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Serological and genetic characterisation of putative new serotypes of bluetongue virus and epizootic haemorrhagic disease virus isolated from an Alpaca / Isabella Maria WrightWright, Isabella Maria January 2014 (has links)
Alpacas were first introduced into South Africa during the year 2000. They are valuable
because of the fine quality wool they produce which has much better insulation properties
than that of merino wool fibres. Alpacas are also used to act as guards of sheep herds
against predators.
During 2008, blood samples from an alpaca that died acutely with severe lung oedema,
respiratory distress and froth exuding from the nose were received at Elsenburg Veterinary
Laboratory. The alpaca was from a herd of 23 alpacas of a British veterinarian in the
Montagu district in the western Cape. Virus isolation attempts on the blood produced
infrequent embryo mortalities. Embryonated chicken egg (ECE) material was send to the
Virology Department at the Onderstepoort Veterinary Institute (OVI). A bluetongue virus
(BTV) PCR performed at the diagnostic PCR laboratory at OVI on the ECE material was
positive. Further intra-venous (IV) inoculations in ECE produced embryo mortalities on two
consecutive days, the 8th and 9th November. The dead embryos were harvested separately
and named and treated as two separate virus samples, Alp8 and Alp9 which were further
passaged on baby hamster kidney (BHK) cells.
The BTV virus neutralisation tests (VNT) performed at the Office International des Epizooties
(OIE) Laboratory on both Alp8 and Alp9 were negative. Because of the close serological
relationship between BTV and epizootic haemorrhagic disease virus (EHDV), an EHDV VNT
was also performed and was also negative.
In the light of the negative VNT and the positive BTV PCR results, more in-depth molecular
analyses were performed. RNA was purified from tissue culture material and agarose gel
electrophoresis (AGE) performed. Both Alp8 and Alp9 had a typical orbiviral electrophoretic
profile, but their respective profiles were different.
A sequence-independent reverse transcriptase PCR amplification method generated ample
complementary DNA (cDNA) of both samples for sequencing. Sanger sequencing was used
to partially sequence genome segments 5 (NS1) and 2 (VP2). BLAST analysis of the partial
information of the genome segments 5 (NS1) of Alp8 confirmed it as being a BTV and Alp9
as being an EHDV. BLAST analysis of the deduced amino acid sequence generated of VP2
of both Alp8 and Alp9 established that these samples were possibly new serotypes of BTV
and EHDV respectively. The complete genome of both Alp8 and Alp9 was sequenced with
next generation 454 Pyrosequencing. This confirmed the partial sequencing results. BLAST analysis of the complete sequence of S2 (VP2) of Alp8 showed that it has 73 % nucleotide
and 77 % deduced amino acid identity to BTV15. In contrast the nucleic acid sequence of
genome segment S2 (VP2) of Alp9 had no nucleotide sequence identity to any virus, but its
deduced amino acid sequence had 71 % amino acid identity to EHDV2.
Hyper immune guinea pig (GP) serum prepared against the putative new BT (Alp8) and EHD
(Alp9) virus serotypes were tested for serological cross-reactivity against the 24 OIE
reference antigen strains of BTV and the 8 OIE reference antigen strains of EHDV. Alp8 had
a neutralising antibody (NAb) titre of > 32 against BTV15. Alp9 did not cross react with any of
the OIE BTV and EHDV strains.
Six out of the remaining 22 alpacas on the farm had NAbs to a greater or lesser extend
against Alp8 (BTV) and Alp9 (EHDV) viruses, which confirmed that the viruses were also
present in other alpacas in the herd. Very few cases of EHDV in alpacas have ever been
reported in literature.
A small scale pilot vector susceptibility study showed that vector competence of C. imicola
for both Alp8 and Alp9 was low, below 2 %. The fact that neutralising antibodies to Alp8 and
Alp9 were detected in other alpacas in the herd raises the question as to whether there are
other Culicoides species circulating in the area that could vector the viruses.
In conclusion, the results from the serological and virological analyses as well as the nucleic
acid sequence data of the genomes of two virus samples, Alp8 and Alp9, from an alpaca that
died in the Montagu district in the western Cape identified Alp9 as a definite new serotype of
EHDV and Alp8 as a possible new serotype of BTV most closely related to BTV15. / MSc (Biochemistry), North-West University, Potchefstroom Campus, 2014
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Novel sulfanyl- and sulfinylcaffeine analogues as inhibitors of monoamine oxidase / Wayne MentzMentz, Wayne January 2013 (has links)
Parkinson’s disease (PD) is a neurodegenerative disorder, which is progressive in nature and
usually associated with the elderly. It is the second most common age-related
neurodegenerative disorder after Alzheimer’s disease (AD). PD occurs when there is a dramatic
loss of dopamine (DA) in the striatum, a substructure of the basal ganglia, of the brain due to
the degeneration of the nigrostriatal pathway that contains the dopaminergic neurons. Motor
symptoms of PD include bradykinesia, muscular rigidity and resting tremors. Non-motor
symptoms include speech and sleep problems, hallucinations and depression. Diverse
treatment options are available to treat the symptoms of PD, including levodopa (L-Dopa), DA
agonists and monoamine oxidase B (MAO-B) inhibitors.
The MAOs are flavoproteins that are bound to the outer membrane of the mitochondria and
catalyze the oxidative deamination of neurotransmitters such as serotonin (5-HT), noradrenaline
(NA) and DA. Two isoforms occur, namely MAO-A and –B, which share a 70% sequence
identity. MAO-A catalyzes the oxidation of 5-HT and MAO-B has a substrate specificity towards
benzylamine and 2-phenylethylamine. DA, NA, adrenaline and tryptamine are oxidized by both
forms. MAO-A plays an important role in depression while MAO-B plays an important role in PD.
The two isoforms are not evenly distributed in the brain. Of particular relevance to PD is the
observation that, in the basal ganglia, MAO-B is the predominant form and the oxidation of DA
in this region is largely due to MAO-B activity. Also, with an increase in age, there is an up to
fourfold increase in MAO-B activity in the brain. In the aged parkinsonian brain, MAO-B is
therefore a major DA metabolizing enzyme and MAO-B inhibitors have an important role in the
therapy of PD. MAO-B inhibitors may potentially reduce the metabolic destruction of DA and
thereby provide relief from the symptoms of PD. MAO-B inhibitors may also exert a
neuroprotective effect in PD. In the catalytic cycle of MAO-B, one mole each of an aldehyde,
hydrogen peroxide and ammonia are formed for each mole of primary amine substrate oxidized.
Ferrous iron, which is abundant in the basal ganglia, may react with the hydrogen peroxide to
form hydroxyl radicals in the Fenton reaction. The hydroxyl radical damages virtually all types of
biomolecules including proteins, DNA, lipids, carbohydrates and amino acids. The aldehyde, in turn, may react with amino groups of proteins, and thus lead to cell injury. Inhibitors of MAO-B
may reduce the MAO-catalyzed formation of hydrogen peroxide and aldehydes in the basal
ganglia, and thus act as neuroprotective agents.
MAO-B inhibitors that are currently being used in the treatment of PD are selegiline and
rasagiline. Both are irreversible inhibitors of MAO-B. While irreversible inhibitors of MAO have
been used extensively as drugs, irreversible inhibition has a number of disadvantages. These
include the loss of selectivity as a result of repeated drug administration and a slow and variable
rate of enzyme recovery following termination of drug treatment. The turnover rate for the
biosynthesis of MAO-B in the human brain may require as much as 40 days while with
reversible inhibition, enzyme activity is recovered when the inhibitor is eliminated from the
tissues. For these reasons the discovery of novel MAO-B inhibitors, which interact reversibly
with the enzymes are of value in the therapy of PD.
The goal of this study was to design novel and reversible inhibitors of MAO-B, which may find
application in the therapy of PD. In the current study, caffeine was used as scaffold for the
design of new MAO inhibitors. Caffeine is reported to be a weak inhibitor of MAO-B, with an IC50
value of 5084 μM. Substitution at C-8 of the caffeine moiety, however, yields compounds with
potent MAO-B inhibitory properties. Of particular importance to this study is a recent report that
a series of 8-sulfanylcaffeine analogues acts as selective inhibitors of human MAO-B. Among
the compounds examined, 8-[(phenylethyl)sulfanyl]caffeine was found to be a particularly potent
MAO-B inhibitor with an IC50 value of 0.223 μM. In an attempt to further enhance the MAO-B
inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine, and possibly to discover highly potent
MAO-B inhibitors, a series of five 8-[(phenylethyl)sulfanyl]caffeine analogues was synthesized
and evaluated as inhibitors of human MAO-A and –B. For the purpose of this study 8-
[(phenylethyl)sulfanyl]caffeine homologues containing C-3 alkyl (CF3, CH3 and OCH3) and
halogen (Cl and Br) substituents on the phenyl ring were considered. Furthermore, a series of
two 8-sulfinylcaffeine analogues and one 8-sulfonylcaffeine were synthesized and their MAO
inhibitory potencies were measured. The purpose with these compounds was to compare the
MAO inhibitory properties of the 8-sulfinylcaffeine analogues and 8-sulfonylcaffeine with those
of the 8-sulfanylcaffeine analogues. This study also investigates the MAO inhibition properties of
three selected 8-[(phenylpropyl)sulfanyl]caffeine and two 8-(benzylsulfanyl)caffeine analogues.
Chemistry: The target 8-sulfanylcaffeine analogues were synthesized according to the literature
procedure. 8-Chlorocaffeine was reacted with an appropriate mercaptan in the presence of NaOH, to yield the target 8-sulfanylcaffeine analogues in yields of 6.4–50.7%. 8-Chlorocaffeine,
in turn, was conveniently synthesized in high yield by reacting chlorine with caffeine in
chloroform. In certain instances, the mercaptan starting materials were not commercially
available and were thus synthesized according to the literature procedure by reacting an
appropriate alkylbromide with thiourea. The resulting thiouronium salt was hydrolyzed in the
presence of NaOH to yield the target mercaptan. The 8-sulfinylcaffeine analogues and 8-
sulfonylcaffeine were synthesized by reacting the 8-sulfanylcaffeines with H2O2 in the presence
of glacial acetic acid and acetic anhydride. The structures and the purities of the inhibitors were
verified by NMR, MS and HPLC analyses.
MAO inhibition studies: The MAO inhibitory properties of the test compounds were examined
using the recombinant human enzymes. The mixed MAO-A/B substrate, kynuramine, was
employed as substrate for both enzymes and the inhibition potencies were expressed as the
IC50 values.
The 8-[(phenylethyl)sulfanyl]caffeine analogues were found to be highly potent inhibitors of
MAO-B. The IC50 values recorded for these homologues ranged from 0.017–0.125 μM, making
them twofold to 13-fold more potent MAO-B inhibitors than the lead compound, 8-
[(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM). For comparison, the reversible MAO-B
selective inhibitor, lazabemide, exhibits an IC50 value of 0.091 μM under the same conditions
(unpublished data from our laboratory). Interestingly, both alkyl (CF3, CH3 and OCH3) and
halogen (Cl and Br) substitution lead to highly potent MAO-B inhibition. It may therefore be
concluded that substitution on C-3 is a general strategy to enhance the MAO-B inhibition
potency of 8-[(phenylethyl)sulfanyl]caffeine. The results of the MAO inhibitory studies with the 8-
[(phenylpropyl)sulfanyl]caffeine analogues showed that these compounds are also inhibitors of
MAO-B with IC50 values of 0.061–0.500 μM. Those homologues substituted with chlorine on the
para and meta positions of the phenyl ring were found to be exceptionally potent inhibitors with
IC50 values of 0.061 μM and 0.062 μM, respectively. For the series of 8-
(benzylsulfanyl)caffeines, meta substitution with chlorine (IC50 = 0.227 μM) and bromine
(IC50 = 0.199 μM) was also found to enhance the MAO-B inhibition potency of 8-
(benzylsulfanyl)caffeine (IC50 = 1.86 μM). The results document that the 8-sulfinylcaffeines are
also inhibitors of MAO-B with IC50 values of 11.8–131 μM. The 8-sulfonylcaffeine was also found
to be a MAO-B inhibitor. Compared to the 8-sulfanylcaffeines, these homologues are, however,
weaker inhibitors. It may, therefore, be concluded that 8-sulfinylcaffeines and 8-sulfonylcaffeines are comparatively weak MAO-B inhibitors and less suited for the design of high potency MAO-B
inhibitors.
The results also document that the 8-[(phenylethyl)sulfanyl]caffeines are relatively weak MAO-A
inhibitors with IC50 values of 5.66–141 μM, with one homologue exhibiting no inhibition under
the experimental conditions. As evident from the selectivity indices (SI values), the 8-
[(phenylethyl)sulfanyl]caffeines were all selective inhibitors of the MAO-B isoform. Two
compounds exhibited SI values in excess of 1000. Since these compounds are also highly
potent MAO-B inhibitors, they represent suitable leads for the design of potent and selective
MAO-B inhibitors. The 8-sulfinylcaffeines and 8-sulfonylcaffeine were found to be weak MAO-A
inhibitors with IC50 values of 166–250 μM. The SI values demonstrate that these compounds are
MAO-B selective inhibitors, although to a lesser degree than the 8-
[(phenylethyl)sulfanyl]caffeines. The 8-[(phenylpropyl)sulfanyl]caffeines are also MAO-A
inhibitors with IC50 values of 0.708–6.48 μM. It is noteworthy that these homologues are the
most potent MAO-A inhibitors among the compounds evaluated in this study. In fact, one of the
8-[(phenylpropyl)sulfanyl]caffeines, 8-{[3-(4-chlorophenyl)propyl]sulfanyl}caffeine (IC50 = 0.708
μM), is the only compound with an IC50 value for the inhibition of MAO-A in the submicromolar
range. The 8-[(phenylpropyl)sulfanyl]caffeines display, in general, lower degrees of selectivity
for MAO-B than the corresponding 8-[(phenylethyl)sulfanyl]caffeines.
Reversibility studies: The reversibility of the interaction of a representative inhibitor, 8-{[2-(3-
(trifluoromethyl)phenyl)ethyl]sulfanyl}caffeine, with MAO-B was investigated by evaluating the
recovery of the enzymatic activity after dilution of the enzyme-inhibitor complex. For this
purpose, MAO-B was preincubated with the test compound at concentrations of 10 × IC50 and
100 × IC50 for 30 min. The reactions were subsequently diluted 100-fold to 0.1 × IC50 and 1 ×
IC50, respectively. The results show that, after dilution to 0.1 × IC50 and 1 × IC50, the MAO-B
catalytic activities are recovered to 35% and 22%, respectively, of the control value. For
reversible enzyme inhibition, the enzyme activities are expected to recover to levels of
approximately 90% and 50%, respectively, after 100-fold dilution of the preincubations
containing inhibitor concentrations of 10 × IC50 and 100 × IC50. After preincubation of MAO-B
with the irreversible inhibitor (R)-deprenyl (at 10 × IC50), and dilution of the resulting complex to
0.1 × IC50, MAO-B activity is not recovered (3.0% of control). These data indicate that the test
compound does indeed react reversibly with MAO-B but because enzyme activities are not
recovered to the expected 90% and 50% respectively, it may suggest that the test compound
possess a quasi-reversible or tight-binding component. Hansch-type structure activity relationship studies: A limited Hansch-type QSAR study was
performed for the inhibition of MAO by the 8-[(phenylethyl)sulfanyl]caffeines. For this purpose,
five parameters were used to describe the physicochemical properties of the C-3 substituents
on the phenyl rings of the inhibitors. The Van der Waals volume (Vw) and Taft steric parameter
(Es) served as descriptors of the bulkiness of the substituents, while the lipophilicities were
described by the Hansch constant (π). The electronic properties were described by the classical
Hammett constant (σm) and the Swain-Lupton constant (F). A one-parameter fit with the Taft
steric parameter versus the inhibition potency (logIC50) yielded the best correlation with a
correlation coefficient (R2) of 0.912 and a statistical F value of 41.27 (Fmax = 35). The positive
sign of the Es (+0.47) parameter coefficient indicated that the inhibition potencies of the 8-
[(phenylethyl)sulfanyl]caffeines towards MAO-B may be enhanced by substitution with sterically
large groups at C-3 of the phenyl rings of the inhibitors. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
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The relevance of specific c-reactive protein genetic variants towards cardiovascular disease risk in a black South African population undergoing an epidemiological transition / Bianca Swanepoel.Swanepoel, Bianca January 2013 (has links)
Introduction: In Africa, it is estimated that cardiovascular disease (CVD) will affect approximately 1.3 million people per annum over the following 20 years. C-reactive protein (CRP) is a predictor of CVD risk and certain CRP gene polymorphisms can result in altered CRP concentrations. The distribution of CRP gene polymorphisms is ethnic-specific and extrapolating information from other populations to the black South African population, reported to harbour considerable genetic variation, should be avoided. This highlights the fact that genetic research among black South Africans is necessary.
Objectives: The main aim of this dissertation was to determine the association between various polymorphisms (reported and novel [single nucleotide polymorphisms (SNPs)] within the CRP gene with CRP concentrations [measured as high sensitivity (hs)-CRP concentrations] in a black South African population undergoing an epidemiological transition. Interactions between specific CRP polymorphisms and certain environmental factors on hs-CRP concentrations were also investigated.
Methods: This cross-sectional study (n=1,588) was nested within the Prospective Urban and Rural Epidemiological (PURE) study. Genotyping was performed using Illumina VeraCode technology on the BeadXpress® platform. Hs-CRP concentrations were measured by the use of a sequential multiple analyser computer (SMAC) through a particle-enhanced immunoturbidometric assay.
Results: All the SNPs adhered to the assumptions of Hardy-Weinberg equilibrium, although the distribution of several SNPs differed from that reported in other population groups. Three SNPs (rs3093058, rs3093062 and rs3093068) were associated with a significant (p ≤ 0.05) increase in CRP concentrations. Five SNPs (rs1205, rs1341665, rs2794520, rs7553007 and rs2027471) were associated with a significant (p ≤ 0.05) decrease in CRP concentrations. This difference in effect was most probably due to changes in gene function brought about by the localisation of these SNPs in the CRP gene. Men and urban individuals were more likely to present with significant associations between the SNPs investigated and CRP concentrations. The difference in the prevalence of the alleles associated with higher CRP concentrations in this population compared to non-African populations could possibly explain the increased CRP concentrations that are observed in the black South African population. Gene-gender (rs1205, rs1341665 and rs2027474) as well as gene-environmental (rs3093068) interactions were also observed.
Conclusions: CRP concentrations are in themselves a complex trait and there are many factors at play that influence their expression. Numerous factors (both genetic and environmental) are involved and no single factor acting alone is likely to have enough of an
influence to be used as a clinical diagnostic test of CRP concentrations. These results provide valuable information on the regulation of CRP in a black South African population as well as contribute to the literature of CRP on a global level. / Thesis (MSc (Nutrition))--North-West University, Potchefstroom Campus, 2013.
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Physical activity related to health components and medical costs in employees of a financial institution / Madelein Smit.Smit, Madelein January 2012 (has links)
Physical activity has several advantages for health. The first objective of this research was to determine the relationship between physical activity and selected physical and psychological health components. The physical components include: diabetes risk, obesity, cholesterol and cardiovascular disease. The psychological health components include stress and depression. Secondly, this research aimed to determine the relationship between physical activity and medical costs. Medical costs were divided into pharmaceutical, general practitioners and hospital claims. A total of 9 860 employees of the same financial institution in South Africa, between the ages 18 and 64 (x̄ = 35.3 ± 18.6 years), participated in the study and participation was voluntary. No differentiation was made between race groups. The assessment of selected health risk factors and physical activity was done by using the Health Risk Assessment (HRA) methodology developed by the company, Monitored Health Risk (MHM). Assessment included a physical activity, diabetes risk and cardiovascular risk questionnaire, BMI and random blood glucose measurements, as well as stress and depression scores. The amount of days absent from work in the past six months was also determined by the questionnaire. Participants was categorised in three groups – low, moderate and high physical activity participation. Medical expenditure data was obtained from Monitored Health Risk Management Pty (Ltd). Hospital, pharmaceutical and general practitioners (GP) claims included all costs occurring during a six month period.
The majority of the study group showed low physical activity participation (78.27%). The results also showed that both men and women showed an increased risk for diabetes, and high physical activity levels have a practically and statistically significant effect on the reduction of diabetes risk. In this study all the physical activity groups of both males and females showed an increased average body mass index (BMI) and therefore are considered to be an increased risk according to the classification as stipulated by the study perimeters. The average means for cholesterol in all groups are categorised as low risk. No significant differences are seen between the female groups as well as between the different male groups. The men in the study group showed higher cardiovascular risk than women. There are no statistically significant differences between the women’s groups. However, regarding the male groups, the low physically active male group showed significant differences to the high physical active male group. Thus, in this study it appears that the men participating in high levels of physical activity show the lowest risk for cardiovascular disease and therefore appear to be influenced by physical activity.
The majority of the study group is shown to be in the high stress category (55.48%). It seems that work issues (82%), financial problems (74%) and family problems (69%) contribute most to the population’s high stress levels and depression experience. The Physical activity index (PAI) in relation to stress only shows practical significance in moderate and high physical women. The PAI and stress-related index reports statistically (p≤0.05; 0.001) significant and practice significant difference within the population. There was also a statistically significant (p≤0.05) relation between stress and physical activity in relation to days absent. Although high levels of stress and low levels of physical activity are present in the population, the relation become statistically significant in relation with depression.
The study group was divided into two groups when the medical cost was examined. One group consisted of those individuals who do not use chronic medication and the other group, those individuals that use chronic medication. The majority of the study group (chronic and nonchronic medication use), show low physical activity participation (average of 78.80%). The results show statistically and practically significant differences between the groups that do not use chronic medication and the groups that use chronic medication. The women that use chronic medication show an increase in pharmaceutical costs with an increase in physical activity. However, when investigating the GP cost of women who use chronic medication, there is only a small difference in GP cost in the different physical activity participation categories. The data shows that men have higher pharmaceutical costs than women in all the physical activity categories. The results also indicate that men who use chronic medication, participating in low levels of physical activity do show higher pharmacy and GP costs. Medical cost associated with hospitalisation of those men whose chronic medications show an average higher medical cost (R231.72 versus R672.71). The women who are on chronic medication show about two and a half times higher hospitalisation cost (R253.97 versus R650.82) and the men an almost four times higher cost (R189.34 versus R721.71). No practically significant difference was found between the groups. The women show an increased incidence of low physical activity participation (82.38%), whereas 68.80% of the men show low physical activity participation. Women who use chronic medication and participate in moderate physical activity show lower hospital costs. The women in this study group that use chronic medication and participate in high levels of physical activity show the highest hospital cost. The men’s profile indicates that medical cost due to hospital claims rise with the higher levels of physical activity. / Thesis (PhD (Human Movement Sciences))--North-West University, Potchefstroom Campus, 2013.
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Prescribing patterns of asthma treatment in the private healthcare sector of South Africa / Johannes Marthinus de WetDe Wet, Johannes Marthinus January 2013 (has links)
Asthma is a chronic disease of the airways and affects many people regardless of their age,
gender, race and socioeconomic status. Since asthma is recognised as one of the major
causes of morbidity and mortality in people and especially in South Africa, the prescribing
patterns, prevalence and medication cost of asthma in South Africa are saliently important and
need to be investigated.
A non-experimental, quantitative retrospective drug utilisation review was conducted on
medicine claims data of a pharmaceutical benefit management company in a section of the
private health care sector of South Africa. The study period was divided into four annual
time periods (1 January 2008 to 31 December 2008, 1 January 2009 to 31 December 2009,
1 January 2010 to 31 December 2010 and 1 January 2011 to 31 December 2011). The
prescribing patterns and cost of asthma medication were investigated and stratified according
to province, age and gender. Patients were included if the prescriptions which were
provided by the health care practitioners matched the Chronic Disease List (CDL) of South
Africa and the International Classification of Disease (ICD-10) coding for asthma and chronic
obstructive pulmonary disease (COPD). Data analysis was conducted by means of the SAS
9.3® computer package. Asthma patients were divided according to different age groups
(there were five different age groups for this study), gender and geographical areas of South
Africa.
The study indicated a steady increase in the prevalence of asthma patients from 0.82% (n =
7949) in 2008 to 1.18% (n = 15 423) in 2009 and reached a minimum of 0.79% (n = 8554) in
2011. Analysis of the prevalence regarding geographical areas in South Africa suggested
that Gauteng had the highest number [n = 17 696, (0.85%)] of asthma patients throughout
the study period, followed by KwaZulu Natal [n = 8 628, 1.16%)] and the Western Cape [(n = 8513, 0.97%) (p < 0.05)]. The prevalence of asthma in female patients [0.89% (n = 26
588)] was higher than in their male counterparts [0.79% (n = 19 244)] (p > 0.05). The results
showed that asthma was not as common chronic disease in children. The total number of
asthma patients younger than 7 years represented 0.64% (n = 2 909). It was found that
patients over 65 years of age showed the highest prevalence of the five age groups [1.94%
(n = 13 403) (p < 0.05)].
The average number of asthma prescriptions per patient per year was 8.28 (95% CI, 8.16-
8.40) and 5.15 (95% CI, 5.06-5.23) in 2008 and 2011, respectively. The number of asthma
items per prescription varied from 1.55 (95% CI, 1.55-1.56) in 2008 to 1.40 (95% CI, 1.39-
1.40) in 2011.
Medication from the MIMS® pharmacological group (anti-asthmatics and bronchodilators)
was used to identify asthma medication. The top three asthma medication with the highest
prevalence in the study period were the anti-inflammatory inhaler of fluticasone (n = 39 721)
followed by the single item combination product of budesonide/ formoterol (n = 25 121) and
salbutamol (n = 24 296). The influence of COPD on asthma treatment and the costimplication
thereof were investigated. Medication from the MIMS® pharmacological group
(anti-asthmatics and bronchodilators) was used to identify COPD medication. This study
also showed that COPD had an influence in the economic burden of the South African
asthma population.
The cost of medication is responsible for the single largest direct cost involved in the
economic burden of asthma. This study showed that asthma represented 0.88% of the
direct medication cost in the study (excluding hospitalisation and indirect cost). The average
cost per prescription and average cost per asthma item both increased throughout the study
period.
The prescribing patterns for the different medication used in the treatment of asthma were
investigated and recommendations for further research in this field of study were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014
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Aminopyrimidine derivatives as adenosine antagonists / Janke KleynhansKleynhans, Janke January 2013 (has links)
Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists.
Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after
Alzheimer’s disease) and is characterised by the selective death of the dopaminergic
neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia,
muscle rigidity and tremor, while non-motor symptoms, of which cognitive dysfunction is an
example, also frequently occur. Current therapy provides symptomatic relief mainly by
augmentation of dopaminergic signalling (levodopa, dopamine agonists, MAO and COMT
enzyme inhibitors), but disease progression is not adequately addressed. New therapies that
can prevent further neurodegeneration in addition to providing symptomatic relief are
therefore urgently required.
Adenosine has an important function as neuromodulator in the central nervous system. The
adenosine A2A receptor in particular plays an essential role in the regulation of movement.
This, coupled to the fact that it is uniquely distributed in the basal ganglia, contributes to its
attractiveness as non-dopaminergic target in the treatment of movement disorders, such as
Parkinson’s disease. The efficacy of adenosine receptor antagonists has been illustrated in
animal models of Parkinson’s disease and several adenosine receptor antagonists have also
reached clinical trials. The neuroprotective properties of adenosine A2A receptor antagonists
are further attributed to their ability to modulate neuro-inflammation and decrease the
release of the excitatory neurotransmitter glutamate, which is implicated in neurotoxicity.
While adenosine A1 receptor antagonism has a synergistic effect on the motor effects of
adenosine A2A receptor antagonism, it has the additional benefit of improving cognitive dysfunction, a cardinal non-motor symptom of Parkinson’s disease. Dual antagonism of
adenosine A1 and A2A receptors therefore offers the potential of providing symptomatic relief
as well as the neuroprotection so desperately needed in the clinical environment.
Amino substituted heterocyclic scaffolds, such as those containing the 2-aminopyrimidine
motif, have been shown to exhibit good efficacy as dual adenosine receptor antagonists.
Since the structure activity relationships of 2-aminopyrimidines have not been
comprehensively explored, it is in this regard that this study aimed to make a contribution.
Results - Fourteen 2-aminopyrimidines were synthesised successfully over three steps, (although in
low yields) and characterised by nuclear magnetic resonance and infrared spectroscopy,
mass spectrometry, by determination of melting points and high performance liquid
chromatography. Structure modifications explored included variation of the aromatic
substituent on position 4, as well as variations in the substituents of the phenyl ring, present
on position 6 of the pyrimidine ring.
Radioligand binding assays were performed to determine the affinities of the synthesised
compounds for the adenosine A1 and A2A receptor subtypes. Several high dual affinity
derivatives were identified during this study; the compound with the highest affinity was 4-(5-
methylthiophen-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (39f) with Ki
values of 0.5 nM and 2.3 nM for the adenosine A2A and adenosine A1 receptors,
respectively.
A few general structure activity relationships were derived, which included: The effect of the
aromatic substituent (position 4) on A2A affinity could be summarised (in order of declining
affinity) as follows: 5-methylthiophene > phenyl > furan > pyridine > p-fluorophenyl >
benzofuran. On the other hand, the effect of this substituent on A1 receptor affinity could be
summarised (in order of declining affinity) as follows: phenyl > 5-methylthiophene > pfluorophenyl
> benzofuran > pyridine. The affinities as exhibited by the methylthiophene
derivatives 39f, 39h – 39j, further showed that while piperidine substitution (39f) resulted in
optimal A2A and A1 affinity, pyrrolidine substitution (39j) was less favourable. Substitution at
the 4ʹ position of the phenyl ring, as well as thiazole substitution, generally resulted in poor
adenosine A1 and A2A receptor affinity. However, 4-[2-amino-6-(5-methylfuran-2-yl)pyrimidin-
4-yl]-N-(1,3-benzothiazol-2-yl)benzamide (39l) surprisingly demonstrated good affinity and
selectivity for the adenosine A1 receptor. The results obtained during radioligand binding assays were rationalised by QSAR and
molecular modelling (Discovery Studio 3.1, Accelrys) studies. The inverse relationship seen
between log Ki (as indicator of affinity) and polar surface area, illustrated the importance of
this physico-chemical property in the design of 2-aminopyrimidine A2A antagonists. The
results from the docking study further showed that the orientation adopted by derivatives in
the binding cavity (and particular hydrogen bonding to Asn 253 and Glu 169) is of
importance. Results from the MTT cell viability assay indicated that none of the high affinity
derivatives had a significant effect on cell viability at 1 μM, a concentration much higher than
their Ki values. However, incorporation of the furan, benzofuran and p-fluorophenyl groups
as aromatic substituent and a pyrrolidine as amine substituent, presented liabilities.
Lastly, the haloperidol induced catalepsy assay (in rats) was used to give a preliminary
indication of adenosine receptor antagonism or agonism. Compound 39f failed to reverse
catalepsy under standard conditions, but showed some reversal after an increased time
period. Indications therefore exist that 39f is an adenosine receptor antagonist that suffers
from bioavailability issues. Compound (39c), 4-phenyl-6-[3-(piperidine-1-
carbonyl)phenyl]pyrimidin-2-amine which also demonstrated promising affinity in the
radioligand binding assays however showed a statistically significant reduction in catalepsy,
indicating adenosine A2A receptor antagonism, and in vivo efficacy.
Highly potent, dual affinity aminopyrimidine derivatives with acceptable toxicity profiles were
identified in this study, with compound 39c demonstrating in vivo activity. The aim of
designing and synthesising a promising dual adenosine A1/A2A receptor antagonist is
therefore realised, with compound 39c as the most favourable example. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014
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Serological and genetic characterisation of putative new serotypes of bluetongue virus and epizootic haemorrhagic disease virus isolated from an Alpaca / Isabella Maria WrightWright, Isabella Maria January 2014 (has links)
Alpacas were first introduced into South Africa during the year 2000. They are valuable
because of the fine quality wool they produce which has much better insulation properties
than that of merino wool fibres. Alpacas are also used to act as guards of sheep herds
against predators.
During 2008, blood samples from an alpaca that died acutely with severe lung oedema,
respiratory distress and froth exuding from the nose were received at Elsenburg Veterinary
Laboratory. The alpaca was from a herd of 23 alpacas of a British veterinarian in the
Montagu district in the western Cape. Virus isolation attempts on the blood produced
infrequent embryo mortalities. Embryonated chicken egg (ECE) material was send to the
Virology Department at the Onderstepoort Veterinary Institute (OVI). A bluetongue virus
(BTV) PCR performed at the diagnostic PCR laboratory at OVI on the ECE material was
positive. Further intra-venous (IV) inoculations in ECE produced embryo mortalities on two
consecutive days, the 8th and 9th November. The dead embryos were harvested separately
and named and treated as two separate virus samples, Alp8 and Alp9 which were further
passaged on baby hamster kidney (BHK) cells.
The BTV virus neutralisation tests (VNT) performed at the Office International des Epizooties
(OIE) Laboratory on both Alp8 and Alp9 were negative. Because of the close serological
relationship between BTV and epizootic haemorrhagic disease virus (EHDV), an EHDV VNT
was also performed and was also negative.
In the light of the negative VNT and the positive BTV PCR results, more in-depth molecular
analyses were performed. RNA was purified from tissue culture material and agarose gel
electrophoresis (AGE) performed. Both Alp8 and Alp9 had a typical orbiviral electrophoretic
profile, but their respective profiles were different.
A sequence-independent reverse transcriptase PCR amplification method generated ample
complementary DNA (cDNA) of both samples for sequencing. Sanger sequencing was used
to partially sequence genome segments 5 (NS1) and 2 (VP2). BLAST analysis of the partial
information of the genome segments 5 (NS1) of Alp8 confirmed it as being a BTV and Alp9
as being an EHDV. BLAST analysis of the deduced amino acid sequence generated of VP2
of both Alp8 and Alp9 established that these samples were possibly new serotypes of BTV
and EHDV respectively. The complete genome of both Alp8 and Alp9 was sequenced with
next generation 454 Pyrosequencing. This confirmed the partial sequencing results. BLAST analysis of the complete sequence of S2 (VP2) of Alp8 showed that it has 73 % nucleotide
and 77 % deduced amino acid identity to BTV15. In contrast the nucleic acid sequence of
genome segment S2 (VP2) of Alp9 had no nucleotide sequence identity to any virus, but its
deduced amino acid sequence had 71 % amino acid identity to EHDV2.
Hyper immune guinea pig (GP) serum prepared against the putative new BT (Alp8) and EHD
(Alp9) virus serotypes were tested for serological cross-reactivity against the 24 OIE
reference antigen strains of BTV and the 8 OIE reference antigen strains of EHDV. Alp8 had
a neutralising antibody (NAb) titre of > 32 against BTV15. Alp9 did not cross react with any of
the OIE BTV and EHDV strains.
Six out of the remaining 22 alpacas on the farm had NAbs to a greater or lesser extend
against Alp8 (BTV) and Alp9 (EHDV) viruses, which confirmed that the viruses were also
present in other alpacas in the herd. Very few cases of EHDV in alpacas have ever been
reported in literature.
A small scale pilot vector susceptibility study showed that vector competence of C. imicola
for both Alp8 and Alp9 was low, below 2 %. The fact that neutralising antibodies to Alp8 and
Alp9 were detected in other alpacas in the herd raises the question as to whether there are
other Culicoides species circulating in the area that could vector the viruses.
In conclusion, the results from the serological and virological analyses as well as the nucleic
acid sequence data of the genomes of two virus samples, Alp8 and Alp9, from an alpaca that
died in the Montagu district in the western Cape identified Alp9 as a definite new serotype of
EHDV and Alp8 as a possible new serotype of BTV most closely related to BTV15. / MSc (Biochemistry), North-West University, Potchefstroom Campus, 2014
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Novel sulfanyl- and sulfinylcaffeine analogues as inhibitors of monoamine oxidase / Wayne MentzMentz, Wayne January 2013 (has links)
Parkinson’s disease (PD) is a neurodegenerative disorder, which is progressive in nature and
usually associated with the elderly. It is the second most common age-related
neurodegenerative disorder after Alzheimer’s disease (AD). PD occurs when there is a dramatic
loss of dopamine (DA) in the striatum, a substructure of the basal ganglia, of the brain due to
the degeneration of the nigrostriatal pathway that contains the dopaminergic neurons. Motor
symptoms of PD include bradykinesia, muscular rigidity and resting tremors. Non-motor
symptoms include speech and sleep problems, hallucinations and depression. Diverse
treatment options are available to treat the symptoms of PD, including levodopa (L-Dopa), DA
agonists and monoamine oxidase B (MAO-B) inhibitors.
The MAOs are flavoproteins that are bound to the outer membrane of the mitochondria and
catalyze the oxidative deamination of neurotransmitters such as serotonin (5-HT), noradrenaline
(NA) and DA. Two isoforms occur, namely MAO-A and –B, which share a 70% sequence
identity. MAO-A catalyzes the oxidation of 5-HT and MAO-B has a substrate specificity towards
benzylamine and 2-phenylethylamine. DA, NA, adrenaline and tryptamine are oxidized by both
forms. MAO-A plays an important role in depression while MAO-B plays an important role in PD.
The two isoforms are not evenly distributed in the brain. Of particular relevance to PD is the
observation that, in the basal ganglia, MAO-B is the predominant form and the oxidation of DA
in this region is largely due to MAO-B activity. Also, with an increase in age, there is an up to
fourfold increase in MAO-B activity in the brain. In the aged parkinsonian brain, MAO-B is
therefore a major DA metabolizing enzyme and MAO-B inhibitors have an important role in the
therapy of PD. MAO-B inhibitors may potentially reduce the metabolic destruction of DA and
thereby provide relief from the symptoms of PD. MAO-B inhibitors may also exert a
neuroprotective effect in PD. In the catalytic cycle of MAO-B, one mole each of an aldehyde,
hydrogen peroxide and ammonia are formed for each mole of primary amine substrate oxidized.
Ferrous iron, which is abundant in the basal ganglia, may react with the hydrogen peroxide to
form hydroxyl radicals in the Fenton reaction. The hydroxyl radical damages virtually all types of
biomolecules including proteins, DNA, lipids, carbohydrates and amino acids. The aldehyde, in turn, may react with amino groups of proteins, and thus lead to cell injury. Inhibitors of MAO-B
may reduce the MAO-catalyzed formation of hydrogen peroxide and aldehydes in the basal
ganglia, and thus act as neuroprotective agents.
MAO-B inhibitors that are currently being used in the treatment of PD are selegiline and
rasagiline. Both are irreversible inhibitors of MAO-B. While irreversible inhibitors of MAO have
been used extensively as drugs, irreversible inhibition has a number of disadvantages. These
include the loss of selectivity as a result of repeated drug administration and a slow and variable
rate of enzyme recovery following termination of drug treatment. The turnover rate for the
biosynthesis of MAO-B in the human brain may require as much as 40 days while with
reversible inhibition, enzyme activity is recovered when the inhibitor is eliminated from the
tissues. For these reasons the discovery of novel MAO-B inhibitors, which interact reversibly
with the enzymes are of value in the therapy of PD.
The goal of this study was to design novel and reversible inhibitors of MAO-B, which may find
application in the therapy of PD. In the current study, caffeine was used as scaffold for the
design of new MAO inhibitors. Caffeine is reported to be a weak inhibitor of MAO-B, with an IC50
value of 5084 μM. Substitution at C-8 of the caffeine moiety, however, yields compounds with
potent MAO-B inhibitory properties. Of particular importance to this study is a recent report that
a series of 8-sulfanylcaffeine analogues acts as selective inhibitors of human MAO-B. Among
the compounds examined, 8-[(phenylethyl)sulfanyl]caffeine was found to be a particularly potent
MAO-B inhibitor with an IC50 value of 0.223 μM. In an attempt to further enhance the MAO-B
inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine, and possibly to discover highly potent
MAO-B inhibitors, a series of five 8-[(phenylethyl)sulfanyl]caffeine analogues was synthesized
and evaluated as inhibitors of human MAO-A and –B. For the purpose of this study 8-
[(phenylethyl)sulfanyl]caffeine homologues containing C-3 alkyl (CF3, CH3 and OCH3) and
halogen (Cl and Br) substituents on the phenyl ring were considered. Furthermore, a series of
two 8-sulfinylcaffeine analogues and one 8-sulfonylcaffeine were synthesized and their MAO
inhibitory potencies were measured. The purpose with these compounds was to compare the
MAO inhibitory properties of the 8-sulfinylcaffeine analogues and 8-sulfonylcaffeine with those
of the 8-sulfanylcaffeine analogues. This study also investigates the MAO inhibition properties of
three selected 8-[(phenylpropyl)sulfanyl]caffeine and two 8-(benzylsulfanyl)caffeine analogues.
Chemistry: The target 8-sulfanylcaffeine analogues were synthesized according to the literature
procedure. 8-Chlorocaffeine was reacted with an appropriate mercaptan in the presence of NaOH, to yield the target 8-sulfanylcaffeine analogues in yields of 6.4–50.7%. 8-Chlorocaffeine,
in turn, was conveniently synthesized in high yield by reacting chlorine with caffeine in
chloroform. In certain instances, the mercaptan starting materials were not commercially
available and were thus synthesized according to the literature procedure by reacting an
appropriate alkylbromide with thiourea. The resulting thiouronium salt was hydrolyzed in the
presence of NaOH to yield the target mercaptan. The 8-sulfinylcaffeine analogues and 8-
sulfonylcaffeine were synthesized by reacting the 8-sulfanylcaffeines with H2O2 in the presence
of glacial acetic acid and acetic anhydride. The structures and the purities of the inhibitors were
verified by NMR, MS and HPLC analyses.
MAO inhibition studies: The MAO inhibitory properties of the test compounds were examined
using the recombinant human enzymes. The mixed MAO-A/B substrate, kynuramine, was
employed as substrate for both enzymes and the inhibition potencies were expressed as the
IC50 values.
The 8-[(phenylethyl)sulfanyl]caffeine analogues were found to be highly potent inhibitors of
MAO-B. The IC50 values recorded for these homologues ranged from 0.017–0.125 μM, making
them twofold to 13-fold more potent MAO-B inhibitors than the lead compound, 8-
[(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM). For comparison, the reversible MAO-B
selective inhibitor, lazabemide, exhibits an IC50 value of 0.091 μM under the same conditions
(unpublished data from our laboratory). Interestingly, both alkyl (CF3, CH3 and OCH3) and
halogen (Cl and Br) substitution lead to highly potent MAO-B inhibition. It may therefore be
concluded that substitution on C-3 is a general strategy to enhance the MAO-B inhibition
potency of 8-[(phenylethyl)sulfanyl]caffeine. The results of the MAO inhibitory studies with the 8-
[(phenylpropyl)sulfanyl]caffeine analogues showed that these compounds are also inhibitors of
MAO-B with IC50 values of 0.061–0.500 μM. Those homologues substituted with chlorine on the
para and meta positions of the phenyl ring were found to be exceptionally potent inhibitors with
IC50 values of 0.061 μM and 0.062 μM, respectively. For the series of 8-
(benzylsulfanyl)caffeines, meta substitution with chlorine (IC50 = 0.227 μM) and bromine
(IC50 = 0.199 μM) was also found to enhance the MAO-B inhibition potency of 8-
(benzylsulfanyl)caffeine (IC50 = 1.86 μM). The results document that the 8-sulfinylcaffeines are
also inhibitors of MAO-B with IC50 values of 11.8–131 μM. The 8-sulfonylcaffeine was also found
to be a MAO-B inhibitor. Compared to the 8-sulfanylcaffeines, these homologues are, however,
weaker inhibitors. It may, therefore, be concluded that 8-sulfinylcaffeines and 8-sulfonylcaffeines are comparatively weak MAO-B inhibitors and less suited for the design of high potency MAO-B
inhibitors.
The results also document that the 8-[(phenylethyl)sulfanyl]caffeines are relatively weak MAO-A
inhibitors with IC50 values of 5.66–141 μM, with one homologue exhibiting no inhibition under
the experimental conditions. As evident from the selectivity indices (SI values), the 8-
[(phenylethyl)sulfanyl]caffeines were all selective inhibitors of the MAO-B isoform. Two
compounds exhibited SI values in excess of 1000. Since these compounds are also highly
potent MAO-B inhibitors, they represent suitable leads for the design of potent and selective
MAO-B inhibitors. The 8-sulfinylcaffeines and 8-sulfonylcaffeine were found to be weak MAO-A
inhibitors with IC50 values of 166–250 μM. The SI values demonstrate that these compounds are
MAO-B selective inhibitors, although to a lesser degree than the 8-
[(phenylethyl)sulfanyl]caffeines. The 8-[(phenylpropyl)sulfanyl]caffeines are also MAO-A
inhibitors with IC50 values of 0.708–6.48 μM. It is noteworthy that these homologues are the
most potent MAO-A inhibitors among the compounds evaluated in this study. In fact, one of the
8-[(phenylpropyl)sulfanyl]caffeines, 8-{[3-(4-chlorophenyl)propyl]sulfanyl}caffeine (IC50 = 0.708
μM), is the only compound with an IC50 value for the inhibition of MAO-A in the submicromolar
range. The 8-[(phenylpropyl)sulfanyl]caffeines display, in general, lower degrees of selectivity
for MAO-B than the corresponding 8-[(phenylethyl)sulfanyl]caffeines.
Reversibility studies: The reversibility of the interaction of a representative inhibitor, 8-{[2-(3-
(trifluoromethyl)phenyl)ethyl]sulfanyl}caffeine, with MAO-B was investigated by evaluating the
recovery of the enzymatic activity after dilution of the enzyme-inhibitor complex. For this
purpose, MAO-B was preincubated with the test compound at concentrations of 10 × IC50 and
100 × IC50 for 30 min. The reactions were subsequently diluted 100-fold to 0.1 × IC50 and 1 ×
IC50, respectively. The results show that, after dilution to 0.1 × IC50 and 1 × IC50, the MAO-B
catalytic activities are recovered to 35% and 22%, respectively, of the control value. For
reversible enzyme inhibition, the enzyme activities are expected to recover to levels of
approximately 90% and 50%, respectively, after 100-fold dilution of the preincubations
containing inhibitor concentrations of 10 × IC50 and 100 × IC50. After preincubation of MAO-B
with the irreversible inhibitor (R)-deprenyl (at 10 × IC50), and dilution of the resulting complex to
0.1 × IC50, MAO-B activity is not recovered (3.0% of control). These data indicate that the test
compound does indeed react reversibly with MAO-B but because enzyme activities are not
recovered to the expected 90% and 50% respectively, it may suggest that the test compound
possess a quasi-reversible or tight-binding component. Hansch-type structure activity relationship studies: A limited Hansch-type QSAR study was
performed for the inhibition of MAO by the 8-[(phenylethyl)sulfanyl]caffeines. For this purpose,
five parameters were used to describe the physicochemical properties of the C-3 substituents
on the phenyl rings of the inhibitors. The Van der Waals volume (Vw) and Taft steric parameter
(Es) served as descriptors of the bulkiness of the substituents, while the lipophilicities were
described by the Hansch constant (π). The electronic properties were described by the classical
Hammett constant (σm) and the Swain-Lupton constant (F). A one-parameter fit with the Taft
steric parameter versus the inhibition potency (logIC50) yielded the best correlation with a
correlation coefficient (R2) of 0.912 and a statistical F value of 41.27 (Fmax = 35). The positive
sign of the Es (+0.47) parameter coefficient indicated that the inhibition potencies of the 8-
[(phenylethyl)sulfanyl]caffeines towards MAO-B may be enhanced by substitution with sterically
large groups at C-3 of the phenyl rings of the inhibitors. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
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The relevance of specific c-reactive protein genetic variants towards cardiovascular disease risk in a black South African population undergoing an epidemiological transition / Bianca Swanepoel.Swanepoel, Bianca January 2013 (has links)
Introduction: In Africa, it is estimated that cardiovascular disease (CVD) will affect approximately 1.3 million people per annum over the following 20 years. C-reactive protein (CRP) is a predictor of CVD risk and certain CRP gene polymorphisms can result in altered CRP concentrations. The distribution of CRP gene polymorphisms is ethnic-specific and extrapolating information from other populations to the black South African population, reported to harbour considerable genetic variation, should be avoided. This highlights the fact that genetic research among black South Africans is necessary.
Objectives: The main aim of this dissertation was to determine the association between various polymorphisms (reported and novel [single nucleotide polymorphisms (SNPs)] within the CRP gene with CRP concentrations [measured as high sensitivity (hs)-CRP concentrations] in a black South African population undergoing an epidemiological transition. Interactions between specific CRP polymorphisms and certain environmental factors on hs-CRP concentrations were also investigated.
Methods: This cross-sectional study (n=1,588) was nested within the Prospective Urban and Rural Epidemiological (PURE) study. Genotyping was performed using Illumina VeraCode technology on the BeadXpress® platform. Hs-CRP concentrations were measured by the use of a sequential multiple analyser computer (SMAC) through a particle-enhanced immunoturbidometric assay.
Results: All the SNPs adhered to the assumptions of Hardy-Weinberg equilibrium, although the distribution of several SNPs differed from that reported in other population groups. Three SNPs (rs3093058, rs3093062 and rs3093068) were associated with a significant (p ≤ 0.05) increase in CRP concentrations. Five SNPs (rs1205, rs1341665, rs2794520, rs7553007 and rs2027471) were associated with a significant (p ≤ 0.05) decrease in CRP concentrations. This difference in effect was most probably due to changes in gene function brought about by the localisation of these SNPs in the CRP gene. Men and urban individuals were more likely to present with significant associations between the SNPs investigated and CRP concentrations. The difference in the prevalence of the alleles associated with higher CRP concentrations in this population compared to non-African populations could possibly explain the increased CRP concentrations that are observed in the black South African population. Gene-gender (rs1205, rs1341665 and rs2027474) as well as gene-environmental (rs3093068) interactions were also observed.
Conclusions: CRP concentrations are in themselves a complex trait and there are many factors at play that influence their expression. Numerous factors (both genetic and environmental) are involved and no single factor acting alone is likely to have enough of an
influence to be used as a clinical diagnostic test of CRP concentrations. These results provide valuable information on the regulation of CRP in a black South African population as well as contribute to the literature of CRP on a global level. / Thesis (MSc (Nutrition))--North-West University, Potchefstroom Campus, 2013.
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Physical activity related to health components and medical costs in employees of a financial institution / Madelein Smit.Smit, Madelein January 2012 (has links)
Physical activity has several advantages for health. The first objective of this research was to determine the relationship between physical activity and selected physical and psychological health components. The physical components include: diabetes risk, obesity, cholesterol and cardiovascular disease. The psychological health components include stress and depression. Secondly, this research aimed to determine the relationship between physical activity and medical costs. Medical costs were divided into pharmaceutical, general practitioners and hospital claims. A total of 9 860 employees of the same financial institution in South Africa, between the ages 18 and 64 (x̄ = 35.3 ± 18.6 years), participated in the study and participation was voluntary. No differentiation was made between race groups. The assessment of selected health risk factors and physical activity was done by using the Health Risk Assessment (HRA) methodology developed by the company, Monitored Health Risk (MHM). Assessment included a physical activity, diabetes risk and cardiovascular risk questionnaire, BMI and random blood glucose measurements, as well as stress and depression scores. The amount of days absent from work in the past six months was also determined by the questionnaire. Participants was categorised in three groups – low, moderate and high physical activity participation. Medical expenditure data was obtained from Monitored Health Risk Management Pty (Ltd). Hospital, pharmaceutical and general practitioners (GP) claims included all costs occurring during a six month period.
The majority of the study group showed low physical activity participation (78.27%). The results also showed that both men and women showed an increased risk for diabetes, and high physical activity levels have a practically and statistically significant effect on the reduction of diabetes risk. In this study all the physical activity groups of both males and females showed an increased average body mass index (BMI) and therefore are considered to be an increased risk according to the classification as stipulated by the study perimeters. The average means for cholesterol in all groups are categorised as low risk. No significant differences are seen between the female groups as well as between the different male groups. The men in the study group showed higher cardiovascular risk than women. There are no statistically significant differences between the women’s groups. However, regarding the male groups, the low physically active male group showed significant differences to the high physical active male group. Thus, in this study it appears that the men participating in high levels of physical activity show the lowest risk for cardiovascular disease and therefore appear to be influenced by physical activity.
The majority of the study group is shown to be in the high stress category (55.48%). It seems that work issues (82%), financial problems (74%) and family problems (69%) contribute most to the population’s high stress levels and depression experience. The Physical activity index (PAI) in relation to stress only shows practical significance in moderate and high physical women. The PAI and stress-related index reports statistically (p≤0.05; 0.001) significant and practice significant difference within the population. There was also a statistically significant (p≤0.05) relation between stress and physical activity in relation to days absent. Although high levels of stress and low levels of physical activity are present in the population, the relation become statistically significant in relation with depression.
The study group was divided into two groups when the medical cost was examined. One group consisted of those individuals who do not use chronic medication and the other group, those individuals that use chronic medication. The majority of the study group (chronic and nonchronic medication use), show low physical activity participation (average of 78.80%). The results show statistically and practically significant differences between the groups that do not use chronic medication and the groups that use chronic medication. The women that use chronic medication show an increase in pharmaceutical costs with an increase in physical activity. However, when investigating the GP cost of women who use chronic medication, there is only a small difference in GP cost in the different physical activity participation categories. The data shows that men have higher pharmaceutical costs than women in all the physical activity categories. The results also indicate that men who use chronic medication, participating in low levels of physical activity do show higher pharmacy and GP costs. Medical cost associated with hospitalisation of those men whose chronic medications show an average higher medical cost (R231.72 versus R672.71). The women who are on chronic medication show about two and a half times higher hospitalisation cost (R253.97 versus R650.82) and the men an almost four times higher cost (R189.34 versus R721.71). No practically significant difference was found between the groups. The women show an increased incidence of low physical activity participation (82.38%), whereas 68.80% of the men show low physical activity participation. Women who use chronic medication and participate in moderate physical activity show lower hospital costs. The women in this study group that use chronic medication and participate in high levels of physical activity show the highest hospital cost. The men’s profile indicates that medical cost due to hospital claims rise with the higher levels of physical activity. / Thesis (PhD (Human Movement Sciences))--North-West University, Potchefstroom Campus, 2013.
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