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The occurance of genetic variations in the MYH9 gene and their association with CKD in a mixed South African populationMasconi, Katya 12 1900 (has links)
Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The purpose of this study was to investigate the association of the selected MYH9 single nucleotide polymorphisms (SNPs) with chronic kidney disease (CKD) and its related co-morbidities in the South African mixed ancestry population residing in Bellville South, Cape Town. In 2008, two landmark studies identified SNPs in the MYH9 gene which explained most of the increased risk for non-diabetic CKD in African Americans. These polymorphisms were later found to be weakly associated with diabetic nephropathy.
Three SNPs that exhibited independent evidence for association with CKD were selected (rs5756152, rs4821480 and rs12107). These were genotyped using a Taqman genotyping assay on a BioRad MiniOpticon and confirmed by sequencing in 724 subjects from Bellville South, Cape Town, South Africa. Prevalent CKD was defined based on the estimated glomerular filtration rate calculated using the modification of diet in renal disease (MDRD) formula. Chronic kidney disease was present in 214 subjects (29.6%), 96.3% were stage 3 and only 8 subjects were stage 4. In additive allelic models, adjusted for age and gender, rs5756152 demonstrated an association with kidney function whereby each G allele of rs5756152 increased eGFR by 3.67 ml/min/1.73, reduced serum creatinine by 4.5% and increased fasting plasma glucose by 0.51 mmol/L. When an interaction model was used, the effect of rs5756152 on serum creatinine, eGFR and blood glucose levels was retained, and enhanced, but only in diabetic subjects. In addition, rs4821480 T allele increased eGFR while rs12107 A allele decreased glucose levels in diabetic subjects. In contrast to reports that MYH9 SNPs are strongly associated with non-diabetic end stage renal disease, our study demonstrated that rs5756152 and rs4821480 are associated with early kidney function derangements in type 2 diabetes whilst rs12107 is associated with glucose metabolism. Our findings, along with previous reports, suggest that the MYH9 gene may have a broader genetic risk effect on different types of kidney diseases than previously thought. / AFRIKAANSE OPSOMMING: Hierdie studie het ondersoek ingestel na die verband tussen drie gekose MYH9-enkelnukleotied-polimorfismes (SNP’s) en chroniese niersiekte (hierna ‘niersiekte’), wat verwante ko-morbiditeite insluit, onder ’n Suid-Afrikaanse populasie van gemengde afkoms in Bellville-Suid, Kaapstad. Twee rigpuntstudies het in 2008 op SNP’s in die MYH9-geen afgekom wat verklaar het waarom Afro-Amerikaners ’n hoër risiko vir niediabetiese niersiekte toon. Later is bevind dat hierdie polimorfismes ook ’n swak verband met diabetiese nefropatie het.
Drie SNP’s wat elk onafhanklik bewys gelewer het van ’n verband met niersiekte is vervolgens gekies (rs5756152, rs4821480 en rs12107). Die SNP’s is daarná met behulp van die Taqman-toets op ’n BioRad MiniOpticon aan genotipering onderwerp, en is toe deur middel van reeksbepaling by 724 proefpersone van Bellville-Suid, Kaapstad, Suid-Afrika, bevestig. Die voorkoms van niersiekte is bepaal op grond van die geraamde glomerulêre filtrasietempo (eGFR), wat aan die hand van die ‘niersiekte-dieetveranderings’- (MDRD-)formule bereken is. Daar is bevind dat 214 proefpersone (29,6%) aan chroniese niersiekte ly – 96,3% was in fase 3 en slegs agt proefpersone in fase 4. In toegevoegde alleliese modelle wat vir ouderdom en geslag aangepas is, het rs5756152 ’n verband met nierfunksie getoon: Elke G-allel van rs5756152 het eGFR met 3,67 ml/min/1,73 verhoog, serumkreatinien met 4,5% verlaag en vastende plasmaglukose met 0,51 mmol/L verhoog. Toe ’n interaksiemodel gebruik is, is die effek van rs5756152 op serumkreatinien, eGFR en bloedglukosevlakke behou en versterk, hoewel slegs by diabetiese proefpersone. Daarbenewens het die T-allel van rs4821480 eGFR verhoog, terwyl die A-allel van rs12107 ook glukosevlakke by diabetiese proefpersone verlaag het.
In teenstelling met bewerings dat MYH9-SNP’s ’n sterk verband met niediabetiese eindstadiumniersiekte toon, het hierdie studie bewys dat rs5756152 en rs4821480 met vroeë nierfunksieversteurings by tipe 2-diabetes verband hou, terwyl rs12107 weer met glukosemetabolisme verbind word. Tesame met vorige studies, doen hierdie navorsingsbevindinge dus aan die hand dat die MYH9-geen dalk ’n groter genetiese risiko-effek op verskillende tipes niersiekte het as wat voorheen vermoed is. / Cape Peninsula University of Technology Research Fund / University of Stellenbosch Merit Bursary
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The refinement of a booklet on stroke care at homeBotha, J. H. 03 1900 (has links)
Thesis (MScMedSc (Rehabilitation))--University of Stellenbosch, 2008. / Stroke is the second commonest cause of mortality worldwide and remains a leading
cause of adult physical disability. It is estimated that sixty percent of South African
stroke survivors require assistance with at least one activity of daily living. This
burden is predominantly on the shoulders of mostly untrained caregivers.
The process of enabling caregivers to make choices conducive to their own health as
well as the health of the stroke survivors is multidimensional. One of the cornerstones
of this process is the provision of information. In 1995, the Centre for Rehabilitation
Studies of the University of Stellenbosch started to develop a training package for
stroke care at home. The training takes the form of an interactive workshop and a
booklet with practical information. The aim of this study was to refine and pilot this
booklet for implementation with the training.
The study found that existing guidelines to evaluate the appropriateness of written
material for developing communities (measured by Hugo’s grading model), were
inadequate. Consequently, a new checklist, based on twenty existing checklists, was
compiled. This list, as well as the Suitability Assessment of Material (SAM), was used
to evaluate the booklet and make recommendations for a pre-pilot refinement. Even
though this checklist has not been validated, it revealed similar results to the SAM
when applied to the booklet. After cosultation with the authors, improvements were
effected to the booklet
The booklet was tested with four samples of the target audience. The functional
literacy of the participants was determined using a standardised literacy test. A fifth
sample completed a questionnaire on their preference between the pre- and postrefined
booklet. Experts in the field of rehabilitation and graphic design also
commented on the booklet.
This study confirmed the need of stroke survivors and their caregivers for written
health information. The refined booklet was found to be an appropriate tool to
address the needs of the target audience. The participants perceived the booklet as
useful and comprehensible and the readability level was shown to correspond with the tested literacy level of the samples. However, there is a need for printed material on
topics related to stroke not currently covered in the booklet, e.g. spasticity.
This study showed that the checklist could be used to tailor written health information
that is preferred by the target audience. It confirmed that the testing of printed
material with stakeholders could expose additional gaps after applying the checklist.
Recommendations for further improvements were made based on the comments of
the participants.
It is foreseen that the new checklist could be a valuable tool for developing future
written health material. Finally, it is recommended that an interdisciplinary team that
includes a graphic designer be involvement from the planning stages.
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Factors influencing grade 1 school placement and subsequent changes in school placement of learners with cochlear implantsBardien, Faeza 12 1900 (has links)
Thesis (MAud (Interdisciplinary Health Sciences. Speech-Language and Hearing Therapy)--Stellenbosch University, 2008. / Over the past decade an increasing number of learners with cochlear implants have been
placed in mainstream settings in South Africa (Müller & Wagenfeld, 2003). The aim of
the present study was to describe possible factors that influence the initial grade 1 school
placement as well as subsequent changes in placement of learners with cochlear implants.
Data collection consisted of a retrospective record review of the children implanted at the
Tygerberg Hospital-University of Stellenbosch Cochlear Implant Unit and a
questionnaire aimed at assessing parental perceptions regarding the basis of grade 1
school placement for their children. The record review incorporated children implanted in
1988, the year of inception of the unit and included the most recently implanted children
who have already started grade 1. Results of the 47 participants indicated that multiple
factors influenced the selection of grade 1 school placement. Recommendations by
professionals and parental preference were the most important determinants in the
selection process. The mainstreamed learners were implanted at a much younger age than
the learners placed in special school settings and therefore had a longer duration of
implant use at the start of grade 1. Subsequent to grade 1 placement, the number of
learners in mainstream placement, increased from 55% to 70%. The aspects identified in
the study could be utilised when counselling parents during the school placement
decision making process. Long term monitoring of the academic achievement of these learners needs to be an aim of future research.
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The impact of emotional support offered during rehabilitation on the long-term quality of life and satisfaction with living of individuals with spinal cord injury : an exploratory study of individuals re-employed in the South African National Defence ForceParker, S. 03 1900 (has links)
Thesis (MScMedSc (Rehabilitation))--University of Stellenbosch, 2005. / Many South African National Defence Force (SANDF) soldiers have suffered spinal cord
injury either in the line of duty or otherwise. This injury affects all spheres of life
(physical, emotional, social and psychological). Servicemen are often considered heroes
of their country and are often the ones who need to set aside their emotions in order to
fulfil their roles as soldiers. However, it is anticipated that a permanent
impairment/disability e.g. SCI will have an impact on their quality of life (QOL) and
satisfaction with living (SWL).
This study aims to explore whether emotional support offered to soldiers with spinal cord
injury (SCI) during rehabilitation improve their long-term QOL and SWL.
Thirteen soldiers who have been re-employed post injury were asked to complete a selfcompiled,
self-administered questionnaire regarding the emotional support offered during
rehabilitation and the impact thereof on long-term QOL and SWL.
The questionnaire focused on their ratings of the QOL and SWL in different areas of their
lives and circumstances and asked what they would advise newly injured individuals
regarding SCI and rehabilitation. Data was analysed using a combination of qualitative and quantitative methods.
Pearson’s chi-square test and the M-L chi-square tests were used to analyse the data with
the Statistica programme. A p-value of < 0.05 were calculated as statistically significant.
Emotional support during rehabilitation showed a significant impact on QOL (p=0.0497).
Ninety-two percent (n=12) of participants rated their QOL as good or excellent while
77% (n=10) rated their SWL as good. Participants who were older than 26 reported a
significantly higher rate of SWL than younger ones (p=0.0292). Furthermore, results
showed that the family was the most constant source of support during rehabilitation
(54%, n=7). Despite that, 77% (n=10) of participants felt that they received excellent
emotional support from the rehabilitation team.
The study results are intended to facilitate growth and development in the rehabilitation
process and guide professionals in the offering of emotional support.
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A histological and morphometric assessment of endocrine and ductular proliferation in the adult rat pancreas using an occlusive pancreatic duct ligation modelPage, Benedict J. (Benedict John) 03 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Diabetes Mellitus (DM) is synonymous with "B-cell failure". Ligation of the pancreatic
duct distally to its confluence into the bile duct has been shown to induce endocrine
tissue regeneration from a number of probable sources. The cells responsible for
regeneration are supposed to possess either dormant pluripotent stem cell ability and/or
the plasticity to undergo metaplasia to form new and surplus endocrine tissue able to
replace pathologically and/or experimentally compromised pancreas. The sequence of
events (cell lineage) during this process of neogenesis, has been the source of
controversy for quite some time as various studies suggest that the cell lineage differs
from in vivo and in vitro studies, according to experimental model and species of
laboratory animal.
The object of this study was to utilise an established experimental laboratory animal
model to study islet morphological changes, neogenesis and or both in vivo. Further
aims of the study were to determine the extent, sequence and magnitude of pancreatic
duct ligation (PDL) induced endocrine neogenesis/morphogenesis in a laboratory rat
model using occlusive pancreatic duct ligation.
PDL's were performed on six groups of 25 normal adult Sprague-Dawley (SD) rats
(300g+) according to the method of Hultquist and Jonsson (1965). Experimental
animals were sacrificed at 12 hr intervals from day one post-PDL to day 10 and every
24 hrs thereafter to day 14 as described by Wang, Klëppel, Bouwens (1995). Animals
received BrdU (a thymidine marker and cell proliferation indicator) 50mglkg
intraperitoneally as described by Wang et al. (1995), one hour prior to removal of the
pancreas after which it was fixed in Bouin's solution and histologically processed.
Seven consecutive 3-6 urn thick serial sections were sequentially stained with H & E,
insulin (I), glucagon (G), somatostatin (ST), pancreatic polypeptide (PP), neuropeptide
tyrosine (NPY) and peptide tyrosine tyrosine (PYY). Immunolabeling was done
according to the method of Guesdon, Temynck , Avrameas (1979). Double
immunolabeling for BrdU and each pancreatic peptide was performed on the sections
on days 3,5, 7, 9 and 11 as described by Wang et al (1994). Cellular transformation between one and 3Yz days was characterised by simultaneous
total deletion and/or transdifferentiation of the acinar compartment and the appearance
of immunoreactive cells for I (11.53 ±1.5%), G (1.85 ±0.8%), pp (1.50 ±0.09%), and
ST (1.96 ±0.24%). Changes in the endocrine composition in existing islets, occurred
along a pathway that saw PP- and ST-cells invading the islet core, islet mantle glucagon
deletion and random appearance of all endocrine cell types within the inter-islet
interstitium on day 3Yz. Days 4 to 6Yz saw further endocrine expansion while days 7 to
14 were distinguished by islet reconstitution and consolidation. NPY immunoreactivity
appeared on day 4Y2 and persisted intermittently throughout while PVV first appeared
on day 4 and disappeared after day 7Yz.
The results suggest that PDL firstly induced the development of endocrine tissue
distributed haphazardly throughout the space previously occupied by acinar parenchyma.
Secondly, the appearance of insulin is preceded by the appearance of PP, glucagon and
somatostatin by 24-hours. A still to be determined proportion of the ligation induced
endocrine formation appeared to be associated with existing islets, resulting in a number
of very large islets, some of which might have secretory access through the glomerularlike
capillary network known to occupy the islet core. The remainder appeared to form
separate "new" islets, which have a dubious access to the blood stream.
In conclusion, if it is true that the pancreas can regenerate some of its endocrine tissue
then it has potential clinical implication for the stabilising of diabetes mellitus. Ligated
exocrine pancreatic tissue, devoid of its acinar component, has been shown to contain
notable quantities of insulin positive cells. This presents intriguing possibilities as an
alternative for donor tissue, usually obtained from rat foetuses, during foetal rat pancreas
transplantation studies. Pancreas tissue harvested from duct ligated rats could replace
the foetal tissue currently used in the treatment of experimental diabetes mellitus in
laboratory animals in this laboratory. / AFRIKAANSE OPSOMMING: Diabetes Mellitus is sinoniem met B-sel disfunksie. Endokriene regenerasie kan
segmenteel bewerkstellig word deur eksperimentele afbinding van die pankreasbuis
distaal tot sy samesmelting met die gemene galbuis. 'n Verskeidenheid van selle word
vermoedelik by hierdie proses betrek. Dormante stamselle besit die vermoë en/of
plastisiteit om 'n aantal vorms van metaplasie te ondergaan om nuwe en/of oortollige
endokriene weefsel te vorm wat patologiese en/of eksperimenteel gekompromiseerde
weefsel vervang. Die selontwikkelings volgorde wat tydens hierdie proses plaasvind
is al vir 'n geruime tyd die middelpunt van 'n meningsverskil. Sommige studies dui
daarop dat die in vivo selontwikkelingsvolgorde verskil van in vitro, volgens
eksperimentele model en tipe proefdier gebruik.
Die doel van die studie was die gebruik van 'n bestaande eksperimentele laboratorium
proefdier model om pankreas eiland morfologiese verandering en/ofneogenese of beide
in vivo te evalueer. Die oogmerk van die studie was om die omvang en volgorde van
veranderings in die endokriene kompartement (neogenese/morfogenese) te bepaal deur
gebruik te maak van 'n pankreas buis afbindings (PBA) model wat totale afsnyding van
die buis tot gevolg het.
PBA's is uitgevoer op ses groepe van 25 volwasse normale Sprague-Dawley (SD)
laboratorium rotte (±300g) soos beskryf deur Hultquist en Jonsson (1965). Proefdiere
is elke 12 uur geoffer vanaf dag een post-PBA tot dag tien en elke 24 uur daarna tot dag
14 soos beskryf deur Wang, Bouwens, Kloppel (1995) na die toediening van 50 mg/kg
5-Bromo-2-deoksi-uridien intraperitoneaal ('n selprolifererings aanduider) soos beskryf
deur Wang et al. (1995). Die pankreas is werwyder, in Bouin se oplossing gefikseer en
histologies geprosesseer. Sewe openvolgende seriesnitte (3-6 urn) is alternatiewelik
gekleur met H & E, en immunositochemies, soos beskryf deur Guesdon, Terugnek,
Avrameas (1979), vir insulien (I), glukagon (G), somatostatien (ST), pankreatiesepolipeptied
(PP), neuropeptied tirosien (NPY) en peptied tirosien-tirosien (PYY). BrdU
dubbel-immuunkleuring is ingesluit op dae 3,5, 7, 9 en 11 soos beskryf deur Wang et
al. (1994). Sellulêre transformasie tussen dae een en 3~ dae is gekenmerk deur gelyktydige en
totale uitwissing en/ofmetaplasie van die asinêre kompartement en die verskyning van
selle immunorektiefvir I(11.53 ±1.5%), G (1.85 ±0.8%), PP (1.50 ±0.09%), ST (1.96
±0.24%). Metaplasie was verantwoordelik vir merkbare veranderings in bestaande
endokriene weefsel langs In transformasie weg waar eiland insulien kemselle vervang
is deur PP- en ST-selle, glukagon buitelaag uitwissing en die toevallige verskyning van
alle endokriene seltipes in the inter-eiland interstitium teen dag 3Y2. Dae 4Y2deur 6~
is gekenmerk deur verdere endokrinetoename terwyl dag 7 deur 14 gekenmerk is deur
eiland hersamestelling en konsolidering. NPY immunoreaktiwiteit was vanaf dag 4~,
met afwisseling, te bespeur terwyl PVV slegs tussen dae 4 en 7 In verskyning gemaak
het.
. Die resultate suggereer eerstens, PBA induseer die ontwikkeling van oortollige
endokriene weefsel op In lukrake wyse versprei deur die ruimte voorheen deur asinêre
parenchiem beset. Tweedens, dat die verskyning van insulien deur dié van PP,
glukagon en somatostatien met minstens 24-uur voorafgegaan is. Die verhouding, van
nuutgevormde endokriene weefsel wat met bestaande eilande assosieer om In aantal baie
groot eilande te vorm, moet nog vasgestel word. Sulke strukture mag moontlik
afskeidings toegang hê tot die bloedstroom, deur die glomerulusagtige kapillêre netwerk,
in die eilandkern teenwoordig terwyl die oorblywende nuutgevormde endokrine weefsel
"nuwe" apparte eilande vorm wat wel of gladnie toegang tot die bloedstroom mag hê nie.
As gevolgtrekking, indien dit waar is dat volwasse pankreas eilandweefsel wel
regenerasie kan ondergaan, dan het dit kliniese implikasie vir die stabilisering van
diabetes mellitus. Weefsel verkry uit PBA bevat geen asinêre weefsel nie maar wel
merkbare hoeveelhede endokriene weefsel, veral insulin positief. Dit bied dan
interessante alternatiewe as skenker weefsel by fetal rot pankreas oorplantings. PBA
en/of die oorplanting van pankreasbuis afgebinde weefsel, na in vitro weefsel kultuur,
bied moontlikhede vir die behandeling van diabetes mellitus.
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The effect of highly active antiretroviral therapy on Human Papilloma Virus Infection and Cervical Dysplasia in women living with HIVZeier, Michele D. 04 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Title
The Effect of Highly Active Antiretroviral Therapy on Human Papilloma Virus Infection and Cervical
Cytological Abnormalities in Women Living With HIV
Background
Human Papillomavirus (HPV) infection causes cervical cancer. The prevalence of HPV-related
dysplastic lesions is significantly higher in patients co-infected with the HI virus and thought to be
linked to possible more persistent HPV infection. There is, however, conflicting evidence as to
whether treatment of Human Immunodeficiency Virus (HIV) infection with antiretroviral agents may
influence cervical HPV infection and the behaviour of Squamous Intraepithelial Lesions (SIL).
Aims
To examine the effect of the initiation of combination antiretroviral therapy (cART) on: 1) the
persistence of cervical Low-grade SIL (LSIL); 2) The progression of cervical LSIL to High-Grade
SIL (HSIL); 3) The effectiveness of excision treatment of HSIL 4) HPV genotypes detected, in HIVinfected
and uninfected women at the Infectious Diseases Clinic and the Colposcopy Clinic,
Tygerberg Teaching Hospital, Cape Town, South Africa.
Design and Methods
We conducted a retrospective cohort analysis of 1720 women with LSIL of the survival of
progression-free-time or time-to-clearance. Time to progression or persistence was compared
according to HIV status, antiretroviral treatment and CD4 count. In another retrospective cohort
analysis, we investigated the effectiveness of excision treatment in 1848 women who underwent
LLETZ or CKC biopsy was used. Logistic regression and survival analysis were used to compare
excision treatment failure and recurrence-free time between groups according to HIV status,
antiretroviral therapy and CD4 count.
To investigate the effect of antiretroviral therapy on the cervical HPV infection, 300 HIV-infected
women were prospectively enrolled and followed at 6-monthly interval. Cytological testing and
cervical HPV sampling were done at each visit. Biopsy of suspicious lesions and excision treatment
were done at colposcopy clinic according to standard a protocol. The Roche Linear array HPV
genotyping test was used for HPV detection. Generalized Estimating Equation (GEE) multivariate
analysis was applied to investigate the effect of cART on the detection of HPV infection, while
adjusting for time-dependent covariates such as CD4 count, sexual activity and excision treatment.
The effect on each HPV type was then also compared to the effect on HPV16.
Results
Overall, we found that there was no difference between the progression of LSIL to HSIL by HIV
status. However, among HIV-infected patients, those who started ART before first LSIL had a
significantly lower risk for progression (HR 0.66, 95% CI 0.54-0.81). CD4 count did not have an
impact on the risk for progression. We also found lower persistence of SIL in the HIV uninfected
group (HR 0.69, 95% CI 0.57-0.85) and that cART was independently associated with decreased
persistence of LSIL. On the other hand, a higher CD4 count at the time of first LSIL was not
associated with lower persistence of the lesion. HIV infected women with HSIL experienced much higher excision treatment failure than uninfected
women (53.8% vs. 26.9%, p<0.001). Factors that improved outcome were higher CD4 count and
complete excision.
cART reduced the risk of detection of any HPV type by 47% (OR 0.53, 95% 0.49-0.58, p<001).
When adjusted for covariates, time of exposure to cART and CD4 had a stronger effect. Every month
of cART exposure reduced the risk detection of any HPV type with 7%. The effect was also
significant on HPV16 alone (OR 0.93, 95% CI 0.90-0.95). All non-oncogenic subtypes were
influenced similarly or more strongly than HPV16, as well as oncogenic HPV52. Only one oncogenic
subtype HPV subtype, HPV39, was influenced marginally less (ratio of OR 0.95, CI 0.90-0.99,
p=0.04).
There was an increased risk for any HPV detection at CD4 count<200 (OR 1.63, 95% CI:1.50-1.77),
but when adjusted, the time of cART exposure again remained the strongest predictor of risk (OR
0.94, 95% CI:0.93-0.95).
Conclusion
cART impact the outcome of cervical HPV infection by increasing clearance, decreasing progression
of LSIL and recurrence after excision treatment. This effect is time dependent and also associated
with CD4 count. Specifically, HPV16 detection risk is also reduced by cART, and all HPV types are
influenced at least as much as HPV16, except possibly HPV39. It seems that increased cervical HIVproviral
load is associated with HPV detection risk, and both are lowered by cART time. / AFRIKAANSE OPSOMMING: Titel
Die Effek van Kombinasie Antiretrovirale Terapie op Menslike Papilloomvirusinfeksie en Servikale
Sitologiese Abnormaliteite in Menslike Immuniteitsgebrekvirus-geïnfekteerde Vroue
Agtergrond
Menslike Papilloomvirusinfeksie (MPV) veroorsaak servikale kanker. Die prevalensie van MPVverwante
displastiese letsels is betekenisvol hoër in pasiënte wie ook met Menslike
Immuniteitsgebrekvirus (MIV) geïnfekteer is en dit word gereken dat dit te wyte is aan meer
persisterende MPV infeksie. Daar is egter teenstrydige bewyse oor of die behandeling van MIV
infeksie met antiretrovirale (ART) middels die infeksie met MPV en die gedrag van Plaveisel
Intraepiletiële letsels (PIL) kan beïnvloed.
Doelwitte
Om die effek van die inisiasie van kombinasie ART op: 1) die persistering van Laegraadse PIL
(LPIL); 2) die progressie van servikale LPIL na hoëgraadse PIL (HPIL) 3) die sukses van
eksisiebehandeling van HPIL; 4) MPV genotypies waarneembaar, in MIV-geïnfekteerde vroue by die
Infeksiesiektekliniek en die Kolposkopiekliniek,Tygerberghospitaal, Kaapstad, Suid-Afrika, te
ondersoek.
Studie-ontwerp en Metodes
`n Retrospektiewe kohort-analise op 1720 vroue met LPIL van die oorlewing van progressive-vrye
tyd en tyd tot opklaring van PIL is gedoen. Tyd tot progressie of opklaring is vergelyk na aanleiding
van die pasiënt se MIV status, behandeling met antiretrovirale terapie en CD4-telling. In nog `n
retrospektiewe kohort-analise is die effektiwiteit van eksisiebehandeling in 1848 vroue wie LLETZ or
Kouemeskonus eksisie ondergaan het, ondersoek. Logistiese regressie en oorlewingsanalise is
toegepas om die voorkoms van onsuksesvolle uitkoms en tyd sonder herhaling van letsels tussen
groepe te vergelyk na aanleiding van MIV status, ART en CD4-telling.
Om die effek van antiretroviral therapie op servikale MPV infeksie te ondersoek, is 300 MIVgeïnfekteerde
vroue opgeneem in `n prospektiewe studie en sesmaandeliks opgevolg. Sitologiese en
MPV servikale smere is met elke besoek geneem. Biopsies van verdagte letsels en eksisiebehandeling
is by die Kolposkopiekliniek gedoen volgens die standaardpraktyk. Die Roche Linear Array HPV
Genotyping toets is gebruik vir MPV deteksie. Algemeen-beraamde vergelyking (GEE)
meerveranderlike analise is toegepas om die effek van die anti-MIV terapie op die teenwoordigheid
van MPV op die serviks te ondersoek. Die aangepaste effek is ook getoets deur die CD4-telling, die
seksuele aktiwiteits- en eksisiebehandelingstatus by elke besoek in ag te neem. Die effek op elke
MPV genotipe is laastens dan ook vergelyk met die effek op ‘n spesifieke basislyn genotype; in
hierdie geval was MPV16 gekies.
Resultate
Daar was geen statisties beduidende verskil tussen die progressie van LPIL na HPIL na aanleding van
HIV status nie, maar pasiënte wie met ART begin het voordat hulle vir die eerste keer met LPIL
gediagnoseer was, het ‘n laer risiko gehad vir progressie (HR 0.66, 95% VI 0.54-0.81). Daar is ook
gevind dat dit onafhanklik van die CD4 telling was. Die persistering van PIL was laer in die MIV
negatiewe groep (HR 0.69, 95% VI 0.57-0.85), maar ook hier was antiretrovirale behandeling
geassosieer met verminderde persistering. Weer eens was daar nie ‘n verband met die CD4 telling nie. MIV-geinfekteerde vroue met HPILwas baie meer geneig tot gefaalde eksisiebehandeling (53.8%
teenoor 26.9%, p<0.001). Verbeterde uitkoms was geassosieer met ‘n hoër CD4-telling en ‘n eksisie
wat as volledig beskryf was. ART wat reeds voor die eksisiebehandeling begin was, het nie die risiko
vir onsuskesvolle uitkoms statisties beduidend verminder nie, maar het egter die risiko vir herhaling
van letsels na die eksisie sterk verlaag.
ART het die kans dat enige MPV tipe waargeneem sou word, met 47% verlaag (OR 0.53, 95% VI
0.49-0.58, p<001). Wanneer aangepas vir ander faktore, was die tyd wat verloop het sedert ART
begin was, sowel as vir die CD4 telling, sterker. Vir elke maand sedert ART begin was, het die kans
dat enige MPV tipe waargeneem word, met 7% verminder. `n Soortgelyke effek is op HPV16 alleen
gevind (OR 0.93, 95%, VI 0.90-0.95). Die effek was net so sterk of sterker op alle subtipes. Slegs een
onkogeniese subtipe, MPV39, was gering minder beïnvloed (ratio van OR 0.95, VI 0.90-0.99,
p=0.04).
Die kans vir waarneming van enige MPV subtype is hoër wanneer die CD4 telling laer as 200 selle/ɥl
is (OR 1.63, 95% VI: 1.50-1.77), maar wanneer aangepas, was die tyd van ART weer eens die sterkste
voorspeller van MPV infeksie (OR 0.94, 95% VI:0.93-0.95).
Gevolgtrekkings
ART verbeter die uitkoms van servikale infeksie met MPV deur progressie en persistering van LPIL
en herhaling van PIL na eksisie te verminder. Die effek is tydsafhanklik en word ook deur die CD4
telling beïnvloed. Die kanse dat MPV16 spesifiek waargeneem word, word ook deur ART verminder,
en all MPV tipes ondervind dieselfde of groter verlaging van waarnemingsrisiko as MPV16, behalwe
miskien MPV39. Ons kon aandui dat verhoogde teenwoordigheid van servikale MIV verband hou met
die risiko vir die waarneming van MPV infeksie, en beide word verminer deur die tyd waarmee die
pasiënt met ARV terapie behandel is.
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A candidate and novel gene search to identify the PFHBII-causative geneFernandez, Pedro (Pedro Wallace) 12 1900 (has links)
Dissertation (PhD)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: Heart failure due to cardiomyopathy or cardiac conduction disease is a major cause of
mortality and morbidity in both developed and developing countries. Although defined as
separate clinical entities, inherited forms of cardiomyopathies and cardiac conduction
disorders have been identified that present with overlapping clinical features and/or have
common molecular aetiologies.
The objective of the present study was to identify the molecular cause of progressive familial
heart block type II (PFHBII), an inherited cardiac conduction disorder that segregates in a
South African Caucasian Afrikaner family (Brink and Torrington, 1977). The availability of
family data tracing the segregation of PFHBII meant that linkage analysis could be employed
to identify the chromosomal location of the disease-causative gene. Human Genome Project
(HGP) databases have provided additional resources to facilitate the identification of
positional candidate genes.
Clinical examinations were performed on individuals of the PFHBII-affected family, and,
where available, clinical records of subjects examined in a previous study by Brink and
Torrington (1977) were re-assessed. Retrospective data suggested redefining the classification
of PFHBII. Subsequently, linkage analysis was used to test described dilated cardiomyopathy
(DCM), hypertrophic cardiomyopathy (HCM) and cardiac conduction-causative loci on
chromosomes 1, 2, 3, 6, 7, 9, 11, 14, 15 and 19 for their involvement in the development of
PFHBII. Once a locus was mapped, bioinformatics tools were applied to identify and
prioritise positional candidate genes for mutation screening.
The retrospective and prospective clinical study redefined PFHBII as a cardiac conduction
and DCM-associated disorder and simultaneously allowed more family members to be traced.Fortuitously, candidate loci linkage analysis mapped the PFHBII locus to chromosome 1q32,
to a region that overlapped a previously described DCM-associated disorder (CMD1D), by
the generation of a maximum pairwise lod score of 3.13 at D1S3753 (theta [θ]=0.0) and a
maximum multipoint lod score of 3.7 between D1S3753 and D1S414. However, genetic fine
mapping and haplotype analysis placed the PFHBII-causative locus distal to the CMD1D
locus, within a 3.9 centimorgan (cM) interval on chromosome 1q32.2-q32.3, telomeric of
D1S70 and centromeric of D1S505. Bioinformatics analyses prioritised seven candidate genes
for mutation analysis, namely, a gene encoding a potassium channel (KCNH1), an
extracellular matrix protein (LAMB3), a protein phosphatase (PPP2R5A), an adapter protein
that interacts with a cytoskeletal protein (T3JAM), a putative acyltransferase (KIAA0205) and
two genes encoding proteins possibly involved in energy homeostasis (RAMP and VWS59).
The PFHBII-causative mutation was not identified, although single sequence variations were
identified in four of the seven candidate genes that were screened.
Although the molecular aetiology was not established, the present study defined the
underlying involvement of DCM in the pathogenesis of PFHBII. The new clinical
classification of PFHBII has been published (Fernandez et al., 2004) and should lead to
tracing more affected individuals in South Africa or elsewhere. The identification of a novel
disease-causative locus may point toward the future identification of a new DCM-associated
aetiology, which, in turn, might provide insights towards understanding the associated
molecular pathophysiologies of heart failure. / AFRIKAANSE OPSOMMING: Hartversaking as gevolg van kardiomiopatie of kardiale geleidingsiekte is ‘n hoof-oorsaak
van mortaliteit and morbiditeit in beide ontwikkelde en ontwikkelende lande. Alhoewel
gedefinieer as verskillende kliniese entiteite is oorerflike vorms van kardiomiopatie en
kardiale geleidingsstoornisse geïdentifiseer met oorvleuelende kliniese eienskappe en/of
molukulêre oorsake.
Die doelwit van hierdie studie was om die molukulêre oorsaak van progressiewe familiële
hartblok tipe II (PFHBII), ‘n oorerflike kardiale geleidingsstoornis, wat in ‘n Suid-Afrikaanse
Kaukasiër familie segregeer (Brink en Torrington, 1977), te identifiseer. Die beskikbaarheid
van familie data, beteken dat koppelingsanalise gebruik kan word om die chromosomale
posisie van die siekte-veroorsakende geen te identifiseer. Menslike Genoom Projek (MGP)
databanke het addisionele hulpbronne beskikbaar gestel om die identifikasie van posisionele
kandidaat gene te vergemaklik.
Kliniese ondersoeke is uitgevoer op PFHBII-geaffekteerde familielede, en waar beskikbaar is
kliniese rekords van persone, wat in ‘n vorige studie deur Brink en Torrington (1977)
geassesseer was, herontleed. Retrospektiewe data-analise het die kliniese herdefinisie van
PFHBII voorgestel. Daarna is koppelingsanalise gebruik om dilateerde kardiomiopatie
(DKM), hipertrofiese kardiomiopatie (HKM) en kardiale geleidingssiekte-veroorsakende loki
op chromosoom 1, 2, 3, 6, 7, 9, 11, 14, 15 en 19 te ondersoek vir hul moontlike bydrae tot die
ontwikkeling van PFHBII. Toe die lokus gekarteer was, is bioinformatiese ondersoeke
gebruik om posisionele kandidaat gene te identifiseer en prioritiseer vir mutasie analise.
Die retrospektiewe en prospektiewe kliniese ondersoek het PFHBII herdefinieer as ‘n
geleidingsstoornis en DKM-verbonde siekte, en terselfde tyd het dit gelei tot die opsporingvan nog familielede. Toevallig het kandidaat loki-analise die PFHBII lokus op chromosoom
1q32 gekarteer, na ‘n gebied wat met ‘n voorheen-beskyfde DKM-verbonde stoornis
(CMD1D) oorvleuel, met die opwekking van ‘n makisimum paargewyse lod-getal van 3.13
by D1S3753 (theta [θ] = 0.0) en ‘n maksimum multipunt lod-getal van 3.7 tussen D1S3753 en
D1S414. Genetiese fynkartering en haplotipe-analise het die PFHBII-veroorsakende lokus
afwaards van die CMD1D lokus geplaas, in ‘n 3.9 centimorgan (cM) gebied op chromosoom
1q32.2-q32.3, telomeries van D1S70 en sentromeries van D1S505. Bioinformatiese analise
het daarnatoe gelei dat sewe kandidaat gene vir mutasie analise geprioritiseerd is, naamlik,
gene wat onderskeidelik ‘n kalium kanaal (KCNH1), ‘n ekstrasellulêre matriksproteïen
(LAMB3), ‘n proteïen fosfatase (PPP2R5A), ‘n aansluiter proteïen wat met ‘n sitoskilet
proteïen bind (T3JAM), ‘n asieltansferase (KIAA0205) en twee gene moontlik betrokke in
energie homeostase (RAMP en VWS59) enkodeer. Die PFHBII-veroorsakende geen is nie
geïdentifiseer nie, alhoewel enkele volgorde-wisselings geïdentifiseer is in vier van die sewe
geanaliseerde kandidaat gene.
Alhowel die molekulêre oorsaak van die siekte nie vasgestel is nie, het die huidige studie die
onderliggende betrokkenheid van DKM in die pathogenese van PFHBII gedefinieer. Die
nuwe kliniese klassifikasie van PFHBII is gepubiliseer (Fernandez et al., 2004) en sal lei tot
die identifisering van nog geaffekteerde persone in Suid Afrika of in ander lande. Die
identifikasie van ‘n nuwe siekte-verbonde lokus mag lei tot die toekomstige identifikasie van
‘n nuwe DKM-verbonde genetiese oorsaak wat, opsig self, dalk insig kan gee in die
molekulêre patofisiologie van hartversaking.
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128 |
A candidate and novel gene search to identify the PFHBII-causative geneFernandez, Pedro 12 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2004. / Bibliography / ENGLISH ABSTRACT: Heart failure due to cardiomyopathy or cardiac conduction disease is a major cause of
mortality and morbidity in both developed and developing countries. Although defined as
separate clinical entities, inherited forms of cardiomyopathies and cardiac conduction
disorders have been identified that present with overlapping clinical features and/or have
common molecular aetiologies.
The objective of the present study was to identify the molecular cause of progressive familial
heart block type II (PFHBII), an inherited cardiac conduction disorder that segregates in a
South African Caucasian Afrikaner family (Brink and Torrington, 1977). The availability of
family data tracing the segregation of PFHBII meant that linkage analysis could be employed
to identify the chromosomal location of the disease-causative gene. Human Genome Project
(HGP) databases have provided additional resources to facilitate the identification of
positional candidate genes. Clinical examinations were performed on individuals of the PFHBII-affected family, and,
where available, clinical records of subjects examined in a previous study by Brink and
Torrington (1977) were re-assessed. Retrospective data suggested redefining the classification
of PFHBII. Subsequently, linkage analysis was used to test described dilated cardiomyopathy
(DCM), hypertrophic cardiomyopathy (HCM) and cardiac conduction-causative loci on
chromosomes 1, 2, 3, 6, 7, 9, 11, 14, 15 and 19 for their involvement in the development of
PFHBII. Once a locus was mapped, bioinformatics tools were applied to identify and
prioritise positional candidate genes for mutation screening.
The retrospective and prospective clinical study redefined PFHBII as a cardiac conduction
and DCM-associated disorder and simultaneously allowed more family members to be traced. Fortuitously, candidate loci linkage analysis mapped the PFHBII locus to chromosome 1q32,
to a region that overlapped a previously described DCM-associated disorder (CMD1D), by
the generation of a maximum pairwise lod score of 3.13 at D1S3753 (theta [θ]=0.0) and a
maximum multipoint lod score of 3.7 between D1S3753 and D1S414. However, genetic fine
mapping and haplotype analysis placed the PFHBII-causative locus distal to the CMD1D
locus, within a 3.9 centimorgan (cM) interval on chromosome 1q32.2-q32.3, telomeric of
D1S70 and centromeric of D1S505. Bioinformatics analyses prioritised seven candidate genes
for mutation analysis, namely, a gene encoding a potassium channel (KCNH1), an
extracellular matrix protein (LAMB3), a protein phosphatase (PPP2R5A), an adapter protein
that interacts with a cytoskeletal protein (T3JAM), a putative acyltransferase (KIAA0205) and
two genes encoding proteins possibly involved in energy homeostasis (RAMP and VWS59).
The PFHBII-causative mutation was not identified, although single sequence variations were
identified in four of the seven candidate genes that were screened. Although the molecular aetiology was not established, the present study defined the
underlying involvement of DCM in the pathogenesis of PFHBII. The new clinical
classification of PFHBII has been published (Fernandez et al., 2004) and should lead to
tracing more affected individuals in South Africa or elsewhere. The identification of a novel
disease-causative locus may point toward the future identification of a new DCM-associated
aetiology, which, in turn, might provide insights towards understanding the associated
molecular pathophysiologies of heart failure. / AFRIKAANSE OPSOMMING: Hartversaking as gevolg van kardiomiopatie of kardiale geleidingsiekte is ‘n hoof-oorsaak
van mortaliteit and morbiditeit in beide ontwikkelde en ontwikkelende lande. Alhoewel
gedefinieer as verskillende kliniese entiteite is oorerflike vorms van kardiomiopatie en
kardiale geleidingsstoornisse geïdentifiseer met oorvleuelende kliniese eienskappe en/of
molukulêre oorsake.
Die doelwit van hierdie studie was om die molukulêre oorsaak van progressiewe familiële
hartblok tipe II (PFHBII), ‘n oorerflike kardiale geleidingsstoornis, wat in ‘n Suid-Afrikaanse
Kaukasiër familie segregeer (Brink en Torrington, 1977), te identifiseer. Die beskikbaarheid
van familie data, beteken dat koppelingsanalise gebruik kan word om die chromosomale
posisie van die siekte-veroorsakende geen te identifiseer. Menslike Genoom Projek (MGP)
databanke het addisionele hulpbronne beskikbaar gestel om die identifikasie van posisionele
kandidaat gene te vergemaklik.
Kliniese ondersoeke is uitgevoer op PFHBII-geaffekteerde familielede, en waar beskikbaar is
kliniese rekords van persone, wat in ‘n vorige studie deur Brink en Torrington (1977)
geassesseer was, herontleed. Retrospektiewe data-analise het die kliniese herdefinisie van
PFHBII voorgestel. Daarna is koppelingsanalise gebruik om dilateerde kardiomiopatie
(DKM), hipertrofiese kardiomiopatie (HKM) en kardiale geleidingssiekte-veroorsakende loki
op chromosoom 1, 2, 3, 6, 7, 9, 11, 14, 15 en 19 te ondersoek vir hul moontlike bydrae tot die
ontwikkeling van PFHBII. Toe die lokus gekarteer was, is bioinformatiese ondersoeke
gebruik om posisionele kandidaat gene te identifiseer en prioritiseer vir mutasie analise.
Die retrospektiewe en prospektiewe kliniese ondersoek het PFHBII herdefinieer as ‘n
geleidingsstoornis en DKM-verbonde siekte, en terselfde tyd het dit gelei tot die opsporing van nog familielede. Toevallig het kandidaat loki-analise die PFHBII lokus op chromosoom
1q32 gekarteer, na ‘n gebied wat met ‘n voorheen-beskyfde DKM-verbonde stoornis
(CMD1D) oorvleuel, met die opwekking van ‘n makisimum paargewyse lod-getal van 3.13
by D1S3753 (theta [θ] = 0.0) en ‘n maksimum multipunt lod-getal van 3.7 tussen D1S3753 en
D1S414. Genetiese fynkartering en haplotipe-analise het die PFHBII-veroorsakende lokus
afwaards van die CMD1D lokus geplaas, in ‘n 3.9 centimorgan (cM) gebied op chromosoom
1q32.2-q32.3, telomeries van D1S70 en sentromeries van D1S505. Bioinformatiese analise
het daarnatoe gelei dat sewe kandidaat gene vir mutasie analise geprioritiseerd is, naamlik,
gene wat onderskeidelik ‘n kalium kanaal (KCNH1), ‘n ekstrasellulêre matriksproteïen
(LAMB3), ‘n proteïen fosfatase (PPP2R5A), ‘n aansluiter proteïen wat met ‘n sitoskilet
proteïen bind (T3JAM), ‘n asieltansferase (KIAA0205) en twee gene moontlik betrokke in
energie homeostase (RAMP en VWS59) enkodeer. Die PFHBII-veroorsakende geen is nie
geïdentifiseer nie, alhoewel enkele volgorde-wisselings geïdentifiseer is in vier van die sewe
geanaliseerde kandidaat gene. Alhowel die molekulêre oorsaak van die siekte nie vasgestel is nie, het die huidige studie die
onderliggende betrokkenheid van DKM in die pathogenese van PFHBII gedefinieer. Die
nuwe kliniese klassifikasie van PFHBII is gepubiliseer (Fernandez et al., 2004) en sal lei tot
die identifisering van nog geaffekteerde persone in Suid Afrika of in ander lande. Die
identifikasie van ‘n nuwe siekte-verbonde lokus mag lei tot die toekomstige identifikasie van
‘n nuwe DKM-verbonde genetiese oorsaak wat, opsig self, dalk insig kan gee in die
molekulêre patofisiologie van hartversaking.
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129 |
Resistance to first line anti-TB drugs by gene mutation and gene modulationLouw, Gail Erika 03 1900 (has links)
Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009.
|
130 |
The effect of creatine supplementation on myocardial metabolism and function in sedentary and exercised ratsWebster, Ingrid 12 1900 (has links)
Thesis (PhD (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Background: There has been a dramatic increase in the use of dietary creatine
supplementation among sports men and women, and by clinicians as a therapeutic
agent in muscular and neurological diseases. The effects of creatine have been studied
extensively in skeletal muscle, but knowledge of its myocardial effects is limited.
Objectives: To investigate the effects of dietary creatine supplementation with and
without exercise on 1) basal cardiac function, 2) susceptibility to ischaemia/reperfusion
injury and 3) myocardial protein expression and phosphorylation and 4) mitochondrial
oxidative function.
Methods: Male Wistar rats were randomly divided into control or creatine supplemented
groups. Half of each group was exercise trained by swimming for a period of 8 weeks, 5
days per week. At the end of the 8 weeks the open field test was performed and blood
corticosterone levels were measured by RIA to determine whether the swim training
protocol had any effects on stress levels of the rats. Afterwards hearts were excised and
either freeze-clamped for biochemical and molecular analysis or perfused on the
isolated heart perfusion system to assess function and tolerance to ischaemia and
reperfusion. Five series of experiments were performed: (i) Mechanical function was
documented before and after 20 minutes global ischaemia using the work heart model,
(ii) A H2O filled balloon connected to a pressure transducer was inserted into the left
ventricle to measure LVDP and ischaemic contracture in the Langendorff model, (iii)
The left coronary artery was ligated for 35 minutes and infarct size determined after 30
minutes of reperfusion by conventional TTC staining methods. (iv) Mitochondrial
oxidative capacity was quantified. (v) High pressure liquid chromatography (HPLC) and
Western Blot analysis were performed on blood and heart tissue for determination of
high energy phosphates and protein expression and phosphorylation.
Results: Neither the behavioural studies nor the corticosterone levels showed any
evidence of stress in the groups investigated. Hearts from creatine supplemented
sedentary (33.5 ± 4.5%), creatine supplemented exercised rats (18.22 ± 6.2%) as well
as control exercised rats (26.1 ± 5.9%) had poorer aortic output recoveries than the
sedentary control group (55.9 ± 4.35% p < 0.01) and there was also greater ischaemic
contracture in the creatine supplemented exercised group compared to the sedentary
control group (10.4 ± 4.23 mmHg vs 31.63 ± 4.74 mmHg). There were no differences in
either infarct size or in mitochondrial oxygen consumption between the groups. HPLC
analysis revealed elevated phosphocreatine content (44.51 ±14.65 vs 8.19 ±4.93
nmol/gram wet weight, p < 0.05) as well as elevated ATP levels (781.1 ±58.82 vs 482.1
±75.86 nmol/gram wet weight, p<0.05) in blood from creatine supplemented vs control
sedentary rats. These high energy phosphate elevations were not evident in heart
tissue and creatine tranporter expression was not altered by creatine supplementation.
GLUT4 and phosphorylated AMPK and PKB/Akt were all significantly higher in the
creatine supplemented exercised hearts compared to the control sedentary hearts.
Conclusion: This study suggests that creatine supplementation has no effects on basal
cardiac function but reduces myocardial tolerance to ischaemia in hearts from exercise
trained animals by increasing the ischaemic contracture and decreasing reperfusion
aortic output. Exercise training alone also significantly decreased aortic output recovery.
However, the exact mechanisms for these adverse myocardial effects are unknown and
need further investigation. / AFRIKAANSE OPSOMMING: Agtergrond: Die gebruik van kreatien as dieetaanvulling het in die afgelope aantal jaar
dramaties toegeneem onder sportlui, sowel as mediese praktisyns wat dit as ‘n
terapeutiese middel vir die behandeling van spier- en neurologiese siektes aanwend.
Die effekte van kreatien op skeletspier is reeds deeglik ondersoek, maar inligting
aangaande die miokardiale effekte van die preperaat is beperk.
Doelwitte: Om die effekte van kreatien dieetaanvulling met of sonder oefening ten
opsigte van die volgende aspekte te ondersoek: 1) basislyn miokardiale funksie, 2)
vatbaarheid vir iskemie/herperfusie besering, 3) proteïenuitdrukking en -fosforilering in
die miokardium en 4) mitochondriale oksidatiewe funksie.
Metodes: Manlike Wistar rotte is ewekansig in kontrole of kreatien aanvullings groepe
verdeel. Helfte van elke groep is aan oefening in die vorm van swemsessies, vir ‘n
periode van 8 weke, 5 dae per week blootgestel. Gedrags- en biochemiese toetse is
aangewend om die moontlike effek van die swemprotokol op die rotte se stres vlakke te
bepaal. In hierdie verband is die oop area toets gebruik, asook bloed kortikosteroon
vlakke gemeet deur radioaktiewe immuunessais. Harte is daarna uit die rotte
gedissekteer en gevriesklamp vir biochemiese en molekulêre analise, of geperfuseer op
die geïsoleerde werkhart perfusiesisteem om sodoende funksie en weerstand teen
iskemie en herperfusie beskadeging te bepaal. Vyf eksperimentele reekse is uitgevoer:
(i) Meganiese funksie is noteer voor en na 20 minute globale isgemie in die werkhart
model; (ii) ‘n Water gevulde plastiek ballon, gekoppel aan ‘n druk omsetter, is in die
linker ventrikel geplaas om sodoende linker ventrikulêre ontwikkelde druk (LVDP),
asook iskemiese kontraktuur te meet; (iii) Linker koronêre arterie afbinding is vir ‘n
periode van 35 minute toegepas en die infarktgrootte bepaal na 30 minute herperfusie
deur gebruik te maak van standaard kleuringsmetodes; (iv) Mitochondriale oksidatiewe
kapasiteit is gemeet; (v) Hoë druk vloeistof chromatografie (HPLC) en Western Blot
analises is uitgevoer op bloed en hartweefsel vir die bepaling van hoë energie fosfate
(HEFe), sowel as proteïenuitdrukking en -fosforilering.
Resultate: Beide gedragsstudies en kortikosteroonvlakke het geen teken van stres in
die betrokke groepe getoon nie. Die groep blootgestel aan kreatienaanvulling en
oefening se harte het na iskemie funksioneel swakker herstel as harte van die
onaktiewe kontrole groep (18.22±6.2% vs 55.9±4.35%; p<0.01), asook ‘n groter
ikgemiese kontraktuur in vergelyking met die onaktiewe kontrole groep ontwikkel
(31.63±4.74 mmHg vs 10.4±4.23 mmHg). Daar was geen verskille in infarktgrootte of
mitochondriale suurstofverbruik tussen die verskillende groepe waargeneem nie. HPLC
analise het verhoogde fosfokreatien (44.51±14.65 vs 8.19±4.93 nmol/gram nat gewig,
p<0.05) en adenosientrifosfaat (ATP) bloedvlakke (781.1±58.82 vs 482.1±75.86
nmol/gram nat gewig, p<0.05) in kreatien aanvullings vergelyk met die kontrole groepe
getoon. Daar was egter geen meetbare veranderings in HEF vlakke in hartweefsel nie.
Gepaardgaande hiermee het kreatienaanvulling geen effek gehad op die uitdrukking va
die kreatien transporter nie. In vergelyking met onaktiewe kontrole harte was GLUT4, en
fosforileerde AMPK en PKB/ Akt beduidend hoër in harte van geoefende rotte met
kreatienaangevulling.
Gevolgtrekking: Hierdie data dui daarop dat kreatienaanvulling geen effek op basislyn
miokardiale funksie het nie. Kreatienaanvulling het egter die miokardium se weerstand
teen iskemiese skade verlaag in harte van rotte blootgestel aan oefening: iskemiese
kontraktuur is verhoog en aorta-uitset tydens herperfusie is verlaag. Die presiese
meganismes hierby betrokke is egter onbekend en vereis dus verdere studie. / Division of Medical Physiology (University of Stellenbosch), The National Research
Foundation and the Harry Crossley Fund for financial support.
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