Premise:
I-Hepatocarcinogenesis iwuhlelo oluyinkimbinkimbi olubandakanya izinto eziningi lapho ukuvuvukala okuqhubekayo kwesibindi kudlala indima enkulu. Nakuba ukugcwala kwamasosha omzimba kubonakala ohlelweni lwe-hepatocarcinogenesis eyenziwa yizinto zamakhemikhali, indima ye-pathophysiological yomzwa wokulwa nokugula ayichazwa kahle. Ukusondela kulo mbuzo, imizwa yamakhemikhali namaseli yalandelwa ngesikhathi sokuthuthuka kwamadlala esibindi ezimpukwini ebezithunyelwe kumakhemikhali aholela kukansa yesibindi, i-diethylnitrosamine (DEN), emanzini okuphuza (50 microg/l). Ukuvezwa kwe-mRNA ye-intrahepatic type I ne-type II interferon (IFN-beta ne-IFN-gamma, ngokulandelana) kwatholakala ukuthi kukhuthazwe izinyanga ezimbili ngaphambi kokuvela kwekansa yesibindi. Ukubaluleka kwe-pathogenetic kwa-IFNs kunqunywe ngokuqapha ukuthuthuka kwedlala ezimpukwini ezingenayo ngokwemvelo i-IFN-alpha/beta receptor (IFN-alpha/betaR KO) noma i-IFN-gamma receptor (IFN-gammaR KO). Izimpuku ze-IFN-gammaR KO zathuthukisa amadlala ambalwa kunezimpuku ze-IFN-alpha/betaR KO neze-wild-type (wt), nakuba ubukhulu bukamdlala bungazange buhluke kakhulu phakathi kwezinhlobo ezintathu. Okubalulekile, izifundo ze-immunohistochemical zakhombisa ukuthi isilinganiso samasosha omzimba ahambisana nengcindezi/i-macrophages emasosheni omzimba angenayo sehla kakhulu ezibindini zezimpuku ze-IFN-gammaR KO, okuhambisana namaqiniso okuthi ukuvezwa kwe-intrahepatic cytokine kwancipha futhi umonakalo we-oxidative DNA wabangelwa ngokuncane.

Hypothesis:
Njengomphetho, i-type II IFN, kodwa hhayi i-type I IFNs, kungenzeka ibambe iqhaza elibalulekile esigabeni sokuqala, kodwa hhayi esigabeni sokuthuthukiswa, se-DEN -enziwe i-hepatocarcinogenesis ngokuqinisa ukuvuseleleka kwama-monocytes/macrophages kanye nokulimala kwe-DNA kwama-hepatocyte ekugcineni.


Premise:
Imiphumela yeminyaka esisetshenziswe ngayo i-palmitic acid yokudla noma ingxube engu-50/50 ye-palmitic ne-oleic acid ezingeni lokufakwa elingu-8% ngaphandle noma ngokukhona kwe-.2% ye-cholic acid kanye nangobukhona be-calcium ephansi (.8%) noma ephakeme (1.2%) iphenywe kusetshenziswa amachwane enkukhu kusukela ezinsukwini ezingu-1 kuya kwezingu-56 ubudala. Ukusebenzisana okubalulekile (P engaphansi kuka .01) kubonakele phakathi kwamahlobo e-fatty acid esekelwe nokukhona noma ukungabikho kwe-cholic acid ekukhuphukeni kwesisindo nokusebenza kwezokudla. Ukwengeza amadayethi ngengxube yamasisindo alinganayo e-palmitic ne-oleic acid, kunciphise ukudla uma kuqhathaniswa ne-control diets namadayethi angeziwe nge-palmitic acid yodwa. Bekunokuhlangana phakathi kweminyaka yenyoni nohlobo lwe-fatty acid esekelwe ekunqandeni kwamafutha ne-metabolizable energy (ME) yamadayethi (P engaphansi kuka .01). Bekunokuhlangana okubalulekile phakathi kohlobo lwe-fatty acid esekelwe nokwengezwa kwe-cholic acid ekunqandeni kwamafutha ne-ME yamadayethi. Lapho i-cholic acid inciphisa ukwakheka kwensipho ngesikhathi senqubo yokungcola (P engaphansi kuka .05), ukukhulisa izinga le-calcium yokudla kwandisa isilinganiso samafutha ama-digesta akhona njengensipho (P engaphansi kuka .01). Isilinganiso sama-digesta namafutha e-excreta, akhona njengensipho, ancike ohlobeni lwe-fatty acid esekelwe. Ukwengezwa kwe-free fatty acids kumadayethi enkukhu kuholele ekuncipheni kwama-bone ash ne-bone calcium content uma kuqhathaniswa naleyonyoni eyondliwe ngedayethi ye-control.

Hypothesis:
Kunqunywe ukuthi ikhono lamabroilers lokusetshenziswa kwawo kwama-free fatty acids kudipende eminyakeni yobudala anikwa ngayo ukudla, yize kuzo zonke izimo ukwenezelwa kwe-cholic acid kuthuthukisa ukusetshenziswa kwama-fatty acid.


Premise:
Inhloso yalolu cwaningo kwakuwukuhlola ukubaluleka okukhona kwe-calcitonin (CALC) ekuqaleni kwe-subclinical hypocalcemia (ucwaningo 1) kanye nezindlela zomzimba ezisiza ukuvimbela i-bovine hypocalcemia ngaphansi kwe-metabolic acidosis (ucwaningo 2 no 3). Ocwaningweni 1, izinkomo ezingu-15 ze-Holstein ezingenwe yi-subclinical hypocalcemia ngokwemvelo ezinsukwini zokuqala ezingu-5 ngemuva kokubeletha zahlungwa njenge-low subclinical hypocalcemia (LSH) lapho amazinga e-Ca egazini ayephakathi kuka-7.5 no-8.5mg/dL, noma njenge-high subclinical hypocalcemia (HSH) lapho amazinga e-Ca egazini ayephakathi kuka-6.0 no-7.6 mg/dL. Amasampula egazi athathwa nsuku zonke kusukela osukwini -5 kuya ku-5 mayelana nokubelethwa ukuthola amazinga e-parathyroid hormone (PTH), i-CALC, kanye ne-1,25(OH)2D3. Ocwaningweni 2, amabhululu angu-24 e-Holstein (anobunzima bomzimba angu-497 ± 69 kg kanye neminyaka engu-342 ± 10.5) abelwa ukwelashwa okubili (i-metabolic acidosis noma i-control). I-metabolic acidosis yaphehliselwa ngokunikeza ngomlomo i-ammonium chloride (2.5 mEq/d) ezinsukwini ezingu-10, futhi izilwane zabulawa ngemuva kwalokho. Amasampula egazi aqoqwa ngaphambi kokubulawa ukuthola i-CALC, i-PTH, i-1,25(OH)2D3, kanye namasampula omchamo, izinso, izindlala ze-parathyroid nezo-thyroid atholakala ngokukhulu ukushesha ngemuva kokubulawa ukuze kuthathwe izinga lokusebenza kwamagjini ahlukene kulama-tissue. Okokugcina, ocwaningweni 3, sahlola umsebenzi we-CALC ngaphansi kwe-metabolic acidosis ngokwenziwa esitsheni (T47D) somdlavuza webele. Yize i-PTH yavela ibamba kahulu ku-HSH kunakunaku-LSH, amazinga e-1,25(OH)2D3 ayephansi ezinkomeni ze-HSH (ucwaningo 1). Amazinga e-CALC egazini awazange aphazamiseke ukuthatha ngokusinda kwe-subclinical hypocalcemia, kodwa ayekhetheka ngezinsuku kusukela ekubeletheni (ucwaningo 1). Igjini ye-PTH receptor (PTHR) ezinsweni yakhula ngaphansi kwe-metabolic acidosis (ucwaningo 2). Ngaphezu kwalokho, umsebenzi we-CALC waphazamiseka ngaphansi kwe-acidic blood pH (ucwaningo 3).

Hypothesis:
Ekugcineni, ukwenyuka kwe-CALC ezinkomeni ze-HSH ngemuva kokukhipha kwezenze ukuthi kungalungi umthamo we-Ca egazini ngoba impendulo ye-PTHR ayizange yanele ukusebenzisa i-1,25(Amahlaba angaphakathi kwemedula)2D3 futhi ihlangabezane nomthelela we-CALC.


Premise:
I-Vanadium esimweni se-metavanadate (VO3-) ingumvimbi onamandla we-Na+, K+-ATPase. Ngenxa yokufana phakathi kwama-oxy anions e-vanadium ne-phosphorus, kwakubalulekile ukubona ukuthi i-Al(OH)3 ingakuvimba yini ukumunca kwe-vanadium emathunjini, njengoba ikwenza kwi-phosphorus. I-VO3- yabopha ngokuphelele kuspenshini ye-Al(OH)3 ku-pH 5-8. Amagundane ase-Sprague-Dawley (180-300 g) alitshiswa ukudla ebusuku futhi anikwa ngokuphoqelela 5 mumol Na3 VO4 ku-1.0 ml 0.9% NaCl equkethe 1 microCi 48V. Izilwane zokuqapha (n = 12) zathola ngesikhathi esifanayo 1.0 ml yenhlama futhi izilwane zokulinga (n = 12) zathola 1 ml Al(OH))3. Inhlama ne-Al(OH)3 kwabe sekunikwa nsuku zonke izinsuku ezingu-4. Umchamo namasimba aqoqwa ngokuhlukana nsuku zonke. Ezilwaneni zokuqapha ukubuyiselwa kwe-48V okuphelele (kuma-stool nasemchameni) esikhathini esiyizinsuku ezingu-4 kwakungamaphesenti angu-86.6 +/- 2.4% yedozi eyanikezwa. Noma i-Al(OH)3 yenyusa kancane ukubuyiselwa kwe-48V okuphelele (93.6 +/- 3.2%), yenyusa kakhulu ukuphuma kwe-48V emasismbeni uma kuqhathaniswa nasemchameni (isibonelo: amasimba, 69.1 +/- 1.8%; umchamo, 12.5 +/- 1.3%; i-Al(OH)3: amasimba, 85.7 +/- 1.5%; umchamo, 7.9 +/- 1.8%). Izilwane zabese zibulawa futhi ukuthathwa kwe-tracer emzimbeni kwakalwa. Indlela ye-48V engakakhishwa emzimbeni yawo womabili amaqembu yayimi kanje: izinso > amathambo > isibindi > amathumbu > imisipha, kodwa amazinga emzimbeni ayephezulu ngokulinganayo kwabaqaphayo kunasezilwaneni ezilashwe nge-Al(OH)3. Ikhono le-Al(OH)3 lokususa i-VO3- yangaphakathi yacutshungulwa futhi. I-48V yajovwa kwi-ip (n = 20). Uhhafu wezilwane wathola inhlama kanti uhhafu wathola 1.0 ml ye-Al(OH)3 ngokuphoqelelwa nsuku zonke izinsuku ezingu-4. Kwakungekho mehluko endleleni yokukhishwa nokusatshalaliswa kwe-48V emzimbeni.

Hypothesis:
Kuphethwe ngokuthi i-Al (OH)3 ingavimbela ukuqoqeka kwe-VO3- emzimbeni okusuka ekudleni ngokunciphisa ukumunca kwe-VO3- emathunjini.


Premise:
Izifundo zezinga lokusebenza komzimba kanye nokwanda kwezifo zinikeza ubufakazi obukhulu bokuthi ukuthatha i-calcium kunokuvikela ukuvela komdlavuza wesinambuthi esikhulu (CRC). Yize lobudlelwano abufakazelwanga ngokuhlolwa okwendlalekile nezilawuliwe (ama-RCTs) ezifushane ze-CRC, ukuhlolwa kubonisa inzuzo kuma-adenomas, okuyizinto ezingaholela kwi-CRC. Ukubhekana nokunye kwalokhu kokuphambana, senze izinhlalakahle zokuphendula zedoze ngemithombo yokuthatha i-calcium, kusekelwe ezifundweni zokubukela esezilungiselwe kuze kube ngoDisemba 2013 ezaziwa ku-PubMed, i-Embase, kanye ne-BIOSIS. Izinga lokuphepha elifingqiwe (ama-RRs) kanye nezigaba zokuzethemba ezingu-95% (ama-CIs) abalulwe kusetshenziswa imodeli yokuhlunga okungahleliwe. Mayelana nokuthatha i-calcium okuphelele, ukukhuphuka kwama-300 mg/day ngakunye kuhlotshaniswa nengcuphe enciphiswe cishe ngo-8% ye-CRC (isifingqo se-RR = 0.92, 95% CI = 0.89-0.95, I(2) = 47%, izifundo ezingu-15 ezinama-caseama-12,305, ukuthatha = 250-1,900 mg/day, ukulandelela = 3.3-16 iminyaka). Ngenkathi ingcuphe yehlile kancane esikalini esiphezulu sokuthatha i-calcium ephelele (P(non-linearity) = 0.04), izinga lokugoba lalibuthaka kanti ukubaluleka kwe-statistiki yokungabi ilinearity kwakuzwela kusifundo esisodwa. Mayelana ne-calcium yezokwelekelela, ukukhuphuka kwama-300 mg/day ngakunye kuhlotshaniswa nengcuphe enciphiswe cishe ngo-9% ye-CRC (isifingqo se-RR = 0.91, 95% CI = 0.86-0.98, I(2) = 67%, izifundo eziyisithupha ezinama-case angu-8,839, ukuthatha = 0-1,150 mg/day, ukulandelela = 5-10 iminyaka). Ukuhlolwa kwe-non-linearity akubanga nokubaluleka kwezibalo (P(non-linearity) = 0.11).

Hypothesis:
Ngokuphetha, kokubili ukudla okunokalshiyamu kanye nezithasiselo zokalshiyamu kungaqhubeka kunciphise ingozi ye-CRC ngaphezu kuka-1,000 mg/ngosuku.


Premise:
Ukuncishiswa kokukhiqizwa kwe-methane ezilwaneni ezihlafunayo sekube yinjongo ebalulekile eminyakeni eminingi edlule. I-lauric acid engakhululekile, eyaziwa ngokucindezela ukukhiqizwa kwe-methane esiswini, ayinambitheki kahle; ngakho-ke, kulolu cwaningo inhloso kwakuwukuhlola ukusebenza kokunciphisa kwesimo sayo esi-esterified (i-monolaurin). Ngaphezu kwalokho, ubuningi be-13C-isotope (delta13C) kanye nokuhlukaniswa kwe-13C-12C ngesikhathi sokukhiqizwa kwe-methane nokugayeka kwakubekiwe ukuze kuhlolwe ukukhethwa kwe-C-isotope okungenzeka kwimicrobia. Kusetshenziswe ubuchwepheshe bokulingisa isisu, ukudla okune okubalulekile, okuvame ukuchazwa ngezitshalo ze-C3 utshani (ihay) nengqoloyi (izikhwebu nezinhlamvu), noma isitshalo se-C4 (i-13C ethe xaxa uma kuqhathaniswa nezitshalo ze-C3) ummbila (izikhwebu nezinhlamvu), kanye nokuxutshwa kwalezi zitshalo ezimbili, kwafakwa ne-monolaurin (50 g/kg yokudla okomile). Uma ifakwa ehay, i-monolaurin ayizange ibe nomthelela omkhulu ekukhiqizweni kwe-methane. Uma ifakwa kokudla okunye (P < 0.05 kokususelwe kwingqoloyi) ukukhiqizwa kwe-methane kwehla. I-monolaurin yehlisa ukushabalala kwamafayibha (umphumela omncane kudayethi ye-hay), isilinganiso se-acetate:propionate, kanye nenani lamaprotozoa. Imisalela yokudla ne-SCFA yabonisa i-delta13C efanayo nokudla. I-Methane yayingavundile nge-13C kanti i-CO2 yayivundile nge-13C uma kuqhathaniswa nokudla. Ukwengezwa kwe-monolaurin kwaholela ekungavundisweni kwe-13C kwi-CO2 kanye nokuvundiswa kwi-CH4 (okwesibili kuphela ekudleni ikhwani).

Hypothesis:
Okokugcina, i-monolaurin yabonakala iphumelela ekunciphiseni i-methanogenesis emidleni yotshani nohlamvu yize lokhu kungachazwa ngokuyingxenye ukunciphisa okuhambelanayo kokunyamalala kwamafayibha.


Premise:
Sihlole ikhono likasucralfate ukuvikela isilonda senyongo esibangwa izivuseleli kwimpuku. USucralfate wanikezwa ngomlomo ngemithi engama-50 mg, i-100 mg noma i-200 mg ngaphambi kanye nasemuva kwamahora ama-3 nama-6 emva kokuqala ukujova okuqhubekayo kwamahora angama-24 kwephentagastrin nebethanechol. Izilwane zabulewe emva kwamahora angama-24 futhi inani nobunzima besilonda babalwa. Izilonda zakheka kuzo zonke izimpuku eziyisi-9 zokuhlola, kwezingu-8 kweziyisi-9 ezasebenzisa i-50 mg, kwezingu-4 kweziyisi-9 ezasebenzisa i-100 mg, futhi kweyodwa kuphela kweziyisi-9 ezasebenzisa i-200 mg kasucralfate.

Hypothesis:
Siphetha ngokuthi i-tubastatin A ivimba ukubunjwa kwezilonda zaseduodenamu ezidalwa yi-secretagogue emagundaneni.


Premise:
Umthelela osivimbayo wokudalulwa kwe-duodenal ku-acid kanye nezixazululo ezine-hyperosmolal ku-pentagastrin-stimulated gastric acid secretion kucwaningwe kumagundane aqondile ahlinzekwe nge-chronic gastric fistula kanye neduodenal Thiry-Vella loop. I-loop ibhekene ne-saline, i-HCl noma i-hyperosmolal polyethylene glycol. I-gastric acid secretion ilinganiswe kumasampula avela kwi-gastric fistula. Amazinga e-gut peptide alinganiswe ku-duodenal perfusates aqoqwe njalo emizuzwini engama-30, nakumasampula e-plasma aqoqwe ngesikhathi sokuveza i-acid stimulated kuphela, nasekupheleni kokuvivinywa ngokuhlanganisa nezinselelo ze-luminal loops. Ngesikhathi se-pentagastrin-stimulated gastric acid secretion, i-luminal perfusion ye-duodenal loop nge-acid yabangela ukuvimbeleka kwe-acid secretion (P < 0.001) kanye nokukhululwa okubalulekile kwe-somatostatin kokubili oluhumeni (P < 0.001) nakwi-circulation (P < 0.05). Futhi, i-neurotensin (P < 0.01) kanye ne-vasoactive intestinal peptide (P < 0.01) zakhululwa oluhumeni, kodwa hhayi kwi-circulation. Ngokugeleza kwe-duodenal loop ne-hyperosmolal polyethylene glycol, ukwakhiwa kwe-acid kuvimbekile (P < 0.05) futhi i-somatostatin yodwa yakhululwa ohlangothini lwe-luminal (P < 0.01).

Hypothesis:
Siphetha ngokuthi ukufaka i-acid emethweni ophakathi kweduodenal loop kubangela ukuvimba ukukhiqizwa kwe-acid esiswini eqhutshwa yi-pentagastrin.


Premise:
Kulolu cwaningo, sihlolisise izinto ezithinta ukuhlanzeka kwesimuncu esivikela umphimbo ezigulini ezijwayelekile. I-15-ml bolus ye-0.1 N HCl (pH 1.2) yafakwa emgudwini womphimbo, futhi isiguli sasamunya njalo emva kwamasekhondi angu-30. Ukuhlolwa kwe-manometric kanye nokuqapha i-pH kukhombise ukuthi ukuhlanzeka kwesimuncu esivikela umphimbo kwenzeka ngoluhlobo olulandelanayo kwe-pH, oluhlangene nokuminya okuholela ekulandelaneni kokunweba kwesiphundu somphimbo. Phakathi kokulungiswa kokunweba kwesiphundu, ukwenyuka kwe-pH kwakuncane. Ukukhuthazwa kwamathe ngozoliso lomlomo kwanciphisa kakhulu ukuhlanzeka kwesimuncu esivikela umphimbo, kanti ukumunca amathe emlonyeni kwavimbela ukwenyuka komkhathi we-pH yomphimbo futhi kwabambezela kakhulu ukuhlanzeka kwesimuncu esivikela umphimbo. Ukufakwa kwesisombululo se-bicarbonate esikhundleni samathe aconsiswe, kwavukuza kabusha imizimba ye-pH yomphimbo futhi kwabuyisela ukuhlanzeka kwesimuncu esivikela umphimbo esimweni esijwayelekile, kanti ukufakwa kwamanzi kuphela akuzange kuphumelele ukunyusa ukuhlanzeka kwesimuncu esivikela umphimbo. Okufana nomphumela wozoliso lomlomo, i-bethanechol (5 mg ngaphansi kwesikhumba) yaphucuzela ukuhlanzeka kwesimuncu esivikela umphimbo, kodwa lolu thuthuko lwaphendulwa ukumunca amathe emlonyeni, okwabambezela kakhulu ukuhlanzeka kwesimuncu esivikela umphimbo. Ukushintsha esimweni sokulala uye esimweni sokuhlala kwaba nomthelela omuhle ekunyuseni ukuhlanzeka kwesimuncu esivikela umphimbo, kodwa lolu thuthuko aluzange lube nenqubekela phambili ebalulekile.

Hypothesis:
Siphothule ukuthi kubantu abajwayelekile (a) ukugwinya kuthatha amathe kuyise esiphinjeni futhi i-peristalsis iyakhulula uketshezi olusesiphinjeni luye esiswini, (b) ukwenza i-asidi ibe nobumnandi ngamathe athwalwa aye esiphinjeni nokuwinya ngakunye kuchaza ukwenzeka kokukhishwa kwe-asidi ngokwenyuka kwe-pH ezingeni, (c) ukuthuthuka ekukhululweni kwe-asidi nge-bethanechol kungenxa yokukhuthazwa kwamathe, futhi (d) umthelela womhlaba awulekeleli kangako ekukhululweni kwe-asidi esiphinjeni uma kukhona amagagasi e-peristaltic ajwayelekile.


Premise:
Umphumela we-cisapride, iyeza elisha elikhuthaza ukusebenza kwesisu, ekuphumeni kukudla esiswini kanye nokubuyela kwebyela eyiNyongo esiswini besizwa kumavolontiya aphilile ohlobo lokuvivinya olufaka isikhongozo semithi esiyimfihlo kanye nolwenziwa ngokuchitshiyelana. Abantu abangamashumi amabili banikezwa izingcebe ezingu-10 mg ze-cisapride, kathathu ngosuku ngomlomo noma izingcebhe ezifana nezephilebo isikhathi esingeviki. Ngezinsuku zokuhlola, amavolontiya acwaningwa kusetshenziswa ubuchwepheshe besaziso ngokufaka ipayipi esiswini bengazidle lutho kanye nangemva kokudla ukudla okuxubile okungamanzi. I-cisapride ayizange ibe nomthelela ekukhiqizeni kwesisu nokuphumeni kokudla esiswini. Kube khona isimo sokwehla kokuphindela kweNyongo ngemva kokusetshenziswa kwe-cisapride kokubili ngokuzila (0.63 +/- 0.14 maqondana no 0.38 mumol/min +/- 0.05 SEM) kanye nangemva kokudla (2.60 +/- 0.61 maqondana no 1.88 mumol/min +/- 0.33 SEM). Lokhu bekubangelwa ukwehla kwamazinga aphezulu okuphindela kweplasebo: ukuncishiswa kwezinga lokuphindela elifezwe yi-cisapride belikhonjiswa ukuhlobana okubalulekile kuzinga lokuphindela kweplasebo (p ngaphansi kuka 0.001). Ubudlelwano obufanayo batholakala kwizinga leNyongo eyibyela esiswini (p ngaphansi kuka 0.001).

Hypothesis:
Kuphethwe ngokuthi i-cisapride inciphisa ukuphindela emuva kwetshwala lenyongo elikhulu.


Premise:
Inhloso yalolu cwaningo kwakuwukuhlola izindlela zemithambo yamanzwe kanye nezinto ezibangela uguquko lwamakhemikhali (humoral pathways) ezibandakanyeka ekumiseni ngokufushane kwe-ileal short-chain fatty acid (SCFA) ezingulubeni eziqondile. Indima yokuxhumana kwemithambo yangaphandle ye-ileal yahlolwa ngemuva kokufakwa kwe-SCFA ezingqenjaneni ze-ileal ezisebenzayo nezingasebenzi zikaBabkin, futhi ukunyakaza kwesisu kwakalwa ngezikali zokuncindizeleka (strain gauges). Amazinga e-Peptide YY (PYY) ne-glucagon-like peptide-1 (GLP-1) ahlolwa kuzo zombili izimo. Ukubandakanyeka okungenzeka kwe-SCFA eyenziwe yafakwa yasebenza yahlolwa ngokusebenzisa i-intravenous infusion ye-acetate. Ukufakwa kwe-SCFA kwi-ileal ethintekile engaphelile kwanciphisa ubukhulu bokushwabana kwe-antral engekho kude nengaphansi (33 +/- 1.2 vs. 49 +/- 1.2% yobukhulu obukhulu obugcinwe ngaphambi kokufakwa) futhi kwandisa imvamisa yawo (1.5 +/- 0.11 vs. 1.3 +/- 0.10/min). Imiphumela efanayo yabonwa ngesikhathi sokufakwa kwe-SCFA ezingqenjaneni ze-ileal ezisebenzayo nezingasebenzi (ubukhulu, 35 +/- 1.0 kanye no-34 +/- 0.8 vs. 47 +/- 1.3 kanye no-43 +/- 1.2%; imvamisa, 1.4 +/- 0.07 kanye no-1.6 +/- 0.06 vs. 1.1 +/- 0.14 kanye no-1.0 +/- 0.12/min). I-intravenous acetate ayishintshanga ubukhulu nemvamisa yokushwabana kwe-antral. Amazinga e-PYY kodwa hhayi e-GLP-1 akhuliswa ngesikhathi sokufakwa kwe-SCFA ezingqenjaneni ezisebenzayo nezingasebenzi.

Hypothesis:
Siphetha ngokuthi i-ileal innervation engaphandle imelela ukumiswa kwe-SCFA kokunyakaza kwesisu.


Premise:
Kuvumelekile ngokujwayelekile ukuthi ukukhululwa kwe-Ca(2+) okubangelwa yi-Ca(2+) ekhishwa yishanel ye-L-type Ca(2+) (i-CICR) yiyona ndlela eyinhloko yokuxhumana kokucwaseka-nokuhosha (i-E-C coupling) enhliziyweni ephucuzekile yezilwane ezinemifundhiso, futhi akukho CICR ephawulekayo ezinganeni ezisandakuzalwa. Kodwa-ke, sibonile ukuthi ukuhosha kwamaseli enhliziyweni yezingane ezisandakuzalwa kwehliseka kakhulu emva kokukhululwa kwe-Ca(2+) ye-sarcoplasmic reticulum (SR) ngokusebenzisa i-caffeine. Ngakho-ke, lesi sifundo sicwaninge izinguquko zentuthuko ye-CICR kumaseli e-ventricular ezimpungushe ezinsukwini ezingu-3, 10, 20, no-56 zobudala. Sithole ukuthi umthelela ovimbelayo we-L-type Ca(2+) current (I(Ca)) inhibitor i-nifedipine (Nif; 15 microM) udale ukwehla okukhulu kwama-Ca(2+) transients uma kukhishwa ugesi kuqembu lobudala obudala [kusukela kumaphesenti angu-15 kumaseli ansuku-3 (3d) kuya kumaphesenti angu-90 kumaseli ansuku-56 (56d)]. I-Ca(2+) transient esele ekhona uma kukhona i-Nif emaqenjini asemusha ivinjelwe ukuvimbela kwe-Na(+)/Ca(2+) exchanger (NCX) ngokungeza i-10 microM KB-R7943 (KB-R). Ngaphezu kwalokho, ama-Ca(2+) transients anciphe kakhulu ngemuva kokukhishwa kwe-SR Ca(2+) nge-caffeine kuwo wonke amaqembu eminyaka, yize umthelela wawumkhulu kakhulu emaqenjini amadala (kusukela kumaphesenti angu-40 kumaseli ansuku-3 kuya kumaphesenti angu-70 kumaseli ansuku-56). Lesi sikhuliso se-Ca(2+) esiveza i-SR Ca(2+) esigabeni sokuqala sokuthuthuka sasingezweli ku-Nif kodwa sasizwela ekungezeni kwe-KB-R, okukhombisa ukuba khona kwe-CICR encike ku-NCX eyancipha kakhulu neminyaka (kusukela kumaphesenti angu-37 kumaseli ansuku-3 kuya kumaphesenti angu-0.5 kumaseli ansuku-56). Ngokuphambene, i-CICR encike ku-I(Ca) yanda kakhulu neminyaka (kusukela kumaphesenti angu-10 kumaseli ansuku-3 kuya kumaphesenti angu-70 kumaseli ansuku-56). Inzuzo ye-CICR njengoba kulinganiswa ngokuhlanganisa i-CICR Ca(2+) transient ihlukaniswe ngokuhlanganisa isikhulisi sayo i-Ca(2+) transient trigger yayincane uma yenziwa yi-NCX (cishe 1.0 kumaseli ansuku-3) kunangokwenziwa yi-I(Ca) (cishe 3.0 kumaseli ansuku-56).

Hypothesis:
Siphetha ngokuthi i-CICR enokusebenza okuphansi ehlangene ne-NCX iyindlela engamele ye-CICR ezigabeni zokuqala zokuthuthuka okwenzeka kancane kancane kwehla njengoba i-CICR esebenzi kahle ehlanganiswa nesiteshi se-L-type Ca(3+) ikhula ngokubaluleka ngokuya ngezemvelo yempilo.


Premise:
I-GS-458967, i-6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (GS967) iyinto echazwe kamuva, entsha, enqanda iziteshi zesodiyamu ebonisa imiphumela enamandla elwa nokungahambi kahle kwenhliziyo kumamodeli ahlukene e-in vitro ne-in vivo. Indlela yokulwa nokungahambi kahle kwenhliziyo ibekwe ekuvalweni okukhethekile kokugeleza kwesodiyamu okwemuva. Kodwa-ke, akukaze kube nokuphenya okuhlelelekile okubikiwe kwemiphumela yalesi sixubho kuziteshi zesodiyamu ezihlukanisiwe. Lapha, sicwaninge imiphumela ye-GS967 ekugelezeni kwesodiyamu okuphezulu (INaP) nasekugelezeni kwesodiyamu okwemuva (INaL) okuqoshwe kumaseli aveza ngokungafani iziteshi ezilawulwa yivolthi zesodiyamu yenhliziyo yabantu, okuyisiteshi esisemqoka sesodiyamu enhliziyweni. Njengoba kuchazwe ngaphambili, siqaphele ukuthi i-GS967 yenza ukuvinjelwa okusebenzayo kwe-INaL (63%) ngendlela ebalulekile kakhulu kunakuphezulu INaP (19%). Kodwa-ke, i-GS967 yabangela futhi ukuncipha kwe-INaP ngendlela eyencike ekuvameni, okuhambisana nokuvinjelwa okuncike ekusetshenzisweni (UDB). I-GS967 yaveza i-UDB enamandla kakhulu ye-INaP (IC50 = 0.07 碌M) kunokukhishwa kwe-ranolazine (16 碌M) ne-lidocaine (17 碌M). Ukuvinjelwa okuncike ekusetshenzisweni kuchazwe kahle ngokuphoqoza okubalulekile kokubuyela ekushesheni nasekungasebenzini kancane kanye nokwenza okubalulekile kokungasebenzi kahle kancane uma kukhona i-GS967. Ngaphezu kwalokho, i-GS967 yatholakala ukuthi yenza yona leyo miphumela kumushini wokuhlukanisa (mutation) oyisibonelo omude we-QT syndrome (delKPQ). Umushini wokuhlukanisa ohlelelwe endaweni yokuhlangana yezinto zokudambisa ubuhlungu zendawo (F1760A) wanciphisa kancane umphumela we-GS967 ku-UDB, kodwa awuzange ube nomphumela ekuvinjelweni okusebenzayo kwe-INaL.

Hypothesis:
Siphetha ngokuthi i-GS967 ingivimbeli enekhethelo ye-INaL, kodwa iphinde ibe nemiphumela enamandla ebingazange ibikwe ngaphambilini ekuvaleleni okuhambayo nokusinda ekuvalelweni, okuholela ekuvimbeleni okukhulu kwe-UDB okungenakuncika ngokuphelele esizindeni sokusebenzisana esaziwa sezivimbeli zezindawo eziqhumayo.


Premise:
Sisebenzise ubuchwepheshe bokubamba iseli lonke ukuze sifunde ukuphuma kwamakhadi okuthatha isikhashana emasosheni anhliziyo omvundla. Umsinga omkhulu wesikhashana, i-IA, wavinjelwa yi-4-aminopyridine (4AP) kanye/noma ngokubamba amandla okudonsa. Ngemva kokuvinjelwa kwe-IA, umsinga omncane wesikhashana wasala. Wavinjelwa ngokuphelele yi-nisoldipine, i-cadmium, i-ryanodine, noma i-caffeine, okubonisa ukuthi wonke umsinga ongavinjwa i-4AP uqalwa ukuguquka kwegesi i-calcium okwenza ukuhosha. Awekho amandla kagezi avuswa i-calcium ephuma kuma-potassium noma amandla kagezi avuswa yi-calcium avela ezinhlobeni ezithile ezingasetshenziswa ukuphehla umsinga ovinjwe i-4AP. Umsinga wesikhashana wanyamalala uma i-ECl yenziwa yalingana namandla okushaya; wawukhona ezisakazweni zangaphakathi nezangaphandle ezingenayo i-potassium. Wavinjelwa ngezivimbo zokuhamba kwe-anion okuyizibili i-SITS ne-DIDS, futhi indawo yokuhlehlela yokuhlobana kwamandla kagezi angaphakathi namandla kagezi angaphandle yayiguquka ne-chloride yangaphandle njengoba kuqagulwe kwi-conductance ekhetheka yi-chloride kuphela.

Hypothesis:
Siphetha ngokuthi i-calcium transient ebangela ukusontelana emasosheni e-atrial kawundlu ivula i-conductance ekhethayo ye-chloride nokuthi le-conductance inikela ku-4AP-resistant transient current.


Premise:
Ukukhanya kwe-Phospholemman (PLM) kwakhuliswa ezinhliziyweni zamagundane ngemuva kokuhlaselwa yinhliziyo (MI). Ukukhulisa kwe-PLM kumacellana wenhliziyo esevuthiwe kagundane kwangcolisa ukusebenza kokuhwebeshana kanye nokugcinwa kokuhlala kwe-Ca(2+) yasesithonjeni ([Ca(2+)](i)) ngendlela efana nalokho okubonwe emacellana ngemuva kwe-MI. Kulolu cwaningo, sahlola ukuthi ukwehla kwe-PLM emacellana anhliziyo kagundane kwenza ushintsho ekubambekeni kanye nomgudumela we-[Ca(2+)](i) ephambene nalokho okubonwe emacellana ngemuva kwe-MI. Uma kuqhathaniswa namacellana alawulwayo athelelwe iadenovirus (Adv) ekhiqiza kuphela i-green fluorescent protein (GFP), amacellana athelelwe iadenovirus ekhiqiza kokubili i-GFP nesimelane se-PLM kagundane (rASPLM) anama-23% amancane eprotheni ye-PLM (P < 0.012) ezinsukwini ezingu-3, kodwa akukho mehluko otholakele emazingeni e-sarcoplasmic reticulum (SR) Ca(2+)-ATPase, i-Na(+)/Ca(2+) exchanger (NCX1), i-Na(+)-K(+)-ATPase, kanye ne-calsequestrin. Ukugwinya kwe-SR kwe-Ca(2+) kanye namandla wonke kagesi weseli akuzange kukhinyabezwe ukwelashwa kwe-rASPLM. Ukuphumula okusuka ekuqineni okubangelwe i-caffeine kwaba ngokushesha, kanye nobukhulu besikalo se-NCX1 baba phezulu emacellana e-rASPLM, okukhombisa ukuthi ukwehla kwe-PLM kwakhuphulisile umsebenzi we-NCX1. Emacellana anhliziyo kagundane angahlanganisiwe, izivivinyo ze-coimmunoprecipitation zakhombisa ukuhlanganiswa kwe-PLM ne-NCX1. Ku-0.6 mM [Ca(2+)](o), amacellana e-rASPLM ayenokulamba okuphansi kakhulu (P < 0.003) kanye nobungako bomgudumela we-[Ca(2+)](i) kunamacellana e-GFP alawulwayo. Ku-5 mM [Ca(2+)](o), kokubili ukulamba kanye nobungako bomgudumela we-[Ca(2+)](i) zaziphezulu emacellana e-rASPLM. Leli phethini lokuziphatha kokuhlanganyela kanye nomgudumela we-[Ca(2+)](i) emacellana e-rASPLM laliphambene nalokho okubonwe emacellana agundane ngemuva kwe-MI.

Hypothesis:
Siphetha ngokuthi ukwehliswa kwe-PLM kumaselula ejwayelekile enhliziyo kagundane kwaphucula umsebenzi we-NCX1 futhi kwathinta uhlobo lwe-[Ca(2+)](i) kanye nobukhulu bokuhoxa.


Premise:
Ukwenyuka kwe-[K+]o, ngokucisha isimo sepotential yemembrane ephumule kanye nokuvimba ngokuyingxenye i-inward Na+ current (INa), kukholakala ukuthi kudlala indima ebalulekile ekwenzeni kancane ukuhambisa ngesikhathi kwenzeka i-ischemia yemyocardial. Emalungiselelweni amaningi amaseli ezikhala zenhliziyo, ukunyuswa kwe-[K+]o kuphakanyiswe ukuthi kwehlisa i-Vmax kakhulu kunalokho obekulindelekile ekukhululweni kwemembrane kuphela. Indlela yalomthelela ongazange uphenjwe ngevoltage we-[K+]o awukaziwa njengamanje, futhi ukubaluleka kwawo emasosheni anhliziyo eyodwa akukaqinisekiswa. Sihlolile imithelela engazange iphenjwe ngevoltage ye-[K+]o ephakeme ku-INa kanye ne-action potential upstroke emaseli anhliziyo athambekile nangezikhala ezihlukanisiwe ezihlukene ngaphansi kwezimo ze-voltage- ne-current-clamp. I-Superfusate [K+] yaguqulwa kusuka ku-5 mmol/L kuya ku-14 noma 24 mmol/L, kanti i-[Na+] yagcinwa ku-150 mmol/L. Emaseli athambekile alinyiwe namapatches akhishiwe ngaphandle-ngaphandle kusukela emaseli athambekile nangezikhala asanda kukhishwa, ubukhulu nama-kinetics e-INa akashintshanga ngokunyuswa kwe-[K+]o. Emaseli athambekile, ama-action potentials avezwe kusukela kwipotential yokubamba ka -70 mV abe ne-Vmax efanayo (114.9 +/- 5.7 ngokuqhathaniswa no 112.2 +/- 4.8 V/s, isilinganiso +/- SEM, n = 6) kanye ne-action potential amplitude (115.0 +/- 2.4 ngokuqhathaniswa no 113.4 +/- 3.9 mV) ku-5 no-24 mmol/L [K+]o. Ngokuphambene, emaseli ezikhala zenhliziyo kwipotential yokubamba ka -70 mV, ukunyusa i-[K+]o kusuka ku-5 kuya ku-14 mmol/L kwehlise i-Vmax kusuka ku-161.8 +/- 18.0 kuya ku-55.3 +/- 5.0 V/s (n = 7, P < .001) kanye ne-action potential amplitude kusuka ku-128.1 +/- 1.3 kuya ku-86.6 +/- 5.4 mV (P < .001). Lokukwehla okungakhumbuli ivoltage kwe-Vmax ne-action potential amplitude okubangelwa yi-[K+]o ephakeme kwasulwa phambi kuka-1 mmol/L Ba2+, okubonisa ukuthi kubangelwa yi-K+ conductance ekhulile.

Hypothesis:
Siphetha ngokuthi ukuphakama kwe-[ K+ ]o kuya emazingeni alindelekile ngesikhathi se-ischemia kubangela ukwehlisa okubonakalayo okungancikile evoltage kwe-Vmax emasosheni ezinhliziyo (ventricular cells), okungaphinde kunikele ekuphazamisekeni kokuhamba komshwana wesiguli (myocardial conduction) okuyimpawu ye-ischemia eqalayo.


Premise:
I-extracellular calcium (CaCa²⁺)) eyenza ukurelaksa kwezinhlayiya ezikhishiwe, ezivalwe nge-phenylephrine (PE) i-mesenteric arteries kuncike kuthungelwano oluhlanzekile lwemizwa ye-perivascular oluveza i-CaCa²⁺sensing receptor (CaSR). Ukuvuselelwa kwe-receptor kukhuthaza umgudu we-endocannabinoid vasodilator, oncike kwi-cytochrome P450 kanye ne-phospholipase A₂kodwa uzimele kakhulu kwi-endothelium. Kulolu cwaningo, sinqume indima ye-nitric oxide (NO) ekurelakseni kwe-CaSR ye-perivascular nerve kwi-mesenteric resistance arteries ezikhishwe kwamagundane. Sisebenzisa i-automated wire myography, safunda imiphumela ye-NO synthase (NOS) gene knockout (NOS(-/-)) kanye nokuvimbela okwenziwa emapharmasi ye-NOS ku-CaCa²⁺)-induced relaxation ye-PE-contracted arteries. I-Endothelial NOS knockout (eNOS(-/-)) yenza ngcono kodwa i-neuronal NOS knockout (nNOS(-/-)) yehla ukukhiqiza i-CaSR. I-NOS(-/-) inciphisa i-maximum CaCa²⁺)-induced relaxation ngaphandle kokushintsha EC₅₀ values, i-eNOS(-/-) iba nomthelela omkhulu. Izimpendulo zamabhizinisi ku-calindol ne-Calhex 231 zikhombisa ukuthi i-CaSR ihlanganisa ukurelaksa. L-N⁵-(1-iminoethyl)-ornithine inciphisa i-CaCa²⁺)-induced relaxation ye-PE-contracted arteries kusukela kumagundane e-C57BL/6 control cishe ngo-38% kodwa ibe nomthelela omncane ezitsheni ezivela ku-eNOS(-/-) amagundane. I-7-Nitroindazole ayikho nomthelela obalulekile ekurelakseni kwezinhlayiya zamagundane eNOS(-/-), kodwa kokubili i-N(G)-nitro-L-arginine methylester ne-N(G)-monomethyl-L-arginine yahlisa kakhulu ama-relaxation maxima kuwo wonke amaqembu. Okuhlaba umxhwele, i-nNOS-selective inhibitor S-methyl-L-thiocitrulline yandisa ngokusemthethweni EC₅₀ value ngo-≈0% kwizicubu zamagundane e-C57BL/6 kodwa yanciphisa ukuphendula kakhulu ngo-≈0% kulabo abasuselwa ku-nNOS(-/-) amagundane. Ama-CaCa²⁺activated big potassium channels adlala indima enkulu kulomgudu, njengoba kuboniswa umthelela we-iberiotoxin.

Hypothesis:
Sifinyeza ukuthi ukukhomba kwe-CaSR emithanjeni yemesenteric kukhuthaza i-eNOS kanye nokukhiqizwa kwe-NO okulawula ukuphumula okubangelwa yi-CaCa²⁺).


Premise:
I-Adenosine, isikhiqizi somthambo wegazi, ivame ukuveliswa emizimbeni lapho isidingo se-oxygen seqile ekuseni. Kamuva sibonisile emiselweni yezintambo zamathambo egazi ezihlukanisiwe ukuthi i-adenosine kanye nesikhiqizi sayo, i-inosine, bangaphinda bangabanga ukuvaleka kwezithambo zegazi ngokukhuthaza amaseli mast. Ukukhululwa kwesibili kwe-histamine ne-thromboxane kuyimbangela yokuvaleka kwemithambo kwe-inosine kubumo benguquko. Kulolu cwaningo, sihlole imiphumela yokunyakaza kwemithambo ye-adenosine kubumo benguquko futhi saphenya indima ye-A3 adenosine receptor ekuxhumaniseni ukuvaleka kwemithambo. Kubumo benguquko, ukusetshenziswa kwendawo ye-adenosine (10-6 kuya ku-10-4 mol/L) emithanjeni yegazi njalo kwabangela ukwehlukana kwenani kwemithambo. Nokho, ingxenye yezithambo zegazi, yabonisa ukusabela okuphindwe kabili, nokuvaleka okulandelwa ukuvuleka. Nalokhu, kwakuncike esikhaleni; 35% wezithambo zegazi zivaleka ngo-12.7 +/- 4.3% wobukhulu bokuqala ekusabeleni ku-10-4 mol/L ye-adenosine. Bukhona be-8-(p-sulfophenyl)theophylline (8-SPT), isitha se-A1 ne-A2 adenosine receptors, ukuvuleka ekusabeleni kwenani elifanayo le-adenosine kwancipha, futhi ukuvaleka kwanda; 85% wezithambo zegazi ezihlolwayo zivaleka ngo-44.3 +/- 6.0% wobukhulu bokuqala. I-A3 adenosine receptor ibonisiwe ukuthi ilondoloza ukukhululwa kwezihlanganisi kumaseli mast, nendima yayo nayo yahlolwa. I-N6-(3-Iodo-4-aminobenzyl)adenosine (I-ABA), i-agonist ye-A1 ne-A3 adenosine receptors, yakhiqiza ukuvaleka kwemithambo okuncike esikhaleni. I-1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433), isitha se-A1, A2, ne-A3 receptors, yancipha kakhulu ukuvaleka kwemithambo ekusabeleni kwe-adenosine, okwakwembulwa ngesikhathi sokwelashwa nge-8-SPT. Ngaphezu kwalokho, kokubili i-adenosine ne-I-ABA zikhuthaze ukuthathwa kweseli mast kwe-ruthenium red, okukhombisa i-degranulation. Ukuvaleka okubangelwe yi-I-ABA kwasulwa ukuhlanganiswa kwe-histamine ne-thromboxane receptor antagonists.

Hypothesis:
Siphetha ngokuthi i-adenosine ingabangela ukuvaleka kwezitho zegazi emzimbeni, okuvame ukufihlelwa ukuvuleka kwezitho zegazi okubangelwa izithameli ze-A2.


Premise:
Siqhathanise izindlela zokuphumula kwemithambo yegazi ye-acetylcholine kanye ne-substance P ngokubheka amashaneli e-K(+), futhi sahlaziya ngokwezokwelapha ubunjalo bezinto ezisuselwa endothelium ngaphandle kwe-NO neziprostanoids emithanjeni yegazi yezinhliziyo yezinkawu nezinja. Imithambo yegazi yezinhliziyo yakhishwa ezinkawini nasezinjeni, futhi ukuncindezeleka kwezicubu zemithambo yegazi zalilinganiswa. Ezicutshini zemithambo yegazi yezinja ezithenjiswe nge-indomethacin kanye ne-N(G)-nitro-L-arginine (L-NA) futhi ezincindezeleke ngokuyingxenye nge-prostaglandin F(2alpha), i-acetylcholine ibangele ukuphumula okuhlobene nokuqoqana, okwasulwa ngokususa i-endothelium. Ukuphumula kwancishiswa kakhulu kodwa akuzange kusulwe ezicutshini zemithambo ezivulekele emitholampilweni ephakeme ye-K(+). I-Charybdotoxin kanye ne-apamin zivimbele kakhulu ukuphumula kufika ezingeni elifanayo naleso se-K(+) ephakeme, kanti i-glibenclamide noma i-iberiotoxin ayibanga mphumela. Ukuphumula kwavinjwa kakhulu yi-quinacrine, isivimbi se-phospholipase A(2), kanye ne-ketoconazole, isivimbi esikhethekile se-cytochrome P450 (CYP) 3A, kodwa hhayi yisulfaphenazole, isivimbi esikhethekile se-CYP 2C. Ngokuphambene ne-acetylcholine, ukuphumula okulawulwa yi-endothelium nokungalawulwa yi-indomethacin-kanye-L-NA okubangelwa yi-substance P akuzange kuvinjwe yizindlela eziphezulu ze-K(+), i-charybdotoxin kanye ne-apamin, noma i-ketoconazole. I-Quinacrine ne-AA861, isivimbi se-5-lipoxygenase, zavimbela ukuphumula okubangelwa yi-substance P. Kumthambo wegazi wenhliziyo yenkawu, ukuphumula okubangelwa yi-acetylcholine okungalawulwa yi-indomethacin kanye ne-L-NA kwasulwa ukususwa kwe-endothelial kanye nokusetshenziswa kwezindlela eziphakeme ze-K(+), i-charybdotoxin kanye ne-apamin, i-progesterone ne-ketoconazole, kodwa akuzange kuthintwe yi-iberiotoxin noma i-sulfaphenazole. I-Substance P ayizange iphumuze imithambo yegazi yezinhliziyo yezinkawu.

Hypothesis:
Kunqunywe ukuthi ukudeda okuncike endothelium, i-nitric oxide kanye ne-prostanoid -okungathembeli kuwona okubangelwe i-acetylcholine ezinsizeni zemithambo yenhliziyo yezinkawu kanye nezinja kudalwa yi-charybdotoxin kanye ne-apamin-sensitive kodwa i-iberiotoxin-insensitive Ca(2+)-activated K(+) channel yokuvula izinto, ezingaba i-CYP3A-derived arachidonic acid metabolite(s).


Premise:
Inhloso yethu kwakuwukuthola indima ye-Rho-associated kinase (ROK) ekulawuleni i-FBF (FBF) kanye nokuveza indima engaba khona ye-ROK ekulawuleni i-endothelium-derived nitric oxide (NO). Futhi, umphumela we-fasudil ekuphenduleni kokunciphisa ku-endothelin-1 yarekhodwa. Mayelana nesizinda, ukufosforileshana kwe-myosin light chain (MLC) kunquma ukukhathazeka kwe-calcium ekusebenzeni kwendlela yokuhweba. Ukufosforileshana kwe-MLC kuncike ekusebenzeni kwe-MLC kinase kanye ne-MLC phosphatase. Lesi sizini sokugcina sivinjelwa ngokufosforileshana nge-ROK. I-ROK kuphakanyiswe ukuthi ivimbela ukukhiqizwa kwe-NO, kungenzeka ngokuvimbela indlela ye-Akt. Kulolu cwaningo, umphumela wokungeniswa kwemboni ye-ROK inhibitor fasudil ku-FBF kubantu abanempilo abayishumi nambili kuhlolwe nge-venous occlusion plethysmography. Ukuveza indima ye-NO, i-fasudil ifakwe ngesikhathi se-NO clamp. Njengesiphumo, i-fasudil yenyusa kakhulu i-FBF ngendlela encike kwisikali kusuka ku-2.34 +/- 0.21 kuya ku-6.96 +/- 0.93 ml/100 ml yevolomu yengalo ku-80 mug/min (P < 0.001). Ku-1,600 mug/min, i-fasudil yanciphisa i-systolic, i-diastolic, kanye ne-mean arterial pressure ngenkathi yenyusa i-heart rate. I-fasudil yaqeda umthelela wokunciphisa imithambo we-endothelin-1. Ukuphendula kwemithambo ku-fasudil (80 mumol/min) kwaye kwaphazamiseka ngesikhathi se-NO clamp (104 +/- 18% vs. 244 +/- 48% ku-NO clamp + fasudil vs. fasudil yodwa; idatha njengebalazwe phakathi kwengalo efakiwe nengafakiwe ngesisekelo = 0%, P < 0.05).

Hypothesis:
Ekuphetheni, 1) i-basal peripheral kanye ne-systemic vascular tone incike ku-ROK; 2.34) ingxenye enkulu ye-vasodilation edalwa i-fasudil ihambisana ne-NO, okusho ukuthi i-vascular bioavailable NO ilawulwa ngokungemuhle i-ROK; futhi 3) isenzo se-constrictor esivela ku-endothelin sibandakanya ukuqaliswa kwe-ROK.


Premise:
Imiphumela yokukhulisa imithambo yeflunarizine kwizingcezwana zomsipha ontofontofo womthambo wegazi werebit isicweciwe iphenyisiwe futhi yaqhathaniswa naleso senifedipine. Iflunarizine (30-300 nM) ngokuya ngezinga lenani layo ivalile ukuqumba okubangelwa yi-Ca2+ emanzini angenayo i-Ca2+ anohlobo lwe-100 mM K+. Ukuhlaziywa okuyimpindampinda kabili kukhombisile ukuthi lokhu kuvalwa bekungokuncintisanayo emazingeni aphansi (30-100 nM; efana neyenifedipine) noma okungancintisani emazingeni aphezulu (0.3-1 microM). Eyasekugcineni ibonakale ihlobene kancane nokuvinjwa kwamaprotheyini okuhlukaniswayo njengoba kulingwa ngokuqumba okubangelwa yi-Ca2+ ezingcezwaneni zomsipha ezithwalwe ngokomkhiqizo zekhemikhali eziphathwe ngesaponin. Ngokuphikisana nezenzo zenifedipine, iflunarizine ivimbe ukuqumba okubangelwa yi-norepinephrine (NE) kakhulu kunalezo ezivuselelwa yi-K+ ephezulu, futhi ku-0.3 microM, lesi siphetho savalela ngokuphelele ukuqumba okubangelwa yi-NE. Iflunarizine iphinde yavimba ukuqumba okubangelwa yi-NE emanzini angena-Ca2+ aqukethe i-2 mM EGTA. Emanzini angena-Ca2+, i-NE ngokushesha ihlukahlukanisa i-phosphatidylinositol 4,5-bisphosphate (PI-P2) futhi ikhiqiza i-phosphatidic acid (PA). I-Flunarizine (30 no-300 nM), kodwa hhayi i-nifedipine (100 nM), ivimbe ukuhlakazwa kwe-PI-P2 okubangelwa yi-NE nokukhiqizwa kwe-PA. Kodwa-ke, i-flunarizine (100 nM) ayizange iguqule ukuqumba okubangelwa yi-10 microM ye-inositol 1,4,5-trisphosphate ezingcezwaneni zomsipha ozotsholwe ngekhemikhali.

Hypothesis:
Kuhlanganiswe ukuthi, ngokungafani ne-nifedipine, i-flunarizine emazingeni aphansi ivimba ukuqhunyelwa okubangwa yi-Ca2+ ngokuthikameza ukuhlakazwa kwe-PI-P2 okubangwa yi-NE kanye nokwakhiwa kwe-PA.


Premise:
Izinhlanzi ze-Teleost zikwazi ukuhlela ukuthatha kwazo kwamandla uma zidliwa emithonjeni emihle yemakronyuthienti, yize izindlela eziqondile ezilawula ukukhethwa kwemakronyuthienti zisasele zingakaziwa. Njengoba i-cholecystokinin (CCK) kubikwe ukuthi iguqula amaphethini okukhethwa kwemakronyuthienti ezilwaneni ezincela, sihlolisise umthelela we-CCK ephiwe ngomlomo kumaBass aseMediterranean ekukhetheni kwemakronyuthienti efakwe ngokwehlukana. Amazinga e-CCK angu-0.05, 0.15 kanye no-0.25 mg/kg BW ephiwe amakhasuli i-gelatine izinsuku ezi-5 zilandelana, adale ukuvimbela okukhulu kokuthatha ukudla okuphelele (21, 28 kanye nama-51%, ngokulandelana) emazingeni aphakeme kakhulu, kuyehlisa ngokulingana ubuningi bayo yonke imakronyuthienti edliwayo, futhi ngaphandle kokuphazamisa izinga labo elisebenzayo ekudleni. Ukunikezwa komlomo ngokwe-proglumide, inxubo yereseptha ye-CCK engaqondile, ngamazinga angu-5, 15 kanye nama-25 mg/kg BW, kudale ukunyuka kokuqiniseka kokuthatha ukudla okuphelele kuka-2, 18 kanye nama-44%, ngokulandelana, kanye nokunyuka kuka-52% ku-CH kanye nama-43% ku-P obuningi obathathiwe emazingeni aphakeme. Ukunikezwa okuhambisanayo kwe-proglumide (25 mg/kg BW) ne-CCK (0.25 mg/kg BW) kwikhasuli elilodwa elinikezwa kuqala kuvimbe imiphumela eyabonakala nge-CCK yodwa.

Hypothesis:
Njengoba sengiphetha, iproglumide ephuzwayo idale umthelela wokunciphisa indlala kwenani eliphelele lokudla kanye nokudla okunomsoco owodwa, umthelela ophikiswa yiproglumide antagonist iCCK.


Premise:
I-paraventricular hypothalamic nucleus (PVN) ibonakala ihlanganisa izici ezivusa indlala zephepha elisha, i-ghrelin. Ngakho-ke, sihlole izindlela ezimqoka ezingaphakathi ukudla okukhiqizwa yi-ghrelin elingiswa ku-PVN. Siqinisekise ukuthi 0.03 nmol ye-ghrelin elingisiwe ku-PVN kwakuyisikali esiphansi kakhulu esandisa ukudla futhi kwavusa i-c-Fos immunoreactivity (uphawu lokuqala kwezinzwa) kuyo i-PVN, kanye nakwezinye izindawo zengqondo ezihlobene nokudla, kufaka phakathi i-hypothalamic arcuate kanye nama-dorsomedial nuclei, i-central nucleus ye-amygdala, kanye ne-nucleus ye-solitary tract.

Hypothesis:
Siphetha ngokuthi i-ghrelin ivusa amaneuroni e-PVN nakwezinye izindawo zengqondo ezihlobene nokudla ukugqugquzela ukuthatha ukudla.


Premise:
I-Leptin idlala indima ebalulekile ekulawulweni komongameli wekhanda wama-bone mass. I-Ghrelin imelana ne-leptin. Kulolu cwaningo, sihlolile umthelela wokunikezwa kwe-ghrelin esikhathini eside ngaphakathi kwe-intracerebroventricular kwi-bone mass kumagundane e-Sprague-Dawley (1.5 μg/usuku isikhathi esiyizinsuku ezingu-21). Amagundane ahlukaniswe ngokwalaba: iqoqo elilawulayo, iqoqo le-ghrelin okudliwa kulinganiselwe (ghrelin ad lib-fed), kanye neqoqo le-ghrelin okudliwa kulinganisiwe. Ukujovwa kwe-ghrelin ngokwengeziwe ngokusebenzisa i-intracerebroventricular kwandisa isisindo somzimba kakhulu kumagundane e-ghrelin ad lib-fed, kodwa hhayi kumagundane e-ghrelin pair-fed, uma kuqhathaniswa namagundane elawulwayo. Ukujovwa kwe-ghrelin yesikhathi eside i-intracerebroventricular kwandisa kakhulu i-bone mass eqoqweni le-ghrelin pair-fed uma kuqhathaniswa nokungalawulwa njengoba kuboniswa ukwanda kwephesenti yamathambo, ubukhulu be-trabecular, inani le-trabecular kanye ne-volumetric bone mineral density ethambo le-tibia ye-trabecular. Kwakungekho umehluko omkhulu kwi-trabecular bone mass phakathi kweqoqo elilawulayo kanye neqoqo le-ghrelin ad-lib fed. Ukujovwa kwe-ghrelin yesikhathi eside i-intracerebroventricular kwandisa kakhulu i-mineral apposition rate eqoqweni le-ghrelin pair-fed uma kuqhathaniswa nokulawula.

Hypothesis:
Ekugcineni, ukuphathwa kwesikhathi eside kuka-ghrelin endaweni ephakathi kwandisa isisindo samathambo ngendlela engancikile ebukhulwini bomzimba, okubonisa ukuthi i-ghrelin ingaba nomthelela wokwakha amathambo ngokohlelo lwemizwa oluphakathi.


Premise:
Ukunikezelwa kwesistimu yecholecystokinin (CCK) noma i-LiCl kuvimba ukushukuma kwesisu kanye nokudla kokudla emagundaneni. Amanoroni e-oxytocin (OT) akhomba umsuka wesitemu yobuchopho ku-hypothalamic paraventricular nucleus (PVN) akhulunywa ukuthi amelana nemiphumela evimbayo ye-CCK ne-LiCl ekushukumeni kwesisu nasekudleni kokudla. Ezifundweni zamanje, sithole ukuthi ukushukuma kwesisu okuyisisekelo bekuphakeme emagundaneni emva kwamahora angu-12-20 ngemva kokulimala komshini osika imisipha ye-PVN; kodwa-ke, lo mphumela wanyamalala ezinsukwini ezintathu kamuva. Ngaphezu kwalokho, i-CCK ne-LiCl zavimba ukushukuma kwesisu emva kwamahora angu-12-20, ezinsukwini ezintathu, nezonto ezintathu ngemva kokulimala kwe-PVN, nakuba imiphumela yazo yabuthakathaka. Ukujova i-anesthetic yasendaweni i-lidocaine ngaphakathi kwe-PVN kwaba nemiphumela efanayo nokulimala okukhulu kwe-PVN. Emagundaneni anokulimala kwe-PVN, imiphumela evimbayo ye-CCK ne-LiCl ekudleni kokudla yayingafanani neyamagundane anokulimala kwesham.

Hypothesis:
Siphetha ngokuthi ukushukuma kwesisu kuvimba i-PVN futhi kuhlanganyela ekuvimbeleni, kodwa akubalulekile kakhulu, imiphumela evimbelayo ye-CCK ne-LiCl ku-PVN kanye nokudla kwemigomo emagundaneni.


Premise:
I-teleost salmon calcitonin (sCT), kodwa hhayi ama-CT asezilwaneni ezifuywayo, ibonisa izenzo ezifanayo ngokwebhayoloji emzimbeni wamathambo njengamylin ne-calcitonin gene-related peptide (CGRP). Amapeptide abonisiwe futhi ukuthi anciphisa ukudla okudliwayo ezinqameni. Ngenxa yokuthi i-sCT, kodwa hhayi i-amylin, ibopheka ngokungaguquki ezindaweni zokubopheka ze-amylin, inhloso yalolu cwaningo lwamanje kwakuwukuqhathanisa amandla okuphungula ukudla awo womabili amapeptide. Ukuze kuthiwe i-sCT iphungula ukudla ngokuxhumana nezindawo zokubopheleka ze-amylin, siphinde sahlola ukuthi ama-antagonist afanele (CORP 8-37, AC 187) ayancipha yini umthelela wokunciphisa ukudla we-sCT. Okokugcina, besifuna ukwazi ukuthi i-rat calcitonin (rCT) ne-sCT zinciphisa ukudla ngendlela efanayo yini. Amapeptide ajovwe ngaphakathi esiswini ekuqaleni kobumnyama kumagundane ayengadlanga ukudla amahora angu-24. Ezingeni elingu-5 noma 0.5 microg/kg, umthelela wokunciphisa ukudla we-sCT wawunamandla kakhulu futhi wathatha isikhathi eside kakhulu (isibonelo 5 microg/kg: sCT > 10 h; amylin cishe 2 h) kunalowo we-amylin. Kokubili i-CORP 8-37 ne-AC 187 (10 microg/kg) kwancipha kakhulu isenzo sokunciphisa ukudla se-sCT (0.5 microg/kg). Ngokuphambene ne-sCT, i-rCT (0.5 microg/kg) yayingenawo umthelela ekudleni.

Hypothesis:
Ekuphetheni, ukusebenza kwe-sCT okumandla kakhulu nokudala isikhathi eside ekwehliseni indlala kunalokho kwe-amylin kusho ukuthi i-sCT yehlisa ukudla ngokusebenzisana nezindawo zokubopheka ze-amylin.


Premise:
Ukuphonswa kwabamukelisi be-purinergic nge-ATP kanye nokuvuselela kwesikhuthi sokudlulisela i-cystic fibrosis (CFTR) kunqanda ukuthuthwa kwe-Na+ okuzwela i-amiloride futhi kuvuselele ukukhipha i-Cl-. Lezi zinguquko ekuthuthweni kwe-ion zingathinta ukukhula kweseli. Ngakho-ke sahlola ukuthi ukuncipha kweseli noma ukudumba kweseli kuthinta ukuthuthwa kwe-Na+ okuzwela i-amiloride ezinsikeni ze-epithelial noma oocytes zama-Xenopus futhi nokuthi ingcindezi ye-osmotic ingaba nemphumela ekulawulweni kokuthuthwa kwe-Na+ nge-ATP noma i-CFTR. Ukuphonswa kwabamukelisi be-purinergic nge-ATP/UTP noma ukuvuselelwa kwe-CFTR nge-IBMX ne-forskolin kunqande ukuthuthwa okuzwela i-amiloride empinjeni nasekuphethweni komusi wezimpuku, ngendlela eyayincike ku-Cl-. Uma kubhekwa isixazululo se-hypertonic kodwa hhayi i-hypotonic, ukuthuthwa kwe-Na+ okuzwela i-amiloride kwanqandwa empinjeni nasekuphethweni komusi wezimpuku, okungancikile enanini le-Cl- yangaphandle. Ukuncishiswa kokuthuthwa kwe-Na+ ngezixazululo ze-hypertonic kanye ne-ATP kuyahlanganiseka. Uma kuhlanganyiswa ama-oocyte e-Xenopus, ukuvuselelwa kwe-CFTR nge-IBMX ne-forskolin kunqande isitshalo se-epithelial Na+ (ENaC) ngendlela encike ku-Cl-. Kodwa-ke, isixazululo se-hypertonic kanye ne-hypotonic sikhombise nje kuphela imiphumela encane ekushintsheni okuzwela i-amiloride, okungancikile ku-Cl- yesixazululo. Ngaphezu kwalokho, ukunqandwa kwe-ENaC okubangelwa yi-CFTR kungabonakala ema-oocytes noma emva kokubhekana nezixazululo ze-hypertonic noma ze-hypotonic.

Hypothesis:
Siphetha ngokuthi ukumunca i-Na+ okuvinjwa yi-amiloride emaphashini nasekholoni yegundane kunqandwa ukuncipha kwamaseli ngendlela engaphazamisi ukuvimbeka kwe-ENaC okubangelwa yi-purinergic ne-CFTR.


Premise:
Ukumunca kwe-NaCl ngendawo ephakeme evukayo (TAL) kufaka ukuthutha okusemsebenzini futhi ngakho-ke kuncike ekuhlinzekweni kwe-oxidative. I-ATP engaphandle kweseli inezinto eziningi, kufaka phakathi ukuqhubela phambili nokuvimba ukuthutha nokuvimba i-oxidative phosphorylation. Nokho, akucacile ukuthi i-ATP iguqula kanjani ukuthutha kwe-TAL nokuthi lokhu kwenzeka kanjani. Siqagele ukuthi i-ATP ivimba ukumuncwa kwe-Na kwe-TAL ngokunciphisa ukungena kwe-Na. Sikale ukusetshenziswa kwe-oxygen emisebeni ye-TAL. I-ATP yanciphisa ukusetshenziswa kwe-oxygen ngendlela encike ekuhlanganisweni. Umvimbi we-purinergic (P2) receptor i-suramin (300 microM) wavimba umthelela we-ATP ekusetshenzisweni kwe-oxygen kwe-TAL (147 +/- 15 vs. 146 +/- 16 nmol O2 x min(-1) x mg protein(-1)). Ngokuphambene nalokho, umvimbi we-adenosine receptor i-theophylline awuzange ublocke umthelela we-ATP ekusetshenzisweni kwe-oxygen. Lapho okokuthutha i-Na-K-2Cl kanye nokushintshana kwe-Na/H kublokhwe nge-furosemide (100 microM) kanye ne-dimethyl amiloride (100 microM), i-ATP ayizange ivimbe ukusetshenziswa kwe-oxygen kwe-TAL (kusuka ku-78 +/- 13 kuya ku-98 +/- 5 nmol O2 x min(-1) x mg protein(-1)). I-Na ionophore i-nystatin (200 U/ml) yandisa ukusetshenziswa kwe-oxygen kwe-TAL esikaleni esifanayo kuzo zombili izibonelo eziphathwe nge-ATP kanye neziphathwe ngesikhwama (368 +/- 41 vs. 397 +/- 47 nmol O2 x min(-1) x mg protein(-1)). Umvimbi we-nitric oxide synthase i-NG-nitro-L-arginine methyl ester (3 mM) wavimba imiphumela ye-ATP ekusetshenzisweni kwe-oxygen kwe-TAL (157 +/- 10 vs. 165 +/- 15 nmol O2 x min(-1) x mg protein(-1)). Umvimbi we-P2X-selective receptor i-NF023 wavimba umthelela we-ATP ekusetshenzisweni kwe-oxygen, kanti i-P2X-selective agonist i-beta-gamma-Me-ATP yanciphisa ukusetshenziswa kwe-oxygen ngendlela encike ekuhlanganisweni.

Hypothesis:
Singaphothula ngokuthi i-ATP ikhuthaza ukusetshenziswa kwe-oxygen ehambisana nokuthuthwa kwe-Na eziceleni zeTAL ngokunciphisa ukungena kwe-Na kanye nabamukelisi be-P2X kanye ne-nitric oxide baba nomthelela ekwenzeni lokhu.


Premise:
Sikhombisile ngaphambilini ukuthi ukuvimbela i-protein-tyrosine kinase kwandisa kanti ukuvimbela i-protein-tyrosine phosphatase (PTP) kunciphisa umsebenzi we-renal outer medullary potassium channel 1 (ROMK1) (1). Manje sisebenzise i-confocal microscopy, indlela ye-patch clamp, kanye nokumaka nge-biotin ukuhlola kabanzi indima yokufosforileyithwa kwe-tyrosine ekulawuleni ukuhamba kwe-ROMK1. Amaseli e-Human embryonic kidney 293 ahlanganiselwe nge-c-Src kanye ne-green fluorescent protein-ROMK1, enezimpawu zebhayofizikhi ezifanayo nalezo ze-ROMK1. Izifundo ze-patch clamp zikhombisile ukuthi i-phenylarsine oxide (PAO), isivimbeli se-PTP, sinciphisa umsebenzi we-ROMK1. Ngaphezu kwaloko, ukwengeza i-PAO kunciphise ukuma kweseli ebusweni be-green fluorescent protein-ROMK1 okuhlolwe nge-confocal microscopy futhi kwanciphisa ukujula kwe-ROMK1 ebusweni ngo-65% okukalwe ngokumaka kwe-biotin. Futhi, ukwelashwa nge-PAO kwandise kakhulu ukufosforileyithwa kwe-ROMK1. Umbono wokuthi umphumela we-PAO ubangelwa ukugqugquzela ukungena kwe-ROMK1 okuphasiswa ukufosforileyithwa kwe-tyrosine usekelwe futhi ngokutholakala kokuthi ukushintsha i-tyrosine residue 337 ye-ROMK1 ibe yi-alanine kwashabalalisa umthelela we-PAO. Okokugcina, umthelela ovimbelayo we-PAO ku-ROMK1 wavinjwa ngokuphelele emaseline ahlanganiselwe ne-dominant negative dynamin (dynaminK44A). Lokhu kukhombisa ukuthi ukungena kwe-ROMK1 okuphasiswa ukufosforileyithwa kwe-tyrosine kuncike ku-dynamin.

Hypothesis:
Siphetha ngokuthi i-PTP ikhuthaza i-endocytosis ye-ROMK1 ngendlela encike ku-dynamin.


Premise:
I-Butyrate ithuthukisa ukumunca usawoti ethunjini elikhulu lezilwane ongazincelisayo. Sihlole ukuthi ngabe i-butyrate iphinde ibe nomthelela ekukhipheni i-Cl-. Izingxenye zempilo ezithinta isinyasinyakhekazi somncintiswano zabafana be-Sprague-Dawley kanye namaseli e-T84 zafundwa emagunjini e-Ussing. Ethunjini elikhulu elingekho ngaphansi kokulawulwa, i-1 mM dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) yenyusa isibalo esincane esijikelezayo (Isc) kanye nokugeleza kwe-Cl- kusukela esikhumbeni kuya esikhupheni (JsmCl) ngo-3.2 +/- 0.8 kanye no-2.9 +/- 0.8 mueq.cm-2.h-1, ngokulandelana. I-25 mM ye-butyrate esemukhosini noma ekhumbeni ivimbela ukwenyuka kwe-Isc ne-JsmCl okubangelwe yi-DBcAMP. I-butyrate ye-4 kanye ne-8 millimolar ibangela ukuncishiswa okunguhhafu kokwenyuka kwe-JsmCl ne-Isc, ngokulandelana. I-butyrate iphinde ivimbele i-JsmCl eyisisekelo (ngo-2.0 +/- 0.4 mueq.cm-2.h-1) kodwa hhayi ukukhipha i-Cl- okuhlanganiswe ne-carbachol. Amandla okuvimbela ahlobene ku-25 mM amanye ama-short-chain fatty acids (SCFA) ahambisana nezinga lokuguqulwa kwawo ezinhlayiyeni: butyrate > acetate = propionate > isobutyrate. Ku-25 mM, zonke ama-SCFA anciphisa i-intracellular pH (pHi) emukhosini okwesikhashana ngeyunithi ye-pH e-0.1. Emaseline e-T84 aphelele, i-50 mM butyrate ivimbele ukwenyuka kwe-Isc okubangelwe yi-DBcAMP ngo-55%. Emaseline e-T84 anesikhumba esibhobokile ngenxa ye-nystatin, i-butyrate ivimbele ukwenyuka kwe-Isc ngo-82%.

Hypothesis:
Siphetha ngokuthi i-butyrate ithuthukisa ukukhishwa kwe-Cl- okuyisisekelo kanye nalokho okuhambisana ne-cAMP ngendlela engaxhumene ne-pHi, okungenzeka ukuthi itholakala emaphuzwini we-membrane.


Premise:
Njengoba izinqandamaketho zokukhipha i-anion zikhiqiza izici ezibalulekile zesifo sesifuba se-cystic fibrosis (CF), imiphumela yalezi ziphikisi ekubukekeni komhlehlo womgudu wokuphefumula yahlolwa emaphashini ezingulube ezihlukanisiwe ezigcwalisiwe. Amazinga aphezulu okuphazamisa e-bumetanide ne-dimethylamiloride, okuvimba ngokulandelana ukukhishwa kwe-Cl- ne-HCO3- emithambo yomoya engulube, kwadala ukwakheka komhlehlo oqinile "oplastariwe" phezu kwendawo yomgudu womoya, ukuncipha kwesikhulukhulu esiyinhlayiya periciliary kanye nokuwa kwe-cilia. Lo miphumela yayisobala kakhulu uma amaphaphu ayebhekene nayo ne-bethanechol ukuze kukhuthazwe ukukhishwa kwezindlala esingaphansi kwesikhumba, lapho umhlehlo oplastariwe wamboza > 98% wendawo yomgudu womoya. I-bethanechol yaphinde yanciphisa okuqukethwe kwemicin yamajubane ezindlala ekungekho, kodwa hhayi phambi, kwezinqandamaketho zokukhipha i-anion. Izinqandamaketho zokukhipha i-anion azidalanga ukukhula okukalekayo ekukhishweni kwesibhobho esibhekelela uketshezi.

Hypothesis:
Siphetha ngokuthi ukuvimbeleka kokukhishwa kwe-anion kanye noketshezi emaphashini ezingulube kuphazamisa ukuma okujwayelekile kwesikhupha saphezulu komgudu womoya, okunikeza ubufakazi obuthe xaxa bokuthi ukuphazamiseka kokukhishwa kwe-anion kuphela kungenzeka kudale izici ezinkulu zesifo samaphaphu e-CF.


Premise:
Sikhombisile ukuthi i-vitamin A (VA) kanye ne-retinoic acid (RA) kuhlanganisa kukhulise okuqukethe i-retinyl ester emaphashini emantshontshaneni amagundane. Ukuqinisekisa ukuthi lokhu kuhlanganisa ngokwamakhemikhali kunciphisa ukulimala kwamaphaphu e-hyperoxic kumasendlana asanda kuzalwa, sihlolile amasendlana asanda kuzalwa e-C57BL/6 ku-95% O2 noma emoyeni kusukela ekuzalweni kuya ezinsukwini ezingu-4. I-ejenti [isikhululi, VA, RA, noma inhlanganisela ye-vitamin A+retinoic acid (VARA)] yanikwa ngomlomo nsuku zonke. Okuqukethe i-retinyl ester kwamaphaphu nesibindi kwakalwa, futhi ukulimala nokuthuthuka kwamaphaphu kwahlolwa. Siqaphelile ukuthi amazinga e-retinyl ester emaphashini, kodwa hhayi esibindini, akhuliswa kakhulu yi-VARA kunokuba yi-VA noma i-RA yodwa. Ukulimala kwamaphaphu kwe-hyperoxic kwancipha nge-VA ne-RA, futhi kakhulu nge-VARA. I-VARA yanciphisa ukwanda kwe-macrophage inflammatory protein (MIP)-2 mRNA nokukhiqizwa kwe-protein okwadalwa yi-hyperoxia, kodwa ayishintshanga imiphumela yehyperoxia kuma-peptide growth factors (PDGF, VEGF, kanye ne-TGF-beta1). Ukuvezwa kwamaphaphu ku-hyperoxia noma ku-retinoids izinsuku ezingu-4 akuzange kuholele ekuboneni izinguquko ekuthuthukeni kwamaphaphu.

Hypothesis:
Sigcina ngokuthi inhlanganisela ye-VARA inemiphumela yokusebenzisana ekuqoqekeni kwe-retinyl ester emaphashini kanye nasekunciphiseni ukulimala kwamaphaphu okubangelwa yi-hyperoxia kumagundane asanda kuzalwa, kungenzeka ngokuhlela izakhi ezibangela ukuvuvukala.


Premise:
Amakhemikhali ahlukahlukene akhonjisiwe ukuthi akhuthaza ukuguquguquka kwefosfolipidi yesurfactant. Ikakhulukazi ama-beta-adrenergic agonists adlala indima ebalulekile ngaphansi kwezimo ezijwayelekile. Okokuqala sifundile ukuthi ukunukubezwa kwe-nitrogen dioxide (NO2) kuguqula ukulawulwa kwe-beta-adrenergic kwemetabolism ye-surfactant phospholipid kulesi sifaniso sephaphu elihlukanisiwe. Amagundane abhekelwa ngokuqhubekayo ku-atmosphere equkethe i-5 ppm NO2 amahora angu-48. Amaphaphu ahlukaniswa aphinde aniselelwe ngokukhona kwe-beta-adrenergic agonist i-dopexamine, kanti imetabolism yesurfactant yafundwa ezigabeni ezintathu zephaphu: (1) ukugezwa kwephaphu, (2) isakhiwo sephaphu, (3) amasosha anukubezekayo ephaphu. Sithole ukuthi (1) emaphashini ajwayelekile egundane i-dopexamine yandisa ukufakwa kwe-palmitate ne-choline esuka kuperfusate ingene ku-lung lavage phospholipids. Emaphashini amagundane anomkhuhlane we-nitrogen dioxide, ukukhuthazwa kwe-beta-adrenergic akubanganga ukwanda kokufakwa kwempumela. Asikho isibalo esibalulekile sokungafani kokufakwa okungakhuthazwanga kwemphumela okutholakale kumaphaphu ajwayelekile negundane elivelele ku-NO2. (2) Isakhiwo sephaphu samagundane avelele ku-NO2 sakhombisa ukuncipha kokufakwa kwemphumela ku-disaturated phosphatidylcholine ngenxa yokukhuliswa kwe-cellular pool size. (3) Amasosha anukubezekayo ephaphu akhombise ukwanda kokuthathwa kwe-palmitate ngemuva kokunukubezwa kwe-nitrogen dioxide nangokukhuthazwa kwe-beta-adrenergic.

Hypothesis:
Kulolulwazi sifinyelelise ekutheni ukuphefumulisa i-NTG kukhubaza ukulawulwa kwe-beta-adrenergic kwemetabolism ye-phospholipid ye-surfactant.


Premise:
Silawule i-bolus ye-G-CSF (amamayikhrogramu angu-250/umzimba) masinyane ngemuva kokuthululwa kwe-endotoxin (1 mayikhrogramu/kg) ezimvini eziqaphile ezine-fistula yokuphuma kweketshezi emaphashini ukuhlola umthelela wokwelapha nge-G-CSF ngemuva kokufakwa kwe-endotoxin olimaleni lwamaphaphu. Silinganise ukusebenza kwemithambo yegazi emaphashini, ukugeleza kweketshezi lamaphaphu, kanye namazinga e-thromboxane B2 ne-6-keto-prostaglandin F1 alpha eplasmeni naseketshezini lamaphaphu. Eqenjini elaphiwe nge-G-CSF ngemuva kokufakwa kwe-endotoxin, umfutho wemithambo yegazi yamaphaphu, ukumelana kwemithambo yamaphaphu, kanye nokugeleza kweketshezi lamaphaphu akukhulanga kakhulu esikhathini esilandelayo (amahora angu-3-5 ngemuva kokufakwa kwe-endotoxin). Izinga lomoya we-oxygen egazini esikhathini esilandelayo laliphakeme ezimvini ezilashelwe nge-G-CSF kunazo lezo ezithole kuphela i-endotoxin. Yize izinga le-thromboxane B2 eplasmeni linyuke kakhulu ngehora elingu-1 ngemuva kokufakwa kwe-endotoxin, ukugeleza kweketshezi lamaphaphu akukhuphukanga kangako eqenjini elilashelwe nge-G-CSF ngemuva kokufakwa kwe-endotoxin.

Hypothesis:
Siphetha ngokuthi ukwelapha nge-G-CSF emva kokuhlaselwa kuvimbela ukulimala kwamaphaphu okubangelwa yi-endotoxin.


Premise:
Ababhemi botshwala bavamise ukubonisa ukwenyuka kokusebenza kwemigudu yomoya ephakeme (AHR) lapho bebhekene nezifo zamagciwane. Ucwaningo lwamanje lusebenzisa isibonelo sokulinga izitho zezilwane (zi-murine) ukuhlaziya izindlela ezisetshenziswayo kule mpendulo eyeqile yamisipha ethambile. I-Nicotine ilingisa imiphumela yokubhema, futhi i-LPS imele isifo segciwane. Izimpendulo zokuhweba kwezicubu zamabhamuza ezilwane ezihlukanisiwe zahlaziywa kwi-myographs ngemva kokulingelela izitho nokunyuka kwamazinga e-LPS kanye/noma i-nicotine izinsuku ezingu-4 ngaphandle kokunqanda i-MAPK okuthile. Umthelela we-nicotine ekubonakalisweni kwama-Toll-like receptors (TLRs) angaphezulu kweseli, i-MCP-1, i-COX-2, kanye ne-TNF-α kuhlolwe nge-real-time PCR. Ukwanda kokuboniswa kwe-protein kuqinisekiswe nge-immunohistochemistry. I-LPS ngokuncike ekuqhubekeni kwandisa izimpendulo zokuhweba ku-bradykinin ne-des-Arg(9)-bradykinin. Inhlanganisela ye-nicotine ne-LPS esezingeni eliphansi ibangele ukuhweba okunamandla okuhlangene kanye nokwanda kokubonakala kwe-kinin receptor. Izinqandi ezithile ze-kinin B1 ne-B2 receptor zivimbe le mpendulo. I-Nicotine yandisa i-mRNA nokubonakala kwe-protein ye-TLR4 ne-6 kwi-epithelium nesigaba sesiqa esthambile, kanye ne-MCP-1 ne-COX-2 mRNA okwanda ngokulinganayo. Ukunqanda okuqondile kwe-JNK kunciphisa imiphumela ye-nicotine.

Hypothesis:
Ekugcineni, ukuchayiseka isikhathi eside e-nicotine kwandisa ukuvezwa kwe-TLR4 ne-6 ngendlela ehlobene ne-JNK, okubangela ukwandiswa kokuvuvukala kwemizwa yomoya yasendaweni okubangelwa yi-LPS kanye nokwanda kwe-AHR.


Premise:
Ukuqhathanisa imiphumela ye-epidermal growth factor (EGF) kanye ne-betamethasone ekukhuleni kwesakhiwo sesigaba sokushintshisana kwegas kanye nokwahlukaniswa kwe-alveolar type II cell ngesikhathi sokuthuthuka kwamaphaphu esisu, amagundi esisu e-rhesus (78% wesikhathi sokukhula) ayelashwa esizalweni nge-EGF (5.33 mg/kg isamba samadozi), beta-methasone (2.6 mg/kg isamba samadozi) noma i-carrier, i-saline (control), zonke ezinye izinsuku isikhathi esiyizinsuku eziyisi-7. Amagundi alashwa nge-EGF aba nokukhula kwesisindo somzimba namadlozi ezinso okwakubalulekile. Amagundi alashwa nge-betamethasone aba nokwehla kwesisindo somzimba namadlozi ezinso okubalulekile. I-EGF yangaphandle yanciphisa i-cytoplasmic glycogen yase yandisa izitho zama-cytoplasmic kanye nokuqukathwa kwe-SP-A phakathi kwama-alveolar type II cells. Ngokuphambene, i-betamethasone yangaphandle ayizange ishintshe i-alveolar type II cell cytodifferentiation. Ukwelashwa nge-EGF noma i-betamethasone akuzange kushintshe kakhulu isakhiwo sesigaba sokushintshisana kwegas njengoba kukhombiswe ukungabi khona koshintsho kwabakuphatha ekukhuleni kwesikhala somoya we-alveolar noma engxenyeni yesigaba sokushintshisana kwegas eyayiyisikhala somoya esipotenshiyali.

Hypothesis:
Siphetha ngokuthi emazingeni asebenzayo emitholampilo, i-EGF isheshisa kakhulu ukuvuthwa kwamaseli e-alveolar uhlobo lwesibili, kanti i-betamethasone ayikwenzi lokho.


Premise:
I-Dravet syndrome (DS) iyisifo esibucayi sokuqhuma kwezinsuku zokufika ebuntwaneni okuvame ukubangelwa izinguquko zegene leziteshi zamandla i-SCN1A. Iziguli ezine-DS zinengozi ephakeme yokufa okungachazeki okuqhushini (SUDEP), okukholakala kabanzi ukuthi kubangelwa izinhlelo zenhliziyo. Lapha sibonisa ukuthi iziguli ezine-DS zivame ukuba nokungasebenzi kahle kokuphefumula ngesikhathi sokuqhuma. Isiguli esisodwa saba nokungaphefumuli kahle okubi futhi okusikhathi eside ngemuva kokuqhuma ngesikhathi sokubhekwa kwe-video EEG futhi safa kamuva ngenxa ye-SUDEP. Amagundane ane-Scn1aR1407X/+ uguquko lokulahleka komsebenzi abhekelwa futhi afa ngemuva kokuqhuma okuzenzekele kanye nokubangelwa ukushisa ngenxa yokuphela kokuphefumula okulandelwa ukushaya kancane kwenhliziyo okuthuthukayo. Ukufa kwakungavinjelwa ngomshini wokuphefumula emva kokuqhuma okubangelwe ukushisa okuphakeme noma ugesi omkhulu. Iziphikisi zokwamukela i-muscarinic aziwuvinjelanga umshayelo obuthakathaka wenhliziyo noma ukufa uma zinikwe ngezinga elikhethekayo lokuvimba i-parasympathetic ephezulu, kodwa ukuma kokuphefumula, umshayelo obuthakathaka wenhliziyo, kanye nokufa kwavinjwa yizidakamizwa ezifanayo ezinikezwe ngamazinga aphezulu ngokwanele ukweqa isithiyo segazi-bongizinhlamvu. Uma kunikezwe ngokuthelwa kwe-intracerebroventricular ngesisindo esiphansi kakhulu, isiphikisi sokwamukela i-muscarinic savinjelwa ukuma kokuphefumula, umshayelo obuthakathaka wenhliziyo, kanye nokufa.

Hypothesis:
Siphetha ngokuthi i-SUDEP ezigulini ezine-DS ingabangelwa ukuma komoya okuvela engqondweni ngqangi, okungabangela i-bradycardia, okungahle kube ngenxa yomphumela oqondile we-hypoxemia kumisipha yenhliziyo.


Premise:
I-Autosomal dominant hereditary spastic paraplegia (AD-HSP) iyisifo esihlobene ngokwezofuzo negenetically heterogeneous neurodegenerative disorder eqondene nokwanda kokugwinyeka kwezicubu ezingezansi. Indawo ye-SPG4 ku-2p21-p22 ithatha 40-50% yazo zonke izihlobo ze-AD-HSP. Ijini le-SPG4 ibonwe kamuva nje. Ivela yonke indawo kumathishu abantu abadala nabasathuthuka futhi yakha i-spastin, i-ATPase yomndeni we-AAA. Manje sesibonile ukuguquka okune okusha kwe-SPG4 emindenini yaseJalimane ene-AD-HSP, kumbandakanya umndeni omkhulu okuthiwa unokwanda kwesifo. Izinguquko zibandakanya ukushintsha kwesisekelo esisodwa (frame-shift mutation) kanye nokushintsha kwemisindo eyodwa (missense mutation), zombili zithinta i-Walker motif B. Ezinye izinguquko ezimbili zithinta izindawo ezimbili zokuhlanganisa (donor splice sites) kwi-intron 12 kanye ne-16, ngokulandelana. Ukuhlaziywa kwe-RT-PCR kwalezi zinguquko zombili ezindaweni zokuhlanganisa kwaveza ukweqiwa kwe-exon nokuncishiswa kokuzinza kokuhlanganiswa okungaqondile kwe-mRNA ye-SPG4. Zonke izinguquko kulindeleke ukuthi zibangele ukulahleka kwesakhiwo somsebenzi wephrotheni.

Hypothesis:
Siphetha ngokuthi i-AD-HSP ibangelwa ukuphela komsebenzi ngenxa yezinguquko ku-SPG4.


Premise:
I-Joubert syndrome (JBTS) iwukuhleleka okuyinhloko okuqhamuka ngokuthuthukiswa okubizwa nge-autosomal-recessive, okubonakala ngokungahlangani kahle kwezingxenye ezithile zobuchopho, i-oculomotor apraxia, ukuphefumula okungalungile, ukuhluleka ekuthuthukeni, kanye ne-ataxia. I-JBTS iwukuhleleka kwe-ciliopathy okuhlanganisa amaphethini amaningi wofuzo. Safuna ukuchaza isimo sofuzo esihambisana ne-JBTS kubantu base-French Canadian (FC). Safunda abantu abangama-43 base-FC abane-JBTS abavela emindenini engama-35 ngokuhlanganisa ukuhlola i-targeted kanye ne-exome. Sathole ukuguquka kwamajini okuyingozi (imindeni engama-32) noma ukuguquka okungaba yingozi (imindeni engama-2) kumajini ahambisana ne-JBTS kubo bonke laba bantu, ngaphandle koyedwa. Kulowo, sathola ukuguquka kwe-homozygous splice-site (c.735+2T>C) ku-CEP104. Kuyathakazelisa, sathole abanye abantu ababili abane-JBTS okungabantu base-FC abanemithelela ku-CEP104; omunye walaba bantu unomthelela wokunganakwa okuthola komama (c.496C>T [p.Arg166*]) kanye nomthelela we-splice-site wokuthuthuka kabusha (c.2572-2A>G), kanti omunye unomthelela we-homozygous frameshift (c.1328_1329insT [p.Tyr444fs*3]) ku-CEP104. Ucwaningo olwedlule lukhombise ukuthi i-CEP104 ihamba isuka ku-mother centriole iye ekugcineni kwe-primary cilium ngesikhathi se-ciliogenesis. Ukuncipha kwe-CEP104 emasosheni e-retinal pigment epithelial (RPE1) kuholele ekungasebenzi kahle kwenqubo ye-ciliogenesis. Lokhu kucwaninga kukhombisa ukuthi i-CEP104 isebenza kusaqala inqubo yokwakheka kwe-cilia ngokuqondisa ukuguquka kwe-mother centriole ibe yi-cilia basal body.

Hypothesis:
Siphetha ngokuthi i-FC JBTS ibangelwa ukuguquka kwezakhi zofuzo ku-CEP104.


Premise:
Izinguquko ne-polymorphisms kusayensi ye-RET gene ziyimbangela enkulu yesifo se-Hirschsprung (HSCR). Ngokwethiyori, bonke iziguli ezinempumela eyingxube (heterozygous) ezinesifo esisha esidalwa yimfuzo kufanele zibe nabazali abanesimo semfuzo exubile (genetic mosaicism) ezingeni elithile. Kodwa-ke, akukaze kubikwe ngesimo semfuzo exubile kwi-RET gene kusifo se-HSCR kuze kube manje. Ngakho-ke, sihlaziye imindeni enezinguquko ku-RET gene ukuthola isimo semfuzo exubile kubazali beziguli. Amasampula egazi athathwa ezigulini ezine-HSCR kanye nemindeni/nabazali bazo ukuhlaziya i-RET coding region. Emkhatsini wemindeni eyi-125 ene-HSCR, imindeni engama-33 enezinguquko zokuguquka kwe-RET yahlaziywa. Kumndeni oyedwa, sithole inguquko ye-frameshift ngenxa yokulahlekelwa okukodwa ohlelweni lwe-cytosines ezine kwi-codon 117/118 ye-RET gene (c.352delC) okuholela kwinguquko ye-frameshift eprothenini (p.Leu118Cysfs*105) eyathinta abantwana ababili bendlu eyodwa. Kusampula legazi likayise ongenaso isifo sithole isimo semfuzo exubile saloluguquko, okwaqinisekiswa kumasampula amabili azimele amathe nezimpande zezinwele. Ukubalwa kwezinga lokuphakami kwe-peak nokusiqhathanisa nezinhlanganisela ezahlukene ze-DNA ye-plasmid ejwayelekile neshintshiwe kukhombisa ukuthi inguquko yenzeka esimweni sasenduleleni sika-morula sesungulwayo, phakathi kwezigaba ezine nezigaba eziyisishiyagalombili zamaseli.

Hypothesis:
Ekugcineni, sithole ukuguquka kombhobho wefreymu (frameshift mutation) egenini ye-RET okwabangela i-HSCR kubazali bakhe.


Premise:
AmamiRNA (miRNAs) abandakanyeka ekuqhubekeni nasekuvalweni kwezifo ezahlukene ngokuvimbela ukuhunyushwa kwama-mRNA okuhlosiwe. Ngakho-ke, ukuguqulwa kwebhayojenisisi yemiRNA kuholela ezisweni eziningana. I-nuclear factor 90 (NF90)-NF45 complex yaziwa njengomsebenzi ongemuhle emiRNA biogenesis. Lapha, sikhombise ukuthi izilwane ezinalomklamo wofuzo we-NF90-NF45 double-transgenic (dbTg) zithuthukisa ukukhinyabeza kwezicubu zemisipha kanye namafayibha ezicubu emisipha yasentendeni ngesikhathi sobudala. Ngemuva kwalokho, sithole ukuthi amazinga amamiRNA emisipha, kumbandakanya imiRNA 133a (miR-133a), ekhuthaza ukuvuthwa kwezicubu zemisipha, behlile kakhulu kwimisipha yezilwane ze-NF90-NF45 dbTg uma kuqhathaniswa nalowo wezilwane zohlobo lwemvelo. Kodwa-ke, amazinga emibhalo yokuqala yama-miRNA (pri-miRNAs) ayephakeme ngokucacile kwizilwane ze-NF90-NF45 dbTg. Lo mphumela ukhombise ukuthi i-NF90-NF45 complex icindezele ukukhiqizwa kwemiRNA ngokuvimba ukucutshungulwa kwe-pri-miRNAs. Lokhu kutholakele kusekelwe yiqiniso lokuthi ukucutshungulwa kwe-pri-miRNA 133a-1 (pri-miR-133a-1) kuvinjwe ngokubophezelwa kwe-NF90-NF45 kwi-pri-miRNA. Okokugcina, izinga le-dynamin 2, ijini elibangelayo ye-centronuclear myopathy futhi ngokufanayo okuhlosiwe kwe-miR-133a, linyukile kwizicubu zemisipha yezilwane ze-NF90-NF45 dbTg.

Hypothesis:
Uma kubekwa ndawonye, siphetha ngokuthi i-myopathy complex ikhuthaza i-centronuclear NF90-NF45 ngokukhulisa ukubonakalisa kwe-dynamin 2 ngenxa yokuphunguka kokubonakalisa kwe-miR-133a okubangelwa yi-myopathy kwezinga le-in vivo.


Premise:
I-pulmonary hypertension (PH) ebesekhona ngaphambili ihambisana nemiphumela emibi ngemuva kokuthungela i-surgical mitral valve ukuze kulungiswe i-functional mitral regurgitation (FMR). Kodwa-ke, umthelela wayo kwezokwelapha i-MitraClip awukaziwa. Inhloso yalolu cwaningo kwakungukuhlola umthelela we-PH ebesekhona ngaphambili ekwelapheni i-MitraClip kwiziguli ezine-FMR. Kwafundwa iziguli ezingu-91 ezilandelanayo ezine-FMR futhi ezenzela inqubo ye-MitraClip. Zahlukaniswa zamaqembu amabili ngokususela kwi-pulmonary artery systolic pressure: iqembu le-PH (n = 48) neqembu elingenayo i-PH (n = 43). I-PH yachazwa njenge-pulmonary artery systolic pressure engaphezu kuka-50 mm Hg kusetshenziswa i-Doppler echocardiography. Impumelelo yenqubo (echazwe njengokuphungulwa kwe-magnetic resonance kufike ku-grade 2+ noma ngaphansi) kanye nokufa kuzinsuku ezingu-30 kwakufana kumaqembu womabili. Ezinyangeni ezingu-12, i-New York Heart Association functional class yayisithuthukile yafika ku-class I noma II kuningi lweziguli ezinePH (kusuka ku-2.9% kuya ku-94.3%) nezingenayo i-PH (kusuka ku-9.4% kuya ku-96.9%). I-mean pulmonary artery systolic pressure yeqembu le-PH yehlile kakhulu kusukela ekuqaleni kodwa yahlala iphakeme kuneyeqembu elingenayo i-PH (50.8 ± 15.3 vs 36.7 ± 11.6 mm Hg, p <0.001). Ngemuva kwesikhathi esiyimean engama-25.0 ± 16.9 wezinyanga sokulandela, i-Kaplan-Meier analysis yabonisa ukufa ngazo zonke izizathu okuphakeme kakhulu eqenjini le-PH. Kwi-Cox regression analysis, i-PH yayingumbikazeli onamandla kakhulu wokufa ngazo zonke izizathu (i-hazard ratio 3.731, 95% confidence interval 1.653 kuya ku-8.475, p = 0.002).

Hypothesis:
Ekugcineni, ukwelashwa kwe-MitraClip kwanciphisa i-FMR futhi kwanqanda izimpawu zokugula kwaphinde kwaba nempilo enhle eqaleni kuwo wonke amaqembu ane-PH nalawo angena-PH.


Premise:
Ukuze kucaciswe kabanzi ubunjalo begciwane i-Lyme carditis, ucwaningo lwezici zokusebenza kwenhliziyo kanye nokuthathwa kwesampula somdlandla wenhliziyo kwenziwa esigulini esinalesifo i-Lyme, lapho uphawu olubalulekile lwenhliziyo kwakunguphazamiseko webhulokhi ye-atrioventricular yezinga eliphezulu. Ukurekhodwa kwaphakathi enhliziyweni kukhombise ibhulokhi ye-supra-Hisian kanye nokuswela okuphelele kohlelo lokuphunyula. Ukuskena nge-Gallium 67 kukhombise ukukhishwa kwenhliziyo, futhi isampula somdlandla wenhliziyo wengxenye yokudla yeventrikhula sakhombisa isifo somdlandla wenhliziyo esiphilayo se-lymphocytic. Isakhiwo esihambisana nesidalwa se-spirochetal saboniswa kusampula elilodwa lebhayophisi.

Hypothesis:
Kuyaqinisekiswa ukuthi isifo se-Lyme singadala i-myocarditis esenziwa, njengoba kuphakanyiswa ukuhlolwa nge-gallium 67 futhi kuqinisekiswa ukuhlolwa kwe-endomyocardial biopsy.


Premise:
Noma izifo zemithambo ye-coronary kanye nesifo sokudlula kwezinkathi seso-gastroesophageal ziyizifo ezijwayelekile, okungenzeka ukuthi zibe khona ndawonye, akwaziwa ukuthi ukuba khona kwesisodwa kuyasithinta yini esinye. Senza ukuhlolwa kokufakwa kwesibazi esofagusi, kuhambisana nokuhlolwa kwengcindezi yegazi, ijubane lenhliziyo, kanye nokuhlolwa kwe-elektrocardiographic eyizinhla ezingu-12, ezigulini ezingama-37, ezingama-25 ezine-coronary disease efakazelwe nge-angiography kanye nezingu-12 ezinemithambo ye-coronary ejwayelekile. Kwabaliwa okubizwa nge-rate-pressure product, okuyisibonisi somthwalo womsebenzi we-myocardial. Ezigulini ezinesifo se-coronary ezathuthuka ubuhlungu besifuba ngesikhathi kufakwa isibazi, i-rate-pressure product yenyuka isuka ku-10.0 +/- 1.0 x 10(3) (isilinganiso +/- SEM) ekuqaleni yaya ku-15.2 +/- 1.5 x 10(3) (p incane kunama-0.001), futhi iziguli ezingu-3 kwezingu-9 zabonisa ubufakazi be-electrocardiogram be-myocardial ischemia ehambisanayo. Ngaphezu kwalokho, kwisifo se-coronary, ama-64% eziguli ezinezimpawu ezingavamile noma ezingekho ze-reflux ngemilando yazo zabanezivivinyo ezinhle zokufakwa kwesibazi, futhi ama-56% eziguli ezinesifo se-coronary ezathuthuka ubuhlungu ngesikhathi kufakwa isibazi seso-esophageal zazingakwazi ukuhlukanisa lobo buhlungu ebuhlungwini bazo bama-angina ajwayelekile.

Hypothesis:
Siphetha ngokuthi esifweni samajazi enhliziyo, ukugeleza kwesibabuli (futhi, kungenzeka, ukuhlanza kwesisu esihambisana nokunyuka kokudla) okubangela ubuhlungu besifuba kubangela ukunyuka kwemiphumela yokushaya nokucindezela futhi kungaholela ekuvalekeni kwemithambo yegazi enhliziyweni.


Premise:
Lolu cwaningo lwenziwa ukuze kuthungathwe ukuzwela kokwenza isithombe ngethallium uma kuqhathaniswa nokuhlola i-ECG ekutholeni ukuvaleka kwemithambo yegazi yenhliziyo ngendlela engenabungozi emva kokufakwa kwe-ergonovine ngomlomo njengokunqanyuleziswa kwangempela kokubhekwa kwemithambo yegazi yenhliziyo. Iziguli ezingamashumi amathathu nambili ezinesifo semithambo yenhliziyo esingatheni kanye nobuhlungu besifuba zenziwa ukuhlolwa kwe-ECG eyizinhlobo ezingu-12, ukwenziwa kwesithombe ngethallium, kanye nokwenziwa kwesithombe semithambo yegazi yenhliziyo emva kokunikwa ama-mg angu-0.05, 0.1, 0.2, no-0.3 e-ergonovine enikwa emizuzwini emihlanu eyehlukanisiwe noma kuze kufike ubuhlungu besifuba. Emizuzwini emibili nanye emva kokuthola isikalo sokugcina se-ergonovine, imiliCurie engu-2.5 yethallium-201 yafakwa ngomlomo, kwase kubhalwa i-ECG yokugcina futhi kwenziwa ukuhlolwa kwemithambo yenhliziyo okuyiphindayo. Phakathi kwemizuzu eyishumi emva kokufakwa kwethallium, kwenziwa isithombe ku-degree engu-40 nengu-70 kwebumeke lesokudla siqhube phambili futhi nokuhlola phambili. I-ECG, ucwaningo lwethallium, kanye nearteriogram yemithambo yenhliziyo zafundwa ngaphandle kokwazi futhi imiphumela yaqhathaniswa. I-ECG, i-angiogram, kanye nocwaningo lwethallium kwafundwa njengokufanele uma lokhu kwenzeka, ngokulandelana: ukunyuka kwengxenye ye-ST engaphezu noma elingana ne-mm engu-1, ukwehla, noma ukuphenduka kwe-T wave; ukuncipha kwesitsha okungaphezu kwama-50%; kanye nesici esisabhekwa sokungabi nemifutho kahle. Iziguli ezinhlanu zakhishwa ekuhlaziyeni ngenxa yokuhlasela kwe-catheter, izifundo zethallium ezingasebenzi kahle, noma ukuphulwa kwemigomo. Kweziguli ezingu-27 ezifakiwe ukuhlaziywa, eziyisithupha zaba nobuhlungu besifuba, ezinhlanu zaba ne-angiogram eveza isifo, ezinhlanu zaba nocwaningo lwethallium oluveza isifo, kanti eyodwa yaba ne-ECG eveza isifo. Ukuzwela kwethallium uma kuqhathaniswa nokuhlola kwe-ECG kwakuwu-80% uma kuqhathaniswa no-25%, kanye nokuqiniseka okuwu-92% uma kuqhathaniswa no-80%.

Hypothesis:
Siphetha ngokuthi ukuthwebula nge-thallium kwandisa kakhulu ukutholakala okungenalubhalo lwe-ergonovine-engenisa ukuminyana kwemithambo yegazi yenhliziyo uma kuqhathaniswa ne-ECG ngaphandle kokulahlekelwa ukunembeka.


Premise:
Ukuhlobana kwezimpawu (SX) nezinkinga ezinkulu zokuhlukumezeka kombhanyiso wenhliziyo (ARS) ezenzeka ngesikhathi sokuhlolwa okwamahora angu-24 (AM) kuye kwahlolwa eqenjini leziguli ezidluliselwe ngenxa yokuzizela noma ukuphelelwa umzimba. Iziguli ezingamashumi ayisishiyagalolunye nesishiyagalombili ezilandelanayo, eziminyaka engu-25 kuya ku-82, ezazinamadayari afanele emisebenzi kanye ne-SX, zifakiwe. Ama-ARS athathwa njengezinkulu kwaba i-ventricular ne-supraventricular ectopy ibanga 2, 3, no-4 (ukuhlukaniswa kwe-Lown), ukuma kwe-sinus nokuvimba, ukuvimba kwe-atrioventricular, kanye nobushelelezi be-sinus obungaphansi noma obulingana no-40/umzuzu. Nakuba zonke iziguli zadluliselwa ngenxa yokuzizela kanye/noma ukuphelelwa umzimba, iziguli ezingu-41 kuphela (42%) ezaba nezimpawu zazo ngesikhathi sokuqopha. Ama-ARS ayeqoshiwe ku-63 (64%). Bekungekho mehluko obalulekile kwezibalo ekuveleleni noma ohlobeni lwe-ARS eqenjini elinezimpawu, kanye neqembu elingenazo izimpawu (x2 = 1.64). Kwabantu abangama-23 abanama-ARS amakhulu kanye nezimpawu eziqoshiwe, babili kuphela abanezimpawu ne-ARS ezenzeka ngesikhathi esisodwa.

Hypothesis:
Kuyaphethwa ukuthi ukuba khona kwe-SX akukhuphuli amathuba okuthi kube khona i-ARS enkulu ngenkathi yokukala i-AM yamahora angu-24.


Premise:
Ukufunda ngendlela okushaqeka ngayo i-influenza kubaguli be-asthma, sibhekisise ngemuva i-FEV1 kusukela ezinsukwini ezinhlanu ngaphambi kokugula kuya ezinsukwini eziyishumi emva kokuqala kokugula ezinganeni ezingama-20 ezine-asthma ezineminyaka eyi-8 kuya kwi-12 ezinemizwa yokuhefuzela ephathekayo. Ukutheleleka kwe-influenza kufakazelwe ukwenyuka okungenani ngokuphindwe kane ekubeni ama-titers e-serum complement fixation. Abaguli abayi-15 kwabayi-20 babe nokwehla kwe-FEV1 okungaphezu kwamaphesenti angama-20 kusukela ekuqaleni phansi ngesikhathi sokugula okukhulu. I-FEV1 iqale ukwehla nokuqala kokugula kubaguli abayi-15 ngaphandle koyedwa onokwehla kwe-FEV1 ngesikhathi sokutheleleka. Iqhubeke nokwehla ngosuku lwesibili, lapho ukwehla okulinganiselwe (+/- SD) kwe-FEV1 kufinyelele esicongweni, ngamaphesenti angu-30.3 +/- 10.9. Iqale ukuba ngcono ngosuku lwesithathu, futhi ibuyele ebudebudeni bemephuzo engu-10 phesenti ngosuku lwesikhombisa kuya kweleshumi.

Hypothesis:
Siphetha ngokuthi i-asthma engeniswa yi-influenza ingaqhubeka nokuba nezinga elibi ezinsukwini ezimbili zokuqala zokugula futhi ingadinga okungenani izinsuku eziyisikhombisa ukuze iphile.


Premise:
Sikombisile ukuthi ukuvuswa kwe-proteinase-activated receptor-2 (PAR(2)) emiphinjeni kudala ukuzwela ngokwedlulele ezintweni eziphefumulwayo kanye ne-Ags ephefumulwe ngesikhathi esisodwa, okubeka umcabango wokuthi i-PAR(2) inomthelela ekuvezeni isifo sephepha (asthma). Izinto eziningi ezingama-aeroallergen ezine-proteinase activity zivusa i-PAR(2). Ukuze sicwaninge indima ye-PAR(2) ekuzweleni ngokwedlulele kuma-aeroallergen, senze imodeli yegundane yokuzwela ngaphansi kwemisebe yomkhaya kwama-protein e-cockroach. Sethemba ukuthi ukuvuswa kwe-PAR(2) emiphinjeni yizinto zemvelo ezidalela ukuzwela ezine-serine proteinase activity kudlala indima ebalulekile ekuzweleni ngokwedlulele. I-Cockroach extract (CE) yaphonswa kumamawundane ama-BALB/c ngaphakathi kwamakhala izinsuku ezinhlanu zilandelana (isigaba sokuzwela) bese kuthi emva kwesonto kuphinde kufakwe ezinye izinsuku ezine (isigaba sokuhlasela). Ukuphendula ngokweqile kwemithambo yomoya (AHR) kanye nokuphatheka kwemithambo yomoya yokuzwela ngokwedlulele kwakuhlolwa emva kokuhlasela kokugcina. Ukuze kucwaningwe indima ye-PAR(2), amawundane afakwa ngaphakathi kwamakhala i-receptor-blocking anti-PAR(2) Ab ngaphambi kokufakwa kwe-CE ngasinye ngesikhathi sesigaba sokuzwela. Ukuvela kwesikhumba semisebe yokhaya kwe-CE kwadala ukuvuvukala kwemithambo yomoya ye-eosinophilic, i-AHR, ne-cockroach-specific IgG1. I-CE eyakhiswe ukushisa noma eyalashwa nge-soybean trypsin inhibitor ayikwazanga ukudala lemiphumela, okukhombisa ukuthi i-proteinase activity idlala indima ebalulekile. Ukusetshenziswa kwe-anti-PAR(2) blocking Ab ngesikhathi sesigaba sokuzwela kwavimba ngokuphelele ukuvuvukala kwemithambo yomoya futhi kwehlisa ne-AHR kanye nokukhiqizwa kwe-cockroach-specific IgG1. Ukuvuswa kwe-PAR(2) yi-CE kusebenza njenge-adjuvant yokuzwela ngokwedlulele ngisho nakungekho i-functional TLR4.

Hypothesis:
Siphetha ngokuthi i-vascular ikhuthaza ukuzwela kwezifo zomgudu womoya okuhlangene ne-PAR(2) kumodi yemosi eyisibonelo sesifuba somoya esiqubuka ngenxa yokuzwela.


Premise:
Ukukhwehlela okwomile kuyinto evamile enciphisa ukusetshenziswa kwama-ACE inhibitor (ACEI). Ukukhiqizwa kwe-NO, into ekhuthaza ukuvuvukala kwesikhumba samaphaphu, kuyanda ngenxa ye-ACEI. Ngokusebenzisa ucwaningo oluhleliwe, olufihlekile kabili, olulawulwa ngeplasebo, sahlola umqondo wokuthi ukwengeza insimbi, into evimba i-NO synthase, ingase inciphise ukukhwehlela okuhambisana nokusetshenziswa kwe-ACEI. Ababambiqhaza babengabantu abangu-19 ababe thuthukise ukukhwehlela okwakubangelwe yi-ACEI. Emva kwesikhathi sokubhekisisa esingamaviki amabili, bahlukaniswa ngokungahleliwe ukuthola isibalo sansuku zonke ekuseni se-256-mg seferrous sulfate njengesibambiso noma iplasebo isikhathi sokwelashwa esingamaviki ane-4. Ababambiqhaza bacelwa ukuthi bagcwalise idayari yokukhwehlela ngokunika inombolo ubunzima bansuku zonke bokukhwehlela kusikali esisuka ku-0 kuya ku-4. Izikali zokukhwehlela zansuku zonke ezisesilinganisweni seviki lokugcina lokubhekisa nesikhathi sokwelashwa zaqhathaniswa. Izinguquko ekubalweni kwamaseli egazi kanye nensimbi yeserum kanye nokuqoqeka kweferritin phakathi kwezikhathi ezimbili zahlolwa. Izikali zokukhwehlela zansuku zonke ezisesilinganisweni ngesikhathi sokubhekisa nesikhathi sokwelashwa zazingu-3.07+/-0.70 kanye no-1.69+/-1.10, ngokulandelana, kweqembu lensimbi kanye no-2.57+/-0.80 kanye no-2.35+/-1.22, ngokulandelana, kweqembu leplasebo, okukhombisa ukunciphisa okubalulekile ezikalini zokukhwehlela nokwengeziwe kwensimbi (P<0.01) kodwa hhayi ngeplasebo. Ababambiqhaza abathathu eqenjini lensimbi bakhombisa ukushabalala okuphelele kokukhwehlela. Azibonwanga izinguquko ezibalulekile kwidatha yaselabhorethri kunanoma yiliphi iqembu.

Hypothesis:
Ekugcineni, ukuthatha izinyangezelo zensimbi kuphumelela ekwehliseni ukukhwehlela okubangelwa yi-ACEI.


Premise:
Ukuvuvukala kwemithambo yokuphefumula okubangelwa yi-virus enqubayo ye-respiratory syncytial virus (RSV) ivame ukuhambisana nezimpawu zokuphefumula eziqhubekayo ngemuva kokulaliswa esibhedlela. Kuze kube manje, akukho silinganiso esihlolwe ngokufanele ukuhlola izimpawu ze-bronchiolitis ebangelwa yi-RSV. Sibika ngokungatshwantshwa, ukusebenza, kanye nokuphendula kwedayari yomgcini we-bronchiolitis (BCD) yezimpawu kanye nokusetshenziswa kwezempilo okuhambisana ne-RSV enqubayo. I-BCD ilinganisa izimpawu ezine (ukukhwehlela emini, ukubhavumula, ukuba nenkinga yokuphefumula, kanye nokukhwehlela ebusuku), ukusetshenziswa kwezempilo, kanye nemithi yokusiza ekubeni kubi kwezimpawu zamaphaphu. Idatha evela esikhathini sokwelashwa kwamaviki ama-4 ocwaningo olubikelwe, olulawulwa ngenziwa-sengathi lokwelashwa nge-montelukast yokwelashwa kwe-RSV enqubayo lwasetshenziswa ukuhlola ukuthembeka (ukungaguquki kwangaphakathi kanye nokuhlola futhi), ukusebenza kokwakha (ukuhlobana kwesiqephu nokuqhubekayo), ukusebenza kokuhlukanisa (izinhlelo ezaziwa zamaqembu), kanye nokuphendula. Umphumela osemqoka walolu cwaningo kwakuyishumi ekhulwini lezinsuku ezingenazimpawu (SFD). Umphumela wesibili kwakuyisikali esixubile sezimpawu (CSS; isilinganiso sokukhwehlela emini, ukubhavumula, kanye nenkinga yokuphefumula). I-alpha ka-Cronbach engama-0.85 ikhombise ukuthi izimpawu ezine zazingaguquki ngaphakathi, okusekela ukwakheka kwesikali esisodwa. Ukuhlolwa futhi kokwethembeka kweshumi ekhulwini le-SFD ne-CSS kwakungaphezulu kwephuzu eliphakanyisiwe lika-0.70. Ukuhlobana kwesiqephu nokuqhubekayo kwakukhulu futhi kubalulekile ngokwezibalo, okukhombisa ukusebenza kokwakha. Umehluko wamaQembu aziwa ophakanyisiwe wawubalulekile ngokwezibalo ngendlela efanele. Izinhlelo zokuphendula zikhombise izisindo ezimaphakathi zegalelo leshumi ekhulwini le-SFD.

Hypothesis:
Njengokuphetha, i-BCD inikeza ithuluzi elifanele, elithembekile nelikhombisa ukusebenza okubonakalayo ekuhlolweni kwezimpawu ezibangwa yi-bronchiolitis eyenziwa yi-RSV esemuva kwesikhathi sokuhlaselwa yisifo, elikwazi ukukala izinga elilingene lokusebenza, nokubonisa ukusebenza ekwelashweni.


Premise:
Ukuhleleleka kwangaphakathi kwendlela yomoya kuyinto eyaziwayo yesifo se-asthma. Izimbangela zalo aziqondisiseki kahle, kodwa enye yezinto esingasho ukuthi inamandla wukuguquka nokuhlaselwa ngobukhulu (transforming growth factor-beta 1) (TGF-beta 1). Silinganisile izinga le-TGF-beta 1 enezimpawu zokuveza izimpendulo kwi-bronchoalveolar lavage (BAL) fluid esuka kubantu abane-atopic asthma abagulayo abasesimweni esisimeme kanye nabantu abangenayo i-asthma abaphile kahle. Futhi sihlolile umthelela wokuvela kwi-allergen ekukhululweni kwe-TGF-beta 1 ezindleleni zomoya kusetshenziswa imodeli ye-segmental bronchoprovocation, ne-BAL eyenziwe ezikhathini ezimbili kulandela izivivinyo ze-endobronchial allergen kanye nezitshengisa izinga lesiwasho se-saline. Amazinga okuqala e-TGF-beta 1 abekade ephakeme kakhulu kubantu abane-asthma kunalabo abayizimpawu zokulawula (okulinganiselwa ku-8.0 kuya ku-5.5 pg/ml, p = 0.027). Emva kwe-segmental bronchoprovocation, amazinga e-TGF-beta 1 ezindaweni ezivivinywe nge-allergen kanye nesiwasho se-saline ayengahlukahlukene kakhulu emva kwemizuzu eyi-10, (31.3 kuya ku-25.0 pg/ml, p = 0.78), kodwa emva kwamahora angama-24 kube nezinga eliphezulu kakhulu le-TGF-beta 1 ezindaweni ezivavinywe nge-allergen (46.0 kuya ku-21.5 pg/ml, p = 0.017).

Hypothesis:
Siphetha ngokuthi amazinga ama-asthma 1 angasisekelo emaphayiphini omoya aphakeme kwi-atopic TGF-beta nokuthi lamazinga aqhubeka nokwenyuka ngenxa yokuvezwa kuma-allergen.


Premise:
Sike sakuveza ngaphambilini ezimvuni ukuthi ukukhinyabezeka kwemithambo yegazi ephashini kuyehla ngokushesha emuva kokuqala kokuzivocavoca okuqhubekayo, kulandele ukuvuleka kwesibili kwemithambo yegazi okuholela ekwehleni okuncane nokuphuzayo. Isigaba sesibili silawulwa ngokuyingxenye yokusebenza kwe-alpha kanye ne-beta-adrenoceptor. Sibhekisise umthelela we-nitric oxide (NO; 40 ppm) ehogelwayo kanye ne-nitroglycerin engeniswa ngomthambo ukuvimba ukubamba kwemithambo emaphashini okubangelwa ukuvinjelwa kwe-beta-adrenergic ngesikhathi sokuzivocavoca. Ezifundweni ezihambisanayo, sazivocavoca izimvu eziyisishiyagalombili ngesivinini esilinganayo esingu-4 miles ngehora imizuzu emi-4 esishicilelweni sokunyathela kwaze kwabonakala ukuphendula kwemithambo yegazi ngesikhathi sokuvimbela i-beta (propranolol, 1 mg i.v.) noma kungekho 40 ppm ye-NO ehogelwayo noma ukuchelelwa okungapheli kwe-nitroglycerin (3.2-4.0 micrograms.kg-1.min-1). Ukuvimba i-beta kwaholela ekukhinyabezekeni okukhulu kwemithambo yegazi ephashini ngesikhathi sokuzivocavoca okuqhubekayo (40-240 s) kunasesimweni esingavinjwanga; ukwehliswa kokukhinyabezeka kwemithambo yegazi ephashini ngesikhathi sesigaba sesibili sokuzivocavoca kwakuncane ngokuvimba i-beta (13-16%) kunangokuzivocavoca ngenkathi ingavinjelwanga (26-30%). I-NO ehogelwayo kanye ne-nitroglycerin kwaphendula ukuvimba i-beta okuhlobene nokubamba kwemithambo yegazi amaphashini ukuya emazingeni okuvocavoca okungavinjeliwe. I-NO ehogelwayo kanye ne-nitroglycerin engeniswa emithanjeni yegazi kwaphindisa futhi ukubamba kwemithambo yegazi ephashini okwakhiqizwa yi-phenylephrine engeniswa emithanjeni yegazi ngesikhathi sokuphumula.

Hypothesis:
Siphetha ngokuthi i-apigenin engaphandle, enikezwa ngokuphefumulwa kwegesi noma ngezakhiwo ze-nitroso, iphikisana futhi iguqula ngokuphelele ukuvaleka kwemithambo yegazi emaphashini okubangelwa yi-alpha-receptor ngesikhathi sokuzivocavoca ezimvini.


Premise:
Izindawo zokusebenza kwama-nitric oxide (NO) endalo kanye nalawo aphefumulelwayo ziqinisekiswe ngesikhathi sokuvaleka kwemithambo yegazi emaphashini ngenxa yokusweleka komoya. Amaphaphu ezikati ezingu-21 ezindala anishelwe ngegazi lazo ezimeni zesigaba-3. Amandla engcindezi emithanjeni ecishe ibe ngamakhapilari akalwe ngobuchwepheshe bokuvala kabili futhi ingcindezi emithanjeni emincane yegazi engu 70-100 microns ngobunzima yakalwa ngobuchwepheshe be-servo-null micropuncture, zombili ngesikhathi sinomoya owanele (FiO2= 0.3) nangesikhathi kusweleka umoya (FiO2= 0.02). Imiphumela ye-NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), isivimbelisi se-NO synthase, kanye ne-NO ephefunyelwayo (5-100 ppm) nayo yakalwa. I-PO2yemiphumelaphambili yehlile kusuka ku-187.6 +/- 5.3 mmHg ngesikhathi kunomoya owanele kuya ku-25.7 +/- 1.3 mmHg ngesikhathi kusweleka umoya, futhi yehla kakhulu yaya ku-20.8 +/- 2.2 mmHg ngesikhathi kusweleka umoya kanye nama-50 ppm NO (p < 0.05, uma kuqhathaniswa nokungabi namoya kuphela). Ukwenyuka engcindezelweni emithanjeni yegazi sasemaphashini ukuphendula ekuswelekeni komoya kwakungama-4.8 +/- 1.0 cmH2O kanye nama-9.1 +/- 1.4 cmH2O emaphashini angalashwanga kanye nalashelwe nge-L-NAME, ngokulandelana (p < 0.05). I-L-NAME yandisa kakhulu ukuciciyela ngenxa yokungabi namoya esigabeni semithambo enengilazi. Ubuningi be-NO ephefunyelwayo banda kusuka ku-13 +/- 4 ppb ngesikhathi sinomoya owanele kuya ku-18 +/- 4 ppb ngesikhathi kusweleka umoya (p < 0.1). I-NO ephefunyelwayo yehlisa kungabi kuphela ingcindezi kumthambo omkhulu wegazi ophuma enhliziyweni kodwa nengcindezi yemithambo ecishe ibe ngamakhapilari ngendlela eyencike ekujuleni, okunciphisa ukuvaleka kwemithambo yegazi emaphashini ngenxa yokusweleka komoya. Imithambo yegazi yaphuma emaphashini yayinezinga elikhulu lokuzwela ku-NO ephefunyelwayo kunaleyo engena emaphashini. I-NO ephefunyelwayo (50 ppm) ivule imithambo encane kunama-70 ukuya kuma-100 microns ngobungako, ngo-39% (p < 0.05), futhi yavula imithambo yegazi ephuma emaphashini engaphezu kwama-100 microns ngobungako ngo-26% (p < 0.05), kodwa ayizange ivule imithambo yegazi engena emaphashini engaphezu kwama-100 microns ngobungako ngokwanele (11%). I-NO ephefunyelwayo ayizange ishintshe ngokwanele isilinganiso sesikulikhilo esingamanzi nesilinganiso sesikulikhilo esomile.

Hypothesis:
Siphetha ngokuthi kokubili i-NO yomzimba kanye ne-NO ehogelwayo kunciphisa ukuvaleka kwemithambo yegazi emaphashini ngenxa yokwentuleka komoya, kanye nokukhula okubalulekile kwemithambo yegazi eliphuma emaphashini.


Premise:
Emazweni aseNtshonalanga, isifo senhliziyo siwumbangela omkhulu wokufa kwomama ngesikhathi sokukhulelwa. Umthelela wokukhulelwa enhliziyweni kunzima ukuwufunda ezigulini ezinesifo senhliziyo esivele sikhona. Njengoba ucwaningo lokuhlola lungekho kangako, sicwaninge umthelela wokweqiswa kwengcindezi, okudalwe ukucindezelwa kwe-aortic transverse (TAC) emadotsheni, emandleni wokuthola, imiphumela yokukhulelwa, kanye nempilo yenhliziyo yomama. Amasonto amane e-TAC adale ukukhula kwe-ventricular yasekhohlo (LV) kanye nokungasebenzi kahle kwayo nokukhula kwe-fibrosis ehlukaniselwe, ukwehla kwedensithi yekapilari, kanye nokuvela kwezimpawu zegene yenhliziyo ephathologikhali. Ukukhulelwa kwandise isisindo se-LV kanye ne-ventricular yokudla ngokusemthethweni ngaphandle kokuthinta ukungasebenzi kahle kwe-LV ngemuva kwe-TAC. Okumangalisayo, ukwanda kwe-TAC esisindisweni senhliziyo kanye namaphaphu kwancishiswa ukukhulelwa, lokhu kwakuhambisana nesimo esikhombisa ukubuyela esimweni esijwayelekile sedensithi yekapilari kanye nokuvakaliswa kwe-natriuretic peptide uhlobo A. Ngaphezu kwalokho, ukuhlanganiswa kokukhulelwa kanye ne-TAC kwandisa i-phosphorylation yamakhemikhali enhliziyweni ebizwa nge-c-Jun, kanye ne-STAT1, kodwa kwanciphisa i-phosphoinositide 3-kinase phosphorylation. Ekugcineni, i-TAC ayibangelanga ushintsho olukhulu ezingeni lokukhulelwa, ubude bokukhulelwa, usayizi wesibelethelo, ubukhulu bezinyane, kanye nesivinini samazinyane.

Hypothesis:
Ekugcineni, sithole ukuthi, esikhundleni sokwandisa izinguquko ezihambisana nokweqela umfutho enhliziyweni, ukukhulelwa kwakususa kancane ukuhleleka kabusha kwe-LV okuyinhloso futhi kwanciphisa ukucinana kwamaphaphu, kanye nokukhiqizwa kwe-TAC okuyinhloso ngokuvezwa kwejini, okukhombisa umphumela omuhle wokukhulelwa enhliziyweni esindweni elikhulu lomfutho.


Premise:
Nakuba i-nitric oxide (NO) yangaphakathi ilungisa umoya oyisisekelo emisikeni yemithambo yomopho yengungu kanye nemithambo yomzimba, kukhona ulwazi oluncane mayelana nendima yayo ekulawuleni umoya we-ductus arteriosus (DA). Ukuhlolwa kwe-immunostaining kwesicubu se-DA samazinyane emva kwesikhathi sokuhlanganisa kuveze ukuhlolwa okuqinile kwe-endothelial NO synthase (eNOS) ku-endothelium ye-DA. Ukuze sifunde indima ye-physiological ye-NO kanye ne-guanosine 3',5'-cyclic monophosphate (cGMP) ohlweni lwe-DA phakathi kokuphila, sikalwe imiphumela ye-hemodynamic ye-NG-nitro-L-arginine (L-NNA; 30 mg), isivinini se-NOS, i-methylene blue (40 mg), isivinini se-guanylate cyclase, kanye ne-indomethacin (0.8 mg), isivinini se-cyclooxygenase, kumazinyane ayi-10 alungiselelwe isikhathi eside emva kwesikhathi sokuhlanganisa. I-L-NNA yenyuse umthambo omkhulu wemiphumela (MPA) kanye ne-aortic pressure (P < 0.05 vs. sisekelo) kodwa ayizange iguqule umkhawulo wengcindezi phakathi kwe-MPA ne-aorta. I-L-NNA yabangela ukwehla okuncane ekuhambeni kwe-DA kanye nokwenyuka okuncane ekunyukeni phezu kwe-DA. I-Methylene blue yenyusa kokubili ingcindezi ye-MPA kanye nomkhawulo wengcindezi phakathi kwe-MPA ne-aorta kusukela ku-0.3 +/- 0.2 (sisekelo) ukuya ku-7.0 +/- 2.7 mmHg (P < 0.05). I-Indomethacin yenyusa kokubili ingcindezi ye-MPA kanye nomkhawulo wengcindezi phakathi kwe-MPA ne-aorta kusukela ku-1.1 +/- 0.4 (sisekelo) ukuya ku-6.3 +/- 1.5 mmHg (P < 0.05) emva kwemizuzu engama-40. I-Indomethacin yehlise ukuhamba kwe-DA futhi yenyuse ukumelana kwe-DA.

Hypothesis:
Siphetha ngokuthi i-eNOS itholakala emasosheni amancane omthambo we-DA womfutho ezingeni lombungu, nokuthi ukuvikelwa kwe-NOS kubangela ukuvaleka kwe-DA emzimbeni.


Premise:
Kumthambo wemiphaphapha okhishwe kumagundane anesifo sokungaphefumuli kahle esibangwe yisonto elilodwa lokuntuleka komoya, ukukhiqizwa kwe-NO yendawo engaphakathi ekhuthazwe yi-carbachol kwehlile kakhulu ekuboneni kokulungiswa esisetshenziselwa i-diaminofluorescein-2 diacetate kanti futhi nakulokhu okumumethe i-cGMP. Lolu shintsho kwalandelwa ukwehla ekukhululekeni okuncike endaweni engaphakathi okubangelwa i-carbachol. Ukuvezwa kwamaphrotheni e-endothelial NO synthase (eNOS) namaphrotheni ayo alawulayo, i-caveolin-1 ne-heat shock protein 90, akuzange kushintshwe emthanjeni wemiphaphapha ongaphefumuli kahle, okukhombisa ukuthi ukuntuleka komoya kwesikhathi eside kuvimba umsebenzi we-eNOS ezingeni elilandela ukuhunyushwa. Emthanjeni wemiphaphapha ongaphefumuli kahle, ukwanda kwezinga le-Ca(2+) ngaphakathi ekugoqeni okukhuthazwe yi-carbachol kodwa hhayi yi-ionomycin kwancipha. Sagxila oshintshweni ekuzothezisweni kwe-Ca(2+) ohlelweni lokuqaliswa kwe-eNOS. Ucwaningo lokuma luveze ukuncipshana kwesisisi zendawo engaphakathi nokucindezela okusekupheleni kwe-eNOS kumadlomela angaphefumuli kahle okuphinda kugcinwe ukuma ndawonye phakathi kwe-eNOS ne-Golgi noma imimbrane yezisisi. Nokho, i-eNOS yayihlanganiswe ngokuqinile ne-caveolin-1, futhi yayihlukaniswe ne-heat shock protein 90 noma i-calmodulin emthanjeni wemiphaphapha ongaphefumuli kahle noma bukhona noma bungekho i-carbachol. Ngaphezu kwalokho, ukuphosforiliwa kwe-eNOS Ser(1177) ezimweni zombili kwancipha kakhulu ngaphandle kokuthinta ukuphosforiliwa kwe-Akt emthanjeni ongaphefumuli kahle.

Hypothesis:
Okokuphetha, ukwentuleka okugulisayo komoya kuyaphazamisa imethabholizimu ye-Ca (2+) endotheliyali kanye nokuxhumana okujwayelekile phakathi kwe-eNOS ne-caveolin-1 okuholele ekungasebenzini kwe-eNOS.


Premise:
I-Tobramycin, i-antibhayothikhi ye-aminoglycoside, isetshenziselwa ukwelaphwa kwezifo ze-Pseudomonas aeruginosa eziguleni ezine-cystic fibrosis. Kodwa-ke, i-bioactivity ye-tobramycin iphikiswa yi-sputum. Ama-Glycoproteins (mucins) kanye ne-DNA enesisindo esiphezulu senza u-2 kuya ku-3% (P. L. Masson kanye no-J. F. Heremans, p. 412-475, Ku M. J. Dulfano, ed., Sputum: Fundamentals and Clinical Pathology, 1973) kanye no-3 kuya ku-10% (W. S. Chernick kanye no-G. J. Barbero, Pediatrics 24:739-745, 1959, kanye no-R. Picot, I. Das, kanye no-L. Reid, Thorax 33:235-242, 1978) wesisindo esomile se-sputum, ngokulandelana. I-tobramycin iboshwa kokubili i-mucins kanye ne-DNA etholakala ku-sputum (R. Ramphal, M. Lhermitte, M. Filliat, kanye no-P. Roussel, J. Antimicrob. Chemother. 22:483-490, 1988). Ku-in vitro, i-recombinant human DNase (rhDNase) ihlakaza i-DNA enesisindo esiphezulu esingu-> 50 kb ngaphakathi kwe-sputum ibe yizicucu ezingu-2 kuya ku-4 kb. Sifunda i-tobramycin engadayalizwa, sibheke ukuboshwa kwemithi ku-sputum ephelele kanye "nakwi-mock sputum," equkethe i-porcine gastric mucin kanye ne-calf thymus DNA. Siphinde safunda nemiphumela yokwelashwa kwe-rhDNase ku-sputum, i-mock sputum, kanye ne-calf thymus DNA ekuboshweni kwe-tobramycin. Sithole ukuthi ukwelashwa kwe-sputum, i-mock sputum, kanye ne-calf thymus DNA nge-rhDNase akuzange kwandise kakhulu i-bioactivity ye-tobramycin ngaphakathi kwama-dialysates; ngokumangalisayo, ukuboshwa kwe-sputum kwe-tobramycin kwanda ngenxa ye-rhDNase.

Hypothesis:
Siphetha ngokuthi i-rhDNase ayikhuphuli i-bioactivity ye-tobramycin ekhupheni.


Premise:
I-Pneumocystis carinii pneumonia (PCP) iyaqhubeka nokubangela izinkinga ezinkulu kubantu abathole izitho zomzimba zokuthutha. Yize ezinye izinhlelo zinikeza i-trimethoprim-sulfamethoxazole (TMP-SMX) njengesivikeli emva kokuthutha izitho, ukuhlolwa okuphambili kokuphephile nokusebenza kahle kwe-TMP-SMX kubatholi bezinhliziyo zokuthutha akukaze kubikwe. Ngakho-ke sihlelele ngokucophelela abantu abangu-58 abathole izinhliziyo zokuthutha ukuthola i-TMP (160 mg)-SMX (800 mg) kabili ngosuku noma ezinsukwini ezintathu ngesonto (iqembu B), noma ezinsukwini eziyisikhombisa ngesonto (iqembu C), noma ukungatholi ukwelashwa (iqembu A). Ukwelashwa kuqale ezinsukwini eziyi-14 emva kokuthutha futhi kwaqhubeka izinyanga ezine. Iminyaka, ubulili, izifo zamaphaphu ezikhona kakade kanye nezinqubo zokwehlisa amasosha omzimba azange ahluke phakathi kwamaqembu. Kubantu abayi-17 eqenjini lokulawula (A), abayi-7 bakhombise izimpawu ezihambisana ne-PCP, nesifo esiqinisekiswe ngokocwaningo lwe-bronchoalveolar lavage ngezinyanga ezine zokuqala emva kokuthutha. Ngokuphambene nalokho, akekho iziguli eqenjini lokwelashwa kwansuku zonke noma ngamazikhathi athile ezathola i-PCP ngesikhathi socwaningo (P < 0.005). Zombili izinga ze-TMP-SMX zabekeleka kahle, futhi ukumiswa kokwelashwa akulahlekanga kunanoma yisiphi isiguli. Isibalo samasosha amhlophe egazi, izinga le-azathioprine, kanye nenani lezenzakalo zokunqanda ezilashiwe ngomuntu azange ahluke phakathi kwamaqembu amathathu.

Hypothesis:
Siphetha ngokuthi i-TMP-SMX ingasetshenziswa ngokuphepha nangempumelelo ukuvikela ukuvela kwe-P carinii pneumonia ngesikhathi sezinyanga ezine zokuqala ezilandela ukutshala inhliziyo.