School of Laboratory Medicine & Medical Sciences

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An investigation into kojic acid-associated mitochondrial toxicity and inflammation in melanoma cells (SK-MEL-1) = Uphenyo ku-esidi yekojiki ehlobaniswa nokukhinyabezeka kwemayithokhondriya nokuvuvukala ezinhlayiyeni zemelanoma (SK-MEL-1).
(2023) Suritham, Tamzin Kimera.; Chuturgoon, Anil Amichund.; Ghazi, Terisha.
ojic acid (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, is used in agriculture, food, and cosmetics. KA is known to have antimicrobial, antifungal, antioxidant, and anti-inflammatory properties. The cosmetic industry's increasing interest in KA is due to its ability to inhibit tyrosinase activity resulting in skin lightening. The mitochondria play a key role in maintaining homeostasis and ensuring efficient melanin production. Therefore, mitochondrial dysfunction has severe effects on the skin. This study investigates mitochondrial stress, antioxidant responses, protein kinase signalling and inflammation in human melanoma (SK-MEL-1) cells. The mitochondria are important in processing metabolites and supplying the cell with energy in the form of ATP. KA interacts with key mitochondrial homeostasis proteins. Our results found an increase in macromolecule damage specifically lipid peroxidation and protein oxidation. Due to oxidative conditions, increased Nrf2 expression was observed. LON protease is ATP-dependent and regulated by Sirtuin 3 expression. Mitochondrial function was affected illustrated by decreased ATP production leading to decreased LON protease and Sirtuin 3 protein expression. Following increased oxidative stress, KA suppressed the expression of protein kinases but increased inflammatory mediators. There was decreased expression of phospho-Akt, Akt, phospho-GSK3β, p38 and ERK1/2. The mediation of the NLRP3 inflammasome involves priming and activation. At concentrations with high proliferation, NFκB gene and protein expression was activated. The protein kinase signalling pathways are known as mediators of inflammation; however, protein and gene expression of inflammatory mediators was increased following KA treatment. The inflammasome was subsequently activated as shown by an increase in intracellular caspase 1 levels as well as NLRP3, ILβ and IL-6 expression. KA induced mitochondrial stress and suppressed mitochondrial homeostasis proteins. The increased Nrf2 expression could have further downregulated LON protease expression and increased macromolecule damage. Oxidative conditions could have activated the inflammasome pathway independent of protein kinase signalling. In conclusion, KA displayed mitochondrial toxicity following acute exposure by suppressing mitochondrial homeostasis, protein kinase pathways and initiating inflammation. Iqoqa. I-esidi yeKojic (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4- eyodwa, iyasetshenziswa kwezolimo, ekudleni nasezimonyweni. I-KA yaziwa ngokuba ne-antimicrobial, antifungal, antioxidant, nezinto ezibanga ukuvuvukala. Luyakhula uthando lwezimboni zezimonyo ekuthandeni i-KA ngenxa yobukhona bayo ukuphazamisa ukusebenza kwetyrosinase okuholela ekutheni isikhumba sibe mhlophe. Kunokumqoka kakhulu okwenziwa imayithokhondriya ekugcineni usimamisoluzinzo lobunjalomzimba nokuqinisekisa ukukhiqizwa okwanele kwemvikelambala, imelanin. Ngakho ke, ukungasebenzi kwemayithokhondriya kunemithelela emibi esikhunjeni. Lolu cwaningo luphenya ngengcindezi yemayithokhondriya, ukusebenza kwe-antioxidant, ukukhombisa iphrotheyini khinasi nokuvuvukala kwezinhlayiya (SK-MEL-1) zemelanoma yomuntu. Imayithokhondriya ibalulekile ekuqhubeni umsebenzi wokugaya ukudla nokunika inhlayiya amandla ayisimo se-ATP. I-KA iyahlangana namaphrotheyini asemqoka osimamisoluzinzo lobunjalomzimba bemayithokhondriya. Imiphumela yethu yathola kukhula ukulimala emolekhiyulini enkulu okuyiliphidi iphreroksideyishini nokuncipha kwezinhlayiyabugesi ezihambayo zamaphrotheyini. Ngenxa yezimo zokuncipha kwezinhlayiyabugesi ezihambayo, kwabhekwa ukukhula kokuziveza kweNrf2. Okubalulekile empilweni nasekusebenzeni kwezinhlayiya, kuyi-LON, I-LON phrothizi kuncike kuyi-ATP futhi kulawulwa ukuziveza kweSirtuin 3. Umsebenzi wemayithokhondriya kwaphazamiseka kwaboniswa ukuncipha komkhiqizo we-ATP okwaholela ekuncipheni kweLON phrothizi nokuziveza kwephrotheyini iSirtuin 3. Ukulandela ukukhula kwengcindezi yokuncipha kwezinhlayiyabugesi zamaphrotheyini, i-KA yacindezela ukuziveza kwephrotheyini yekinases kodwa kwakhulisa ukuvuvukala kwezixhumanisi zengxube ezihlanganisayo. Kwaba nokuncipha kokuziveza kwephospho-Akt, i-Akt, i-phospho-GSK3β, i-p38 a ne-ERK1/2. Isihlanganisi seNLRP3 inflammasome sibandakanya ukulungiselela nokukhuthaza. Kusilinganisobungako esineproliferation ephezulu, ukuziveza kofuzo lweNFκB kanye nephrotheyini kwakhuthazeka. Ukukhombisa izindlela kwephrotheyini ikinase kwaziwa ngokuthi ukuvuvukala kwezixhumanisi; nokho, ukuziveza kwezixhumanisi zamaphrotheyini nawofuzo avuvukele kwakhula kulandela ukwelashwa kweKA. I-inflammasome yakhuthazwa njengoba yayiboniswa ngokukhula kwamazinga loku-1 lezinhlayiya zokufanayo kwecaspase nokuziveza kweNLRP3, i--β ne- IL-6. I-KA iletha ingcindezi yemayithokhondriya ibuye icindezele amaphrotheyini osimamisoluzinzo lobunjalomzimba bemayithokhondriya. Ukukhula kokuziveza kweNrf2 bekungeza ukwehlisa ukulawulwa kokuziveza kweLON phrothizi nokukhula kokulimala kwemolekhiyuli enkulu. Izimo zokuncipha kwezinhlayiyabugesi ezihambayo ngabe kukhuthaze izindlela ze-inflammasome ezizimele ezikhombisa iphrotheyini yekhinasi. Ucwaningo lwaphetha ngokuthi i-KA yabonisa ubuthi bemayithokhondriya kulandela ukungavimbeki kwabo okunamandla ngokuthi bucindezele usimamisoluzinzo lobunjalomzimba lwemayithokhondriya, izindlela zephrotheyini khinasi nokuqala kokuvuvukala.
An investigation on the effects of a rhenium (V) compound with uracil-derived ligands on markers associated with hepatic, cardiovascular and renal complications in diet-induced prediabetic rats = Ucwaningo ngemiphumela yerhenium (V) compound ene-uracil ezifweni eziyamene nesibindi, inhliziyo kanye nezinso emagundaneni ayedla kodwa esengcupheni yesifo sikashukela.
(2023) Siboto, Angezwa.; Khathi, Andile.; Ngubane, Phikelelani Siphosethu.; Sibiya, Ntethelelo Hopewell.
Prediabetes is a metabolic disorder that often precedes the onset of type 2 diabetes mellitus. This development of this asymptomatic condition is associated with chronic consumption of high calorie diets and sedentary lifestyles. Prediabetes results in decreased insulin sensitivity in the peripheral tissues resulting in elevated blood glucose levels that are not high enough for a diagnosis of type 2 diabetes. This moderate hyperglycaemia has been shown to lead to trigger complications such as non-alcoholic fatty liver disease, renal dysfunction and cardiovascular disease which are generally only diagnosed during type 2 diabetes. The current management strategy for prediabetes consists of a combination of pharmacological and lifestyle intervention. The pharmacological agents such as metformin while lifestyle intervention involves dietary modification to lower calorie diets. Studies show that prediabetic patients tend to be more dependent pharmacological intervention and struggle with changing diets thus lowering the efficacy of drugs such as metformin. This often leads to the eventual development of prediabetes. Therefore, there is a need for new pharmacological agents that can remain effective in both the presence and absence of dietary intervention. In our laboratory we have synthesised a novel rhenium (v) compound with uracil-derived ligands that has shown promising biological activities that include anti-hyperglycaemic effects in diet-induced prediabetic rats. This compound was shown to improve insulin sensitivity in peripheral tissues in prediabetic rats. To advance from this knowledge, this study sought to investigate the effects of the rhenium (V) compound with uracil-derived ligands on markers associated with hepatic, cardiovascular and renal complications in diet induced prediabetic rats model. Iqoqa. Isendlalelo: Iziguli ezisengcupheni yokungenwa yisifo sikashukela zibhekene nokuba sengcupheni yokungenwa yizifo ezinhlobonhlobo, okubalwa kuzo isifo sesibindi, isifo senhliziyo, kanye nokulimala kwezinso ngenxa yesifo sikashukela. Uma sesihlahliwe isifo, indlela ephakanyiswayo ibandakanya ukuxutshwa kokwelapha ngemithi kanye nokushintsha indlela yokuphila. Kodwa-ke, kunenkinga eqoshwe phansi yokwahluleka kweziguli ezihluphekayo ukugcina imithetho eyamene nendlela yokudla, bagxile kakhulu ekusebenziseni imithi, okuholela ekutheni imithi ingasebenzi kahle. Ngenxa yalokhu, kunesidingo semithi emisha ezokwazi ukwelapha ngempumelelo ngisho indlela yokudla ingashintshiwe. Lolu cwaningo luhlose ukuhlola umthelela werhenium (V) compound ene-uracil-derived ligands kwabaqokiwe asebecishe bangenwe ushukela, kubhekwa kokubili ukuba khona nokungabi khona kokungenelela ngokudla. Izindlela zokuqhuba ucwaningo: Amagundane ajovwa ngeprediabetes ewuhlobo oluhlala amasonto angama-20 anomsoco wamafutha kanye nezinikamandla. Emuva kokujovwa, amagundane aqokwa ngokuwola afakwa ekulashweni ngemithi ehlukahlukene. Ajovwa ngerhenium (V) compound elinganiselwa ku-15 mg/kg kanye ngosuku, njalo ngosuku lwesithathu Isikhathi esingamasonto ayi-12, kunganakwa ukuthi uhlobo lokudla kunjani. Imiphumela: Engxenyeni yokuqala (1), ukujovwa ngerhenium (V) compound kwadala ukulapheka kwesibindi, ukunonophala komzimba kanye nokwakheka kwamafutha. Okokugcina, lokhu kwelashwa kwavimbela ukonakala kwesibindi okwafakazelwa ukwehla kwama-enzyme biomarkers esibindi. Engxenyeni yesibili (2), ukusebenzisa irhenium (V) compound kwadala ukwehla kokhwantalala kanye namapro-inflammatory cytokines markers. Lokhu kwehla kwayamaniswa nokwehla kwamazinga amatriglycerides anesisindo samafutha esiphansi. Ngaphezu kwalokho, kwaba nokubuyela esimweni kokukhiqizwa kwamafutha anesisindo esiphezulu kulawo magundane afakwa irhenium (V) compound. Engxenyeni yesithathu (3), ukusebenza kwezinso kwabuyela esimweni, okwabonakala ngokwenyuka kweGRF nokwehla kweKIM 1, ipodocin ne-aldosterone. Irhenium (V) compound yathuthukisa ukusebenza kwezinso ngokuvimbela ukhwantalala oluyamene nokwehla kukashukela ezinsweni kukona kokubili ukuba khona nokungabi bikho kokushintsha indlela yokudla. Isiphetho: Imiphumela yakhombisa ukuthi irhenium (V) compound yaphumelela ukuvikela isibindi nezinso, kanti yathuthukisa ukusebenza kwenhliziyo kulawo magundane ayejovwe ngeprediabetic enokudla. Yize kunjalo, lusadingeka ucwaningo oluzocacisa kabanzi ngokusebenza nokulethwa kwemiphumela yalo muthi.
Coevolution of mutations in HIV-1 ENV and GAG-PR genes: implications for the development of protease inhibitors resistance.
(2023) Maphumulo, Ntombikhona Fortunate.; Gordon, Michelle Lucille.
Cross-resistance in PIs-exposure has been reported to be driven by Gag, however recent studies suggest Env also contributes to PIs resistance. Although studies have reported gp41 mutations in PI failures, the impact of the full-length Env on PI resistance remains unclear. We investigate the prevalence of subtype C Env mutations in patients failing PIs, the coevolution of Env mutations with Gag-PR mutations and determine whether mutations in gp120 as a result of PI resistance, affect coreceptor usage. Lastly, determine the structural changes in the Env during PI failure. The study used generated sequences from subtype C infected patients failing LPV/r inclusive treatment and HIV-1 subtype C drug-naïve sequences downloaded from the Los Alamos HIV database to compare the frequency of Env mutations in patients failing LPV/r. Bayesian network probability was applied to determine the relationship between mutations occurring within the Env and Gag-PR regions and LPV/r treatment. Furthermore, Los Alamos sequence database tools, Geno2Pheno[coreceptor], and Molecular dynamics simulations were used to demonstrate structural changes and to understand how gp120 mutations affect co-receptor usage. Lastly, Molecular dynamics simulation followed by Ring server was used to determine the structural changes caused by mutations in gp41, and gag mutations, and to look for interaction (hydrogen bond contact and VDW) between mutations and the nearby residues. Thirty-five mutations in the Env region had significantly higher frequencies in LPV/r treated patients. Env mutations were shown to coevolve with Gag-PR and they form a potential pathway to LPV/r resistance. Gp120 sequences from the PIs treated patients showed to modulate viral entry by protecting the virus from antibody recognition through the increased length in V1/V2 and V5 variable loops and the number of N-glycosylation sites observed in VI/V2. Results further showed that gp120 mutations could modulate viral entry through coreceptor switching induced by a higher charge in the V3 region, mutations in coreceptor-specific sites, and those that interact with the coreceptor binding site. Three mutations in gp41 (D632E-HR2, I688-TM, and P724Q/S-CT) were shown to influence folding by stabilizing the β-turns in their respective regions. Env coevolution with Gag-PR (mainly MA and CA) was shown through the pathway to LPV/r resistance. The gp120 mutations were also shown to contribute to viral entry through coreceptor usage and immune escape, while gp41 and Gag mutations played a role in stabilizing the α-helices which might influence the fusion of the virus. Further investigations using site-directed mutagenesis are needed to determine the effect of mutations on replication capacity. Iqoqa. Isingeniso Ukungezweli okuthelelanayo ekuvezekeni kwama-PIs kwabikwa ukuthi kuphushwa yi-Gag, kodwa ucwaningo olusanda kwenziwa luphakamisa ukuthi i-Env inomthelela ekungazweleni kwama-PIs. Nakuba ucwaningo lubike izinhlobo ze-gp41 ekwehlulekeni kwe-PI, umthelela wobude obuphelele be-Env ekungezwelini kwe-PI kuhlezi kungacacile. Siphenya ukwanda kwezinhlobo eziyisubtype C envelope nezinhlobo ze-Gag-PR nokuhlonza ukuthi izinhlobo kwi-gp120 njengomphumela wokungezweli kwe-PI, okunomthelela wokusetshenziswa kwesisizisemukeli. Okokugcina, ukuhlonza ushintsho lwesakhiwo emvilophini ngesikhathi sokwehluleka kwe-PI. Izindlelakwenza zocwaningo Ucwaningo lwasebenzisa ukulandelana okwenziwe lususelwa ezigulini ezitheleleke ngesubtype C okwehluleka kokwelapha okufaka konke kwe-LPV/r kanye ne-HIV-1 subtype C nokulandelana okungezwani nemithi yokwelapha okudawunilodwe kwisizindalwazi seLos Alamos HIV ukuqhathanisa nezikhawu zezinhlobo ze-Env ezigulini ze-LPV/r eyehlulekayo. Ukuba khona kobuxhakaxhaka beBayesian basetshenziswa ukuhlonza ubudlelwane phakathi kwezinhlobo ezenzeka kwi-Env nezindawo ze-gag-PR nemithi yokwelapha i-LPV/r. Ngaphezu kwalokho, izisetshenziswa zesizindalwazi zokulandela zeLos Alamos, i-Geno2Pheno[coreceptor], nezinhlobo zamadayinamikhi amamolekhyuli asetshenziswa ukuveza ushintsho lomumo nokuqonda ukuthi izinhlobo zama-gp120 nokunomthelela ekusetshenzisweni kwesisizisemukeli. Okokugcina, uhlobo lokwehluka kwamamolekhyuli lulandelwa yi-Ring server yasetshenziswa ukuhlonza ushintsho lomumo oludalwe yizinhlobo zakwi- gp41, nezinhlobo ze-gag, nokubheka ukuxhumana (ukuthintana nokuxhumana nehayidrojini ne-VDW) phakathi kwezinhlobo nezinsalela eziseduze. Imiphumela Izinhlobo ezingamashumi amathathu nanhlanu esifundeni se-Env yaba nezivuvabakwenzeka eziphezulu ezigulini ezelashelwa i-LPV/r. Izinhlobokuxetshulwa ze-Env zakhonjiswa njengeziguquke ne-Gag-PR nokwakha indlela engaba khona ukumelana ne-LPV/r. Ukulandelana kwe-Gp120 ezigulini ezelashelwa ama-PIs kwakhombisa ukuguqulela ukungena kwegciwane ngokuvikela igciwane ekubonakaleni emasosheni omzimba ngobude obunwetshiwe kumavariyebhuli e- V1/V2 ne-V5 kanye nenombolo yezindawo ze-N-glycosylation ezibhekwe kwi-VI/V2. Imiphumela iphinde yakhombisa ukuthi izinhlobo ze-gp120 engaguqula ukungena kwegciwane ngokuguqula okudalwa yisisizisemukeli equbuka kakhulu endaweni eyi-V3, izinhlobo zezindawo yezisizizemukeli eziqondile, nalezo ezisebenzisana nendawo efaka nesisizisemukeli. Izinhlobo ezintathu kwi-gp41 (D632E-HR2, I688-TM, ne-P724Q/S-CT) zakhombisa ukuba nomthelela ngokusimamisa ama-β-turns ezindaweni zawo. Isiphetho Lolu cwaningo luphakamisa ukuthi i-gp120 iqhube ngendlela engaqondile ukusebenza ngokungezweli kwe-PI ngokuthola izinhlobo eziphakamisa ubude be-V1/V2, njengomphumela yenyusa inani jikelele lezindawo ze-N-glycosylation, kanjalo nokwenyuka nokushaja okuphelele kwi-V3. Ngale ndlela, lezi zinhlobo zenza ukungena kwegciwane ngokuputshuka kwamasosha, nokuhambisa uguquko emagciwaneni e-CXCR4 okungaphucula ukuziphindaphinda kwegciwane. Ngaphezu kwalokho, izinhlobo ze-gp41 ezibikwe kulolu cwaningo zithinta ukuziguquguqukela kwephrotheyni. Ekugcineni, izinhlobo ze-Env zifaka isandla ekungezwelini komuthi we-PI ngokuguquka nezinhlobo kwi-Gag ezaziwa ngokufaka isandla ekwehlulekeni kwe-PI nokuchibiyela ukulahlekelwa amandla kwegciwane, okuveza ukuthi kunokusebenzisana phakathi kwamasosha nokuphakama kokungezweli komuthi.
Defining HIV persistence and host immune responses in lymph nodes of combined antiretroviral therapy (cART) suppressed individuals and the determination of the impact of HIV infection on SARS-COV-2 specific t cell responses in South Africa = Ukuchazwa kokuphikelela kwe-HIV kanye nokulwisana nayo kwamasosha okwelashwa ngemishanguzo exubile eyaziwa nge-cART okubonakala ezimbilaphweni kubantu abangakhombisi ukuthi banegciwane le-HIV, kanye nokuvela kwemithelela yokutheleleka ngegciwane le-HIV ekulweni kwamaseli awuhlobo lwe-T kwi-SARS-CoV-2 eNingizimu Afrikha.
(2023) Chasara, Caroline.; Ndhlovu, Zaza Mtine.
Abstract 1 People living with HIV (PLWH) who have unsuppressed HIV are at a greater risk of acquiring infectious diseases such as Coronavirus disease of 2019 (COVID-19). More recent data has shown that unsuppressed HIV is associated with severe COVID-19 symptoms, but the mechanisms underpinning this susceptibility are still unclear. In our study we used flow cytometry and culture T lymphocyte expansion to assess the impact of HIV infection on the quality and epitope specificity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. We observed that HIV-seronegative individuals had significantly greater CD4+ T cell responses against the Spike protein compared to the viremic individuals living with HIV. In addition, there was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identified four mutations in the Beta variant that resulted in the abrogation of T cell recognition. These findings partly explain the increased susceptibility of PLWH to diseases such as COVID-19 and highlight their vulnerability to emerging SARS-CoV-2 variants of concern. Abstract 2 The major keys to developing an HIV cure is through understanding HIV reservoir dynamics. The role of tissue macrophages in HIV reservoirs is complex and not yet fully understood. However, their ability to support viral replication, longevity, localization in immune sanctuaries, and potential for viral latency all contribute to the persistence and resilience of HIV reservoirs in various tissues throughout the body. Understanding and targeting these reservoirs is a critical area of research in the quest for an HIV cure. To gain insight into the macrophage reservoir, we used a combination of flow cytometry and immunofluorescence microscopy to characterize and investigate HIV persistence in lymph node (LN) macrophages. We detected pro-inflammatory (CD68+ ) macrophages harboring HIV Gag p24 and HIV1 RNA in the germinal centers of HIV positive early and late treated individuals suggesting their potential role as an HIV reservoir. In contrast, anti-inflammatory (CD206+ ) macrophages were localized along lymphatic vessels and outside the germinal centers. Importantly, we show the presence of longlived CD4+ TIM-4+ macrophages in LNs. The data reported in this thesis will go a long way in furthering our understanding of macrophage HIV reservoirs in lymph node macrophages. Iqoqa 1. Abantu abaphila ne-HIV (PLWH) abakhombisayo ukuthi bane-HIV basengozini enkulu yokuthola izifo ezithathelwanayo njenge-Coronavirus ka-2019 (COVID-19). Imininingo yakamuva ibonise ukuthi i-HIV ebonakalayo ihlotshaniswa nezimpawu ezinzima ze-COVID-19, kodwa izindlela ezisekela lokhu kuba sengozini azikacaci. Ocwaningweni lwethu siqale sasebenzisa i-flow cytometry kanye nokwandiswa kokuhlolwa kwamaseli egazini angamasosha okulwisana nezifo ukuze kubonakale umthelela wokuchaphazeleka nge-HIV kwikhwalithi nokucaciswa kokuvela kwezimpawu zezinkinga zokuphefumula kanzima ze-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kanye nendlela amaseli ayi-T cell alwa ngayo ekugaseleni kuqala kanye nokwesibili kobhubhane lwe-COVID-19 eNingizimu Afrika. Siqaphele ukuthi abantu abangenalo igciwane le-HIV, amaseli abo ayi- CD4+ T ayelwa ngendlela enamandla amakhulu ngokumelene ne-Spike protein uma kuqhathaniswa nabantu abanegciwane egazini abaphila ne-HIV. Ukwengeza, kube nokuncipha kokuqashelwa kwe-T cell phakathi kwalezi ziwombe zokugasela ezimbili, okwakubonakala kakhulu kubantu abane-HIV engacashile. Okubalulekile, sihlonze izinguquko ezine kwi-DNA yo hlobo lwe-Beta okuholele ekucindezelekeni kokusebenza kweseli ye-T. Imiphumela ichazile nakuba kungaphelele ukuhlaseleka kwe-PLWH ezifweni ezinjenge-COVID-19 kanti futhi kugqamisa nokuba sengozini kwabo kwezinye izinhlobo ze-SARS-CoV-2 ezisaqubuka ngendlela eyethusayo. Iqoqa 2. Izindlela ezinqala zokuthuthukisa ikhambi lokwelapha i-HIV zisekuqondeni iziguquguquli zesidlekemagciwane se-HIV. Iqhaza lamaseli ayi-macrophage ezicutshini zesidlekemagciwane se-HIV liyinkimbinkimbi futhi alikaqondakali ngokugcwele. Kodwa-ke, amandla awo okusekela ukuphindaphindeka kwegciwane, ukuphila isikhathi eside, ukutholakala kwawo ezindaweni ezivikela amasosha omzimba, kanye nokukwazi ukungazivezi njengegciwane, konke kunomthelela ekuphikeleleni nasekuqineni kwesidlekemagciwane se-HIV ezicutshini ezihlukahlukene emzimbeni wonke. Ukuqonda kanye nokuhlasela lezi zidlekemagciwane kuyingxenye ebaluleke kakhulu kulolu cwaningo emizamweni yokuthola ikhambi lokwelapha i-HIV. Ukuthola ukuqonda ngesidlekemagciwane se-macrophage sisebenzise inhlanganisela yeqhinga elaziwa nge-flow cytometry kanye ne-immunofluorescence microscopy ukuze kutholakale futhi kuphenywe ukuphikelela kwe-HIV kuma-macrophage asezimbilaphweni. Sithole ama-macrophage avunana nokuvuvukala i-(CD68+) okucashe kuwo i-HIV-Gag p24 kanye ne-HIV-1 RNA ezindaweni la kumila khona igciwane le-HIV kubantu abane-HIV abasaqala ukwelashwa nalabo asebenesikhathi eside belashwa, okukhombisa indima angayidlala njengesidlekemagciwane se-HIV. Ngokuphambene nalokho, ama-macrophage alwa nokuvuvukala i-(CD206+) atholakala emithanjeni yezimbilapho kanye nangaphandle kwezindawo okumila kuzo igciwane. Okubalulekile ukuthi sibonisa ukuba khona kwama-macrophage CD4+TIM-4+ asemadala ezimbilaphweni. Imininingo ebikwe kulo mqingo izohamba ibanga elide ekuqhubekiseleni phambili ukuqonda kwethu izidlekemagciwane zama-macrophage e-HIV kuma-macrophage atholakala ezimbilaphweni.
Drug transporter expression and genetic polymorphisms in HIV endemic settings = Indlela yokuthutheka kwemithi emzimbeni nesakhiwo esingxube sofuzo ezimweni zokubhebhetheka kwesandulela ngculazi.
(2023) Zondo, Nomusa Margaret.; Archary, Derseree.; Sobia, Parveen.
Pre-exposure prophylaxis (PrEP) in the form of oral Truvada® remains the standard of care for HIV prevention in South Africa. Despite the availability of PrEP, HIV infections continue in young women significantly more than in men. Clinical trials testing antiretrovirals containing tenofovir as topical or oral PrEP formulations in African women, produced inconsistent patterns of efficacies against HIV. Effectiveness of oral and topical PrEP is dependent on adequate drug delivery and availability to cells and tissues targeted by HIV. Our study, therefore, focused on how different biological factors: drug transporter expression, single nucleotide polymorphisms (SNPs) in drug transporter genes and genital inflammation modulate PrEP disposition in African women. We characterized drug transporter mRNA expression in two compartments, the female genital tract (FGT) and blood, at baseline, 3 and 6 months in 45 women taking oral PrEP-Truvada®. Additionally, the impact of SNPs in 393 women and genital inflammation in 45 women on circulating tenofovir and drug transporter mRNA expression were determined. SNPs in drug transporter genes: ABCB1 3435G>A; ABCC1 198217T>C; ABCC2 1249G>A; ABCC4 3463T>C; ABCC4 4131A>C and ABCC4 4976A>G were evaluated using real-time PCR. mRNA expression of efflux P-gp, MRP-2, MRP-4, MATE-1 and influx OAT-1 and OAT-3 drug transporters was evaluated using quantitative real-time PCR. Genital inflammation was measured in cervicovaginal specimens using a 28-cytokine multiplexed platform. Results showed that ABCC4 4976A>G and ABCC4 3463T>C SNPs alter circulating tenofovir differently. While the ABCC4 4976A>G SNP significantly increased the mRNA expression of the ABCC4 gene (p=0.0132), there was inverse association with circulating tenofovir (p=0.018). In contrast, although the ABCC4 3463T>C SNP did not significantly impact mRNA expression of the ABCC4 gene, it was significantly and directly associated with circulating tenofovir (p<0.05). Correlation analyses showed moderately significant associations between the mRNA expression of the influx drug transporter OAT-1 in the FGT and blood pre- and post- PrEP exposure (rs<1, p<0.05). In contrast efflux drug transporters P-gp, MATE-1, MRP-2 and MRP-4 showed significance after PrEP initiation (3 and 6 months) (rs<1, p<0.05). For pro-inflammatory cytokines, linear mixed models showed negatively correlated trends between IL-1β and MCP-1 and influx drug transporter OAT-1 and OAT-3 (p<0.1), while IL1Rα and TNF-α showed these correlations with efflux drug transporters MRP-2 and MRP-4 (p<0.1). Collectively our results suggested that PrEP disposition can be modified through a convergence of host genetics and different biological factors: drug transporter expression, SNPs in drug transporter genes and inflammation. Findings from such studies may be used to better understand PrEP pharmacokinetics and aid in the implementation of optimal PrEP dosages. This 14 will ultimately inform on effective and safe PrEP for HIV prevention especially in vulnerable and at-risk African women. Iqoqa. ENingizimu Afrika ipre-exposure prophylaxis (PrEP) oral-Truvada® kuseyiyona ndlela yokunakekela ekuvimbeleni isandulela ngculazi, i-HIV. Kodwa ukutheleleka nge-HIV kuyaqhubeka kakhulu kwabesifazane abasebancane. Ukuvivinywa kwemithi lapho kuhlolwa i-PrEP egcotshwayo/neyasemlonyeni kulabo besifazane abangama-Afrika kuveza izimo ezingazinzile ekulweni ne-HIV. Ukuphumelela kwale mithi egcotshwayo/neyasemlonyeni kuncike kakhulu ekuhambisekeni komuthi okwanele nasebukhoneni bama-cells aqondwe ngqo yi-HIV; izinto ezihambisana nomzimba ezibalulekile zibonakele ekulawuleni ukusebenza kwe-PrEP ezindaweni ezithelelekile. Lolu cwaningo, lwabheka ukuthi izimo zomzimba: indlela yokuthuthwa komuthi emzimbeni, isakhiwo esisodwa ekuthuthweni komuthi emzimbeni isingle nucleotide polymorphisms (SNPs) kanye nokuvuvukala kwezitho zangasese kunomthelela muni ekusebenzeni kwePrEP kwabesifazane abangama-Afrika. Kwakhethwa isithuthi semithi i-mRNA-expression ngezindlela ezimbili: umgudu wezitho zangasese kwabesifazane, ifemale genital tract (FGT) kanye negazi, ekuqaleni kocwaningo, izinyanga ezi-3 neziyi- 6 kwabesifazane abangama-N=45 abathatha i-PrEP-Truvada® ngomlomo. Kwabe sekubhekwa i-mRNA-expression ye-P-gp, MRP-2, MRP-4, MATE-1 kanye ne-OAT-1 kanye ne-OAT-3 okuyizithuthi zemithi ezahlolwa kusetshenziswa ucwaningozibalo lwereal-time-PCR. Umthelela we-SNPs (N=393) kanye nokuvuvukala kwezitho zangasese (N=45) ekuzungeziseni i-tenofovir kanye nesithuthimithi i-mRNA-expression kwabonakala. Ukubonakala kwe-SNPs kwizithuthimithi zofuzo: ABCB1[3435G>A]; ABCC1[198217T>C]; ABCC2[1249G>A]; ABCC4[3463T>C]; ABCC4[4131A>C] kanye ne-ABCC4[4976A>G] kwahlolwa kusetshenziswa ireal-time-PCR. Ukuvuvukala kwezitho zangasese kwakalwa kumasampula ayethathwe ebuntwini babesifazane kusetshenziswa indlela ye-28-cytokine-multiplexed platform. Imiphumela yakhombisa ukuthi i-ABCC4[4976A>G] kanye ne-ABCC4[3463T>C] SNP ishintsha ukuzungeza kwetenofovir ngendlela ehlukile. I-ABCC4[4976A>G] SNP yakhulisa kakhulu i-mRNA-expression ye-ABCC4 gene (p=0.0132), kodwa yanomthelela ophambene ekuzungezeni kwetenofovir (p=0.018). Uma kuqhathaniswa, yize i-ABCC4[3463T>C] SNP ingabanga namthelela otheni kwi-mRNA-expression yofuzo i-ABCC4, yayamana kakhulu nokukhula ekuzungeziseni itenofovir (p<0.05). Ukuhlaziya kwalokhu kuhlobana kwakhombisa ukuhambisana okubalulekile phakathi kwe-mRNA-expression ye-OAT-1 kwiFGT kanye negazi ngaphambi nangemuva kokusetshenziswa kwe-PrEP. Kanti i-P-gp, MATE-1, MRP-2 kanye ne-MRP-4 kwakhombisa ukubaluleka emuva kokuqalwa kwe-PrEP ezinyangeni ezi-3 kuya kweziyi-6 (rs<1, p<0.05). Ekuvuvukaleni kwezitho zangasese, izindlela eziqondile ezingxube zakhombisa ukungahlobani phakathi kwe-IL-1β kanye ne-MCP-1 ene-OAT-1 kanye ne-OAT-3; IL-1Rα kanye ne-TNF-α ene-MRP-2 kanye ne-MRP-4 (p<0.1). Seyihlangene yonke le miphumela yakhombisa ukuthi ukusebenza kwe-PrEP kuyashintshashintsha ngokubambisana kwezimo ezahlukene emzimbeni: yindlela umuthi othutheka ngayo, ama-SNPs, kanye nokuvuvukala kwezitho zangasese. Imiphumela yalolu cwaningo ingasetshenziselwa ukuba kuqondwe kangcono amandla okusebenza kwe-PrEP kanye nokuqalwa kokukala ubungako bomuthi we-PrEP ngendlela efanele. Ngaleyo ndlela, kungaba nokusebenziseka ngempumelelo nangendlela ephephile kwe-PrEP ukuze kunqandwe isandulela ngculazi kwabesifazane bama-Afrika abasengcupheni.
An exploration of binge drinking and coping behaviour during covid-19 among students in a major tertiary institution in KwaZulu-Natal.
(2023) Faborode, Joy Adebowale.; Kathree, Tasneem.
Background: The COVID-19 pandemic has profoundly impacted human lives. At the emergence of the novel disease, several restrictive measures, including lockdowns, were implemented to mitigate the spread of COVID-19. These measures created stressful challenges that affected people’s mental wellbeing, including that of tertiary students. There is a dearth of information on the strategies students use to cope with COVID-19-related stress. This study aimed to understand how students experienced and coped with changes attributed to the lockdowns in South Africa, including factors that influenced alcohol use among students at a major tertiary institution in KwaZulu Natal during the COVID-19 lockdown. Method: A qualitative approach was used. Twenty students were recruited from two campuses at the University of KwaZulu-Natal (UKZN), Durban, South Africa, using purposive sampling. Individual indepth interviews were conducted using a semi-structured interview guide comprising open-ended questions. The NVivo software program was used for analysis. Results: The majority (60%) of participants were male and ranged from 20 to 36 years old. The results of this study indicate drinking patterns among the study sample. Results indicate that despite implementing an alcohol sale ban during the COVID-19 lockdowns, alcohol use was not eliminated, but there was some reduction in the intake of alcohol. Apart from alcohol restrictions, some factors influencing drinking included drinking location and people with whom participants consumed alcohol. Many participants also indicated that they preferred to consume alcohol with friends because it helped them to bond with their friends and improved their social interactions. In addition, over 50% of the students stated that they drank alcohol because they felt happy, socialized with others, had fun, and that they enjoyed the taste. In contrast, only a few (four) reported drinking as a coping mechanism. Respondents were also aware of the negative consequences of drinking alcohol, especially when it is in large quantities. Results also indicate that half of the participants felt stressed, depressed, anxious and sad during the lock down. In addition, they also experienced problems related to eating and sleeping. The study highlighted the various coping mechanisms participants used to deal with stress. These included emotion-based coping strategies such as social support, sleeping, exercise, reading, watching television, listening to music, and maintaining a positive attitude, problem-based coping strategies (e.g., positive thinking and planning), as well as avoidance forms of coping (such as ignoring the situation). Conclusion: This study found that alcohol misuse was common in this sample of university students prior to the onset of COVID-19, and they experienced some distress during the COVID-19 lockdown. Factors that influenced alcohol use were also identified in this study sample which provided insight into how they experienced and coped with changes directly caused by the lockdowns in South Africa. 11 Despite these findings, sampling students from only one tertiary institution in KwaZulu Natal and being unable to interview students in their home language or the language of fluency if this was not English are identified as limitations. This study recommends that health promotion and education on alcohol use and coping strategies should be encouraged at tertiary institutions to curb alcohol misuse and improve students’ wellbeing.
Investigating the effects of oral contraceptives on thrombotic-risk markers.
(2024) Mahlobo, Mthokozisi.; Mxinwa, Vuyolwethu.; Nkambule, Bongani Brian.
Abstract available in a PDF.
Molecular epidemiology of Antibiotic-Resistant Escherichia coli from companion animals attending veterinary practices in Durban, KwaZulu-Natal, South Africa.
(2023) Ntuli, Nondumiso Lungile.; Essack, Sabiha Yusuf.; Mbanga, Joshua.; Abia Akebe, Luther King.
Background: Companion animals are globally documented to harbour antibiotic-resistant E. coli. This study aimed to investigate the molecular epidemiology of antibiotic-resistant E. coli from companion animals presenting at veterinary practices in Durban, KwaZulu-Natal, South Africa. Methods: E. coli were isolated on selective media from rectal swabs sampled from dogs and cats attending veterinary practices in Durban, KwaZulu-Natal, South Africa. All isolates were confirmed using real-time polymerase chain reaction (PCR) of the uidA gene. Antibiotic susceptibility testing was done against 20 antibiotics using the Kirby-Bauer disk diffusion method. Selected antibiotic-resistance genes (ARGs) that confer resistance to third-generation cephalosporins (blaTEM, blaSHV, and blaCTX-M), tetracycline (tetA, and tetB), and tigecycline (tetX/X2, tetX3, and tetX4), were detected using conventional PCR. PCR amplicons were confirmed by DNA sequencing and bioinformatics analysis. Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) was carried out to determine the clonality of E. coli (101) isolates that showed resistance to at least one antibiotic. Results: A total of 330 E. coli isolates from dogs (234) and cats (96) formed the study sample. Overall resistance was high in tetracycline (24.2%), ampicillin (18.8%), trimethoprim-sulfamethoxazole (14%), cephalexin (11.2%) and nalidixic acid (9.7%). Whilst lower resistance was observed in amikacin (0.3%), ceftazidime (0.3%), and piperacillin-tazobactam (0.6%). Third-generation cephalosporin-resistant E. coli retrieved from cats (26%) was more prevalent compared to dogs (9.8%). E. coli from dogs (2.1%) and cats (2%) were resistant to forth-generational cephalosporins. E. coli (3%) retrieved from dogs was resistant to tigecycline, which is regarded as a medically important antimicrobial (MIA) in human medicine. No resistance was observed against carbapenems. Thirty-five (10.6%) E. coli were multidrug-resistant (MDR) and exhibited twenty-two different phenotypic patterns. Amongst the E. coli that were not susceptible to third-generation cephalosporin, and tetracycline, it was observed that the blaCTX-M-15 (8%), and tetA (24%) were the most prevalent resistance genes. Thirty-one (9.3%) isolates were non-susceptible to third-generation cephalosporins and had the corresponding extended-spectrum beta-lactamase (ESBL) genes. The blaCTX-M-15 type gene was prevalent in all 25 E. coli isolates that tested positive for the blaCTX-M. The blaTEM-1 (17) was the second most prevalent β-lactamase gene. A total of 80/330 (24%) isolates were phenotypically not susceptible to tetracycline and carried either one, or both of tetA and tetB resistance genes. Only one tetracycline-resistant E. coli isolate did not harbour either tetA, or tetB genes. The blaSHV, tetX/X2, tetX3, and tetX4 were not detected in all the isolates. Using a 75% similarity cut-off, forty-eight clusters with isolates from both dogs and cats were identified. The ERIC-PCR types depicted a variety of clusters within veterinary practices in Durban, indicating that a high diversity of E. coli is in circulation in Durban, South Africa. Conclusion: Companion animals are reservoirs of antibiotic-resistant E. coli and ARGs. However, there was no evidence of transmission of antibiotic-resistant E. coli in Durban, South Africa. Resistance of E. coli from companion animals to MIA for humans is of particular concern and requires measures to control the spread of antibiotic-resistant bacteria, and ARGs between companion animals, veterinary practice personnel, and owners.
Mortality trends during the first three waves of the covid- 19 pandemic at an urban district hospital in KwaZulu-Natal.
(2023) Hirachund, Omishka.; Naidoo, Mergan.
Introduction Severe Acute Respiratory Syndrome Corona Virus 2 (SARS COV 2) is the virus responsible for the COVID -19 (C19) pandemic. South Africa (SA) experienced multiple periods of increased transmission during which tertiary, regional and central hospitals were overwhelmed, resulting in a low acceptance rate of referrals from district hospitals (DHs). Thus, many severely ill, complex patients were managed at DHs while awaiting an Intensive Care Unit (ICU) bed. This study aims to describe mortality trends in a comparative analysis of the first three C19 waves at Wentworth Hospital (WWH). Literature Review Known risk factors for mortality are older age; male sex; Black African, Coloured and Indian compared to white race; admission in the public sector; comorbid diseases and obesity. Waves 2 and 3 had higher mortality rates compared to wave 1. Methods The study is a single-centre retrospective analysis of WWH’s clinical records and included all patients infected with C19 (based on clinical, biochemical or radiological features suggestive of infection) who were admitted and subsequently demised in-hospital during the defined waves. Data was collected using a pre-piloted data extraction tool. Demographic and presenting features of the patients along with investigations and management strategies were compared by the primary investigator across the three waves. Results Wave one, two and three yielded case fatality rates of 14.5%, 27.6% and 6.3%, respectively, and crude fatality rates of 16.7%, 33.0% and 12.2%, respectively. Black Africans were less likely to demise during the third wave (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.31 to 0.94). Obesity was most prevalent in the second wave (OR 1.87; CI 1.01 to 3.46). Patients in the second wave had clinical frailty scores of less than five (OR 2.51; CI 1.56 to 4.03). Severe ground glass appearance on chest radiographs was most common during the second wave (OR 2.37; CI 1.49 to 3.77). Conclusion The beta variant dominated the second wave and was the most virulent, as highlighted by the highest case- and crude fatality rates. This study identified the need to understand if case fatality 2 rates and mortality trends at a DH were significantly higher than those at regional or tertiary hospitals. It is hoped that this study will provide clinical and hospital managers, and provincial and national healthcare policy makers with insight into challenges faced in the health system in the public health sector and allow implementation of improved public health and planning strategies for future pandemics.
Pneumatization of the temporal bone, its petromastoid part and related vasculature in a South African population from early childhood to early adulthood: an anatomical and radiological study.
(2023) Aladeyelu, Okikioluwa Stephen.; Rennie, Carmen Olivia.; Sibiya, Lindokuhle Andile.; Mbatha, Wonder-boy Eumane.
Introduction: The pneumatization of the temporal bone is important in various clinical settings. These include serving as a prognostic factor in middle ear surgeries and acting as a shock absorber in patients sustaining lateral skull trauma. The size and growth rate of its air cell system have been associated with middle-ear pathology. The degree of temporal bone pneumatization is highly relevant when planning temporal bone-related surgeries and has been hypothesized to influence anatomical variations of temporal bone-related vessels. This study aimed to investigate the size of temporal bone pneumatization (air cell volume) with age, the association between temporal bone pneumatization and the morphologies of some temporal bone-related vessels, as well as their morphometrical relationship with ear regions, and to propose a simple and concise classification of the degree of temporal bone pneumatization using reference structures and landmarks. Materials and Methods: A retrospective review of 496 temporal bone computed tomography (CT) images of 248 head and neck/brain CTs of patients from public hospitals in KwaZulu-Natal, South Africa, was conducted. The sample consisted of 133 males and 115 females, 0 to 35 years old (median age 13.0 years) of three population groups (202 South African Black, 28 South African Indian, and 18 South African White). The age range of 0 to 35 years was further divided as follows: 0-2 (infant); 3-5 (young child); 6-9 (middle child); 10-14 (early adolescent); 15-18 (middle adolescent); 19-25 (young adult stage I); 26-35 (young adult stage II). High-resolution CT images with fine slices of ≤ 0.625 mm were analyzed using IntelliSpace Portal (ISP) Version 11.1 viewer software. The volume of temporal bone pneumatization was achieved using three dimensional (3D) volumetric rendering technique. At the same time, the morphologies of the sigmoid sinus, jugular bulb, and internal carotid artery and their morphometrical relationships with ear regions were analyzed using the measuring tools on the ISP. Additionally, an inter-observer assessment was conducted among otologists to classify the degree of temporal bone pneumatization utilizing temporal bone CT images at two levels (landmarks): the malleoincudal junction and the lateral semicircular canal using sigmoid sinus as a reference. Results: Size (volume) of temporal bone pneumatization with age: The volume of temporal bone pneumatization increased significantly (p<0.001) with age up to the adult stage I (19-25 years), followed by a significant decline in young adult stage II (26-35 years). Females showed a significant early increase compared to males. Regarding population groups, Black South Africans (SA) showed a higher increase in volume with age than the SA Whites and Indian population groups. Influence of pneumatization on temporal bone-related vessels: Four degrees of pneumatization (hypo, moderate, good, and hyper) were analyzed. Hyper-pneumatization was observed to be more common. Vascular variants such as high jugular bulb, jugular bulb dehiscence, and internal carotid artery dehiscence were observed and significantly associated (p<0.01) with hyper-pneumatization. Also, as pneumatization increases, sigmoid sinus and jugular bulb distances to ear regions were observed to increase significantly (p<0.01, p<0.05). The sigmoid sinus and its variant shapes were also observed but were not significantly associated with the degrees of pneumatization (right- p=0.070; left- p= 0.645). Classification of degree of pneumatization: In the survey conducted among cohort otologists, the percentage of participants that correctly rated temporal bone CT images taken at the level of lateral semicircular canal according to their respective degrees of pneumatization was significantly higher (p < 0.05) regardless of their year of experience compared to those that correctly rated corresponding images taken at the level of malleoincudal junction. A 76% positivity in their agreement with the use of sigmoid sinus in evaluating mastoid pneumatization was observed. Discussion and Conclusion: This study concludes that the pneumatization of a healthy temporal bone is expected to show a significant linear increase from infant up until at least the early adult stage I (19-25 years) in the South African population. The high incidence of high JB, JB dehiscence, and internal carotid artery dehiscence, and the increase in distances of sigmoid sinus and JB to ear regions reported in this study population due to increased pneumatization validates temporal bone pneumatization as a factor that influences jugular bulb variants and internal carotid artery dehiscence as well as the distances of sigmoid sinus and jugular bulb to ear regions. The study also concludes that using the lateral semicircular canal as a landmark on axial CT, and evaluating air cells around the sigmoid sinus was suitable in classifying the degree of temporal bone pneumatization into hypo-, moderate, good, and hyper-pneumatization. This study proposes this classification system as an easier and quicker method for clinical applications. Iqoqa Isingeniso: Izikhala zomoya ezisethanjeni elaziwa ngetemporal bone zibalulekile kwezokwelapha ezihlukahlukene. Lokhu kubandakanya ukuba usizo kwalezi zikhala lapho kuhlinzwa indlebe futhi zinciphisa umonakalo odalekayo lapho umuntu eshaywa yinto ethile ekhanda. Ubukhulu nezinga lokukhula kwamangqamuzana omoya kuye kwahlotshaniswa nesifo sendlebe. Ubungako bezikhala zomoya ethanjeni itemporal bone kubaluleke kakhulu lapho kuhlelwa ukuhlinza okuzothinta leli thambo futhi kucatshangwa ukuthi kunomthelela oshintshweni oluba semithanjeni yegazi esondelene naleli thambo. Lolu cwaningo luhlose ukuthola ukuthi zinkulu kangakanani izikhala zomoya ezisethanjeni itemporal bone (umthamo wamangqamuzana omoya) kuye ngobudala bomuntu, ukuthola ukuhlobana phakathi kwezikhala zomoya ezisethanjeni itemporal bone noshintsho oluba khona emithanjeni yegazi esondelene naleli thambo, ukuthola indlela ubukhulu nokuma kwalezi zinto okuchaphazela ngayo ezinye izindawo eziseduze kwendlebe, kanye nokwenza iziphakamiso ezilula nokunikeza incazelo efingqiwe yokuthi zingakanani ubukhulu izikhala zomoya ethanjeni itemporal bone, kusetshenziswa izingxenye okuzobhekiselwa kuzo. Okuzosetshenziswa Nezinqubo: Kwacutshungulwa izithombe ezingama-496 zetemporal bone ezithwetshulwe ngomshini owaziwa ngecomputed tomography (CT) zamakhanda nezintamo/nobuchopho okungama-248 eziguli zasezibhedlela zikahulumeni KwaZulu-Natali, eNingizimu Afrika. Isampula lalihlanganisa abesilisa abayi-133 nabesifazane abayi-115, abaneminyaka esukela e-0 kuya kwengama-35 ubudala (iminyaka emaphakathi eyi-13.0) bezinhlanga ezintathu (abaNsundu baseNingizimu Afrika abangama-202, amaNdiya aseNingizimu Afrika angama-28, naBelungu baseNingizimu Afrika abayi-18). Iminyaka yobudala esukela e-0 kuya kuma-35 yaphinde yahlukaniswa ngale ndlela elandelayo: 0-2 (usana); 3-5 (ujahidada); 6-9 (ingane encane); 10-14 (ingane esizothomba noma esithomba); 15-18 (intsha); 19-25 (isigaba sokuqala sabantu abadala); 26-35 (isigaba sesibili sabantu abadala). Kwacutshungulwa izithombe ze-CT ezigqamile eziwugqinsana oluncane luka-≤ 0.625 mm kusetshenziswa uhlelo lwekhompyutha okuthiwa yi-IntelliSpace Portal (ISP) Version 11.1. Umthamo womoya osethanjeni itemporal bone watholakala ngokusetshenziswa kwendlela yokuhlola umthamo engumumo onxantathu, othree dimensional (3D). Ngesikhathi esifanayo, kwacutshungulwa ukwakheka kwesigmoid sinus, ijugular bulb, nomthambo i-internal carotid kanye nokuhlobana kwalezi zinto nezingxenye eziseduze kwendlebe kusetshenziswa amathuluzi okukala e-ISP, okuwuhlelo lwekhompuyutha. Ukwenezela kulokho, kwaqoqwa umbiko walokho okuphawulwe odokotela bezifo zendlebe ukuze kukalwe ubukhulu bezikhala zomoya ethanjeni itemporal bone kusetshenziswa izithombe ze-CT zethambo itemporal bone ezindaweni ezimbili: imalleoincudal junction kanye nelateral semicircular canal kusetshenziswa isigmoid sinus njengesibonelo. Imiphumela: Usayizi (umthamo) wezikhala zomoya ezisethanjeni itemporal bone kuya ngobudala bomuntu: Umthamo wezikhala zomoya ezisethanjeni itemporal bone ukhuphuka kakhulu (p<0.001) njengoba umuntu ekhula kuze kufike esigabeni sokuqala sabantu abadala (iminyaka eyi-19-25), bese wehla ngokuphawulekayo kubantu abadala besigaba sesibili (abaneminyaka engama-26-35). Kwabesifazane kwaphawulwa ukuthi ushesha kakhulu ukukhuphuka uma kuqhathaniswa nabesilisa. Ngokuphathelene nezinhlanga, kubantu abaNsundu base-South Africa (SA), umthamo unyuka kakhulu njengoba bekhula uma kuqhathaniswa naBelungu namaNdiya ase-SA. Umthelela wokwakheka kwezikhala zomoya emithanjeni yegazi ehlobene nethambo itemporal bone: Kwacutshungulwa amazinga amane obukhulu bezikhala zomoya (eliphansi, elilingene, elikahle neliphakeme). Ukwakheka kwezikhala zomoya ngezinga eliphakeme kwabonakala kuvame kakhulu. Kwaphawuleka izinkinga ezihlukahlukene zemithambo yegazi ezifana nenkinga yomthambo osuka ekhanda wehlele entanyeni obizwa ngehigh jugular bulb, inkinga yomthambo odlula engxenyeni engaphakathi yendlebe, ebizwa ngejugular bulb dehiscence, kanye nenkinga yomthambo omkhulu oyisa igazi ebuchosheni ebizwa nge-internal carotid artery dehiscence futhi lezi zinkinga zahlotshaniswa kakhulu (p<0.01) nokwakheka ngamandla kwezikhala zomoya. Kanti futhi njengoba zikhula izikhala zomoya, kwaphawuleka ukuthi ukuqhelelana phakathi kwesigmoid sinus nejugular bulb kanye nezindawo ezakhelene nendlebe nako kukhula ngokuphawulekayo (p<0.01, p<0.05). Kwaphawuleka nesikhala somoya okuthiwa yisigmoid sinus nezindlela ezihlukahlukene esakheke ngazo kodwa lokhu akuzange kuhlotshaniswe kakhulu nobukhulu bezikhala zomoya (kwesokudla- p= 0.070; kwesobunxele- p= 0.645). Ukuhlukaniswa ngezigaba kwamazinga ezikhala zomoya ezisemathanjeni: Kunhlolovo eyenziwa eqenjini lochwepheshe bezifo zendlebe, kulabo ababamba iqhaza ayephakeme kakhulu amaphesenti abanikeza isilinganiso esinembile sobukhulu bezikhala zomoya lapho behlola izithombe ze-CT zethambo itemporal bone ezathwetshulwa maqondana nengxenye engaphakathi yendlebe ebizwa ngokuthi yilateral semicircular canal (p <0.05), noma ngabe base bechithe isikhathi esingakanani bekulo mkhakha uma kuqhathaniswa nalabo ababekale kahle izithombe ezihambisanayo ezithathwe maqondana nemalleoincudal junction. Kwaphawuleka ukuthi abangamaphesenti angama-76 bavumelana nokuba kusetshenziswe isikhala somoya okuthiwa yisigmoid sinus lapho kuhlolwa isikhala somoya esisethanjeni imastoid. Ingxoxo nesiphetho: Lolu cwaningo luphetha ngokuthi izikhala zomoya ezisethanjeni eliphile kahle itemporal bone kulindeleke ukuba zikhule ngokuphawulekayo kusukela lapho umuntu eselusana kuze kufike okungenani esigabeni sokuqala sabantu abadala (iminyaka eyi-19-25) kubantu baseNingizimu Afrika. Amazinga aphakeme ezinkinga zemithambo yegazi njengenkinga okuthiwa yi-JB, inkinga ebizwa nge-JB dehiscence nenkinga ebizwa nge-internal carotid artery dehiscence kanye nokukhula kwezikhala ezihlukanise isigmoid sinus nejugular bulb nezingxenye ezisendlebeni ezibikiwe kubantu abahlolwe kulolu cwaningo ngenxa yokukhula kwezikhala zomoya emathanjeni kuqinisekisa ukuthi izikhala zomoya ezisethanjeni itemporal bone zinomthelela ekudalekeni kwezinkinga zemithambo yegazi ezihlukahlukene okuyijugular bulb ne-internal carotid artery dehiscence kuhlanganise nebanga eliphakathi kwesigmoid sinus nejugular bulb kanye nezinye izindawo esisendlebeni. Lolu cwaningo lufinyelele nesiphetho sokuthi ukusebenzisa ilateral semicircular canal lapho kwenziwa i-CT scan, nokuhlola amangqamuzana omoya ezindaweni eziseduze nesigmoid sinus kuyafaneleka lapho kubekwa ngezigaba ubukhulu bezikhala zomoya ezisethanjeni itemporal bone ngokwamazinga amane; izinga eliphansi, elilingene, elihle neliphakeme kakhulu lokwakheka kwezikhala zomoya. Lolu cwaningo luphakamisa ukuba kusetshenziswe le nqubo njengendlela elula nesheshayo kwezokwelapha.
Strategic application of in silico drug discovery approaches to discover novel TB drugs = Ukusetshenziswa komqondosu womuthi wokwelapha i-in silico ngezindlelakwenza ukuze kutholakale imithi yokwelapha i-TB emisha.
(2023) Kisten, Kimona.; Mhlongo, Ndumiso Nhlakanipho.; Kumalo, Hezekiel Mathambo.
Tuberculosis is one of the major causes of mortality worldwide due to the onset of bacterial infection. It remains a continuous field of study as a result of the emergence of drug resistant strains whereby first- and second-line drugs are ineffective. Variations associated with proteins in the bacteria, Mycobacterium tuberculosis, can be attributed largely to poor compliance of patients and the existence of co-morbidities within a person, inevitably leading to coinfections and a diminished immune response. This evolution of the bacteria therefore calls for extensive research to be carried out on enhanced drug design and development techniques. Re-evaluation of previously identified drug targets, determination of newly viable drug targets and the identification and design of small molecule inhibitors form a basis on the forefront of this research. Computer aided drug design techniques provide a novel method exponentially gaining popularity. Molecular modelling utilizing in silico developed methods, paired with drug repurposing, pose a viable, cost effective and efficient solution for drug design strategies. The use of chemical interaction data associated with small molecules forming complexes with drug targets of interest help understand the behaviour and mechanism of a protein before graduating to wet method techniques. Using the fundamentals of docking, molecular dynamics and virtual screening, various small molecules with the potential to provide extensive inhibition capability can be identified. This study investigates three major drug targets of Mycobacterium tuberculosis (Mtb): Enoyl-[acyl-carrier-protein] reductase (inhA), β-ketoacyl ACP synthase (KasA), and Dihydropteroate synthase (DHPS/folP1) involved in the mycolic acid and folate pathways. Various tools inclusive of gene ontology, network-based inference, virtual screening and tailored pharmacophore as a function of molecular modelling and drug repurposing were used to identify potential potent inhibitors and comprehend the understanding of the structural changes, conformations and interactions associated with the protein and the response to suggested drug hits with the potential to affect an overall protein structure in consideration with the formation of a complex. This approach can potentially serve as a platform to the development and discovery of novel drugs against a wide range of drug targets. Iqoqa. Isifo sofuba singezinye zezimbangela ezinkulu zokushona emhlabeni jikelele ngenxa yokuthathelwana kwezifo zamagciwane. Silokhu siqhubeka nokuba wumkhakha ocwaningwayo ngenxa yokuqubuka kwezinhlobo ezingezweli emithini yokwelapha lapho imithi esetshenziswe ezingeni lokuqala nelesibili ingasebenzi. Umehluko ohlobene nezakhamzimba amaphrotheyni asegciwaneni iMycobacterium tuberculosis, kungahlotshaniswa kakhulu nokuhambisana okungekuhle kweziguli nobukhona bezinye izifo kumuntu, okuholela ekuthelelekeni ngokuningi nokwenza izinga lamasosha omzimba ehle. Le nguqukomumo yegciwane ibiza ukuba kube nocwaningo olunzulu okumele lwenziwe ngohlelo lwemithi ephuculiwe namasu okuluphucula. Ukuhlola kabusha kwemithi ebihlonzwe esikhathini esedlule ukuhlonzwa kokuhloswe ngemithi yokwelapha nesakhiwo sezivimbi zamamolekhyuli amancane kuyisisekelo esiphambili kulolu cwaningo. Amasukhono emithi ehlanganiswe ngokwekhompyutha ahlinzeka indlela esazanywa enokuthandwa okukhula kakhulu. Ukuqondisa amamolekhyuli asetshenziswa ezindleleni ezakhelwe i-in silico, ahambelaniswa nokusetshenziselwa ezinye izifo kwemithi, okuqhamuka isixazululo esinezindleko eziphansi nezisebenza ngezindlela zamasu okwakha imithi. Ukusetshenziswa kwemininingo yokuxutshwa kwamakhemikhali okuhlobene namamolekhyuli amancane kwakha izinhlanganisela zemithi okusoshwe ukusiza ukuqonda insebenzo kanye nendlela yephrotheyni ngaphambi kokuba kwedlulelwe emaswini ayizindlela zokumanzisa. Kusetshenziswa izingqikithi zokuzimelelisa, amadayinamikhi amamolekhyuli nokuskrina ungekho endaweni, amamolekhyuli amancane ayizinhlobo ezehlukene ezingakwazi ukuhlinzeka ukukwazi ukuvimbela okusezingeni elikhulu okungahlonzwa. Lolu cwaningo luphenya izinhlobo ezintathu zemithi esoshelwe ukusetshenziselwa i-Mycobacterium tuberculosis (Mtb): i-Enoyl-[acyl-carrier-protein] reductase (inhA), i-β-ketoacyl ACP synthase (KasA), neDihydropteroate synthase (DHPS/folP1) efakwe emigudwini yemycolic acid nefolate. Amathuluzi ehlukene ezinsizakusebenza ezisuselwa ekucwaningeni ngobunjalobukhona bofuzo, ukuqagulwa okususelwa ebuxhakaxhakeni, ukuskrina ungekho lapho kusetshenzelwa khona nensebenzomithi ehleliwe njengokomgomo wokwakhiwa kwamamolekhyuli nokusetshenziswa ngendlela entsha kwemithi kwenziwelwa ukuhlonza izivimbinsebenzobuthi ezikhona nokuzwa ukuqonda ushintsho lokomumo, okuhambelana nokuxhumana okuhambelana namaphrotheyni nempendulo yemithi ephakanyisiwe engaba nomthelela emumweni ophelele wephrotheyni uma kubhekwa isakhiwo senkimbingxube. Leli su lingakwazi ukuba yinkundla yentuthuko nokuthola imithi esazanywa esetshenziselwa izinhloso ezehlukene zokwelapha.
Type I, II, and III interferon responses in the female genital tract.
(2024) Ngubane, Slindile Brilliant Lyzeth.; Sivro, Aida.
Abstract available in PDF.
Waist circumference, waist-to height ratio, or body mass index: which is the better predictor of hypertension in patients living with diabetes mellitus in low-to-middle-income countries?
(2022) Konar, Kylie Divashnee.; Pillay, Somasundram.
Background Hypertension (HPT) in low and middle-income countries (LMICs) remains a leading preventable factor for death and disability. Approximately 20-60% of patients living with diabetes (PLWD) have HPT which doubles the mortality risk and accelerates the progression of complications. Obesity is a well-known preventable risk factor for HPT. Despite this, countries in Sub-Saharan Africa (SSA) faces an increasing challenge of obesity. Current evidence on anthropometric indices as a predictor for HPT in PLWD remain unclear. Methods A scoping review was performed to determine the association between anthropometry and HPT in PLWD in LMICs in SSA, by using PubMed, Google, Scopus and Cochrane between 2011- 2021. A total of 4590 records were identified. The associations between body mass index (BMI), waist circumference (WC) or waist-to-height ratio (WTHR) in PLWD and HPT in LMICs in SSA were assessed. Results We analyzed 21 studies with 11 057 patients included in this review. BMI was the most common anthropometric index used with more than 80% of studies suggesting a positive association with HPT. Varying associations between other anthropometric indices and HPT were found. Conclusions Our scoping review highlighted a positive association between HPT and anthropometry in most studies. Limited data was available comparing the different anthropometric indices. We found that additional studies are warranted to evaluate anthropometric indices in PLWD.

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