emathishini njengamashidi aqoshiwe beta (beta-pleated sheets). Uhlobo lwesifo lunqunywa ukuthi iyiphi iprotheni eyenza lokhu kugqwala; yize izinhlobo ezingamashumi zichazwe, eziningi zazo zitholakala kancane kakhulu noma azinakho ukubaluleka okukhulu. Lolu hlaziyoluzogxila kakhulu ezinhlobeni eziyinhloko ze-amyloidosis ezisabalele emzimbeni wonke (systemic forms), zombili zivame ukuthinta inhliziyo.


Ukuphathwa ikhanda kubukeka kunguhlelo-mfanekiso lwezimo kunokuba kube ukugula okulula ukukuhlola. Manje ziningi izindlela ezintsha neziqhubekayo zokwelapha ukuphathwa ikhanda, kodwa kubukeka sengathi indlela ngayinye yokwelapha ibhekana kuphela nohlelo oluncane lwezimo; isibonelo, indodakazi yami izame izindlela eziningi zokwelapha ezahlukene ("QEEG", "HEG", "TMS", "topamax", ...) ngaphandle komphumela omuhle. Ngabe kukhona ucwaningo olwenziwe ukuchaza ukuthi yiziphi izinhlobo zokwelapha ezisebenza kahle kuziphi izinhlobo zokuphathwa ikhanda yini?

Akukho ukwelapha okuphelele kwesifo sokuphathwa ikhanda ngoba indlela esebenza ngayo emzimbeni (i-pathophysiology) ayikaziwa ngokugcwele. Kunezindlela ezimbili zokwelapha isifo sokuphathwa ikhanda ngokusebenzisa imithi: ukuvimbela ukuqubuka, noma ukudambisa izimpawu ngesikhathi kuqubuka. Ukuvimbela kuhlanganisa ukusebenzisa imithi kanye nokushintsha indlela yokuphila. Imithi eyenzelwe isifo sokuwa, ukudangala, noma umfutho wegazi ophezulu ukuvimbela ukuqubuka esikhathini esizayo ibonakele isebenza kahle kakhulu ekwelapheni isifo sokuphathwa ikhanda.

I-Botulinum toxin A (ubuthi obuthile obusetshenziselwa ukwelapha) ibonakele isebenza kahle ekuvikeleni isifo sokuphathwa ikhanda esikhathini eside. Ngokwendlela yokuphila, amasu okulawula ingcindezi angasiza, njengokuzivocavoca, izindlela zokuphumula, izindlela zokuzilawula (njenge-biofeedback), kanye nezinye izindlela zokwelapha ezihloselwe ukunciphisa ukungaphatheki kahle kwansuku zonke. Lokhu kunganciphisa inani nobungozi bokuqubuka kwesifo sokuphathwa ikhanda.

Ukwenza uhlu lwezinto ezikuhlasela ngesifo sokuphathwa ikhanda kungasiza ekushintsheni indlela yokuphila ukuze kugwemeke lokho okuhlasela. Lokhu kuhlanganisa ukucabangela ukudla, ukudla ngesikhathi esihleliwe nezidlo ezanele, ukuphuza amanzi ngokwanele, ukuyeka imithi ethile, kanye nokusungula uhlelo lokulala olufanayo nsuku zonke.

Ukwelashwa ngamahomoni ezokwelapha kungasiza abanye abesifazane abathi isifo sabo sokuphathwa ikhanda sibonakala sixhumene nesikhathi sabo sokuya esikhathini. Uhlelo lokulawula isisindo olwenziwa ngaphansi kweliso likadokotela luyanconywa kubantu abakhuluphele abane sifo sokuphathwa ikhanda.

Ukwelapha izimpawu, noma ukwelapha okuphuthumayo, ngesikhathi kuqubuka kuhlanganisa i-sumatriptan (uhlobo lwemithi yokwelapha ikhanda elibuhlungu), imithi ye-ergotamine, kanye nezidambisi zobuhlungu njenge-ibuprofen ne-aspirin. Uma lezi zindlela zokulaphwa ziqala ngokushesha, zisebenza kangcono.


Ungakwazi nini  futhi kanjani ukuthi unokungaboni ebusuku (i-congenital night blindness)?

Ukungaboni ebusuku okuxhumene ne-X okuzalwa nakho okungazishintshi yisifo somkayi, okuyinto eyisitho esikhethekile ngemuva kweso esibona ukukhanya nombala. Abantu abanalesi simo ngokuvamile baba nobunzima bokubona ekukhanyeni okuncane (ukungaboni ebusuku). Baphinde babe nezinye izinkinga zokubona, kufaka phakathi ukulahlekelwa ukucaca (ukwehla kwamandla okubona), ukungaboni kakhulu kwezinto eziseduze (ukubona kabi okushaqile), ukuzamazama kwamehlo okungenakugwemeka (ukuthikazisa kwamehlo), namehlo angabheki ngakunye (ukuphambana kwamehlo). Ukubona umbala ngokuvamile akuthinteki yilesi simo. Izinkinga zokubona ezihambisana nalesi simo zizalwa nazo, okusho ukuthi zikhona kusukela ekuzalweni. Zivame ukuhlala zingashintshi ngokuhamba kwesikhathi. Abacwaningi sebekwazile ukubona izinhlobo ezimbili ezinkulu zalesi simo: isimo esiphelele nesimo esingaphelele. Lezi zinhlobo zinezimpawu ezifanayo kakhulu. Kodwa-ke, bonke abantu abanesimo esiphelele abakwazi ukubona ebusuku, kanti hhayi bonke abantu abanesimo esingaphelele abangaboni ebusuku. Lezi zinhlobo zahlukene ngenxa yesizathu sazo sezofuzo nangemiphumela yohlolo olukala ukusebenza komkayi.


Izinguquko zegene noma izinguquko zekromozomi ze-MSUD (isifo sokuchama okumnandi sezingane)? Yiluphi ulimi lwezokwelapha nolimi olulula lwe-MSUD? Zikhona yini izindlela zokwelapha ezitholakalayo ze-MSUD?

Ukuguquka kwama-gene e-BCKDHA, BCKDHB, ne-DBT kungabanga isifo somchamo se-maple syrup. Lama-gene amathathu anikeza imiyalelo yokwenza amaphrotheni asebenza ndawonye njengezingxenye ezixhumene. Lezi zingxenye zephrotheni ezixhumene zibalulekile ekuhlukaniseni ama-amino acid e-leucine, i-isoleucine, ne-valine, atholakala ezinhlobeni eziningi zokudla, ikakhulukazi ukudla okunomsoco wephrotheni njengobisi, inyama, namaqanda.

Ukuguquka kwanoma yiliphi kulama-gene amathathu kunciphisa noma kususwe umsebenzi wezingxenye zephrotheni ezixhumene, kuvimbela ukuhlukaniswa okujwayelekile kwe-leucine, i-isoleucine ne-valine. Ngenxa yalokho, lama-amino acid nemiphumela yawo ayaqoqana emzimbeni.

Amazinga aphezulu alezi zinto ayadlubulundisa kubuchopho nakwezinye izitho zomzimba. Ukuqoqana kwazo kuholela ezinkingeni ezinzima zempilo ezihambisana nesifo somchamo se-maple syrup.


Ngazalwa nesifo sokuphuma komchamo omningi (Diabetes Insipidus, isifo sokuchama kakhulu) futhi ngisalokhu nginezinkinga eziningi kusukela iseli lasuswa ngesikhathi ngineminyaka engu-22, kanye nesifo se-Acute Lymphoblastic Leukemia (isifo segazi esingalapheki).

I-Diabetes insipidus (isifo sokungazibambi amanzi) yisifo esingajwayelekile lapho izinso zehluleka ukuvimba ngokwanele ukuphuma kwamanzi.


Ngingahle ngibe nezibazi ezimbalwa endaweni yomgquba, futhi ngifuna ukukhuluma nomuntu othile ukuze ngithole ulwazi kanye nokusekela. Ngicela uxolo ngokukhuluma ngalesi sihloko esizwakala siyimfihlo.

Umdabuko womgodi wokuzikhulula yincozana encane noma ukudabuka kwesikhumba esithambile esihlobisa ingxenye engaphansi yomgodi wokuzikhulula (i-anus).


Ngabe lukhona yini ucwaningo oluveza ukuthi kusasele kangakanani ukuthi umuntu aqale ukubona izimpawu ze-Rheumatoid Arthritis?

Ukuvuvukala Kanye Nobuhlungu Emajoyintini Izinhlobo ezahlukene ze-arthritis (isifo samathambo) zinezimpawu ezahlukene. Ngokujwayelekile, abantu abanezinhlobo eziningi ze-arthritis baba nobuhlungu nokungaqini emajoyintini abo. I-Rheumatoid arthritis (isifo samathambo esibangela ukuvuvukala) ikhombisa ukuvuvukala kwesembatho sejoyinti. Loku kuvuvukala kubangela ukushisa, ukubomvu, ukudumba, kanye nobuhlungu ezungeze amajoyinti. Umuntu uphinde azizwe egula, ekhathele, futhi ngezinye izikhathi abe nomkhuhlane. I-Rheumatoid arthritis ivame ukwenzeka ngendlela efanayo macala omabili omzimba. Uma idlini elilodwa noma isandla silodwa sithintekile, nelinye idlini noma isandla nalo kungenzeka sithinteke.

Ukuhlolwa Kokuhlaziyo I-Rheumatoid arthritis ingaba nzima ukuyihlola ezigabeni zayo zokuqala ngenxa yezizathu eziningi. Akukho kuhlolwa okukodwa kwesifo. Ngaphezu kwalokho, izimpawu zihluka kumuntu nomuntu futhi zingaba nzima kwabanye abantu kunakwabanye. Ukuhlolwa okujwayelekile kwe-rheumatoid arthritis kufaka:

- Ukuhlolwa kwe-rheumatoid factor. I-Rheumatoid factor iwu-antibody otholakala egazini labantu abaningi abane-rheumatoid arthritis njengoba isifo siqhubeka. Kodwa-ke, hhayi bonke abantu abane-rheumatoid arthritis bahlola kahle kwe-rheumatoid factor, ikakhulukazi ekuqaleni kwesifo. Futhi, abanye abantu abahlola kahle abaze bathuthuke isifo.

- Ukuhlolwa kwe-citrulline antibody. Loku kuhlolwa kwegazi kuthola ama-antibody ku-cyclic citrullinated peptide (anti-CCP) (izakhi ezithile egazini). Loku kuhlolwa kuvame ukuba kahle kubantu abaningi abane-rheumatoid arthritis futhi kungaba kahle iminyaka ngaphambi kokuthi izimpawu ze-rheumatoid arthritis ziqale. Uma kusetshenziswa nokuhlolwa kwe-rheumatoid factor, imiphumela yokuhlolwa kwe-citrulline antibody ibaluleke kakhulu ekuqinisekiseni ukuhlaziyo kwe-rheumatoid arthritis.

- Okunye ukuhlolwa okujwayelekile kwe-rheumatoid arthritis kufaka i-erythrocyte sedimentation rate (isilinganiso sokuzika kwamaseli abomvu egazini), ekhombisa ubukhona bokuvuvukala emzimbeni, ukuhlolwa kwenani lamaseli amhlophe egazini, kanye nokuhlolwa kwegazi kwe-anemia (ukwehla kwamaseli abomvu egazini).

Ukuhlaziyo Kungathatha Isikhathi Izimpawu ze-rheumatoid arthritis zingafana nezezinye izinhlobo ze-arthritis kanye nezimo zamajoyinti, futhi kungathatha isikhathi ukubona ukuthi akuzona ezinye izimo. Zonke izimpawu zithuthuka ngokuhamba kwesikhathi, futhi kungaba nezimpawu ezimbalwa kuphela ezigabeni zokuqala. Funda kabanzi ngendlela yokuhlaziwa kwe-rheumatoid arthritis esiZulwini sethu.


Ngabe zikhona yini izincwadi zocwaningo ezikhombisa ukuthi umuntu angaqala nini ukubona izimpawu noma izinkomba ze-Rheumatoid Arthritis?

I-rheumatoid arthritis ikhombisa ukuvuvukala kwesigabashisibi sezitho zomzimba. Loku kuvuvukala kubangela ukushisa, ukubomvu, ukudumba, nokunye ubuhlungu ezithweni zomzimba. Ubuhlungu be-rheumatoid arthritis buhluka kakhulu ngendlela kumuntu nomuntu, ngezizathu odokotela abangakaziqondi ngokuphelele. Izinto ezibanga ubuhlungu zibandakanya ukuvuvukala ngaphakathi kwesitho somzimba, ubungako bokushisa noma ukubomva okukhona, noma umonakalo osuke wenzeka ngaphakathi kwesitho somzimba.


Esithombeni sakho esichaza 'isifo sokudideka kwengqondo' (conversion disorder), [http://www.nlm.nih.gov/medlineplus/ency/article/000954.htm], kuthiwa: "Isifo sokudideka kwengqondo siyisimo sengqondo lapho umuntu engaboni, abe nokundindibala, noma abe nezinye izimpawu zohlelo lwemizwa ezingachazeki ngokuhlolwa kwezempilo". Lokhu kubonakala kusho ukuthi izimpawu zomzimba ziyiqiniso, kodwa udokotela akakwazi ukuthola imbangela.

Omunye umthombo uthi lesi sifo "siyikhubazeka komzimba okungenziwa ukugula komzimba". Ngakho-ke, ngiqonda ukuthi lezi zimpawu zibonakala ngamehlo, kodwa uma kuhlolwa imizwa noma amathambo, akutholakali bufakazi.

Isibonelo, umuntu angathi akaboni. Uthisha wami uchaze ukuthi uma lomuntu ebekwa eduze kwemphetho, akaweli. Ngiqagela ukuthi nokuhlolwa kwamehlo akukhombisi lutho olungaqinisekisa ukungaboni kwakhe.

Ukuhlolwa kwezokwelapha akutholi imbangela ephathekayo yezimpawu. Udokotela uzokwenza ukuhlolwa komzimba futhi angayalela ukuhlolwa kwezokwelapha. Lokhu kwenzelwa ukuqinisekisa ukuthi azikho izimbangela eziphathekayo zezimpawu.


Sengilwe nesifo somdabuko womgodi wokuzikhulula (anal fissure) cishe iminyaka emibili manje, futhi sinqabile ukuphola sonke lesi sikhathi. Ngicela usizo: yini engingayenza? Ngiyabonga

Iningi lezingqwanga zendawo yangasese liyaphola ngokwalo futhi alidinga ukwelashwa. Ukuvimbela noma ukwelapha izingqwanga zendawo yangasese ezinganeni, qiniseka ukuthi ushintsha inabukeni njalo futhi uhlanze indawo ngokucophelela.

IZINGANE NABANTU ABADALA
Ukukhathazeka ngokubuhlungu ngesikhathi sokukaka kungabangela umuntu ukugwema ukukaka. Kodwa ukungakaki kuzokwenza indle ibe lukhuni kakhulu, okungenza izingqwanga zendawo yangasese zibe zimbi kakhulu.

Vimbela indle elukhuni nokungakwazi ukukaka ngoku:
- Yenza izinguquko ekudleni - ukudla amakhabhu amaningi noma okokugcwalisa, njengezithelo, izitshalo, nezinhlamvu
- Phuza amanzi amaningi
- Sebenzisa izinto ezithambisa indle

Ukufaka lezi zinsinda noma amakhilimu endaweni kungathambisa isikhumba:
- Ikhilimu yokuthulisa ubuhlungu, uma ubuhlungu buvimbela ukukaka okujwayelekile
- I-petroleum jelly
- I-zinc oxide, ikhilimu ye-1% hydrocortisone, i-Preparation H, neminye imikhiqizo

I-sitz bath (ukugeza ngamanzi afudumele ezingeni elithile) iwukugeza okusetshenziswa ukwelapha noma ukuhlanza. Kufanele uhlale kulokhu kugeza kabili noma kathathu ngosuku. Amanzi kufanele ambozele kuphela amahlombe nezinqe zakho.

Uma izingqwanga zendawo yangasese zingapholi ngezindlela zokunakekela ekhaya, ukwelashwa kungahlanganisa:
- Ukujova i-Botox esihluthulweni sendawo yangasese (umsipha wokuvala wendawo yangasese)
- Uqhaqho oluncane lokuphumuza umsipha wendawo yangasese
- Amakhilimu amiswayo njenge-nitrates noma ama-calcium channel blockers, afakwa phezu kwengqwanga ukusiza ukuphumuza imisipha


Indodakazi yami ine-Menkes syndrome futhi ngifisa ukwazi ukuthi ngingenza kanjani ukuze athola usizo. Ngiyabonga

Lezi zinsiza zibhekana nokuhlolelwa noma ukuphathwa kwe-Menkes syndrome:
- Ukubuyekezwa Kwegene: Ukubuyekezwa Kwegene: Ukuhanjiswa kwekhopela okuhlobene ne-ATP7A
- Irejista yokuhlolwa kwegene: I-Menkes kinky-hair syndrome (isifo sezinwele ezigwegwile)
- I-Encyclopedia ye-MedlinePlus: Ikhopela emadleni
- I-Encyclopedia ye-MedlinePlus: I-Menkes syndrome

Lezi zinsiza ezivela ku-MedlinePlus zinikeza ulwazi mayelana nokuhlolelwa nokuphathwa kwezimo ezahlukene zezempilo:
- Ukuhlolwa kokuxilonga
- Ukwelashwa ngomuthi
- Ukuhlinzwa nokuBuyiselwa emuva esimweni
- Ukwelulekwa ngegene
- Ukunakekelwa kweziguli ezingenakwelapheka (ukunakekela kweziguli eziphethwe kanzima)


ALUKHO UNAKEKELO  LWEZEMPILO ENDODANENI YAMI EHLUPHEKA NGOKUNGAHAMBELANI KOBULILI SINGENZANI UKUYISIZA IQEDE ISIKOLE ESIPHAKEME NGAPHANDLE KWEZINKINGA MANJE AYISEBENZI FUTHI IYAZITSHELA EKAMELWENI LAYO 24/7 AKUKHO LUTHO NGALESI SIMO ENDAWENI YETHU SIHLALA E-[INDAWO]. AYIKHO USIZO ENDAWENI SINGENZANI SEYIBE NEMICABANGO EMIBI KAKHULU KAKADE SICELA NISISIZE NGOLWAZI OLUNZULU OLUTHILE SIYABONGA [IGAMA] [INDAWO] [IMINININGWANE YOKUXHUMANA]

Ukwelashwa komuntu ngamunye kanye nokwelashwa komndeni kuyanconywa ezinganeni ukuze kwakhiwe isimo esisekela ekhaya kanye nasezikoleni. Ukwelashwa komuntu ngamunye kanye, uma kufanele, ukwelashwa kwababili kuyanconywa kubantu abadala. Ukushintsha ubulili ngokuhlinzwa kanye nokwelashwa ngamahormoni kuyikhetho elikhona. Kodwa izinkinga zokuzazisa zingaqhubeka ngemuva kwalokhu kwelashwa.


Umama wami ushone kamuva ngenxa ye-Bowel Ischemia kanye ne-Septic Shock. Umbuzo wami uthi, wayehlale ema-ER amahora angu-12 ngaphambi kokuba abonwe udokotela wokuhlinza, futhi wayengakakholwa ukuthi kwakuyilesi simo. Wathi uzomubheka ekuseni uma esefakwe egumbini le-ICU (lokhu kwakungamahora angu-11 ntambama). Ngakhuluma naye okugcina ngo-12 ebusuku ngalobo busuku futhi leso kwakuyisikhathi sokugcina lapho ayenolwazi. Ngesikhathi efika e-ICU emva kwamahora angu-2-3 nje, wayengasaphenduli futhi wafakwa kwimishini yokusekela impilo. Ukuhlinzwa kwenziwa kamuva ngalolosuku futhi amaphesenti angu-90 esinyamazane sakhe esincane kwadingeka sisuswe. Washona ekuseni ngosuku olulandelayo. Umbuzo wami kuwena uthi ngabe balinde isikhathi eside kakhulu ukwenza okuthile kuye? Ngabe wayengasindiswa ukube ukuhlinzwa kwenziwe masinyane? Ngicabanga ukuletha icala lomthetho... Ngicela ungaluleke ngezimpendulo zanoma yimiphi imibuzo yami onganginika yona. Ngiyabonga!

I-septic shock inenani eliphezulu lokufa. Inani lokufa lincike eminyakeni yesiguli nesimo sempilo saso sonke, imbangela yokutheleleka, inani lamalunga omzimba angasebenzi, nokuthi ukwelashwa okuqinile kuqalwa ngokushesha kangakanani.


Umyeni wami watholwa enesifo esibizwa nge-Rocky Mountain Spotted fever (isifo sokuqubuka esibangwa yi-tick) cishe eminyakeni eyisi-6 1/2 edlule. Emva kwalokho, cishe eminyakeni eyi-1 1/2 edlule, watholwa enesifo se-Lyme Disease (esinye isifo esibangwa yi-tick). Ngokuba naye enalezi zifo zombili, yimuphi umonakalo, uma ekhona, ongenzeka emzimbeni wakhe? Ubeneziningi izinkinga zezempilo kusukela ngaleso sikhathi. Manje utholakale ene-Type II diabetes (isifo sikashukela sohlobo lwesibili).

Uma kutholakala ngesikhathi sisesigabeni sokuqala, isifo sika-Lyme singalapheka ngama-antibiotics. Ngaphandle kokwelashwa, izinkinga ezithinta amahlangano amathambo, inhliziyo, kanye nohlelo lwemizwa zingenzeka. Kodwa lezi zimpawu zisalapheka futhi ziyaphela. Kwesinye isikhathi esincane, umuntu uqhubeka nokuba nezimpawu eziphazamisa impilo yakhe yansuku zonke ngemva kokuba esethole ukwelashwa ngama-antibiotics. Lokhu kuphinda kwaziwe ngokuthi yi-syndrome yesifo sika-Lyme esilandelayo. Imbangela yalolu hlobo akwaziwa. Izimpawu ezivela ngemva kokuma ukusebenzisa ama-antibiotics kungenzeka zingabi yizimpawu zosuleleko oluqhubekayo futhi kungenzeka zingaphenduli ekwelashweni ngama-antibiotics.


Ubaba wami unesifo senhliziyo esibizwa nge-cardiomyopathy azalwa naso ngokofuzo. Useneminyaka engu-83 manje. Bekejwayele ukuba sezingeni eliqondile lempilo kuze kube manje. Kamuva nje, uzwe ephelelwa umoya. Futhi ulaliswe esibhedlela kabili. Odokotela bathi izifo eziningi ezahlukene zihlasela inhliziyo yakhe. Ngifuna nje ukwazi ukuthi kwenzakalani ngempela nokuthi yiziphi izinto okufanele aziqaphe ngokuzayo. Amathuba akhe okuphila athini? Ngicela usizo.

Umphumela uncike ezintweni eziningi ezahlukene, okuhlanganisa:
- Imbangela kanye nohlobo lwe-cardiomyopathy
- Ukuthi isimo siphendula kahle kangakanani ekwelashweni
- Ubungozi benkinga yenhliziyo

Ukuhluleka kwenhliziyo (i-heart failure) kuvamise ukuba yisifo sesikhathi eside (isikhathi eside, noma i-chronic). Kungase kube kubi kakhulu ngokuhamba kwesikhathi. Abanye abantu bathuthuka babe nenkinga enzima yenhliziyo. Kulesi simo, imithi, ukuhlinzwa, kanye nokunye ukwelashwa kungase kungasasizi. Iziguli ezinezinhlobo ezithile ze-cardiomyopathy (isifo samamasela enhliziyo) zisengozini yezinkinga eziyingozi zokushaya kwenhliziyo ngokungalungile (i-heart rhythm problems).


Sawubona, igama lami ngu-[NAME] ovela eNdiya. Nginombuzo owodwa. Ngihlaselwe isifo setyphoid. Ngicela ungisize. Ngithole ukwelashwa kusukela ngonyaka odlule kodwa angikaphili kahle manje. Ngicela unginikeze isixazululo? Ngiyabonga.

Amanzi kanye nama-electrolytes anganikezwa nge-i-IV (kungena emthanjeni) noma ungacelwa ukuthi uphuze amanzi anama-electrolyte packets. Ama-antibiotics anikezwa ukubulala ama-bacteria. Kukhona amazinga akhulayo okungezwani nama-antibiotics emhlabeni wonke, ngakho udokotela wakho uzohlola izincomo zamanje ngaphambi kokuqoka i-antibiotic.


i-pneumonia engajwayelekile. kungenzeka yini ukuthi i-pneumonia engajwayelekile iphinde yenzeke ngaphansi kwenyanga eyodwa emva kokwelashwa?

Iningi leziguli ezine-pneumonia (isifo sophaphu) esibangelwa yi-mycoplasma noma i-chlamydophila ziba ngcono ngokusebenzisa ama-antibiotics (imishanguzo yokulwa nezifo) afanele. I-pneumonia ebangelwa yi-Legionella ingaba sibi kakhulu. Ingaholela ezinkingeni, ikakhulukazi ezigulini ezinenkinga yezinso, isifo sikashukela, i-COPD (isifo sophaphu esivimbelayo), noma uhlelo lokuvikela umzimba olubuthakathaka. Le pneumonia ingaholela nasekufeni.


Ngicela ningithumelele imininingwane ngesifo se-fibromyalgia

I-Fibromyalgia yisifo esijwayelekile lapho umuntu ehlupheka ngobuhlungu obuqhubekayo isikhathi eside, obusakazeke emzimbeni wonke. Ubuhlungu buvame ukuhambisana nokukhathala okusheshayo, izinkinga zokulala, ikhanda elibuhlungu, isifo sokudumala, kanye nokwesaba. Abantu abane-fibromyalgia bangaba nokuba buthaka noma ubuhlungu emajoyintini, emisipha, emasinini, kanye nakokunye okuthambile emzimbeni.


Ngicela ungithumelele ulwazi mayelana ne-fibromyalgia.

Isifinyezo

I-Fibromyalgia (isifo sobuhlungu bemisipha) yisifo esibangela ubuhlungu bama-muscle kanye nokukhathala. Abantu abane-fibromyalgia bane "zindawo ezibuhlungu kakhulu" emzimbeni. Lezi zindawo ezibuhlungu kakhulu zitholakala ezindaweni ezithile entanyeni, emahlombe, emhlane, esinqeni, ezingalweni, nasemilenzeni. Lezi zindawo zibuhlungu uma zithintwa. Abantu abane-fibromyalgia bangaba nezinye izimpawu, ezifana nalezi:

• Ukuxakeka kokulala
• Ukuqina ekuseni
• Ubuhlungu bekhanda
• Isikhathi sokuya enyangeni esibuhlungu
• Ukubanda nokungezwa ezandleni nasezinyaweni
• Izinkinga zokucabanga nokukhumbula (ngezinye izikhathi kubizwa ngokuthi "i-fibro fog" noma ukuphazamiseka komqondo)

Akekho owaziyo ukuthi yini ebangela i-fibromyalgia. Noma ubani angayithola, kodwa ivame kakhulu kubantu besifazane abaphakathi nendawo ngeminyaka. Abantu abane-rheumatoid arthritis kanye nezinye izifo zokuzivikela komzimba bavame kakhulu ukuthola i-fibromyalgia. Ayikho imishanguzo yokwelapha i-fibromyalgia, kodwa imithi ingakusiza ukuphatha izimpawu zakho. Ukulala ngokwanele, ukuzivocavoca, nokudla kahle kungase futhi kusize.

NIH (Isikhungo Sikazwelonke Sezempilo eMelika): I-National Institute of Arthritis and Musculoskeletal and Skin Diseases


Kube wusizo olukhulu emva kokufunda ngesifo sikashukela sohlobo lokuqala (i-type 1 diabetes) kodwa ngingathanda ezinye iziphakamiso ezivela kuwe. Umngane wami uneminyaka engama-35 ubudala futhi sekuyinyaka enye enesifo sikashukela. Izinga lakhe likashukela lilinganiselwa phakathi kuka-100 no-120 cishe njalo uma ehlola. Ngabe zikhona yini izinkinga ezingaba khona? Uphinde aye ukuyozivocavoca futhi ahlolwe igazi njalo ezinyangeni ezimbili noma ezintathu. Udla nokudla okulungile njengamasimu aluhlaza ahlutshiwe, amafutha e-olive kanye nokunye. Ngiyalindela impendulo yakho. Ngiyabonga.

Emva kweminyaka eminingi, isifo sikashukela singaholela ezinkingeni ezinzima zempilo:

- Ungaba nezinkinga zamehlo. Lokhu kuhlanganisa ukungaboni kahle (ikakhulukazi ebusuku) nokuzwela ukukhanya. Ungaphelelwa ngokubona nya.

- Izinyawo zakho nesikhumba sakho zingathola amanxeba nokutheleleka. Uma unawo lamanxeba isikhathi eside, unyawo lwakho noma umlenze ungadinga ukusikwa. Ukutheleleka kungabangela ubuhlungu nokukwenyela.

- Isifo sikashukela singenza kube nzima ukulawula umfutho wegazi ne-cholesterol. Lokhu kungaholela ekuhlaselweni yinhliziyo, ukushaywa ubhululu, nezinye izinkinga. Kungaba nzima ukuba igazi ligeleze ezinyaweni nasemilenzeni.

- Imizwa emzimbeni ingalimala, ibange ubuhlungu, ukukwenyela, ukuba nomdlandla, nokungezwa lutho.

- Ngenxa yokulimala kwemizwa, ungaba nezinkinga zokugaya ukudla okudlayo. Ungezwa ubuthakathaka noma ube nenkinga yokuya endlini yangasese. Ukulimala kwemizwa kungenza kube nzima nabesilisa ukuba nenduku.

- Izinga eliphezulu likashukela egazini nezinye izinkinga zingaholela ekulimaleni kwezinso. Izinso zingahle zingasebenzi kahle njengaphambilini. Zingagcina ziyekile ukusebenza, kube sekudingeka ukuba uthole ukuhlanjululwa kwegazi noma ukufakelwa izinso ezintsha.


Ngisanda kufunda isiqephu esithunyelwe nguwe esishilo ukuthi ucwaningo lwakho lukhombisa ukuthi uthole indlela ebanga i-burning mouth syndrome. Futhi ngenxa yalokhu okutholile ungakwazi ukuthola ukwelashwa. Sengibe ne-burning mouth syndrome iminyaka engu-15 futhi ngisazama ukubambelela. Kuzotholakala nini ngokushesha ukwelashwa okuhle? Ngiyingxenye yeqembu elinabantu abangaphezu kwe-500 abane-BMS. Sihlupheka kakhulu futhi sivela emhlabeni wonke. Kuzoba yini lolu kwelashwa?

Uma imbangela yokushisa komlomo itholakele, ukwelashwa kuhloswe ekuqedeni lokho okuyimbangela. Uma kungekho mbangela etholakala, ukwelashwa kungaba nzima. Lezi yizindlela zokwelapha ezingasetshenziswa uma ushiswa umlomo; sincoma kakhulu ukuthi usebenzisane nodokotela wakho ekutheni yiluphi uhlobo lokwelapha olulungele wena. Uhlobo lwemithi eyisibulala-maqhubu olubizwa ngokuthi i-clonazepam (Klonopin) umuthi wokuvimba ukuqhuma kwezicubu Imithi yokwelapha i-thrush yomlomo Imithi evimba ubuhlungu bezinzwa zomzimba Ezinye izinhlobo zemithi yokwelapha ukukhathazeka Amavithamini B Ukwelashwa ngokushintsha indlela yokucabanga nokuziphatha Iziwasho zomlomo ezikhethekile Imikhiqizo yokufaka esikhundleni samathe Icapsaicin Ngaphezu kwale mithi, lezi zinyathelo zinosizo ekunciphiseni izimpawu zokushisa komlomo: Phuza amanzi njalo Ncela izicucu zeqhwa Hlafuna i-gum engenawo ushukela Gwema izinto ezingakhathaza njengogwayi, ukudla okushisayo noma okunomlilo, iziphuzo ezinotshwala, iziwasho zomlomo eziqukethe utshwala, nemikhiqizo enobumanzi obuphezulu, njengezithelo namajusi esithrasi, kanye nomkhanako noma i-mint.


Ngifuna izincwadi ezikhuluma nge-hypotension/ngokunciphisa kwengcindezi yegazi. Ungangisuggestela noma yiziphi engingakwazi ukuzithenga?

Isifinyezo Mhlawumbe usuke wezwa ukuthi umfutho wegazi ophakeme uyinkinga. Ngezinye izikhathi umfutho wegazi ophansi kakhulu ungabanga izinkinga. Umfutho wegazi yingcindezi yegazi lakho ephushela odongeni lwemithambo yegazi. Njalo uma inhliziyo yakho ishaya, igxoba igazi liye emithanjeni yegazi. Umfutho wegazi wakho uphakeme kakhulu uma inhliziyo yakho ishaya, igxoba igazi. Lokhu kubizwa ngokuthi umfutho wegazi wokushaya kwenhliziyo. Uma inhliziyo yakho iphumule, phakathi kwemishayelo, umfutho wegazi wakho uyehla. Lolu umfutho wegazi wokuphumula kwenhliziyo. Ukufundwa komfutho wegazi wakho kusebenzisa lezi zinombolo ezimbili. Ngokuvamile zibhalwa enye ngaphezu noma ngaphambi kwenye, njengokuthi 120/80. Uma ukufundwa komfutho wegazi wakho kungu-90/60 noma ngaphansi, unomfutho wegazi ophansi. Abanye abantu banomfutho wegazi ophansi ngaso sonke isikhathi. Abanazimpawu futhi ukufundwa kwabo okuphansi kuyinto ejwayelekile kubo. Kwabanye abantu, umfutho wegazi wehla ngaphansi kwejwayelekile ngenxa yesimo sezempilo noma imithi ethile. Abanye abantu bangaba nezimpawu zomfutho wegazi ophansi uma besukuma ngokushesha. Umfutho wegazi ophansi uyinkinga kuphela uma ubanga isiyezi, ukuquleka noma ezimweni ezibucayi, ukushayeka. NIH: Isikhungo Sikazwelonke Senhliziyo, Amaphaphu, neGazi


Indodakazi yami inesifo se-Distal renal tubular acidosis. Sivela eMexico, futhi siyacabanga ukuthi ungasithumelela ulwazi olwengeziwe? Mhlawumbe ungasisebenzela inhlangano yezempilo noma yokusekelana? Angazi ncamashi.

I-distal renal tubular acidosis umkhuhlane wezinso ovela uma izinso zingakwazi ukususa ngendlela efanele ama-asidi egazini ziwafake emchanyeni. Ngenxa yalokho, ama-asidi amaningi ahlala egazini (okwaziwa nge-acidosis, okuyisimo sokuba nama-asidi amaningi egazini).


Ngingathanda ukufunda kabanzi ngesifo sami. Ngicela ungithumelele noma yiziphi izincwadi ocabanga ukuthi ngingazisebenzisa. Ngibonga kakhulu, [NAME]

I-Klinefelter syndrome isimo sezofuzo esenzeka kubesilisa uma benokwengeza i-chromosomu X esingaphezulu.


Ngithanda ukufunda kabanzi ngokwesimo sami sempilo. Ngicela ungithumelele noma yimiphi imibhalo ezifanele ocabanga ukuthi ngingayisebenzisa. Ngibonga kakhulu, [IGAMA]

I-Klinefelter syndrome iyisimo sezikromozomu esithinta ukuthuthuka komzimba kanye nokucabanga kwabesilisa. Izimpawu zayo zihluka phakathi kwabantu abathintekayo. Abantu abathintekayo bavame ukuba namasende amancane angakhiqizi i-testosterone njengenjwayelo. I-testosterone ihomoni elawula ukuthuthuka kowesilisa ngaphambi kokuzalwa nangesikhathi sokuvuthwa.

Ukuntuleka kwe-testosterone kungaholela:
- Ekuvuthweni okubambezelekile noma okungaphelele
- Ukukhula kwamabele (i-gynecomastia)
- Ukuncipha kwezinwele zobuso nomzimba
- Ukungakwazi ukuba nezingane ngokwemvelo (ukungabi nanzalo)

Abanye abantu abathintekayo banamahluko ezitho zangasese kufaka phakathi:
- Amasende angawelanga (i-cryptorchidism)
- Ukuvuleka kwe-urethra ngaphansi komsila (i-hypospadias)
- Umsila omncane ngokungajwayelekile (i-micropenis)

Izingane ezindala kanye nabantu abadala abane-Klinefelter syndrome bavame ukuba bade kunontanga babo. Uma beqhathaniswa nabesilisa abangathintekile, abantu abadala abane-Klinefelter syndrome basengcupheni enkulu yokuthola umdlavuza webele kanye nesifo esibucayi esibizwa nge-systemic lupus erythematosus. Amathuba abo okuthola lezi zifo afana nawesifazane emphakathini jikelele.

Izingane ezine-Klinefelter syndrome zingaba nobunzima bokufunda kanye nokubambezeleka ekukhulumeni nasekuthuthukeni kolimi. Zivame ukuba bathule, bazwelane, futhi bangabi nesibindi, kodwa izimpawu zobuntu zihluka phakathi kwabantu abathintekayo.


Ngingakwazi kanjani ukususa lezi zinsekabili? Mina nomama sizame izinto eziningi ukususa lezi zinambuzane kodwa azihambanga. Siyimindeni egeza kabili noma kathathu ngosuku. Asikaze siqonde ukuthi zingasihlasela kanjani. Ngicabanga ukuthi ngabe ukuwasha izingubo zethu kuyindlela engcono yini yokuziqeda lezi zinto? Kubonakala sengathi akusebenzanga kithi. Ngakho-ke zikhona yini ezinye izindlela esingazizama?

Ukuze ususe izimbungulu, thatha lezi zinyathelo ezibalulekile:   - Geza njalo ukuze ususe izimbungulu namaqanda azo.   - Shintsha izingubo zakho njalo.   - Geza izingubo ngamanzi ashisayo (okungenani 130°F/54°C) bese uzomisa ngemishini esebenzisa umjikelezo oshisayo.   - Izinto ezingeke zigezwe, njengezinto zokudlala ezigcwaliswayo, amatrasi, noma ifenisha, zingasulwa ngokuphelele ngemishini yokufunxa ukuze kususwe izimbungulu namaqanda awe emzimbeni.   Udokotela wakho angakuchazela ikhilimu yesikhumba noma umuthi wokugeza oqukethe i-permethrin, i-malathione, noma i-benzyl alcohol. Uma isimo sakho sibi kakhulu, udokotela angakuchazela umuthi owuphuza ngomlomo.


Nginohlu lwemibuzo mayelana nesifo sikaTay sachs kanye nesifo sonyawo olugobile   1. Yini isifo sikaTSD/isifo sonyawo olugobile, futhi sihlukumeza kanjani umntwana  2. Yini imbangela yalezi zifo zombili? Ngabe zingavikelwa, zelashwe, noma ziqedwe nya  3. Sivame kangakanani isifo sikaTSD? Sivame kangakanani isifo sonyawo olugobile  4. "I-ejensi" yakho (inhlangano yosizo) ingasiza kanjani owesifazane/izithandani ezikhathazekile ngalesi simo esitholakala ngokuzalwa, futhi ngabe kukhona izindleko? Uma ungaphendula le mibuzo embalwa ngingabonga. Ngicela uphendule ngokushesha okukhulu.

I-Talipes equinovarus isimo somzimba esidalwe ngokuzalwa lapho unyawo luphenduka ngaphakathi futhi phansi. Imbangela yalesi simo ayaziwa, nakuba kungenzeka sidluliswe ngomlando womndeni ezikhathini ezithile. Lesi simo senzeka cishe koyedwa kubantu abayinkulungwane abazalwayo. Ukwelashwa kungahlanganisa ukususa unyawo endaweni efanele nokusebenzisa isigqoko sokunqanda ukulunyakazisa ukulugcina lapho. Le nqubo yenziwa kancane kancane esikhathini eside. Ezimweni ezinzima, ukuhlinzwa kungadingeka.


Nginohlu lwemibuzo mayelana nesifo sikaTay sachs kanye nonyawo olugobile   1. Yini i-TSD/Unyawo olugobile, futhi luhlukumeza kanjani umntwana  2. Yini imbangela yalokhu kokubili? Kungavinjwa, ukwelashwa, noma kuphulukiswe  3. Ivame kangakanani i-TSD? Luvame kangakanani unyawo olugobile  4. "I-ejensi" yakho ingasiza kanjani owesifazane/izithandani ezikhathazekile ngalesi simo somzimba esizalwa naso, futhi kukhona yini izindleko?  Uma ungaphendula le mibuzo embalwa ngingabonga, ngicela ungiphendule ngokushesha okukhulu.

Unyawo olugwegwe luyisimo esijwayelekile kakhulu sokukhubazeka kwezitho zomzimba esizalwa naso ezinyaweni. Singaba sincane futhi silula ukuguquka noma sibe sibi kakhulu futhi siqinile. Imbangela ayaziwa, kodwa lesi simo ezinyaweni singadluliswa emndenini kwamanye amacala. Izinto ezingaba yingozi zifaka phakathi umlando womndeni walesi simo nokuba owesilisa. Lesi simo senzeka cishe koyedwa noma ngaphezulu kubantwana abayi-1,000 abazalwa bephila.


Nginohlu lwemibuzo mayelana nesifo seTay sachs kanye nonyawo oluguqukile   1. Yini isifo seTay sachs/unyawo oluguqukile, futhi luthinta kanjani ingane  2. Yini edala lezi zifo zombili? Kungavikeleka, kulashwe, noma kuphulukiswe yini?  3. Sivame kangakanani isifo seTay sachs? Livame kangakanani unyawo oluguqukile  4. Inhlangano yakho ingasiza kanjani owesifazane/izithandani ezinokwesaba ngalesi simo sokudalwa, futhi kukhona yini izindleko?  Ngingabonga uma ungaphendula le mibuzo embalwa, ngicela uphendule ngokushesha okukhulu.

Isifo sikaTay-Sachs siwukufa okuthile okuthelelwanayo okubangela ukubhujiswa okuqhubekayo kwamaseli emithambo yomzwa ekhanda nasemgogodleni. I-Tay-Sachs ibangelwa ukungabikho kwenzayimu ebalulekile ebizwa nge-hexosaminidase-A (Hex-A) (enzayimu ebalulekile ekusebenzeni kwamaseli). Ngaphandle kwe-Hex-A, isithako esinomafutha, noma i-lipid, esibizwa nge-GM2 ganglioside siqoqana ngokungajwayelekile emaseline, ikakhulukazi emaseline emithambo yomzwa ekhanda. Lokhu kuqoqana okuqhubekayo kubangela umonakalo oqhubekayo emaseline emithambo yomzwa. Isifo sikaTay-Sachs sithelelwana ngendlela ye-autosomal recessive (indlela yokudlulisela isifo lapho zombili izicubu zofuzo kumele zibe nenkinga).


Nginohlu lwemibuzo mayelana nesifo sika-Tay Sachs kanye nonyawo olushaya phansi:

1. Yini i-TSD/unyawo olushaya phansi, futhi luthinta kanjani ingane?

2. Yini imbangela yakho kokubili? Kungagwenyeka? Kungalashwa? Kungaphulukiswa?

3. I-TSD ivame kangakanani? Unyawo olushaya phansi luvame kangakanani?

4. "Inhlangano" yakho ingasiza kanjani owesifazane/izithandani ezikhathazekile ngalesi simo sokuphazamiseka komzimba esizalwa naso, futhi ingabe kukhona izindleko?

Uma ungaphendula le mibuzo embalwa ngingabonga. Ngicela uphendule ngokushesha.

Isifo sikaTay-Sachs siyisifo esitholakala ngokuzalwa esibulala kancane kancane amasosha omzimba (amaneuroni) ebuchosheni nasemgogodleni. Uhlobo olujwayelekile lwesifo sikaTay-Sachs luvela ezinganeni. Izingane ezinalesi sifo zibukeka ziqhelile kuze kufike izinyanga ezintathu kuya kweziyisithupha, lapho ukukhula kwazo kuqala ukuhlehlela emuva futhi imisipha yokuhamba ibe buthakathaka. Izingane ezithintekile zilahlekelwa yikhono lokuphenduka, lokuhlala, kanye nokukhasa. Ziphinde zibe nokwethuka okukhulu uma zizwa umsindo omkhulu. Njengoba isifo siqhubeka, izingane ezinesifo sikaTay-Sachs ziba nezithuthwane, ukulahlekelwa wukubona nokuzwa, ukukhubazeka kwengqondo, kanye nokufa uhlangothi. Inkinga ehlola amehlo ebizwa ngokuthi indawo ebomvu okwesheri, engabonwa uma kuhlolwa amehlo, iyimpawu ekhombisa lesi sifo. Izingane ezinalolu hlobo olubi lwesifo sikaTay-Sachs ngokuvamile ziphila kuphela kuze kube sebuncaneni.

Ezinye izinhlobo zesifo sikaTay-Sachs azivamile kakhulu. Izimpawu zingavela ebunganeni, ebusheni, noma ebudaleni futhi ziba buthakathaka kunalezo ezibonakala ezinganeni. Izimpawu ezijwayelekile zibandakanya ukuba buthakathaka kwemisipha, ukulahlekelwa wukuxhumana kwemisipha (i-ataxia, ukungakwazi ukuhambisa imisipha ngendlela efanele) nezinye izinkinga zokuhamba, izinkinga zokukhuluma, kanye nokuphazamiseka kwengqondo. Lezi zimpawu zihluka kakhulu kubantu abanezinhlobo zesifo sikaTay-Sachs ezivela kamuva.


Nginohlelo lwemibuzo mayelana nesifo sika-Tay Sachs kanye nonyawo olugwegwile   1. Yini i-TSD/unyawo olugwegwile, futhi luthinta kanjani ingane?  2. Yini imbangela yalokhu kokubili? Kungavikelwa, kuyelapheke, noma kuphele nya?  3. Sivame kangakanani isifo sika-Tay Sachs? Livame kangakanani unyawo olugwegwile?  4. "I-ejensi" yakho ingasiza kanjani owesifazane/izithandani ezikhathazekile ngalesi simo esizalwa naso, futhi zikhona izindleko? Uma ungaphendula le mibuzo embalwa ngingabonga, ngicela ungiphendule ngokushesha.

Ayikho indlela eyaziwa yokuvikela lesi simo sezinzwa. Ukuhlolwa kwamajini kungathola ukuthi unegeni engadlulisela lesi simo. Uma wena noma umlingani wakho nivela emphakathini osengcupheni, kukhuthazwa ukuthi nihlolwe ngaphambi kokuqala umndeni. Ukuhlolwa kwamanzi akhisela ingane esibelethweni (umzanyana) kungahlonza isifo sika-Tay-Sachs ngaphambi kokuthi ingane izalwe.


Nginohlelo lwemibuzo mayelana nesifo seTay-Sachs kanye nonyawo olugwegwile   1. Yini isifo seTay-Sachs/unyawo olugwegwile, futhi lubaphatha kanjani abantwana  2. Yini imbangela yalezi zinto zombili? Kungavikelwa, kulashwe, noma kuphulukiswe  3. Sivame kangakanani isifo seTay-Sachs? Sivame kangakanani unyawo olugwegwile  4. "Inhlangano" yakho ingasiza kanjani owesifazane/izithandani ezikhathazekile ngalesi simo esizalwa naso, futhi kukhona yini izindleko ?  Uma ungaphendula le mibuzo embalwa ngingabonga kakhulu , ngicela uphendule ngokushesha okukhulu.

Akukho ukwelashwa kwesifo sikaTay-Sachs ngokwaso, kuphela izindlela zokwenza umuntu azizwe ekhululekile.


Ngabe imidwa yezicubu zezindlebe ihlale ikhombisa isifo senhliziyo futhi iyisiqiniseko sehlaselo lenhliziyo elizokwenzeka noma nini? Yiziphi ezinye izizathu? Ngineminyaka engu-56 futhi nginezindlebe ezinemibobo kodwa angisawagqoki amacici eminyakeni eminingi. Eminyakeni eyisikhombisa edlule ngingadli inyama kakhulu, uma ngiyidla ngidla inkukhu noma inhlanzi, mhlawumbe inyama yenkomo eminyakeni emihlanu noma ngaphezulu futhi kungaba yi-hamburger engenamafutha kakhulu. Uma unesifo se-arteriosclerosis (ukuqina kwemithambo yegazi), ingabe kukhona indlela yokulwa naso noma yokulibuyisela emuva?

Into ethile ebizwa ngokuthi i-plaque ingakheka ezindongeni zemithambo yegazi enhliziyweni (amacoronary arteries). Le plaque yenziwe ngamakolesteroli namanye amaseli. Ukuhlaselwa yinhliziyo kungenzeka uma:   - Kukhona ukudabuka kwe-plaque. Lokhu kuqala amaplatelethi egazi nezinye izinto ukwakha isigaxa segazi (i-blood clot) kuleso sikhala elivimba ingxenye enkulu noma yonke yegazi elithwala i-oxygen ekufanele ligeleze ingxenye yemisipha yenhliziyo. Lena yimbangela evame kakhulu yokuhlaselwa yinhliziyo.   - Ukwakheka kweplaque kancane kunganciphisa omunye wemithambo yegazi enhliziyweni ngendlela yokuthi ucishe uvaliwe.   Kunoma yisiphi isimo, alikho igazi elanele eligelezela umsipha wenhliziyo futhi umsipha wenhliziyo uyafa. Imbangela yokuhlaselwa yinhliziyo ayaziwa njalo.   Ukuhlaselwa yinhliziyo kungenzeka:   - Uma uphumule noma ulele   - Ngemva kokwenyuka okusheshayo kwemisebenzi yomzimba   - Uma wenza imisebenzi yomzimba ngaphandle emakhazeni   - Ngemva kokwethuka okusheshayo, okukhulu ngokomoya noma ngokomzimba, kufaka phakathi ukugula   Izinto eziningi ezingabeka impilo engcupheni (risk factors) zingaholela ekwakhekeni kwe-plaque nokuhlaselwa yinhliziyo.


Ngabe imidwa esezindlebeni ihlale ikhombisa isifo senhliziyo futhi ikhombisa ngokuqinisekile ukuthi ukuhlasela kwenhliziyo kuzokwenzeka? Yiziphi ezinye izizathu? Ngineminyaka engu-56 futhi nginezindlebe ezigqotshiwe kodwa angizange ngigqoke amacici eminyakeni eminingi. Eminyakeni eyisikhombisa edlule ngidla inyama kancane kakhulu, uma ngiyidla kuba yinkukhu noma inhlanzi, mhlawumbe inyama yenkomo eminyakeni emihlanu noma ngaphezulu futhi kungaba yibhega elinganonile kakhulu. Uma unesifo sokuqina kwemithambo yegazi (arteriosclerosis), ngabe kukhona indlela yokusibuyisela emuva?

Isifo senhliziyo esiphathelene nemithambo yegazi

Ukushaywa yinhliziyo (i-heart attack) kwenzeka uma ukuhamba kwegazi elinothile i-oksijeni endaweni yomsipha wenhliziyo kuvinjwa ngokuzuma futhi inhliziyo ingakwazi ukuthola i-oksijeni. Ukushaywa yinhliziyo okuningi kwenzeka ngenxa yesifo senhliziyo esiphathelene nemithambo yegazi (i-CHD).

I-CHD isimo lapho into ebizwa ngeplaque (okuyinto efana namafutha) eyakheka ngaphakathi kwemithambo yegazi yenhliziyo. Le mithambo yegazi ihlinzeka igazi elinothile i-oksijeni enhliziyweni yakho. Uma iplaque ikhula emithanjeni yegazi, lesi simo sibizwa nge-atherosclerosis (ukuqina nokuvala kwemithambo yegazi).

Ukukhula kweplaque kwenzeka eminyakeni eminingi. Ekugcineni, indawo yeplaque ingaqhuma ngaphakathi komthambo wegazi. Lokhu kubangela ukuba igazi libe yiqhwaga phezu kwendawo yeplaque. Uma iqhwaga liba likhulu ngokwanele, lingavimba ukuhamba kwegazi ngomthambo wegazi wenhliziyo.

Uma ukuvinjwa kungalashwa ngokushesha, ingxenye yomsipha wenhliziyo iyafa. Isicubu senhliziyo esiphilile sishintshwa ngesicubu sesibazi. Lolu lonakala lwenhliziyo lungangabonakali, noma lungabangela izinkinga ezinzima.

Ukuhlukumezeka komthambo wegazi wenhliziyo

Imbangela engajwayelekile yokushaywa yinhliziyo ukuhlukumezeka okushaqisayo komthambo wegazi wenhliziyo. Ukuhlukumezeka kuqeda ukuhamba kwegazi ngomthambo wegazi. Kungenzeka emithanjeni yegazi yenhliziyo engathintekile yi-atherosclerosis.

Imbangela yokuhlukunyezwa komthambo wegazi wenhliziyo ayihlale icacile. Kungahlobana nalokhu:
- Ukuthatha izidakamizwa ezithile, njengekhokheyini
- Ukucindezeleka kwemizwa noma ubuhlungu
- Ukuba semazingeni aphansi kakhulu
- Ukubhema

Umdwebo ongezansi ukhombisa ukuthi ukukhula kweplaque noma ukuhlukumezeka komthambo wegazi wenhliziyo kungaholela kanjani ekushayekeni yinhliziyo. Chofoza "qala" ukuze ubuke umdwebo. Izincazelo zinikezwe nomfanekiso ngamunye. Ungasebenzisa izinkinobho ngaphansi ukuze ulawule umdwebo. Umdwebo ukhombisa ukuthi ukuvimbeka kwegazi emthanjeni wegazi wenhliziyo kungaholela kanjani ekushayekeni yinhliziyo.


Indodana yami izalwe ne-alopecia totalis kanye nokuvuvuka okuzungeze amehlo, simenzele i-Whole Exome Sequencing (ukuhlolwa kwegene yonke), bathole ukuguquka okungase kube yingozi ku-SOX18 gene, okusekela ukuhlinzekwa kwesifo se-hypotrichosis-lymphedema-telangiectasia syndrome. Ngifisa ukwazi ukuthi ngingakwelapha lokhu yini noma kukhona yini esingakwenza ukusiza izimpawu. Ngicela usizo oluphuthumayo.

I-Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) isimo esithile esiyinkimbinkimbi esingavamile esihambisana nezinwele ezimbalwa (i-hypotrichosis, okuchaza izinwele ezingekho ziningi), i-lymphedema, kanye ne-telangiectasia, ikakhulukazi ezingaphakathini zezandla. Izimpawu ziqala ngokuvamile ekuzalweni noma ebuncaneni bokuqala futhi ziba zimbi ngokuhamba kwesikhathi. I-HLTS icatshangelwa ukuthi ibangelwa izinguquko (mutations) egene ye-SOX18. Ingalandela ukudluliselwa kofuzo okuhamba ngendlela ye-autosomal dominant (lapho igene elilodwa elingalungile lingenela) noma ye-autosomal recessive (lapho amagene amabili angalungile adingeka), kuye ngomndeni othintekile. Okwamanje akukho ukwelashwa kwalesi simo. Ukwelashwa kusekelwe ezimpawini ezikhona kumuntu ngamunye.


Kwenzakalani esigulini sesifo sikashukela uma izinga likashukela egazini likhushulwa? Yiliphi ingxenye yomzimba phakathi kwebuchopho, isisu noma ibhodlela lomchamo? Kungani ibhodlela lomchamo liba nsundu kakhulu kunezinye izingxenye zomzimba?

Isifinyezo
Isifo sikashukela sisho ukuthi amazinga kashukela (i-glucose) egazini lakho aphakeme kakhulu. Ngesigaba sesibili sesifo sikashukela, esijwayelekile kakhulu, umzimba wakho awukhiqizi noma awusebenzisi kahle i-insulin. I-insulin iwuhlobo lwehomoni elisiza ushukela ukuba ungene emasosheni akho ukuze uwanike amandla. Ngaphandle kwe-insulin, ushukela omningi kakhulu uhlala egazini. Ngokuhamba kwesikhathi, ushukela ophakeme egazini ungaholela ezinkingeni ezinzima zenhliziyo, amehlo, izinso, imizwa, kanye namazinyo nezinsini.

Unethuba elikhulu lokuba nesifo sikashukela sesigaba sesibili uma umdala, unesisindo esikhulu, unezihlobo ezine-diabetes, noma ungajimi. Ukuba nesimo esandulela isifo sikashukela naso senyusa ubungozi bakho. Lesi simo sisho ukuthi ushukela wakho wegazini uphakeme kunokujwayelekile kodwa akuphakeme ngokwanele ukuba sibizwe ngokuthi isifo sikashukela.

Izimpawu zesifo sikashukela sesigaba sesibili zivela kancane. Abanye abantu abaziboni nhlobo izimpawu. Izimpawu zingabandakanya:

• Ukuba nomanzi kakhulu
• Ukuchama kaningi
• Ukuzwa ulambe kakhulu noma ukhathele
• Ukwehla kwesisindo ngaphandle kokuzama
• Ukuba nezilonda eziphola kancane
• Ukuba nokubona okungenami

Ukuhlolwa kwegazi kungakhombisa uma unesifo sikashukela. Olunye uhlobo lokuhlolwa, i-A1C, lungabuye luhlole ukuthi ulawula kanjani isifo sakho sikashukela. Abantu abaningi bangakwazi ukulawula isifo sabo sikashukela ngokudla okunempilo, ukuzivocavoca, nokutesta ushukela wegazini. Abanye abantu badinga nokuthatha imithi yesifo sikashukela.

Isikhungo Sikazwelonke Sesifo Sikashukela Nezifo Zokugaya Nezinso (NIH: National Institute of Diabetes and Digestive and Kidney Diseases)